Ringsted Frank M
Full Text Available Abstract Background Artemether-lumefantrine (ALu replaced sulphadoxine-pymimethamine (SP as the official first-line anti-malarial in Tanzania in November 2006. So far, artemisinin combination therapy (ACT is contra-indicated during pregnancy by the national malaria treatment guidelines, and pregnant women depend on SP for Intermittent Preventive Treatment (IPTp during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may undermine its official use for IPTp through induction of resistance. The main study objective was to perform a baseline study of the private market for anti-malarials in Muheza town, an area with widespread anti-malarial drug resistance, prior to the implementation of a provider training and accreditation programme that will allow accredited drug shops to sell subsidized ALu. Methods All drug shops selling prescription-only anti-malarials, in Muheza town, Tanga Region voluntarily participated from July to December 2009. Qualitative in-depth interviews were conducted with owners or shopkeepers on saleability of anti-malarials, and structured questionnaires provided quantitative data on drugs sales volume. Results All surveyed drug shops illicitly sold SP and quinine (QN, and legally amodiaquine (AQ. Calculated monthly sale was 4,041 doses, in a town with a population of 15,000 people. Local brands of SP accounted for 74% of sales volume, compared to AQ (13%, QN (11% and ACT (2%. Conclusions In community practice, the saleability of ACT was negligible. SP was best-selling, and use was not reserved for IPTp, as stipulated in the national anti-malarial policy. It is a major reason for concern that such drug-pressure in the community equals de facto intermittent presumptive treatment. In an area where SP drug resistance remains high, unregulated SP dispensing to people other than pregnant women runs the risk of eventually jeopardizing the effectiveness of the IPTp
Elmannan, Abeer Abuzeid Atta; Elmardi, Khalid Abdelmutalab; Idris, Yassir Ali; Spector, Jonathan M; Ali, Nahid Abdelgadir; Malik, Elfatih Mohamed
The World Health Organization (WHO) recommends artemisinin-based combination therapies (ACTs) as first-line treatment for uncomplicated malaria. Sudan revised its malaria treatment policy accordingly in 2004. However, eight years after ACTs were introduced in Sudan the patterns of ACT prescribing practices among health care providers remain unclear. We systematically analyzed use of ACTs in a large number of primary health facilities and we discuss the public health implications of our findings. This cross-sectional study was based on WHO's guidance for investigating drug use in health facilities. Data were collected from 40 randomly selected primary health centers in five localities in Gezira State, Sudan. The primary outcome of the study was the proportion of patients who were adequately managed according to Sudan's recommended malaria treatment guidelines. Twelve drug-use indicators were used to assess key ACT prescribing practices. One thousand and two hundred patients diagnosed with uncomplicated malaria were recruited into the study. ACT was prescribed for 88.6%patients and artemether injections were (incorrectly) prescribed in 9.5% of cases. Only 40.9% of patients in the study were correctly diagnosed and 26.9% were adequately managed according to the nationally recommended treatment guidelines. Incorrect prescribing activities included failure to use generic medicine names (88.2%), incorrect dosage (27.7%), and unexplained antibiotic co-prescription (24.2%). Dispensing practices were also poor, with labeling practices inadequate (97.1%) and insufficient information given to patients about their prescribed treatment (50.5%). Irrational malaria treatment practices are common in Sudan. This has important public health implications since failure to adhere to nationally recommended guidelines could play a role in the future development of drug resistance. As such, identifying ways to improve the anti-malarial prescribing practices of heath workers in Sudan may
Background The discovery and development of new anti-malarials are at a crossroads. Fixed dose artemisinin combination therapy is now being used to treat a hundred million children each year, with a cost as low as 30 cents per child, with cure rates of over 95%. However, as with all anti-infective strategies, this triumph brings with it the seeds of its own downfall, the emergence of resistance. It takes ten years to develop a new medicine. New classes of medicines to combat malaria, as a result of infection by Plasmodium falciparum and Plasmodium vivax are urgently needed. Results Natural product scaffolds have been the basis of the majority of current anti-malarial medicines. Molecules such as quinine, lapachol and artemisinin were originally isolated from herbal medicinal products. After improvement with medicinal chemistry and formulation technologies, and combination with other active ingredients, they now make up the current armamentarium of medicines. In recent years advances in screening technologies have allowed testing of millions of compounds from pharmaceutical diversity for anti-malarial activity in cellular assays. These initiatives have resulted in thousands of new sub-micromolar active compounds – starting points for new drug discovery programmes. Against this backdrop, the paucity of potent natural products identified has been disappointing. Now is a good time to reflect on the current approach to screening herbal medicinal products and suggest revisions. Nearly sixty years ago, the Chinese doctor Chen Guofu, suggested natural products should be approached by dao-xing-ni-shi or ‘acting in the reversed order’, starting with observational clinical studies. Natural products based on herbal remedies are in use in the community, and have the potential unique advantage that clinical observational data exist, or can be generated. The first step should be the confirmation and definition of the clinical activity of herbal medicinal products already
Wells Timothy NC
Full Text Available Abstract Background The discovery and development of new anti-malarials are at a crossroads. Fixed dose artemisinin combination therapy is now being used to treat a hundred million children each year, with a cost as low as 30 cents per child, with cure rates of over 95%. However, as with all anti-infective strategies, this triumph brings with it the seeds of its own downfall, the emergence of resistance. It takes ten years to develop a new medicine. New classes of medicines to combat malaria, as a result of infection by Plasmodium falciparum and Plasmodium vivax are urgently needed. Results Natural product scaffolds have been the basis of the majority of current anti-malarial medicines. Molecules such as quinine, lapachol and artemisinin were originally isolated from herbal medicinal products. After improvement with medicinal chemistry and formulation technologies, and combination with other active ingredients, they now make up the current armamentarium of medicines. In recent years advances in screening technologies have allowed testing of millions of compounds from pharmaceutical diversity for anti-malarial activity in cellular assays. These initiatives have resulted in thousands of new sub-micromolar active compounds – starting points for new drug discovery programmes. Against this backdrop, the paucity of potent natural products identified has been disappointing. Now is a good time to reflect on the current approach to screening herbal medicinal products and suggest revisions. Nearly sixty years ago, the Chinese doctor Chen Guofu, suggested natural products should be approached by dao-xing-ni-shi or ‘acting in the reversed order’, starting with observational clinical studies. Natural products based on herbal remedies are in use in the community, and have the potential unique advantage that clinical observational data exist, or can be generated. The first step should be the confirmation and definition of the clinical activity of herbal
Newton, Paul N; Hanson, Kara; Goodman, Catherine
Quality of artemisinin-based combination therapy (ACT) is important for ensuring malaria parasite clearance and protecting the efficacy of artemisinin-based therapies. The extent to which non quality-assured ACT (non-QAACT), or those not granted global regulatory approval, are available and used to treat malaria in endemic countries is poorly documented. This paper uses national and sub-national medicine outlet surveys conducted in eight study countries (Benin, Kinshasa and Kantanga [Democratic Republic of the Congo, DRC], Kenya, Madagascar, Nigeria, Tanzania, Uganda and Zambia) between 2009 and 2015 to describe the non-QAACT market and to document trends in availability and distribution of non-QAACT in the public and private sector. In 2014/15, non-QAACT were most commonly available in Kinshasa (83%), followed by Katanga (53%), Nigeria (48%), Kenya (42%), and Uganda (33%). Non-QAACT accounted for 20% of the market share in the private sector in Kenya, followed by Benin and Uganda (19%), Nigeria (12%) and Zambia (8%); this figure was 27% in Katanga and 40% in Kinshasa. Public sector non-QAACT availability and distribution was much lower, with the exception of Zambia (availability, 85%; market share, 32%). Diverse generics and formulations were available, but non-QAACT were most commonly artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DHA PPQ), in tablet formulation, imported, and distributed in urban areas at either pharmacies or drug stores. The number of unique manufacturers supplying non-QAACT to each country ranged from 9 in Uganda to 92 in Nigeria. Addressing the availability and distribution of non-QAACT will require effective private sector engagement and evidence-based strategies to address provider and consumer demand for these products. Given the variation in non-QAACT markets observed across the eight study countries, active efforts to limit registration, importation and distribution of non-QAACT must be tailored to the country context
Littrell, Megan; Gatakaa, Hellen; Phok, Sochea; Allen, Henrietta; Yeung, Shunmay; Chuor, Char Meng; Dysoley, Lek; Socheat, Duong; Spiers, Angus; White, Chris; Shewchuk, Tanya; Chavasse, Desmond; O'Connell, Kathryn A
Continued progress towards global reduction in morbidity and mortality due to malaria requires scale-up of effective case management with artemisinin-combination therapy (ACT). The first case of artemisinin resistance in Plasmodium falciparum was documented in western Cambodia. Spread of artemisinin resistance would threaten recent gains in global malaria control. As such, the anti-malarial market and malaria case management practices in Cambodia have global significance. Nationally-representative household and outlet surveys were conducted in 2009 among areas in Cambodia with malaria risk. An anti-malarial audit was conducted among all public and private outlets with the potential to sell anti-malarials. Indicators on availability, price and relative volumes sold/distributed were calculated across types of anti-malarials and outlets. The household survey collected information about management of recent "malaria fevers." Case management in the public versus private sector, and anti-malarial treatment based on malaria diagnostic testing were examined. Most public outlets (85%) and nearly half of private pharmacies, clinics and drug stores stock ACT. Oral artemisinin monotherapy was found in pharmacies/clinics (9%), drug stores (14%), mobile providers (4%) and grocery stores (2%). Among total anti-malarial volumes sold/distributed nationally, 6% are artemisinin monotherapies and 72% are ACT. Only 45% of people with recent "malaria fever" reportedly receive a diagnostic test, and the most common treatment acquired is a drug cocktail containing no identifiable anti-malarial. A self-reported positive diagnostic test, particularly when received in the public sector, improves likelihood of receiving anti-malarial treatment. Nonetheless, anti-malarial treatment of reportedly positive cases is low among people who seek treatment exclusively in the public (61%) and private (42%) sectors. While data on the anti-malarial market shows favourable progress towards replacing
Full Text Available Abstract Background Continued progress towards global reduction in morbidity and mortality due to malaria requires scale-up of effective case management with artemisinin-combination therapy (ACT. The first case of artemisinin resistance in Plasmodium falciparum was documented in western Cambodia. Spread of artemisinin resistance would threaten recent gains in global malaria control. As such, the anti-malarial market and malaria case management practices in Cambodia have global significance. Methods Nationally-representative household and outlet surveys were conducted in 2009 among areas in Cambodia with malaria risk. An anti-malarial audit was conducted among all public and private outlets with the potential to sell anti-malarials. Indicators on availability, price and relative volumes sold/distributed were calculated across types of anti-malarials and outlets. The household survey collected information about management of recent "malaria fevers." Case management in the public versus private sector, and anti-malarial treatment based on malaria diagnostic testing were examined. Results Most public outlets (85% and nearly half of private pharmacies, clinics and drug stores stock ACT. Oral artemisinin monotherapy was found in pharmacies/clinics (9%, drug stores (14%, mobile providers (4% and grocery stores (2%. Among total anti-malarial volumes sold/distributed nationally, 6% are artemisinin monotherapies and 72% are ACT. Only 45% of people with recent "malaria fever" reportedly receive a diagnostic test, and the most common treatment acquired is a drug cocktail containing no identifiable anti-malarial. A self-reported positive diagnostic test, particularly when received in the public sector, improves likelihood of receiving anti-malarial treatment. Nonetheless, anti-malarial treatment of reportedly positive cases is low among people who seek treatment exclusively in the public (61% and private (42% sectors. Conclusions While data on the anti-malarial
Shewchuk, Tanya; O'Connell, Kathryn A; Goodman, Catherine; Hanson, Kara; Chapman, Steven; Chavasse, Desmond
Policy makers, governments and donors are faced with an information gap when considering ways to improve access to artemisinin-based combination therapy (ACT) and malaria diagnostics including rapid diagnostic tests (RDTs). To help address some of these gaps, a five-year multi-country research project called ACTwatch was launched. The project is designed to provide a comprehensive picture of the anti-malarial market to inform national and international anti-malarial drug policy decision-making. The project is being conducted in seven malaria-endemic countries: Benin, Cambodia, the Democratic Republic of Congo, Madagascar, Nigeria, Uganda and Zambia from 2008 to 2012.ACTwatch measures which anti-malarials are available, where they are available and at what price and who they are used by. These indicators are measured over time and across countries through three study components: outlet surveys, supply chain studies and household surveys. Nationally representative outlet surveys examine the market share of different anti-malarials passing through public facilities and private retail outlets. Supply chain research provides a picture of the supply chain serving drug outlets, and measures mark-ups at each supply chain level. On the demand side, nationally representative household surveys capture treatment seeking patterns and use of anti-malarial drugs, as well as respondent knowledge of anti-malarials. The research project provides findings on both the demand and supply side determinants of anti-malarial access. There are four key features of ACTwatch. First is the overlap of the three study components where nationally representative data are collected over similar periods, using a common sampling approach. A second feature is the number and diversity of countries that are studied which allows for cross-country comparisons. Another distinguishing feature is its ability to measure trends over time. Finally, the project aims to disseminate findings widely for decision
Full Text Available Abstract Background Policy makers, governments and donors are faced with an information gap when considering ways to improve access to artemisinin-based combination therapy (ACT and malaria diagnostics including rapid diagnostic tests (RDTs. To help address some of these gaps, a five-year multi-country research project called ACTwatch was launched. The project is designed to provide a comprehensive picture of the anti-malarial market to inform national and international anti-malarial drug policy decision-making. Methods The project is being conducted in seven malaria-endemic countries: Benin, Cambodia, the Democratic Republic of Congo, Madagascar, Nigeria, Uganda and Zambia from 2008 to 2012. ACTwatch measures which anti-malarials are available, where they are available and at what price and who they are used by. These indicators are measured over time and across countries through three study components: outlet surveys, supply chain studies and household surveys. Nationally representative outlet surveys examine the market share of different anti-malarials passing through public facilities and private retail outlets. Supply chain research provides a picture of the supply chain serving drug outlets, and measures mark-ups at each supply chain level. On the demand side, nationally representative household surveys capture treatment seeking patterns and use of anti-malarial drugs, as well as respondent knowledge of anti-malarials. Discussion The research project provides findings on both the demand and supply side determinants of anti-malarial access. There are four key features of ACTwatch. First is the overlap of the three study components where nationally representative data are collected over similar periods, using a common sampling approach. A second feature is the number and diversity of countries that are studied which allows for cross-country comparisons. Another distinguishing feature is its ability to measure trends over time. Finally, the
Background Policy makers, governments and donors are faced with an information gap when considering ways to improve access to artemisinin-based combination therapy (ACT) and malaria diagnostics including rapid diagnostic tests (RDTs). To help address some of these gaps, a five-year multi-country research project called ACTwatch was launched. The project is designed to provide a comprehensive picture of the anti-malarial market to inform national and international anti-malarial drug policy decision-making. Methods The project is being conducted in seven malaria-endemic countries: Benin, Cambodia, the Democratic Republic of Congo, Madagascar, Nigeria, Uganda and Zambia from 2008 to 2012. ACTwatch measures which anti-malarials are available, where they are available and at what price and who they are used by. These indicators are measured over time and across countries through three study components: outlet surveys, supply chain studies and household surveys. Nationally representative outlet surveys examine the market share of different anti-malarials passing through public facilities and private retail outlets. Supply chain research provides a picture of the supply chain serving drug outlets, and measures mark-ups at each supply chain level. On the demand side, nationally representative household surveys capture treatment seeking patterns and use of anti-malarial drugs, as well as respondent knowledge of anti-malarials. Discussion The research project provides findings on both the demand and supply side determinants of anti-malarial access. There are four key features of ACTwatch. First is the overlap of the three study components where nationally representative data are collected over similar periods, using a common sampling approach. A second feature is the number and diversity of countries that are studied which allows for cross-country comparisons. Another distinguishing feature is its ability to measure trends over time. Finally, the project aims to disseminate
Kim, Ju-Hwa; Choi, Ae-Ran; Kim, Yong Kee; Yoon, Sungpil
The purpose of this study was to identify conditions that will increase the sensitivity of resistant cancer cells to anti-mitotic drugs. Currently, atovaquine (ATO), chloroquine (CHL), primaquine (PRI), mefloquine (MEF), artesunate (ART), and doxycycline (DOY) are the most commonly used anti-malarial drugs. Herein, we tested whether anti-malarial drugs can sensitize drug-resistant KBV20C cancer cells. None of the six tested anti-malarial drugs was found to better sensitize the drug-resistant cells compared to the sensitive KB cells. With an exception of DOY, all other anti-malarial drugs tested could sensitize both KB and KBV20C cells to a similar extent, suggesting that anti-malarial drugs could be used for sensitive as well as resistant cancer cells. Furthermore, we examined the effects of anti-malarial drugs in combination with an antimitotic drug, vinblastine (VIN) on the sensitisation of resistant KBV20C cells. Using viability assay, microscopic observation, assessment of cleaved PARP, and Hoechst staining, we identified that two anti-malarial drugs, PRI and MEF, highly sensitized KBV20C-resistant cells to VIN treatment. Moreover, PRI- or MEF-induced sensitisation was not observed in VIN-treated sensitive KB parent cells, suggesting that the observed effect is specific to resistant cancer cells. We demonstrated that the PRI and MEF sensitisation mechanism mainly depends on the inhibition of p-glycoprotein (P-gp). Our findings may contribute to the development of anti-malarial drug-based combination therapies for patients resistant to anti-mitotic drugs. Copyright © 2013 Elsevier Inc. All rights reserved.
Background The counterfeiting of anti-malarials represents a form of attack on global public health in which fake and substandard anti-malarials serve as de facto weapons of mass destruction, particularly in resource-constrained endemic settings, where malaria causes nearly 660,000 preventable deaths and threatens millions of lives annually. It has been estimated that fake anti-malarials contribute to nearly 450,000 preventable deaths every year. This crime against humanity is often underestimated or ignored. This study attempts to describe and characterize the direct and indirect effects of counterfeit anti-malarials on public health, clinical care and socio-economic conditions. Methods A search was performed using key databases, WHO documents, and English language search engines. Of 262 potential articles that were identified using a fixed set of criteria, a convenience sample of 105 appropriate articles was selected for this review. Results Artemisinin-based combination therapy (ACT) is an important tool in the fight against malaria, but a sizable number of patients are unable to afford to this first-line treatment. Consequently, patients tend to procure cheaper anti-malarials, which may be fake or substandard. Forensic palynology reveals that counterfeits originate in Asia. Fragile drug regulations, ineffective law-enforcement agencies and corruption further burden ailing healthcare facilities. Substandard/fake anti-malarials can cause (a) economic sabotage; (b) therapeutic failure; (c) increased risk of the emergence and spread of resistant strains of Plasmodium falciparum and Plasmodium vivax; (d) an undermining of trust/confidence in healthcare stakeholders/systems; and, (e) serious side effects or death. Conclusion Combating counterfeit anti-malarials is a complex task due to limited resources and poor techniques for the detection and identification of fake anti-malarials. This situation calls for sustainable, global, scientific research and policy change
The counterfeiting of anti-malarials represents a form of attack on global public health in which fake and substandard anti-malarials serve as de facto weapons of mass destruction, particularly in resource-constrained endemic settings, where malaria causes nearly 660,000 preventable deaths and threatens millions of lives annually. It has been estimated that fake anti-malarials contribute to nearly 450,000 preventable deaths every year. This crime against humanity is often underestimated or ignored. This study attempts to describe and characterize the direct and indirect effects of counterfeit anti-malarials on public health, clinical care and socio-economic conditions. A search was performed using key databases, WHO documents, and English language search engines. Of 262 potential articles that were identified using a fixed set of criteria, a convenience sample of 105 appropriate articles was selected for this review. Artemisinin-based combination therapy (ACT) is an important tool in the fight against malaria, but a sizable number of patients are unable to afford to this first-line treatment. Consequently, patients tend to procure cheaper anti-malarials, which may be fake or substandard. Forensic palynology reveals that counterfeits originate in Asia. Fragile drug regulations, ineffective law-enforcement agencies and corruption further burden ailing healthcare facilities. Substandard/fake anti-malarials can cause (a) economic sabotage; (b) therapeutic failure; (c) increased risk of the emergence and spread of resistant strains of Plasmodium falciparum and Plasmodium vivax; (d) an undermining of trust/confidence in healthcare stakeholders/systems; and, (e) serious side effects or death. Combating counterfeit anti-malarials is a complex task due to limited resources and poor techniques for the detection and identification of fake anti-malarials. This situation calls for sustainable, global, scientific research and policy change. Further, responsible stakeholders in
Full Text Available Abstract Background There is concern about an increasing infiltration of markets by substandard and fake medications against life-threatening diseases in developing countries. This is particularly worrying with regard to the increasing resistance development of Plasmodium falciparum against affordable anti-malarial medications, which has led to a change to more expensive drugs in most endemic countries. Methods A representative sample of modern anti-malarial medications from licensed (public and private pharmacies, community health workers and illicit (market and street vendors, shops sources has been collected in the Nouna Health District in north-western Burkina Faso in 2006. All drugs were tested for their quality with the standard procedures of the German Pharma Health Fund-Minilab. Detected low standard drugs were re-tested with European Pharmacopoeia 2.9.1 standards for disintegration and ultraviolet-visible spectroscopy at the laboratory of the Heidelberg University for confirmation. Results Overall, 86 anti-malarial drug samples were collected, of which 77 samples have been included in the final analysis. The sample consisted of 39/77 (50% chloroquine, 10/77 (13% pyrimethamine-sulphadoxine, 9/77 (12% quinine, 6/77 (8% amodiaquine, 9/77 (12% artesunate, and 4/77 (5% artemether-lumefantrine. 32/77 (42% drug samples were found to be of poor quality, of which 28 samples failed the visual inspection, nine samples had substandard concentrations of the active ingredient, four samples showed poor disintegration, and one sample contained non of the stated active ingredient. The licensed and the illicit market contributed 5/47 (10.6% and 27/30 (90.0% samples of substandard drugs respectively. Conclusion These findings provide further evidence for the wide-spread existence of substandard anti-malarial medications in Africa and call for strengthening of the regulatory and quality control capacity of affected countries, particularly in view of the
Kaur, Harparkash; Clarke, Siȃn; Lalani, Mirza; Phanouvong, Souly; Guérin, Philippe; McLoughlin, Andrew; Wilson, Benjamin K; Deats, Michael; Plançon, Aline; Hopkins, Heidi; Miranda, Debora; Schellenberg, David
This meeting report presents the key findings and discussion points of a 1-day meeting entitled 'Fake anti-malarials: start with the facts' held on 28th May 2015, in Geneva, Switzerland, to disseminate the findings of the artemisinin combination therapy consortium's drug quality programme. The teams purchased over 10,000 samples, using representative sampling approaches, from six malaria endemic countries: Equatorial Guinea (Bioko Island), Cambodia, Ghana, Nigeria, Rwanda and Tanzania. Laboratory analyses of these samples showed that falsified anti-malarials (substandard artemisinin-based combinations were present in all six countries and, artemisinin-based monotherapy tablets are still available in some places despite the fact that the WHO has urged regulatory authorities in malaria-endemic countries to take measures to halt the production and marketing of these oral monotherapies since 2007. This report summarizes the presentations that reviewed the public health impact of falsified and substandard drugs, sampling strategies, techniques for drug quality analysis, approaches to strengthen health systems capacity for the surveillance of drug quality, and the ensuing discussion points from the dissemination meeting.
Full Text Available Abstract Background Interventions to reverse trends in malaria-related morbidity and mortality in Kenya focus on preventive strategies and drug efficacy. However, the pattern of use of anti-malarials in malaria-endemic populations, such as in western Kenya, is still poorly understood. It is critical to understand the patterns of anti-malarial drug use to ascertain that the currently applied new combination therapy to malaria treatment, will achieve sustained cure rates and protection against parasite resistance. Therefore, this cross-sectional study was designed to determine the patterns of use of anti-malarial drugs in households (n = 397 in peri-urban location of Manyatta-B sub-location in Kisumu in western Kenya. Methods Household factors, associated with the pattern of anti-malarials use, were evaluated. Using clusters, questionnaire was administered to a particular household member who had the most recent malaria episode (within Results Stratification of the type of anti-malarial drugs taken revealed that 37.0% used sulphadoxine/pyrimethamine (SP, 32.0% artemisinin-based combined therapy (ACT, 11.1% anti-pyretics, 7.3% chloroquine (CQ, 7.1% quinine, 2.5% amodiaquine (AQ, while 3.0% used others which were perceived as anti-malarials (cough syrups and antibiotics. In a regression model, it was demonstrated that age (P = 0.050, household size (P = 0.047, household head (P = 0.049, household source of income (P = 0.015, monthly income (P = 0.020, duration of use (P = 0.029, dosage of drugs taken (P = 0.036, and source of drugs (P = 0.005 significantly influenced anti-malarial drug use. Overall, 38.8% of respondents used drugs as recommended by the Ministry of Health. Conclusion This study demonstrates that consumers require access to correct and comprehensible information associated with use of drugs, including self-prescription. There is potential need by the Kenyan government to improve malaria care and decrease malaria-related morbidity and
Efferth, Thomas; Ramirez, Tzutzuy; Gebhart, Erich; Halatsch, Marc-Eric
New drugs and combination modalities for otherwise non-responsive brain tumors are urgently required. The anti-malarial artesunate (ART) and the EGFR tyrosine kinase inhibitor OSI-774 reveal profound cytotoxic activity. The effectiveness of a combination treatment and the underlying molecular determinants of cellular response are unknown. In the present investigation, we studied ART and OSI-774 in glioblastoma multiforme (GBM) cell lines. Supra-additive inhibition of cell growth was observed in U-87MG.DeltaEGFR cells transduced with a deletion-mutant constitutively active EGFR gene, while additive effects were present in cells transduced with wild-type EGFR (U-87MG.WT-2N), kinase-deficient EGFR (U-87MG.DK-2N), mock vector controls (U-87MG.LUX), or non-transduced parental U-87MG cells. Among nine other non-transduced GBM cell lines, supra-additive effects were found in two cell lines (G-210GM, G-599GM), while ART and OSI-774 acted in an additive manner in the other seven cell lines (G-211GM, G-750GM, G-1163GM, G-1187GM, G-1265GM, G-1301GM, and G-1408GM). Sub-additive or antagonistic effects were not observed. Genomic gains and losses of genetic material in the non-transduced cell lines as assessed by comparative genomic hybridization were correlated with the IC(50) values for ART and OSI-774 and subsequently subjected to hierarchical cluster analysis and cluster image mapping. A genomic profile of imbalances was detected that predicted cellular response to ART and OSI-774. The genes located at the genomic imbalances of interest may serve as candidate resistance genes of GBM cells towards ART and OSI-774. In conclusion, the combination treatment of ART and OSI-774 resulted in an increased growth inhibition of GBM cell lines as compared to each drug alone.
Ciana, Claire-Lise; Siegrist, Romain; Aissaoui, Hamed; Marx, Léo; Racine, Sophie; Meyer, Solange; Binkert, Christoph; de Kanter, Ruben; Fischli, Christoph; Wittlin, Sergio; Boss, Christoph
A novel series of anti-malarials, based on a hydroxy-ethyl-amine scaffold, initially identified as peptidomimetic protease inhibitors is described. Combination of the hydroxy-ethyl-amine anti-malarial phramacophore with the known Mannich base pharmacophore of amodiaquine (57) resulted in promising in vivo active novel derivatives. Copyright © 2012 Elsevier Ltd. All rights reserved.
Full Text Available Objectives: Malaria has been a major global health problem in recent times with increasing mortality. Current treatment methods include parasiticidal drugs and vaccinations. However, resistance among malarial parasites to the existing drugs has emerged as a significant area of concern in anti-malarial drug design. Researchers are now desperately looking for new targets to develop anti-malarials drug which is more target specific. Malarial parasites harbor a plastid-like organelle known as the ‘apicoplast’, which is thought to provide an exciting new outlook for the development of drugs to be used against the parasite. This review elaborates on the current state of development of novel compounds targeted againstemerging malaria parasites. Methods: The apicoplast, originates by an endosymbiotic process, contains a range of metabolic pathways and housekeeping processes that differ from the host body and thereby presents ideal strategies for anti-malarial drug therapy. Drugs are designed by targeting the unique mechanism of the apicoplasts genetic machinery. Several anabolic and catabolic processes, like fatty acid, isopenetyl diphosphate and heme synthess in this organelle, have also been targeted by drugs. Results: Apicoplasts offer exciting opportunities for the development of malarial treatment specific drugs have been found to act by disrupting this organelle’s function, which wouldimpede the survival of the parasite. Conclusion: Recent advanced drugs, their modes of action, and their advantages in the treatment of malaria by using apicoplasts as a target are discussed in this review which thought to be very useful in desigining anti-malarial drugs. Targetting the genetic machinery of apicoplast shows a great advantange regarding anti-malarial drug design. Critical knowledge of these new drugs would give a healthier understanding for deciphering the mechanism of action of anti-malarial drugs when targeting apicoplasts to overcome drug
Chikowe, Ibrahim; Osei-Safo, Dorcas; Harrison, Jerry J E K; Konadu, Daniel Y; Addae-Mensah, Ivan
The growing concern over the extent of anti-malarial medicine resistance in sub-Saharan Africa, driven largely by administration of sub-therapeutic doses derived from falsified and substandard medicines necessitates regular monitoring of the quality of these medicines to avert any potential public health disaster. This study aimed at determining the active pharmaceutical ingredient (API) content of anti-malarial medicines available in Malawi with respect to the manufacturers' label claim and pharmacopoeia specifications. Samples of anti-malarial medicines (112) collected from both licensed and unlicensed markets throughout Malawi were subjected to visual inspection of dosage form and packaging, and registration verification with the regulatory body. Basic (colourimetric) tests were employed to establish the presence and identity of the requisite APIs. Semi-quantitative thin layer chromatography (SQ-TLC) was employed as a quick assay for the verification of identity and estimation of the API content while HPLC assays were used to quantify the APIs. The results were compared with pharmacopoeia specifications and manufacturers' label claims. For combination therapies, a sample was considered to have failed if one or more of its component APIs did not meet pharmacopoeia specifications. There was 86.6% registration status and 100% compliance with visual inspection and basic tests confirming the presence of requisite APIs. The identification test was confirmed by the SQ-TLC assay. API quantification by HPLC assay however, showed that 88.4% (99/112) of the samples failed the quality tests due to the presence of either insufficient or excessive API. The results suggest the existence of substandard anti-malarial medicines in Malawi. The presence of both excessive and insufficient artemisinin-based and non-artemisinin-based API, clearly points to poor adherence to GMP and improper handling during storage or distribution. The country relies heavily on imported anti-malarial
Active case detection, treatment of falciparum malaria with combined chloroquine and sulphadoxine/pyrimethamine and vivax malaria with chloroquine and molecular markers of anti-malarial resistance in the Republic of Vanuatu
Rogers William O
Full Text Available Abstract Background Chloroquine-resistant Plasmodium falciparum was first described in the Republic of Vanuatu in the early 1980s. In 1991, the Vanuatu Ministry of Health instituted new treatment guidelines for uncomplicated P. falciparum infection consisting of chloroquine/sulphadoxine-pyrimethamine combination therapy. Chloroquine remains the recommended treatment for Plasmodium vivax. Methods In 2005, cross-sectional blood surveys at 45 sites on Malo Island were conducted and 4,060 adults and children screened for malaria. Of those screened, 203 volunteer study subjects without malaria at the time of screening were followed for 13 weeks to observe peak seasonal incidence of infection. Another 54 subjects with malaria were followed over a 28-day period to determine efficacy of anti-malarial therapy; chloroquine alone for P. vivax and chloroquine/sulphadoxine-pyrimethamine for P. falciparum infections. Results The overall prevalence of parasitaemia by mass blood screening was 6%, equally divided between P. falciparum and P. vivax. Twenty percent and 23% of participants with patent P. vivax and P. falciparum parasitaemia, respectively, were febrile at the time of screening. In the incidence study cohort, after 2,303 person-weeks of follow-up, the incidence density of malaria was 1.3 cases per person-year with P. vivax predominating. Among individuals participating in the clinical trial, the 28-day chloroquine P. vivax cure rate was 100%. The 28-day chloroquine/sulphadoxine-pyrimethamine P. falciparum cure rate was 97%. The single treatment failure, confirmed by merozoite surface protein-2 genotyping, was classified as a day 28 late parasitological treatment failure. All P. falciparum isolates carried the Thr-76 pfcrt mutant allele and the double Asn-108 + Arg-59 dhfr mutant alleles. Dhps mutant alleles were not detected in the study sample. Conclusion Peak seasonal malaria prevalence on Malo Island reached hypoendemic levels during the study
Full Text Available Abstract Background Artemisinin-based combination therapy (ACT is presently recommended by the World Health Organization as first-line treatment for uncomplicated Plasmodium falciparum malaria in several countries, as a mean of prolonging the effectiveness of first-line malaria treatment regimens. A three-day course of artesunate-mefloquine (4 mg/kg body weight once daily for three consecutive days, plus 15 and 10 mg/kg body weight mefloquine on the first and second days has been adopted by Malaria Control Programme of Thailand as first-line treatment for uncomplicated falciparum malaria all over the country since 2008. The gametocytocydal anti-malarial drug primaquine is administered at the dose of 30 mg (0.6 mg/kg on the last day. The aim of the present study was to assess patient compliance of this combination regimen when applied to field condition. Methods A total of 240 patients (196 males and 44 females who were attending the malaria clinics in Mae-Sot, Tak Province and presenting with symptomatic acute uncomplicated falciparum malaria, with no reappearance of Plasmodium vivax parasitaemia during follow-up were included into the study. The first dose of the treatment was given to the patients under direct supervision. All patients were given the medication for self-treatment at home and were requested to come back for follow-up on day 3 of the initial treatment. Baseline (day 0 and day 3 whole blood mefloquine and plasma primaquine concentrations were determined by high performance liquid chromatography. Results Two patients had recrudescence on days 28 and 35. The Kaplan-Meier estimate of the 42-day efficacy rate of this combination regimen was 99.2% (238/240. Based on whole blood mefloquine and plasma primaquine concentrations on day 3 of the initial treatment, compliance with mefloquine and primaquine in this three-day artesunate-mefloquine combination regimen were 96.3% (207/215, and 98.5% (197/200, respectively. Baseline mefloquine
Phok, Sochea; Lek, Dysoley
Understanding Cambodia's anti-malarial and diagnostic landscape in 2015 is critical for informing and monitoring strategies and policies as Cambodia moves forward with national efforts to eliminate malaria. The aim of this paper is to present timely and key findings on the public and private sector anti-malarial and diagnostic landscape in Cambodia. This evidence can serve as a baseline benchmark for guiding implementation of national strategies as well as other regional initiatives to address malaria elimination activities. From August 17th to October 1st, 2015, a cross sectional, nationally-representative malaria outlet survey was conducted in Cambodia. A census of all public and private outlets with potential to distribute malaria testing and/or treatment was conducted among 180 communes. An audit was completed for all anti-malarials, malaria rapid diagnostic tests (RDT) and microscopy. A total of 26,664 outlets were screened, and 1303 outlets were eligible and interviewed. Among all screened outlets in the public sector, 75.9% of public health facilities and 67.7% of community health workers stocked both malaria diagnostic testing and a first-line artemisinin-based combination therapy (ACT). Among anti-malarial-stocking private sector outlets, 64.7% had malaria blood testing available, and 70.9% were stocking a first-line ACT. Market share data illustrate that most of the anti-malarials were sold or distributed through the private sector (58.4%), including itinerant drug vendors (23.4%). First-line ACT accounted for the majority of the market share across the public and private sectors (90.3%). Among private sector outlets stocking any anti-malarial, the proportion of outlets with a first-line ACT or RDT was higher among outlets that had reportedly received one or more forms of 'support' (e.g. reportedly received training in the previous year on malaria diagnosis [RDT and/or microscopy] and/or the national treatment guidelines for malaria) compared to outlets
O'Connell, Kathryn A; Gatakaa, Hellen; Poyer, Stephen; Njogu, Julius; Evance, Illah; Munroe, Erik; Solomon, Tsione; Goodman, Catherine; Hanson, Kara; Zinsou, Cyprien; Akulayi, Louis; Raharinjatovo, Jacky; Arogundade, Ekundayo; Buyungo, Peter; Mpasela, Felton; Adjibabi, Chérifatou Bello; Agbango, Jean Angbalu; Ramarosandratana, Benjamin Fanomezana; Coker, Babajide; Rubahika, Denis; Hamainza, Busiku; Chapman, Steven; Shewchuk, Tanya; Chavasse, Desmond
Artemisinin-based combination therapy (ACT) is the first-line malaria treatment throughout most of the malaria-endemic world. Data on ACT availability, price and market share are needed to provide a firm evidence base from which to assess the current situation concerning quality-assured ACT supply. This paper presents supply side data from ACTwatch outlet surveys in Benin, the Democratic Republic of Congo (DRC), Madagascar, Nigeria, Uganda and Zambia. Between March 2009 and June 2010, nationally representative surveys of outlets providing anti-malarials to consumers were conducted. A census of all outlets with the potential to provide anti-malarials was conducted in clusters sampled randomly. 28,263 outlets were censused, 51,158 anti-malarials were audited, and 9,118 providers interviewed. The proportion of public health facilities with at least one first-line quality-assured ACT in stock ranged between 43% and 85%. Among private sector outlets stocking at least one anti-malarial, non-artemisinin therapies, such as chloroquine and sulphadoxine-pyrimethamine, were widely available (> 95% of outlets) as compared to first-line quality-assured ACT (price of first-line quality-assured ACT ($0.14 [IQR: $0.10, $0.57]) was significantly lower than the most popular treatment (chloroquine, $0.36 [IQR: $0.36, $0.36]). Quality-assured ACT accounted for less than 25% of total anti-malarial volumes; private-sector quality-assured ACT volumes represented less than 6% of the total market share. Most anti-malarials were distributed through the private sector, but often comprised non-artemisinin therapies, and in the DRC and Nigeria, oral artemisinin monotherapies. Provider knowledge of the first-line treatment was significantly lower in the private sector than in the public/not-for-profit sector. These standardized, nationally representative results demonstrate the typically low availability, low market share and high prices of ACT, in the private sector where most anti-malarials
O'Connell Kathryn A
Full Text Available Abstract Background Artemisinin-based combination therapy (ACT is the first-line malaria treatment throughout most of the malaria-endemic world. Data on ACT availability, price and market share are needed to provide a firm evidence base from which to assess the current situation concerning quality-assured ACT supply. This paper presents supply side data from ACTwatch outlet surveys in Benin, the Democratic Republic of Congo (DRC, Madagascar, Nigeria, Uganda and Zambia. Methods Between March 2009 and June 2010, nationally representative surveys of outlets providing anti-malarials to consumers were conducted. A census of all outlets with the potential to provide anti-malarials was conducted in clusters sampled randomly. Results 28,263 outlets were censused, 51,158 anti-malarials were audited, and 9,118 providers interviewed. The proportion of public health facilities with at least one first-line quality-assured ACT in stock ranged between 43% and 85%. Among private sector outlets stocking at least one anti-malarial, non-artemisinin therapies, such as chloroquine and sulphadoxine-pyrimethamine, were widely available (> 95% of outlets as compared to first-line quality-assured ACT ( Conclusions These standardized, nationally representative results demonstrate the typically low availability, low market share and high prices of ACT, in the private sector where most anti-malarials are accessed, with some exceptions. The results confirm that there is substantial room to improve availability and affordability of ACT treatment in the surveyed countries. The data will also be useful for monitoring the impact of interventions such as the Affordable Medicines Facility for malaria.
Evans, Lawrence; Coignez, Veerle; Barojas, Adrian; Bempong, Daniel; Bradby, Sanford; Dijiba, Yanga; James, Makeida; Bretas, Gustavo; Adhin, Malti; Ceron, Nicolas; Hinds-Semple, Alison; Chibwe, Kennedy; Lukulay, Patrick; Pribluda, Victor
Despite a significant reduction in the number of malaria cases in Guyana and Suriname, this disease remains a major problem in the interior of both countries, especially in areas with gold mining and logging operations, where malaria is endemic. National malaria control programmes in these countries provide treatment to patients with medicines that are procured and distributed through regulated processes in the public sector. However, availability to medicines in licensed facilities (private sector) and unlicensed facilities (informal sector) is common, posing the risk of access to and use of non-recommended treatments and/or poor quality products. To assess the quality of circulating anti-malarial medicines, samples were purchased in the private and informal sectors of Guyana and Suriname in 2009. The sampling sites were selected based on epidemiological data and/or distance from health facilities. Samples were analysed for identity, content, dissolution or disintegration, impurities, and uniformity of dosage units or weight variation according to manufacturer, pharmacopeial, or other validated method. Quality issues were observed in 45 of 77 (58%) anti-malarial medicines sampled in Guyana of which 30 failed visual & physical inspection and 18 failed quality control tests. The proportion of monotherapy and ACT medicines failing quality control tests was 43% (13/30) and 11% (5/47) respectively. A higher proportion of medicines sampled from the private sector 34% (11/32) failed quality control tests versus 16% (7/45) in the informal sector. In Suriname, 58 medicines were sampled, of which 50 (86%) were Artecom®, the fixed-dose combination of piperaquine-dihydroartemisinin-trimethoprim co-blistered with a primaquine phosphate tablet. All Artecom samples were found to lack a label claim for primaquine, thus failing visual and physical inspection. The findings of the studies in both countries point to significant problems with the quality of anti-malarial medicines
Full Text Available Abstract Background Despite a significant reduction in the number of malaria cases in Guyana and Suriname, this disease remains a major problem in the interior of both countries, especially in areas with gold mining and logging operations, where malaria is endemic. National malaria control programmes in these countries provide treatment to patients with medicines that are procured and distributed through regulated processes in the public sector. However, availability to medicines in licensed facilities (private sector and unlicensed facilities (informal sector is common, posing the risk of access to and use of non-recommended treatments and/or poor quality products. Methods To assess the quality of circulating anti-malarial medicines, samples were purchased in the private and informal sectors of Guyana and Suriname in 2009. The sampling sites were selected based on epidemiological data and/or distance from health facilities. Samples were analysed for identity, content, dissolution or disintegration, impurities, and uniformity of dosage units or weight variation according to manufacturer, pharmacopeial, or other validated method. Results Quality issues were observed in 45 of 77 (58% anti-malarial medicines sampled in Guyana of which 30 failed visual & physical inspection and 18 failed quality control tests. The proportion of monotherapy and ACT medicines failing quality control tests was 43% (13/30 and 11% (5/47 respectively. A higher proportion of medicines sampled from the private sector 34% (11/32 failed quality control tests versus 16% (7/45 in the informal sector. In Suriname, 58 medicines were sampled, of which 50 (86% were Artecom®, the fixed-dose combination of piperaquine-dihydroartemisinin-trimethoprim co-blistered with a primaquine phosphate tablet. All Artecom samples were found to lack a label claim for primaquine, thus failing visual and physical inspection. Conclusions The findings of the studies in both countries point to
Full Text Available Malaria is a parasite infection affecting millions of people worldwide. Even though progresses in prevention and treatment have been developed, 198 million cases of malaria occurred in 2013, resulting in 584000 estimated deaths. 90% of all malaria deaths occurred in Africa, mostly among children under the age of five. This article aims to review malaria’s history, epidemiology and current treatments, with a particular focus on the potential of molecular farming that use metabolic engineering in plants as effective anti-malarial solution. Malaria indeed represents an example of how a health problem on one hand, may eventually influence the proper development of a country due to the burden of the disease, and on the other hand, constitutes an opportunity for lucrative business of diverse stakeholders. In contrast, plant biofarming is here proposed as a sustainable alternative for the production not only of natural herbal repellents used for malaria prevention but also for the production of sustainable anti-malarial drugs like artemisinin used for primary parasite infection treatments.Artemisinin, a sesquiterpene lactone, is a natural anti-malarial compound that can be found in Artemisia annua plant. However, the low concentration of artemisinin in plant makes this molecule relatively expensive and difficult to meet the worldwide demand of Artemisinin Combination Therapies, especially for economically disadvantaged people in developing countries. The biosynthetic pathway of artemisinin, a process that only takes place in glandular secretory trichomes of A. annua, is relatively well elucidated, and significant efforts using plant genetic engineering have been made to increase the production of this compound. These include studies on diverse transcription factors, which all have been shown to regulate artemisinin genetic pathway and other biological processes. Therefore, genetic manipulation of these genes may be used as a cost-effective potential
Full Text Available Abstract Background The introduction of new anti-malarial treatment that is effective, but more expensive, raises questions about whether the high level of effectiveness observed in clinical trials can be found in a context of family use. The objective of this study was to determine the factors related to adherence, when using the amodiaquine/sulphadoxine-pyrimethamine (AQ/SP association, a transitory strategy before ACT implementation in Senegal. Methods The study was conducted in five rural dispensaries. Children, between two and 10 years of age, who presented mild malaria were recruited at the time of the consultation and were prescribed AQ/SP. The child's primary caretaker was questioned at home on D3 about treatment compliance and factors that could have influenced his or her adherence to treatment. A logistic regression model was used for the analyses. Results The study sample included 289 children. The adherence rate was 64.7%. Two risks factors for non-adherence were identified: the children's age (8–10 years (ORa = 3.07 [1.49–6.29]; p = 0.004; and the profession of the head of household (retailer/employee versus farmer (ORa = 2.71 [1.34–5.48]; p = 0.006. Previously seeking care (ORa = 0.28 [0.105–0.736], p=0.001] satisfaction with received information (ORa = 0.45 [0.24–0.84]; p = 0.013, and the quality of history taking (ORa = 0.38 [0.21–0.69]; p = 0.001 were significantly associated with good compliance. Conclusion The results of the study show the importance of information and communication between caregivers and health center staff. The experience gained from this therapeutic transition emphasizes the importance of information given to the patients at the time of the consultation and drug delivery in order to improve drug use and thus prevent the emergence of rapid drug resistance.
Full Text Available Abstract Background Malaria is a major cause of morbidity and mortality in Kenya, where it is the fifth leading cause of death in both children and adults. Effectively managing malaria is dependent upon appropriate treatment. In Kenya, between 17 to 83 percent of febrile individuals first seek treatment for febrile illness over the counter from medicine retailers. Understanding medicine retailer knowledge and behaviour in treating suspected malaria and dispensing anti-malarials is crucial. Methods To investigate medicine retailer knowledge about anti-malarials and their dispensing practices, a survey was conducted of all retail drug outlets that sell anti-malarial medications and serve residents of the Webuye Health and Demographic Surveillance Site in the Bungoma East District of western Kenya. Results Most of the medicine retailers surveyed (65% were able to identify artemether-lumefantrine (AL as the Kenyan Ministry of Health recommended first-line anti-malarial therapy for uncomplicated malaria. Retailers who correctly identified this treatment were also more likely to recommend AL to adult and paediatric customers. However, the proportion of medicine retailers who recommend the correct treatment is disappointingly low. Only 48% would recommend AL to adults, and 37% would recommend it to children. It was discovered that customer demand has an influence on retailer behaviour. Retailer training and education were found to be correlated with anti-malarial drug knowledge, which in turn is correlated with dispensing practices. Medicine retailer behaviour, including patient referral practice and dispensing practices, are also correlated with knowledge of the first-line anti-malarial medication. The Kenya Ministry of Health guidelines were found to influence retailer drug stocking and dispensing behaviours. Conclusion Most medicine retailers could identify the recommended first-line treatment for uncomplicated malaria, but the percentage that could
Hubbard Alan E; Dorsey Grant; Gupta Vinay; Rosenthal Philip J; Greenhouse Bryan
Abstract Background Molecular genotyping is performed in anti-malarial trials to determine whether recurrent parasitaemia after therapy represents a recrudescence (treatment failure) or new infection. The use of capillary instead of agarose gel electrophoresis for genotyping offers technical advantages, but it is unclear whether capillary electrophoresis will result in improved classification of anti-malarial treatment outcomes. Methods Samples were genotyped using both gel and capillary elec...
Lussiana, Cristina; Floridia, Marco; Martinho do Rosário, Joana; Fortes, Filomeno; Allan, Richard
Artemisinin-based combination therapies (ACTs) against malaria are subsidized in many African countries, but the impact of subsidy programs in reducing the sales of concomitantly available antimalarial monotherapies is poorly defined. Data from The MENTOR initiative, that introduced subsidized artemether-lumefantrine (sAL) in the private sector of Huambo province, Angola, were used. The main response variable was represented by sales of sAL and of monotherapies, measured as number of treatment courses. Sales in private pharmacies of sAL and four antimalarial monotherapies between 2009 and 2013 were organized in four time-periods, and analyzed using generalized linear models for repeated measures. A secondary analysis evaluated changes in relative market share. We analyzed data from 34 pharmacies at four time points, taken from a larger survey that involved 165 pharmacies between June 2009 and March 2013. The sAL, following its introduction, became the dominant antimalarial treatment in the private sector, usually exceeding the total sales of all antimalarial monotherapies combined (1480/2800 total treatment courses, 52.8% of all sales in March 2013). Sales of monotherapies decreased significantly, but did not stop, representing 36.7% (1028/2800) of sales at the end of the survey. Subsidized ACTs can attain rapidly a high relative market share. Their introduction reduced, but did not eliminate the demand for less effective monotherapies, that might favor parasite resistance. © The Author 2016. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org.
Full Text Available Discovered by Youyou Tu, one of the 2015 Nobel Prize winners in Physiology or Medicine, together with many other Chinese scientists, artemisinin, artemether and artesunate, as well as other artemisinins, have brought the global anti-malarial treatment to a new era, saving millions of lives all around the world for the past 40 years. The discoveries of artemisinins were carried out beginning from the 1970s, a special period in China, by hundreds of scientists all together under the “whole nation” system. This article focusing on medicinal chemistry research, briefly introduced the discovery and invention course of the scientists according to the published papers, and highlighted their academic contribution and achievements.
Full Text Available Abstract Background Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD model for predicting within-host parasite response was performed. Methods Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50, derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach. Results The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle. The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i
Achan, Jane; Talisuna, Ambrose O; Erhart, Annette; Yeka, Adoke; Tibenderana, James K; Baliraine, Frederick N; Rosenthal, Philip J; D'Alessandro, Umberto
Quinine remains an important anti-malarial drug almost 400 years after its effectiveness was first documented. However, its continued use is challenged by its poor tolerability, poor compliance with complex dosing regimens, and the availability of more efficacious anti-malarial drugs. This article reviews the historical role of quinine, considers its current usage and provides insight into its appropriate future use in the treatment of malaria. In light of recent research findings intravenous artesunate should be the first-line drug for severe malaria, with quinine as an alternative. The role of rectal quinine as pre-referral treatment for severe malaria has not been fully explored, but it remains a promising intervention. In pregnancy, quinine continues to play a critical role in the management of malaria, especially in the first trimester, and it will remain a mainstay of treatment until safer alternatives become available. For uncomplicated malaria, artemisinin-based combination therapy (ACT) offers a better option than quinine though the difficulty of maintaining a steady supply of ACT in resource-limited settings renders the rapid withdrawal of quinine for uncomplicated malaria cases risky. The best approach would be to identify solutions to ACT stock-outs, maintain quinine in case of ACT stock-outs, and evaluate strategies for improving quinine treatment outcomes by combining it with antibiotics. In HIV and TB infected populations, concerns about potential interactions between quinine and antiretroviral and anti-tuberculosis drugs exist, and these will need further research and pharmacovigilance.
Gebreyohannes, Eyob Alemayehu; Bhagavathula, Akshaya Srikanth; Seid, Mohammed Assen; Tegegn, Henok Getachew
Ethiopia is among countries with a high malaria burden. There are several studies that assessed the efficacy of anti-malarial agents in the country and this systematic review and meta-analysis was performed to obtain stronger evidence on treatment outcomes of malaria from the existing literature in Ethiopia. A systematic literature search using the preferred reporting items for systematic review and meta-analysis (PRISMA) statement was conducted on studies from Pubmed, Google Scholar, and ScienceDirect databases to identify published and unpublished literature. Comprehensive meta-analysis software was used to perform all meta-analyses. The Cochrane Q and the I 2 were used to evaluate heterogeneity of studies. Random effects model was used to combine studies showing heterogeneity of Cochrane Q p 50. Twenty-one studies were included in the final analysis with a total number of 3123 study participants. Treatment outcomes were assessed clinically and parasitologically using World Health Organization guidelines. Adequate clinical and parasitological response was used to assess treatment success at the 28th day. Overall, a significant high treatment success of 92.9% (95% CI 89.1-96.6), p Ethiopia, but associated with high rates of adverse drug reactions (ADRs). However, these ADRs were not serious enough to discontinue anti-malarial treatment. The results of this study suggest that the current anti-malarial medications are effective and safe; however, greater priority should be placed on the discovery of new anti-malarial drugs to achieve successful outcomes as resistance seems inevitable since cases of anti-malarial drug resistance have been reported from other areas of the world.
Full Text Available Abstract Background Poor access to prompt and effective treatment for malaria contributes to high mortality and severe morbidity. In Kenya, it is estimated that only 12% of children receive anti-malarials for their fever within 24 hours. The first point of care for many fevers is a local medicine retailer, such as a pharmacy or chemist. The role of the medicine retailer as an important distribution point for malaria medicines has been recognized and several different strategies have been used to improve the services that these retailers provide. Despite these efforts, many mothers still purchase ineffective drugs because they are less expensive than effective artemisinin combination therapy (ACT. One strategy that is being piloted in several countries is an international subsidy targeted at anti-malarials supplied through the retail sector. The goal of this strategy is to make ACT as affordable as ineffective alternatives. The programme, called the Affordable Medicines Facility - malaria was rolled out in Kenya in August 2010. Methods In December 2010, the affordability and accessibility of malaria medicines in a rural district in Kenya were evaluated using a complete census of all public and private facilities, chemists, pharmacists, and other malaria medicine retailers within the Webuye Demographic Surveillance Area. Availability, types, and prices of anti-malarials were assessed. There are 13 public or mission facilities and 97 medicine retailers (registered and unregistered. Results The average distance from a home to the nearest public health facility is 2 km, but the average distance to the nearest medicine retailer is half that. Quinine is the most frequently stocked anti-malarial (61% of retailers. More medicine retailers stocked sulphadoxine-pyramethamine (SP; 57% than ACT (44%. Eleven percent of retailers stocked AMFm subsidized artemether-lumefantrine (AL. No retailers had chloroquine in stock and only five were selling artemisinin
Dondorp Arjen M
Full Text Available Abstract Background Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT. The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. Methods A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. Results The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with
Khin, Hnin Su Su; Chen, Ingrid; White, Chris; Sudhinaraset, May; McFarland, Willi; Littrell, Megan; Montagu, Dominic; Aung, Tin
Global malaria control efforts are threatened by the spread and emergence of artemisinin-resistant Plasmodium falciparum parasites. In 2012, the widespread sale of partial courses of artemisinin-based monotherapy was suspected to take place in the highly accessed, weakly regulated private sector in Myanmar, posing potentially major threats to drug resistance. This study investigated the presence of artemisinin-based monotherapies in the Myanmar private sector, particularly as partial courses of therapy, to inform the targeting of future interventions to stop artemisinin resistance. A large cross-sectional survey comprised of a screening questionnaire was conducted across 26 townships in Myanmar between March and May, 2012. For outlets that stocked anti-malarials at the time of survey, a stock audit was conducted, and for outlets that stocked anti-malarials within 3 months of the survey, a provider survey was conducted. A total of 3,658 outlets were screened, 83% were retailers (pharmacies, itinerant drug vendors and general retailers) and 17% were healthcare providers (private facilities and health workers). Of the 3,658 outlets screened, 1,359 outlets (32%) stocked at least one anti-malarial at the time of study. Oral artemisinin-based monotherapy comprised of 33% of self-reported anti-malarials dispensing volumes found. The vast majority of artemisinin-based monotherapy was sold by retailers, where 63% confirmed that they sold partial courses of therapy by cutting blister packets. Very few retailers (5%) had malaria rapid diagnostic tests available, and quality-assured artemisinin-based combination therapy was virtually nonexistent among retailers. Informal private pharmacies, itinerant drug vendors and general retailers should be targeted for interventions to improve malaria treatment practices in Myanmar, particularly those that threaten the emergence and spread of artemisinin resistance.
Skinner-Adams, Tina S; Stack, Colin M; Trenholme, Katharine R; Brown, Chris L; Grembecka, Jolanta; Lowther, Jonathan; Mucha, Artur; Drag, Marcin; Kafarski, Pawel; McGowan, Sheena; Whisstock, James C; Gardiner, Donald L; Dalton, John P
The neutral aminopeptidases M1 alanyl aminopeptidase (PfM1AAP) and M17 leucine aminopeptidase (PfM17LAP) of the human malaria parasite Plasmodium falciparum are targets for the development of novel anti-malarial drugs. Although the functions of these enzymes remain unknown, they are believed to act in the terminal stages of haemoglobin degradation, generating amino acids essential for parasite growth and development. Inhibitors of both enzymes are lethal to P. falciparum in culture and kill the murine malaria P. chabaudi in vivo. Recent biochemical, structural and functional studies provide the substrate specificity and mechanistic binding data needed to guide the development of more potent anti-malarial drugs. Together with biological studies, these data form the rationale for choosing PfM1AAP and PfM17LAP as targets for anti-malarial development. Copyright 2009 Elsevier Ltd. All rights reserved.
Full Text Available Abstract Background As a result of widespread chloroquine and sulphadoxine-pyrimethamine resistance, artemisinin-based combination therapy (ACT (which includes artemether-lumefantrine and artesunate-amodiaquine has been recommended as a first-line anti-malarial regimen in Senegal since 2006. Since then, there have been very few reports on the ex vivo susceptibility of Plasmodium falciparum to anti-malarial drugs. To examine whether parasite susceptibility has been affected by the widespread use of ACT, the ex vivo susceptibility of local isolates was assessed at the military hospital of Dakar. Methods The ex vivo susceptibility of 93 P. falciparum isolates from Dakar was successfully determined using the Plasmodium lactate dehydrogenase (pLDH ELISA for the following drugs: chloroquine (CQ, quinine (QN, mefloquine (MQ, monodesethylamodiaquine (MDAQ, lumefantrine (LMF, dihydroartemisinin (DHA and doxycycline (DOX. Results After transformation of the isolate IC50 in ratio of IC50 according to the susceptibility of the 3D7 reference strain (isolate IC50/3D7 IC50, the prevalence of the in vitro resistant isolates with reduced susceptibility was 50% for MQ, 22% for CQ, 12% for DOX, 6% for both QN and MDAQ and 1% for the drugs LMF and DHA. The highest significant positive correlations were shown between responses to CQ and MDAQ (r = 0.569; P r = 0.511; P r = 0.428; P = 0.0001, LMF and MQ (r = 0.413; P = 0.0002, QN and DHA (r = 0.402; P = 0.0003 and QN and MQ (r = 0.421; P = 0.0001. Conclusions The introduction of ACT in 2002 has not induced a decrease in P. falciparum susceptibility to the drugs DHA, MDAQ and LMF, which are common ACT components. However, the prevalence of P. falciparum isolates with reduced susceptibility has increased for both MQ and DOX. Taken together, these data suggest that intensive surveillance of the P. falciparum in vitro susceptibility to anti-malarial drugs in Senegal is required.
Full Text Available BACKGROUND: While WHO recently recommended universal parasitological confirmation of suspected malaria prior to treatment, debate has continued as to whether wide-scale use of rapid diagnostic tests (RDTs can achieve this goal. Adherence of health service personnel to RDT results has been poor in some settings, with little impact on anti-malarial drug consumption. The Senegal national malaria control programme introduced universal parasite-based diagnosis using malaria RDTs from late 2007 in all public health facilities. This paper assesses the impact of this programme on anti-malarial drug consumption and disease reporting. METHODS AND FINDINGS: Nationally-collated programme data from 2007 to 2009 including malaria diagnostic outcomes, prescription of artemisinin-based combination therapy (ACT and consumption of RDTs in public health facilities, were reviewed and compared. Against a marked seasonal variation in all-cause out-patient visits, non-malarial fever and confirmed malaria, parasite-based diagnosis increased nationally from 3.9% of reported malaria-like febrile illness to 86.0% over a 3 year period. The prescription of ACT dropped throughout this period from 72.9% of malaria-like febrile illness to 31.5%, reaching close equivalence to confirmed malaria (29.9% of 584,873 suspect fever cases. An estimated 516,576 courses of inappropriate ACT prescription were averted. CONCLUSIONS: The data indicate high adherence of anti-malarial prescribing practice to RDT results after an initial run-in period. The large reduction in ACT consumption enabled by the move from symptom-based to parasite-based diagnosis demonstrates that effective roll-out and use of malaria RDTs is achievable on a national scale through well planned and structured implementation. While more detailed information on management of parasite-negative cases is required at point of care level to assess overall cost-benefits to the health sector, considerable cost-savings were
Thiam, Sylla; Thior, Moussa; Faye, Babacar; Ndiop, Médoune; Diouf, Mamadou Lamine; Diouf, Mame Birame; Diallo, Ibrahima; Fall, Fatou Ba; Ndiaye, Jean Louis; Albertini, Audrey; Lee, Evan; Jorgensen, Pernille; Gaye, Oumar; Bell, David
Background While WHO recently recommended universal parasitological confirmation of suspected malaria prior to treatment, debate has continued as to whether wide-scale use of rapid diagnostic tests (RDTs) can achieve this goal. Adherence of health service personnel to RDT results has been poor in some settings, with little impact on anti-malarial drug consumption. The Senegal national malaria control programme introduced universal parasite-based diagnosis using malaria RDTs from late 2007 in all public health facilities. This paper assesses the impact of this programme on anti-malarial drug consumption and disease reporting. Methods and Findings Nationally-collated programme data from 2007 to 2009 including malaria diagnostic outcomes, prescription of artemisinin-based combination therapy (ACT) and consumption of RDTs in public health facilities, were reviewed and compared. Against a marked seasonal variation in all-cause out-patient visits, non-malarial fever and confirmed malaria, parasite-based diagnosis increased nationally from 3.9% of reported malaria-like febrile illness to 86.0% over a 3 year period. The prescription of ACT dropped throughout this period from 72.9% of malaria-like febrile illness to 31.5%, reaching close equivalence to confirmed malaria (29.9% of 584873 suspect fever cases). An estimated 516576 courses of inappropriate ACT prescription were averted. Conclusions The data indicate high adherence of anti-malarial prescribing practice to RDT results after an initial run-in period. The large reduction in ACT consumption enabled by the move from symptom-based to parasite-based diagnosis demonstrates that effective roll-out and use of malaria RDTs is achievable on a national scale through well planned and structured implementation. While more detailed information on management of parasite-negative cases is required at point of care level to assess overall cost-benefits to the health sector, considerable cost-savings were achieved in ACT
Thiam, Sylla; Thior, Moussa; Faye, Babacar; Ndiop, Médoune; Diouf, Mamadou Lamine; Diouf, Mame Birame; Diallo, Ibrahima; Fall, Fatou Ba; Ndiaye, Jean Louis; Albertini, Audrey; Lee, Evan; Jorgensen, Pernille; Gaye, Oumar; Bell, David
While WHO recently recommended universal parasitological confirmation of suspected malaria prior to treatment, debate has continued as to whether wide-scale use of rapid diagnostic tests (RDTs) can achieve this goal. Adherence of health service personnel to RDT results has been poor in some settings, with little impact on anti-malarial drug consumption. The Senegal national malaria control programme introduced universal parasite-based diagnosis using malaria RDTs from late 2007 in all public health facilities. This paper assesses the impact of this programme on anti-malarial drug consumption and disease reporting. Nationally-collated programme data from 2007 to 2009 including malaria diagnostic outcomes, prescription of artemisinin-based combination therapy (ACT) and consumption of RDTs in public health facilities, were reviewed and compared. Against a marked seasonal variation in all-cause out-patient visits, non-malarial fever and confirmed malaria, parasite-based diagnosis increased nationally from 3.9% of reported malaria-like febrile illness to 86.0% over a 3 year period. The prescription of ACT dropped throughout this period from 72.9% of malaria-like febrile illness to 31.5%, reaching close equivalence to confirmed malaria (29.9% of 584,873 suspect fever cases). An estimated 516,576 courses of inappropriate ACT prescription were averted. The data indicate high adherence of anti-malarial prescribing practice to RDT results after an initial run-in period. The large reduction in ACT consumption enabled by the move from symptom-based to parasite-based diagnosis demonstrates that effective roll-out and use of malaria RDTs is achievable on a national scale through well planned and structured implementation. While more detailed information on management of parasite-negative cases is required at point of care level to assess overall cost-benefits to the health sector, considerable cost-savings were achieved in ACT procurement. Programmes need to be allowed
Combined effect of rifampicin-induced P-glycoprotein expression and lipopolysaccharide-induced intestinal sepsis on the effective permeability and pharmacokinetics of an anti-malarial candidate CDRI 97/78 in rats.
Singh, Yeshwant; Hidau, Mahendra Kumar; Krishna, Jampala; Singh, Shio Kumar
1. The study aimed to investigate the influences on the pharmacokinetics (PK) of an anti-malarial drug 97/78 in rats pretreated with orally administered rifampicin and bacterial endotoxin lipopolysaccharide (LPS). 2. In-situ intestinal absorption studies were conducted on rats pretreated with rifampicin and LPS or both to estimate effective permeability (Peff) of 97/78. In-vivo studies were then conducted to explore 97/78 PK profile under these conditions. In-situ studies revealed that Peff value decreased to 64% (2.7 ± 0.6) × 10(-4 )cm/s in rats pretreated with rifampicin. This decrease was further enhanced very significantly to 4.5% (0.19 ± 0.03) × 10(-4 )cm/s in rats pretreated both with rifampicin and LPS (p97/78 in rifampicin-pretreated rats. This decrease was further augmented to 12-fold upon rifampicin and LPS pretreatment. 3. Orally administered rifampicin decreased the concentration of 97/78 in circulation. This decrease was further enhanced significantly to a very low level by LPS-induced intestinal sepsis.
Full Text Available Abstract Background The efficacy of anti-malarial drugs is determined by the level of parasite susceptibility, anti-malarial drug bioavailability and pharmacokinetics, and host factors including immunity. Host immunity improves the in vivo therapeutic efficacy of anti-malarial drugs, but the mechanism and magnitude of this effect has not been characterized. This study characterized the effects of 'immune' plasma to Plasmodium falciparumon the in vitro susceptibility of P. falciparum to anti-malarial drugs. Methods Titres of antibodies against blood stage antigens (mainly the ring-infected erythrocyte surface antigen [RESA] were measured in plasma samples obtained from Thai patients with acute falciparum malaria. 'Immune' plasma was selected and its effects on in vitro parasite growth and multiplication of the Thai P. falciparum laboratory strain TM267 were assessed by light microscopy. The in vitro susceptibility to quinine and artesunate was then determined in the presence and absence of 'immune' plasma using the 3H-hypoxanthine uptake inhibition method. Drug susceptibility was expressed as the concentrations causing 50% and 90% inhibition (IC50 and IC90, of 3H-hypoxanthine uptake. Results Incubation with 'immune' plasma reduced parasite maturation and decreased parasite multiplication in a dose dependent manner. 3H-hypoxanthine incorporation after incubation with 'immune' plasma was decreased significantly compared to controls (median [range]; 181.5 [0 to 3,269] cpm versus 1,222.5 [388 to 5,932] cpm (p= 0.001. As a result 'immune' plasma reduced apparent susceptibility to quinine substantially; median (range IC50 6.4 (0.5 to 23.8 ng/ml versus 221.5 (174.4 to 250.4 ng/ml (p = 0.02, and also had a borderline effect on artesunate susceptibility; IC50 0.2 (0.02 to 0.3 ng/ml versus 0.8 (0.2 to 2.3 ng/ml (p = 0.08. Effects were greatest at low concentrations, changing the shape of the concentration-effect relationship. IC90 values were not
Arise Rotimi Olusanya
Full Text Available So far, some prospective metal-based anti-malarial drugs have been developed. The mechanochemical synthesis and characterization of Zn (II complex with amodiaquine and its anti-malarial efficacy on Plasmodium berghei-infected mice and safety evaluation were described in this study.
Magreth Komanya (Bsc Nursing). AMREF. ABSTRACT. Objective: To study malaria and examine determinants of anti-malarial drugs utilization among ..... anti-malarials for prophylaxis and chemotherapy or may be provided with prescription forms to buy drugs. Moreover the general understanding that pregnant women are ...
Communicating the AMFm message: exploring the effect of communication and training interventions on private for-profit provider awareness and knowledge related to a multi-country anti-malarial subsidy intervention
Background The Affordable Medicines Facility - malaria (AMFm), implemented at national scale in eight African countries or territories, subsidized quality-assured artemisinin combination therapy (ACT) and included communication campaigns to support implementation and promote appropriate anti-malarial use. This paper reports private for-profit provider awareness of key features of the AMFm programme, and changes in provider knowledge of appropriate malaria treatment. Methods This study had a non-experimental design based on nationally representative surveys of outlets stocking anti-malarials before (2009/10) and after (2011) the AMFm roll-out. Results Based on data from over 19,500 outlets, results show that in four of eight settings, where communication campaigns were implemented for 5–9 months, 76%-94% awareness of the AMFm ‘green leaf’ logo, 57%-74% awareness of the ACT subsidy programme, and 52%-80% awareness of the correct recommended retail price (RRP) of subsidized ACT were recorded. However, in the remaining four settings where communication campaigns were implemented for three months or less, levels were substantially lower. In six of eight settings, increases of at least 10 percentage points in private for-profit providers’ knowledge of the correct first-line treatment for uncomplicated malaria were seen; and in three of these the levels of knowledge achieved at endline were over 80%. Conclusions The results support the interpretation that, in addition to the availability of subsidized ACT, the intensity of communication campaigns may have contributed to the reported levels of AMFm-related awareness and knowledge among private for-profit providers. Future subsidy programmes for anti-malarials or other treatments should similarly include communication activities. PMID:24495691
Full Text Available Abstract Background The spread of drug resistance is making malaria control increasingly difficult. Mathematical models for the transmission dynamics of drug sensitive and resistant strains can be a useful tool to help to understand the factors that influence the spread of drug resistance, and they can therefore help in the design of rational strategies for the control of drug resistance. Methods We present an epidemiological framework to investigate the spread of anti-malarial resistance. Several mathematical models, based on the familiar Macdonald-Ross model of malaria transmission, enable us to examine the processes and parameters that are critical in determining the spread of resistance. Results In our simplest model, resistance does not spread if the fraction of infected individuals treated is less than a threshold value; if drug treatment exceeds this threshold, resistance will eventually become fixed in the population. The threshold value is determined only by the rates of infection and the infectious periods of resistant and sensitive parasites in untreated and treated hosts, whereas the intensity of transmission has no influence on the threshold value. In more complex models, where hosts can be infected by multiple parasite strains or where treatment varies spatially, resistance is generally not fixed, but rather some level of sensitivity is often maintained in the population. Conclusions The models developed in this paper are a first step in understanding the epidemiology of anti-malarial resistance and evaluating strategies to reduce the spread of resistance. However, specific recommendations for the management of resistance need to wait until we have more data on the critical parameters underlying the spread of resistance: drug use, spatial variability of treatment and parasite migration among areas, and perhaps most importantly, cost of resistance.
Rijpma, S.R.; Heuvel, J.J.; Velden, M. van der; Sauerwein, R.W.; Russel, F.G.; Koenderink, J.B.
BACKGROUND: Therapeutic blood plasma concentrations of anti-malarial drugs are essential for successful treatment. Pharmacokinetics of pharmaceutical compounds are dependent of adsorption, distribution, metabolism, and excretion. ATP binding cassette (ABC) transport proteins are particularly
Ringsted, Frank M; Massawe, Isolide S; Lemnge, Martha M
prescription-only anti-malarials, in Muheza town, Tanga Region voluntarily participated from July to December 2009. Qualitative in-depth interviews were conducted with owners or shopkeepers on saleability of anti-malarials, and structured questionnaires provided quantitative data on drugs sales volume. Results...... women depend on SP for Intermittent Preventive Treatment (IPTp) during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may undermine its official use for IPTp through induction of resistance. The main study objective was to perform...... a baseline study of the private market for anti-malarials in Muheza town, an area with widespread anti-malarial drug resistance, prior to the implementation of a provider training and accreditation programme that will allow accredited drug shops to sell subsidized ALu. Methods: All drug shops selling...
Chikowe, Ibrahim; Osei-Safo, Dorcas; Harrison, Jerry JEK; Konadu, Daniel Y; Addae-Mensah, Ivan
Background The growing concern over the extent of anti-malarial medicine resistance in sub-Saharan Africa, driven largely by administration of sub-therapeutic doses derived from falsified and substandard medicines necessitates regular monitoring of the quality of these medicines to avert any potential public health disaster. This study aimed at determining the active pharmaceutical ingredient (API) content of anti-malarial medicines available in Malawi with respect to the manufacturers? label...
Background Molecular genotyping is performed in anti-malarial trials to determine whether recurrent parasitaemia after therapy represents a recrudescence (treatment failure) or new infection. The use of capillary instead of agarose gel electrophoresis for genotyping offers technical advantages, but it is unclear whether capillary electrophoresis will result in improved classification of anti-malarial treatment outcomes. Methods Samples were genotyped using both gel and capillary electrophoresis from randomized trials of artemether-lumefantrine (AL) vs. dihydroartemisinin-piperaquine (DP) performed in two areas of Uganda: Kanungu, where transmission is moderate, and Apac, where transmission is very high. Both gel and capillary methods evaluated polymorphic regions of the merozoite surface protein 1 and 2 and glutamine rich protein genes. Results Capillary electrophoresis detected more alleles and provided higher discriminatory power than agarose gel electrophoresis at both study sites. There was only moderate agreement between classification of outcomes with the two methods in Kanungu (kappa = 0.66) and poor agreement in Apac (kappa = 0.24). Overall efficacy results were similar when using gel vs. capillary methods in Kanungu (42-day risk of treatment failure for AL: 6.9% vs. 5.5%, p = 0.4; DP 2.4% vs. 2.9%, p = 0.5). However, the measured risk of recrudescence was significantly higher when using gel vs. capillary electrophoresis in Apac (risk of treatment failure for AL: 17.0% vs. 10.7%, p = 0.02; DP: 8.5% vs. 3.4%, p = 0.03). Risk differences between AL and DP were not significantly different whether gel or capillary methods were used. Conclusions Genotyping with gel electrophoresis overestimates the risk of recrudescence in anti-malarial trials performed in areas of high transmission intensity. Capillary electrophoresis provides more accurate outcomes for such trials and should be performed when possible. In areas of moderate transmission, gel electrophoresis
Gupta, Vinay; Dorsey, Grant; Hubbard, Alan E; Rosenthal, Philip J; Greenhouse, Bryan
Molecular genotyping is performed in anti-malarial trials to determine whether recurrent parasitaemia after therapy represents a recrudescence (treatment failure) or new infection. The use of capillary instead of agarose gel electrophoresis for genotyping offers technical advantages, but it is unclear whether capillary electrophoresis will result in improved classification of anti-malarial treatment outcomes. Samples were genotyped using both gel and capillary electrophoresis from randomized trials of artemether-lumefantrine (AL) vs. dihydroartemisinin-piperaquine (DP) performed in two areas of Uganda: Kanungu, where transmission is moderate, and Apac, where transmission is very high. Both gel and capillary methods evaluated polymorphic regions of the merozoite surface protein 1 and 2 and glutamine rich protein genes. Capillary electrophoresis detected more alleles and provided higher discriminatory power than agarose gel electrophoresis at both study sites. There was only moderate agreement between classification of outcomes with the two methods in Kanungu (kappa = 0.66) and poor agreement in Apac (kappa = 0.24). Overall efficacy results were similar when using gel vs. capillary methods in Kanungu (42-day risk of treatment failure for AL: 6.9% vs. 5.5%, p = 0.4; DP 2.4% vs. 2.9%, p = 0.5). However, the measured risk of recrudescence was significantly higher when using gel vs. capillary electrophoresis in Apac (risk of treatment failure for AL: 17.0% vs. 10.7%, p = 0.02; DP: 8.5% vs. 3.4%, p = 0.03). Risk differences between AL and DP were not significantly different whether gel or capillary methods were used. Genotyping with gel electrophoresis overestimates the risk of recrudescence in anti-malarial trials performed in areas of high transmission intensity. Capillary electrophoresis provides more accurate outcomes for such trials and should be performed when possible. In areas of moderate transmission, gel electrophoresis appears adequate to estimate comparative
Hubbard Alan E
Full Text Available Abstract Background Molecular genotyping is performed in anti-malarial trials to determine whether recurrent parasitaemia after therapy represents a recrudescence (treatment failure or new infection. The use of capillary instead of agarose gel electrophoresis for genotyping offers technical advantages, but it is unclear whether capillary electrophoresis will result in improved classification of anti-malarial treatment outcomes. Methods Samples were genotyped using both gel and capillary electrophoresis from randomized trials of artemether-lumefantrine (AL vs. dihydroartemisinin-piperaquine (DP performed in two areas of Uganda: Kanungu, where transmission is moderate, and Apac, where transmission is very high. Both gel and capillary methods evaluated polymorphic regions of the merozoite surface protein 1 and 2 and glutamine rich protein genes. Results Capillary electrophoresis detected more alleles and provided higher discriminatory power than agarose gel electrophoresis at both study sites. There was only moderate agreement between classification of outcomes with the two methods in Kanungu (kappa = 0.66 and poor agreement in Apac (kappa = 0.24. Overall efficacy results were similar when using gel vs. capillary methods in Kanungu (42-day risk of treatment failure for AL: 6.9% vs. 5.5%, p = 0.4; DP 2.4% vs. 2.9%, p = 0.5. However, the measured risk of recrudescence was significantly higher when using gel vs. capillary electrophoresis in Apac (risk of treatment failure for AL: 17.0% vs. 10.7%, p = 0.02; DP: 8.5% vs. 3.4%, p = 0.03. Risk differences between AL and DP were not significantly different whether gel or capillary methods were used. Conclusions Genotyping with gel electrophoresis overestimates the risk of recrudescence in anti-malarial trials performed in areas of high transmission intensity. Capillary electrophoresis provides more accurate outcomes for such trials and should be performed when possible. In areas of moderate transmission
Huang, Yangmu; Pan, Ke; Peng, Danlu; Stergachis, Andy
While China is a major manufacturer of artemisinin and its derivatives, it lags as a global leader in terms of the total export value of anti-malarial drugs as finished pharmaceutical products ready for marketing and use by patients. This may be due to the limited number of World Health Organization (WHO) prequalified anti-malarial drugs from China. Understanding the reasons for the slow progress of WHO prequalification (PQ) in China can help improve the current situation and may lead to greater efforts in malaria eradication by Chinese manufacturers. In-depth interviews were conducted in China between November 2014 and December 2016. A total of 26 key informants from central government agencies, pharmaceutical companies, universities, and research institutes were interviewed, all of which had current or previous experience overseeing or implementing anti-malarial research and development in China. Chinese anti-malarial drugs that lack WHO PQ are mainly exported for use in the African private market. High upfront costs with unpredictable benefits, as well as limited information and limited technical support on WHO PQ, were reported as the main barriers to obtain WHO PQ for anti-malarial drugs by respondents from Chinese pharmaceutical companies. Potential incentives identified by respondents included tax relief, human resource training and consultation, as well as other incentives related to drug approval, such as China's Fast Track Channel. Government support, as well as innovative incentives and collaboration mechanisms are needed for further adoption of WHO PQ for anti-malarial drugs in China.
Maganda, Betty A; Ngaimisi, Eliford; Kamuhabwa, Appolinary A R; Aklillu, Eleni; Minzi, Omary M S
HIV-malaria co-infected patients in most parts of sub-Saharan Africa are treated with both artemether-lumefantrine (AL) and efavirenz (EFV) or nevirapine (NVP)-based antiretroviral therapy (ART). EFV, NVP, artemether and lumefantrine are substrates, inhibitors or inducers of CYP3A4 and CYP2B6, creating a potential for drug-drug interactions. The effect of EFV and/or NVP on lumefantrine pharmacokinetic profile among HIV-malaria co-infected patients on ART and treated with AL was investigated. Optimal lumefantrine dosage regimen for patients on EFV-based ART was determined by population pharmacokinetics and simulation. This was a non-randomized, open label, parallel, prospective cohort study in which 128, 66 and 75 HIV-malaria co-infected patients on NVP-based ART (NVP-arm), EFV-based ART (EFV-arm) and ART naïve (control-am) were enrolled, respectively. Patients were treated with AL and contributed sparse venous plasma samples. Pharmacokinetic analysis of lumefantrine was done using non-linear mixed effect modelling. Of the evaluated models, a two-compartment pharmacokinetic model with first order absorption and lag-time described well lumefantrine plasma concentrations time profile. Patients in the EFV-arm but not in the NVP-arm had significantly lower lumefantrine bioavailability compared to that in the control-arm. Equally, 32% of patients in the EFV-arm had day-7 lumefantrine plasma concentrations below 280 ng/ml compared to only 4% in the control-arm and 3% in the NVP-arm. Upon post hoc simulation of lumefantrine exposure, patients in the EFV-arm had lower exposure (median (IQR)) compared to that in the control-arm; AUC0-inf; was 303,130 (211,080-431,962) versus 784,830 (547,405-1,116,250); day-7 lumefantrine plasma concentrations was: 335.5 (215.8-519.5) versus 858.7 (562.3-1,333.8), respectively. The predictive model through simulation of lumefantrine exposure at different dosage regimen scenarios for patients on EFV-based ART, suggest that AL taken twice
Suksangpleng, Thidarat; Leartsakulpanich, Ubolsree; Moonsom, Saengduen; Siribal, Saranya; Boonyuen, Usa; Wright, George E; Chavalitshewinkoon-Petmitr, Porntip
Background Based on resistance of currently used anti-malarials, a new anti-malarial drug target against Plasmodium falciparum is urgently needed. Damaged DNA cannot be transcribed without prior DNA repair; therefore, uracil-DNA glycosylase, playing an important role in base excision repair, may act as a candidate for a new anti-malarial drug target. Methods Initially, the native PfUDG from parasite crude extract was partially purified using two columns, and the glycosylase activity was monit...
Chance Michael L
Full Text Available Abstract Background This is an investigation of anti-malarial molecular markers coupled with a therapeutic efficacy test of chloroquine (CQ against falciparum malaria in an area of unstable malaria in Lahj Governorate, Yemen. The study was aimed at assessment of therapeutic response to CQ and elucidation of baseline information on molecular markers for Plasmodium falciparum resistance against CQ and sulphadoxine/pyrimethamine (SP. Methods Between 2002 and 2003 the field test was conducted according to the standard WHO protocol to evaluate the therapeutic efficacy of CQ in 124 patients with falciparum malaria in an endemic area in Lahj Governorate in Yemen. Blood samples collected during this study were analysed for P. falciparum chloroquine resistance transporter gene (pfcrt-76 polymorphisms, mutation pfcrt-S163R and the antifolate resistance-associated mutations dihydrofolate reductase (dhfr-C59R and dihydropteroate synthase (dhps-K540E. Direct DNA sequencing of the pfcrt gene from three representative field samples was carried out after DNA amplification of the 13 exons of the pfcrt gene. Results Treatment failure was detected in 61% of the 122 cases that completed the 14-day follow-up. The prevalence of mutant pfcrt T76 was 98% in 112 amplified pre-treatment samples. The presence of pfcrt T76 was poorly predictive of in vivo CQ resistance (PPV = 61.8%, 95% CI = 52.7-70.9. The prevalence of dhfr Arg-59 mutation in 99 amplified samples was 5%, while the dhps Glu-540 was not detected in any of 119 amplified samples. Sequencing the pfcrt gene confirmed that Yemeni CQ resistant P. falciparum carry the old world (Asian and African CQ resistant haplotype CVIETSESI at positions 72,73,74,75,76,220,271, 326 and 371. Conclusion This is the first study to report baseline information on the characteristics and implications of anti-malarial drug resistance markers in Yemen. It is also the first report of the haplotype associated with CQR P. falciparum
Mubjer, Reem A; Adeel, Ahmed A; Chance, Michael L; Hassan, Amir A
This is an investigation of anti-malarial molecular markers coupled with a therapeutic efficacy test of chloroquine (CQ) against falciparum malaria in an area of unstable malaria in Lahj Governorate, Yemen. The study was aimed at assessment of therapeutic response to CQ and elucidation of baseline information on molecular markers for Plasmodium falciparum resistance against CQ and sulphadoxine/pyrimethamine (SP). Between 2002 and 2003 the field test was conducted according to the standard WHO protocol to evaluate the therapeutic efficacy of CQ in 124 patients with falciparum malaria in an endemic area in Lahj Governorate in Yemen. Blood samples collected during this study were analysed for P. falciparum chloroquine resistance transporter gene (pfcrt)-76 polymorphisms, mutation pfcrt-S163R and the antifolate resistance-associated mutations dihydrofolate reductase (dhfr)-C59R and dihydropteroate synthase (dhps)-K540E. Direct DNA sequencing of the pfcrt gene from three representative field samples was carried out after DNA amplification of the 13 exons of the pfcrt gene. Treatment failure was detected in 61% of the 122 cases that completed the 14-day follow-up. The prevalence of mutant pfcrt T76 was 98% in 112 amplified pre-treatment samples. The presence of pfcrt T76 was poorly predictive of in vivo CQ resistance (PPV = 61.8%, 95% CI = 52.7-70.9). The prevalence of dhfr Arg-59 mutation in 99 amplified samples was 5%, while the dhps Glu-540 was not detected in any of 119 amplified samples. Sequencing the pfcrt gene confirmed that Yemeni CQ resistant P. falciparum carry the old world (Asian and African) CQ resistant haplotype CVIETSESI at positions 72,73,74,75,76,220,271, 326 and 371. This is the first study to report baseline information on the characteristics and implications of anti-malarial drug resistance markers in Yemen. It is also the first report of the haplotype associated with CQR P. falciparum parasites from Yemen. Mutant pfcrtT76 is highly prevalent but it
Eberlin Marcos N
Full Text Available Abstract Background To overcome the problem of increasing drug resistance, traditional medicines are an important source for potential new anti-malarials. Caesalpinia pluviosa, commonly named "sibipiruna", originates from Brazil and possess multiple therapeutic properties, including anti-malarial activity. Methods Crude extract (CE was obtained from stem bark by purification using different solvents, resulting in seven fractions. An MTT assay was performed to evaluate cytotoxicity in MCF-7 cells. The CE and its fractions were tested in vitro against chloroquine-sensitive (3D7 and -resistant (S20 strains of Plasmodium falciparum and in vivo in Plasmodium chabaudi-infected mice. In vitro interaction with artesunate and the active C. pluviosa fractions was assessed, and mass spectrometry analyses were conducted. Results At non-toxic concentrations, the 100% ethanolic (F4 and 50% methanolic (F5 fractions possessed significant anti-malarial activity against both 3D7 and S20 strains. Drug interaction assays with artesunate showed a synergistic interaction with the F4. Four days of treatment with this fraction significantly inhibited parasitaemia in mice in a dose-dependent manner. Mass spectrometry analyses revealed the presence of an ion corresponding to m/z 303.0450, suggesting the presence of quercetin. However, a second set of analyses, with a quercetin standard, showed distinct ions of m/z 137 and 153. Conclusions The findings show that the F4 fraction of C. pluviosa exhibits anti-malarial activity in vitro at non-toxic concentrations, which was potentiated in the presence of artesunate. Moreover, this anti-malarial activity was also sustained in vivo after treatment of infected mice. Finally, mass spectrometry analyses suggest that a new compound, most likely an isomer of quercetin, is responsible for the anti-malarial activity of the F4.
Full Text Available Abstract Background Malaria is the leading cause of morbidity and mortality in post-conflict Burundi. To counter the increasing challenge of anti-malarial drug resistance and improve highly effective treatment Burundi adopted artesunate-amodiaquine (AS-AQ as first-line treatment for uncomplicated Plasmodium falciparum malaria and oral quinine as second-line treatment in its national treatment policy in 2003. Uptake of this policy in the public, private and non-governmental (NGO retail market sectors of Burundi is relatively unknown. This study was conducted to evaluate access to national policy recommended anti-malarials. Methods Adapting a standardized methodology developed by Health Action International/World Health Organization (HAI/WHO, a cross-sectional survey of 70 (24 public, 36 private, and 10 NGO medicine outlets was conducted in three regions of Burundi, representing different levels of transmission of malaria. The availability on day of the survey, the median prices, and affordability (in terms of number of days' wages to purchase treatment of AS-AQ, quinine and other anti-malarials were calculated. Results Anti-malarials were stocked in all outlets surveyed. AS-AQ was available in 87.5%, 33.3%, and 90% of public, private, and NGO retail outlets, respectively. Quinine was the most common anti-malarial found in all outlet types. Non-policy recommended anti-malarials were mainly found in the private outlets (38.9% compared to public (4.2% and NGO (0% outlets. The median price of a course of AS-AQ was US$0.16 (200 Burundi Francs, FBu for the public and NGO markets, and 3.5-fold higher in the private sector (US$0.56 or 700 FBu. Quinine tablets were similarly priced in the public (US$1.53 or 1,892.50 FBu, private and NGO sectors (both US$1.61 or 2,000 FBu. Non-policy anti-malarials were priced 50-fold higher than the price of AS-AQ in the public sector. A course of AS-AQ was affordable at 0.4 of a day's wage in the public and NGO sectors
Full Text Available Abstract Background Understanding the impact of malaria rapid diagnostic test (RDT use on management of acute febrile disease at a community level, and on the consumption of anti-malarial medicines, is critical to the planning and success of scale-up to universal parasite-based diagnosis by health systems in malaria-endemic countries. Methods A retrospective study of district-wide community-level RDT introduction was conducted in Livingstone District, Zambia, to assess the impact of this programmed on malaria reporting, incidence of mortality and on district anti-malarial consumption. Results Reported malaria declined from 12,186 cases in the quarter prior to RDT introduction in 2007 to an average of 12.25 confirmed and 294 unconfirmed malaria cases per quarter over the year to September 2009. Reported malaria-like fever also declined, with only 4,381 RDTs being consumed per quarter over the same year. Reported malaria mortality declined to zero in the year to September 2009, and all-cause mortality declined. Consumption of artemisinin-based combination therapy (ACT dropped dramatically, but remained above reported malaria, declining from 12,550 courses dispensed by the district office in the quarter prior to RDT implementation to an average of 822 per quarter over the last year. Quinine consumption in health centres also declined, with the district office ceasing to supply due to low usage, but requests for sulphadoxine-pyrimethamine (SP rose to well above previous levels, suggesting substitution of ACT with this drug in RDT-negative cases. Conclusions RDT introduction led to a large decline in reported malaria cases and in ACT consumption in Livingstone district. Reported malaria mortality declined to zero, indicating safety of the new diagnostic regime, although adherence and/or use of RDTs was still incomplete. However, a deficiency is apparent in management of non-malarial fever, with inappropriate use of a low-cost single dose drug, SP
Pell, Christopher; Tripura, Rupam; Nguon, Chea; Cheah, Phaikyeong; Davoeung, Chan; Heng, Chhouen; Dara, Lim; Sareth, Ma; Dondorp, Arjen; von Seidlein, Lorenz; Peto, Thomas J.
Mass anti-malarial administration has been proposed as a key component of the Plasmodium falciparum malaria elimination strategy in the Greater Mekong sub-Region. Its effectiveness depends on high levels of coverage in the target population. This article explores the factors that influenced mass
Rebelo, Maria; Tempera, Carolina; Fernandes, José F.; Grobusch, Martin P.; Hänscheid, Thomas
In vitro sensitivity assays are crucial to detect and monitor drug resistance. Plasmodium falciparum has developed resistance to almost all anti-malarial drugs. Although different in vitro drug assays are available, some of their inherent characteristics limit their application, especially in the
Pell, Christopher; Tripura, Rupam; Nguon, Chea; Cheah, Phaikyeong; Davoeung, Chan; Heng, Chhouen; Dara, Lim; Sareth, Ma; Dondorp, Arjen; von Seidlein, Lorenz; Peto, Thomas J
Mass anti-malarial administration has been proposed as a key component of the Plasmodium falciparum malaria elimination strategy in the Greater Mekong sub-Region. Its effectiveness depends on high levels of coverage in the target population. This article explores the factors that influenced mass anti-malarial administration coverage within a clinical trial in Battambang Province, western Cambodia. Qualitative data were collected through semi-structured interviews and focus group discussions with villagers, in-depth interviews with study staff, trial drop-outs and refusers, and observations in the communities. Interviews were audio-recorded, transcribed and translated from Khmer to English for qualitative content analysis using QSR NVivo. Malaria was an important health concern and villagers reported a demand for malaria treatment. This was in spite of a fall in incidence over the previous decade and a lack of familiarity with asymptomatic malaria. Participants generally understood the overall study aim and were familiar with study activities. Comprehension of the study rationale was however limited. After the first mass anti-malarial administration, seasonal health complaints that participants attributed to the anti-malarial as "side effects" contributed to a decrease of coverage in round two. Staff therefore adapted the community engagement approach, bringing to prominence local leaders in village meetings. This contributed to a subsequent increase in coverage. Future mass anti-malarial administration must consider seasonal disease patterns and the importance of local leaders taking prominent roles in community engagement. Further research is needed to investigate coverage in scenarios that more closely resemble implementation i.e. without participation incentives, blood sampling and free healthcare.
Full Text Available Abstract Background Artemisinin-based combination therapies (ACT are widely used in African countries, including Cameroon. Between 2005 and 2007, five randomized studies comparing different treatment arms among artesunate-amodiaquine and other ACT were conducted in Cameroonian children aged two to 60 months who had uncomplicated Plasmodium falciparum malaria. In these studies, the categorical criterion proposed by the World Health Organization (WHO to assess the relative effectiveness of anti-malarial drugs was repeatedly evaluated on Days 14, 21 and 28 after treatment initiation. The aim of the present study was to compare the effects of different treatments on this repeated ordinal outcome, hence using the fully available information. Methods The quantitative synthesis was based on individual patient data. Due to the incomplete block design concerning treatment arms between different trials, a mixed treatment comparison (MTC meta-analysis approach was adopted. The repeated ordinal outcome was modelled through a latent variable, as a proportional odds mixed model with trial, period and treatment arms as covariates. The model was further complexified to account for the variance heterogeneity, and the individual log-residual variance was modelled as a linear mixed model, as well. The effects of individual covariates at inclusion, such as parasitaemia, fever, gender and weight, were also tested. Model parameters were estimated using a Bayesian approach via the WinBUGS software. After selecting the best model using Deviance Information Criterion (DIC, mixed treatment comparisons were based on the estimated treatment effects. Results Modeling the residual variance improved the model ability to adjust the data. The results showed that, compared to artesunate-amodiaquine (ASAQ, dihydroartemisinin-piperaquine (DHPP was significantly more efficacious. Artesunate-chlorproguanil-dapsone (ASCD was less efficacious than artesunate
Full Text Available Abstract A “reverse pharmacology” approach to developing an anti-malarial phytomedicine was designed and implemented in Mali, resulting in a new standardized herbal anti-malarial after six years of research. The first step was to select a remedy for development, through a retrospective treatment-outcome study. The second step was a dose-escalating clinical trial that showed a dose-response phenomenon and helped select the safest and most efficacious dose. The third step was a randomized controlled trial to compare the phytomedicine to the standard first-line treatment. The last step was to identify active compounds which can be used as markers for standardization and quality control. This example of “reverse pharmacology” shows that a standardized phytomedicine can be developed faster and more cheaply than conventional drugs. Even if both approaches are not fully comparable, their efficiency in terms of public health and their complementarity should be thoroughly considered.
Rijpma, Sanna R; van den Heuvel, Jeroen J M W; van der Velden, Maarten; Sauerwein, Robert W; Russel, Frans G M; Koenderink, Jan B
Therapeutic blood plasma concentrations of anti-malarial drugs are essential for successful treatment. Pharmacokinetics of pharmaceutical compounds are dependent of adsorption, distribution, metabolism, and excretion. ATP binding cassette (ABC) transport proteins are particularly involved in drug deposition, as they are located at membranes of many uptake and excretory organs and at protective barriers, where they export endogenous and xenobiotic compounds, including pharmaceuticals. In this study, a panel of well-established anti-malarial drugs which may affect drug plasma concentrations was tested for interactions with human ABC transport proteins. The interaction of chloroquine, quinine, artemisinin, mefloquine, lumefantrine, atovaquone, dihydroartemisinin and proguanil, with transport activity of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP) and multidrug resistance-associated proteins (MRP) 1-4 were analysed. The effect of the anti-malarials on the ATP-dependent uptake of radio-labelled substrates was measured in membrane vesicles isolated from HEK293 cells overexpressing the ABC transport proteins. A strong and previously undescribed inhibition of BCRP-mediated transport by atovaquone with a 50% inhibitory concentration (IC50) of 0.23 μM (95% CI 0.17-0.29 μM) and inhibition of P-gp-mediated transport by quinine with an IC50 of 6.8 μM (95% CI 5.9-7.8 μM) was observed. Furthermore, chloroquine and mefloquine were found to significantly inhibit P-gp-mediated transport. BCRP transport activity was significantly inhibited by all anti-malarials tested, whereas BSEP-mediated transport was not inhibited by any of the compounds. Both MRP1- and MRP3-mediated transport were significantly inhibited by mefloquine. Atovaquone and quinine significantly inhibit BCRP- and P-gp- mediated transport at concentrations within the clinically relevant prophylactic and therapeutic range. Co-administration of these established anti-malarials
A-Elbasit, I E; Khalil, I F; Elbashir, M I
Estimation of the prevalence of the molecular markers of sulfadoxine/pyrimethamine (SP) and chloroquine (CQ) resistance and validation of the association of mutations with resistance in different settings is needed for local policy guidance and for contributing to a global map for anti-malarial d...... molecular markers needed before the deployment of SP/artesunate combination therapy in the Sudan....
. Implications of the hypothesis Targeting of the Plasmodium genome using ZFN has great potential for the development of anti-malarial drugs. It allows the development of a single drug against all malarial infections, including multidrug-resistant strains. Availability of multiple ZFN target sites in a single gene will provide alternative drug target sites to combat the development of resistance in the future.
Full Text Available Abstract Background Knowing the safety profile of anti-malarial treatments in routine use is essential; millions of patients receive now artemisinin combination therapy (ACT annually, but the return on information through current systems is as yet inadequate. Cohort event monitoring (CEM is a WHO (World Health Organization-recommended practice; testing its performance and feasibility in routine practice in malaria-endemic is important. Methods A nine-year CEM-based study of the safety of artesunate-amodiaquine (ASAQ at five peripheral health facilities in a rural district of South-western Senegal. Staff (nurses, health workers were trained to collect actively and systematically information on the patient, treatment and events on a purposely designed questionnaire. The occurrence and severity of events was collected before, during and after treatment up to 28 days in order to generate information on all adverse events (AEs as well as treatment-emerging signs/symptoms (TESS. Laboratory tests (haematology, liver and renal was planned for at least 10% of cases. Results During 2001–2009, 3,708 parasitologically-confirmed malaria cases (mean age = 16.0 ± 12.7 years were enrolled (26% and 52% of all and parasitologically-confirmed ASAQ treatments, respectively. Treatment was supervised in 96% of cases. Products changed over time: 49% were a loose combination of individually-packaged products (available 2001–03, 42% co-blistered products (2004–09 and 9% a fixed-dose co-formulation (2006–09; dosing was age-based for 42%, weight-based for 58%. AS and AQ were correctly dosed in 97% and 82% of cases with the loose and 93% and 86% with the fixed combination, but only 50% and 42% with the co-blistered product. Thirty-three per cent (33% of patients had at least one sign/symptom pre-treatment, 12% had at least one AE and 9% a TESS (total events 3,914, 1,144 and 693, respectively. AEs overestimated TESS by 1.2-2 fold (average 1.7. Changes in
Mostafa A Elfawal
Full Text Available Drugs are primary weapons for reducing malaria in human populations. However emergence of resistant parasites has repeatedly curtailed the lifespan of each drug that is developed and deployed. Currently the most effective anti-malarial is artemisinin, which is extracted from the leaves of Artemisia annua. Due to poor pharmacokinetic properties and prudent efforts to curtail resistance to monotherapies, artemisinin is prescribed only in combination with other anti-malarials composing an Artemisinin Combination Therapy (ACT. Low yield in the plant, and the added cost of secondary anti-malarials in the ACT, make artemisinin costly for the developing world. As an alternative, we compared the efficacy of oral delivery of the dried leaves of whole plant (WP A. annua to a comparable dose of pure artemisinin in a rodent malaria model (Plasmodium chabaudi. We found that a single dose of WP (containing 24 mg/kg artemisinin reduces parasitemia more effectively than a comparable dose of purified drug. This increased efficacy may result from a documented 40-fold increase in the bioavailability of artemisinin in the blood of mice fed the whole plant, in comparison to those administered synthetic drug. Synergistic benefits may derive from the presence of other anti-malarial compounds in A. annua. If shown to be clinically efficacious, well-tolerated, and compatible with the public health imperative of forestalling evolution of drug resistance, inexpensive, locally grown and processed A. annua might prove to be an effective addition to the global effort to reduce malaria morbidity and mortality.
Asare, Aquisman Ebenezer
The availability of numerous brands of artesunate in our drug market today places clinicians and pharmacists in a difficult situation of choice of a suitable brand or the possibility of alternative use. Fake artesunate could compromise the hope that ACT (artemisinin combination therapy) offers for malaria control in Africa. In this study, quality of some selected brands of anti - malarial drugs used in the communities of Agona west Municipality, Ghana was determined. Blister or packs of anti – malarial tablets were randomly sampled. The Protocols of the International Pharmacopeia and Global Pharma Health Fund Minilab were used to assess the quality of anti – malarial tablets per blister pack manufactured by Bliss Gvs Pharma Ltd. India, Letap Pharmaceutical Company Ltd. Ghana and Guilin Pharmaceutical Company Ltd. China and sold in chemical sales outlets at the farming communities of Agona West Municipality, Ghana. The identification test was used to confirm the presence of active ingredients in the tablets. A confirmatory test for the active ingredient was achieved with artesunate (ICRS 1302) reference standards and Gsunate reference standard (ICRS4061). The friability test was used to confirm the hardness of the tablets to determine the drug ability to withstand abrasion in packaging, handling and shipping. The disintegration test was used to confirm the time required for the tablets to disintegrate into particles. Titrimetric analysis confirmed the amount of artesunate found in tablets.The results of the study are as follows for Artesunate by GPCL, LPL and Gsunate by BGPL; the identification test confirmed the presence of the active ingredient in all the brands. Based on the International Pharmacopoeia acceptable range of 1 to 15 min for genuine artesunate per tablet, 93.75 % of field selected artesunate blister pack tablets manufactured by GPCL passed the disintegration test and 6.25% failed. Also 85.57% of the sampled artesunate blister pack manufactured by
Aregawi, Maru; Malm, Keziah L; Wahjib, Mohammed; Kofi, Osae; Allotey, Naa-Korkor; Yaw, Peprah Nana; Abba-Baffoe, Wilmot; Segbaya, Sylvester; Owusu-Antwi, Felicia; Kharchi, Abderahmane T; Williams, Ryan O; Saalfeld, Mark; Workneh, Nibretie; Shargie, Estifanos Biru; Noor, Abdisalan M; Bart-Plange, Constance
Since 2005, the Government of Ghana and its partners, in concerted efforts to control malaria, scaled up the use of artemisinin-based combination therapy (ACT) and insecticide-treated nets (ITNs). Beginning in 2011, a mass campaign of long-lasting insecticidal nets (LLINs) was implemented, targeting all the population. The impact of these interventions on malaria cases, admissions and deaths was assessed using data from district hospitals. Records of malaria cases and deaths and availability of ACT in 88 hospitals, as well as at district level, ITN distribution, and indoor residual spraying were reviewed. Annual proportion of the population potentially protected by ITNs was estimated with the assumption that each LLIN covered 1.8 persons for 3 years. Changes in trends of cases and deaths in 2015 were estimated by segmented log-linear regression, comparing trends in post-scale-up (2011-2015) with that of pre-scale-up (2005-2010) period. Trends of mortality in children under 5 years old from population-based household surveys were also compared with the trends observed in hospitals for the same time period. Among all ages, the number of outpatient malaria cases (confirmed and presumed) declined by 57% (95% confidence interval [CI], 47-66%) by first half of 2015 (during the post-scale-up) compared to the pre-scale-up (2005-2010) period. The number of microscopically confirmed cases decreased by 53% (28-69%) while microscopic testing was stable. Test positivity rate (TPR) decreased by 41% (19-57%). The change in malaria admissions was insignificant while malaria deaths fell significantly by 65% (52-75%). In children under 5 years old, total malaria outpatient cases, admissions and deaths decreased by 50% (32-63%), 46% (19-75%) and 70% (49-82%), respectively. The proportion of outpatient malaria cases, admissions and deaths of all-cause conditions in both all ages and children under five also fell significantly by >30%. Similar decreases in the main malaria
Full Text Available Abstract Background There is an urgent need to identify new anti-malarial drug targets for both prophylaxis and chemotherapy, due to the increasing problem of drug resistance to malaria parasites. In the present study, the aim was to discover novel, effective plant-based extracts for the activity against malaria. Methods Ten plants found in Iran were selected by ethnobotanical survey of medicinal plants. The crude ethanolic extracts were tested for in vitro anti-plasmodial activity against two strains of Plasmodium falciparum: K1 (chloroquine-resistant strain and CY27 (chloroquine-sensitive strain, using the parasite lactate dehydrogenase (pLDH assay. The anti-plasmodial activity of the extracts was also assessed in the 4-day suppressive anti-malarial assay in mice inoculated with Plasmodium berghei (ANKA strain. Crude ethanolic extracts showed good anti-plasmodial activity were further fractionated by partitioning in water and dichloromethane. Results Of 10 plant species assayed, three species: Boerhavia elegans (Choisy, Solanum surattense (Burm.f. and Prosopis juliflora (Sw. showed promising anti-plasmodial activity in vitro (IC50 ≤ 50 μg/ml and in vivo with no toxicity. The dichloromethane fraction of three extracts revealed stronger anti-plasmodial activity than the total extracts. Conclusion Anti-plasmodial activities of extracts of B. elegans and S. surattense are reported for the first time.
What happened to anti-malarial markets after the Affordable Medicines Facility-malaria pilot? Trends in ACT availability, price and market share from five African countries under continuation of the private sector co-payment mechanism.
Tougher, Sarah; Hanson, Kara; Goodman, Catherine
The private sector supplies anti-malarial treatment for large proportions of patients in sub-Saharan Africa. Following the large-scale piloting of the Affordable Medicines Facility-malaria (AMFm) from 2010 to 2011, a private sector co-payment mechanism (CPM) provided continuation of private sector subsidies for quality-assured artemisinin combination therapies (QAACT). This article analyses for the first time the extent to which improvements in private sector QAACT supply and distribution observed during the AMFm were maintained or intensified during continuation of the CPM through 2015 in Kenya, Madagascar, Nigeria, Tanzania and Uganda using repeat cross-sectional outlet survey data. QAACT market share in all five countries increased during the AMFm period (p co-payment mechanism for QAACT implemented at national scale for 5 years was associated with positive and sustained improvements in QAACT availability, price and market share in Nigeria, Tanzania and Uganda, with more mixed results in Kenya, and few improvements in Madagascar. The subsidy mechanism as implemented over time across countries was not sufficient on its own to achieve optimal QAACT uptake. Supporting interventions to address continued availability and distribution of non-artemisinin therapies, and to create demand for QAACT among providers and consumers need to be effectively implemented to realize the full potential of this subsidy mechanism. Furthermore, there is need for comprehensive market assessments to identify contemporary market barriers to high coverage with both confirmatory testing and appropriate treatment.
Ogunwande Isiaka A
Full Text Available Abstract Background Adverse drug reactions (ADRs contribute to ill-health or life-threatening outcomes of therapy during management of infectious diseases. The exposure to anti-malarial and use of mobile phone technology to report ADRs following drug exposures were investigated in Sagamu - a peri-urban community in Southwest Nigeria. Methods Purchase of medicines was actively monitored for 28 days in three Community Pharmacies (CP and four Patent and Proprietary Medicine Stores (PPMS in the community. Information on experience of ADRs was obtained by telephone from 100 volunteers who purchased anti-malarials during the 28-day period. Results and Discussion A total of 12,093 purchases were recorded during the period. Antibiotics, analgesics, vitamins and anti-malarials were the most frequently purchased medicines. A total of 1,500 complete courses of anti-malarials were purchased (12.4% of total purchases; of this number, purchases of sulphadoxine-pyrimethamine (SP and chloroquine (CQ were highest (39.3 and 25.2% respectiuvely. Other anti-malarials purchased were artesunate monotherapy (AS - 16.1%, artemether-lumefantrine (AL 10.0%, amodiaquine (AQ - 6.6%, quinine (QNN - 1.9%, halofantrine (HF - 0.2% and proguanil (PR - 0.2%. CQ was the cheapest (USD 0.3 and halofantrine the most expensive (USD 7.7. AL was 15.6 times ($4.68 more expensive than CQ. The response to mobile phone monitoring of ADRs was 57% in the first 24 hours (day 1 after purchase and decreased to 33% by day 4. Participants in this monitoring exercise were mostly with low level of education (54%. Conclusion The findings from this study indicate that ineffective anti-malaria medicines including monotherapies remain widely available and are frequently purchased in the study area. Cost may be a factor in the continued use of ineffective monotherapies. Availability of a toll-free telephone line may facilitate pharmacovigilance and follow up of response to medicines in a resource
Background In recent years an increasing number of public investments and policy changes have been made to improve the availability, affordability and quality of medicines available to consumers in developing countries, including anti-malarials. It is important to monitor the extent to which these interventions are successful in achieving their aims using quantitative data on the supply side of the market. There are a number of challenges related to studying supply, including outlet sampling, gaining provider cooperation and collecting accurate data on medicines. This paper provides guidance on key steps to address these issues when conducting a medicine outlet survey in a developing country context. While the basic principles of good survey design and implementation are important for all surveys, there are a set of specific issues that should be considered when conducting a medicine outlet survey. Methods This paper draws on the authors’ experience of designing and implementing outlet surveys, including the lessons learnt from ACTwatch outlet surveys on anti-malarial retail supply, and other key studies in the field. Key lessons and points of debate are distilled around the following areas: selecting a sample of outlets; techniques for collecting and analysing data on medicine availability, price and sales volumes; and methods for ensuring high quality data in general. Results and conclusions The authors first consider the inclusion criteria for outlets, contrasting comprehensive versus more focused approaches. Methods for developing a reliable sampling frame of outlets are then presented, including use of existing lists, key informants and an outlet census. Specific issues in the collection of data on medicine prices and sales volumes are discussed; and approaches for generating comparable price and sales volume data across products using the adult equivalent treatment dose (AETD) are explored. The paper concludes with advice on practical considerations
Full Text Available Abstract Background Concern over the potential cardiotoxicity of anti-malarial drugs inducing a prolonged electrocardiographic QT interval has resulted in the almost complete withdrawal from the market of one anti-malarial drug - halofantrine. The effects on the QT interval of four anti-malarial drugs were examined, using the guinea pig heart. Methods The guinea pig heart was isolated, mounted on a Langendorff apparatus, and was then perfused with pyruvate-added Klebs-Henseleit solutions containing graded concentrations of the four agents such as quinidine (0.15 - 1.2 μM, quinine (0.3 - 2.4 μM, halofantrine (0.1 - 2.0 μM and mefloquine (0.1 - 2.0 μM. The heart rate-corrected QaTc intervals were measured to evaluate drug-induced QT prolongation effects. Results Quinidine, quinine, and halofantrine prolonged the QaTc interval in a dose-dependent manner, whereas no such effect was found with mefloquine. The EC50 values for the QaTc prolongation effects, the concentration that gives a half-maximum effect, were quinidine Conclusions In this study, an isolated, perfused guinea pig heart system was constructed to assess the cardiotoxic potential of anti-malarial drugs. This isolated perfused guinea pig heart system could be used to test newly developed anti-malarial drugs for their inherent QT lengthening potential. More information is required on the potential variation in unbound drug concentrations in humans, and their role in cardiotoxicity.
Full Text Available Abstract Background In the past many regions of Bangladesh were hyperendemic for malaria. Malaria control in the 1960s to 1970s eliminated malaria from the plains but in the Chittagong Hill Tracts remained a difficult to control reservoir. The Chittagong Hill Tracts have areas with between 1 and 10% annual malaria rates, predominately 90-95% Plasmodium falciparum. In Southeast Asia, multiplicity of infection for hypo-endemic regions has been approximately 1.5. Few studies on the genetic diversity of P. falciparum have been performed in Bangladesh. Anderson et al. performed a study in Khagrachari, northern Chittagong Hill Tracts in 2002 on 203 patients and found that parasites had a multiplicity of infection of 1.3 by MSP-1, MSP-2 and GLURP genotyping. A total of 94% of the isolates had the K76T Pfcrt chloroquine resistant genotype, and 70% showed the N86Y Pfmdr1 genotype. Antifolate drug resistant genotypes were high with 99% and 73% of parasites having two or more mutations at the dhfr or dhps loci. Methods Nested and real-time polymerase chain reaction (PCR methods were used to genotype P. falciparum using antigenic polymorphic markers and to study anti-malarial drug resistance markers in malaria endemic areas of Bangladesh. Results The analysis of polymorphic and drug resistant genotype on 33 paired recrudescent infections after drug treatment in the period 2004 to 2008 in the Chittagong Hill Tracts, which is just prior to countrywide provision of artemisinin combination therapy. Overall the multiplicity of infection for MSP-1 was 2.7 with a slightly smaller parasite diversity post-treatment. The 13 monoclonal infections by both GLURP and MSP-1 were evenly divided between pre- and post-treatment. The MSP-1 MAD block was most frequent in 66 of the samples. The prevalence of the K76T PfCRT chloroquine resistant allele was approximately 82% of the samples, while the resistant Pfmdr1 N86Y was present in 33% of the samples. Interestingly, the post
Haidara, Mahamane; Haddad, Mohamed; Denou, Adama; Marti, Guillaume; Bourgeade-Delmas, Sandra; Sanogo, Rokia; Bourdy, Geneviève; Aubouy, Agnès
Background Plasmodium falciparum malaria is still one of the most deadly pathology worldwide. Efficient treatment is jeopardized by parasite resistance to artemisinin and its derivatives, and by poor access to treatment in endemic regions. Anti-malarial traditional remedies still offer new tracks for identifying promising antiplasmodial molecules, and a way to ensure that all people have access to care. The present study aims to validate the traditional use of Terminalia macroptera, a Malian ...
Haidara, M.; Haddad, Mohamed; Denou, A.; Marti, G.; Bourgeade-Delmas, Sandra; Sanogo, R.; Bourdy, Geneviève; Aubouy, Agnès
Background: Plasmodium falciparum malaria is still one of the most deadly pathology worldwide. Efficient treatment is jeopardized by parasite resistance to artemisinin and its derivatives, and by poor access to treatment in endemic regions. Anti-malarial traditional remedies still offer new tracks for identifying promising antiplasmodial molecules, and a way to ensure that all people have access to care. The present study aims to validate the traditional use of Terminalia macroptera, a Malian...
Simpson, Julie A; Zaloumis, Sophie; DeLivera, Alysha M; Price, Ric N; McCaw, James M
Mechanistic within-host models integrating blood anti-malarial drug concentrations with the parasite-time profile provide a valuable decision tool for determining dosing regimens for anti-malarial treatments, as well as a formative component of population-level drug resistance models. We reviewed published anti-malarial pharmacokinetic-pharmacodynamic models to identify the challenges for these complex models where parameter estimation from clinical field data is limited. The inclusion of key pharmacodynamic processes in the mechanistic structure adopted varies considerably. These include the life cycle of the parasite within the red blood cell, the action of the anti-malarial on a specific stage of the life cycle, and the reduction in parasite growth associated with immunity. With regard to estimation of the pharmacodynamic parameters, the majority of studies simply compared descriptive summaries of the simulated outputs to published observations of host and parasite responses from clinical studies. Few studies formally estimated the pharmacodynamic parameters within a rigorous statistical framework using observed individual patient data. We recommend three steps in the development and evaluation of these models. Firstly, exploration through simulation to assess how the different parameters influence the parasite dynamics. Secondly, application of a simulation-estimation approach to determine whether the model parameters can be estimated with reasonable precision based on sampling designs that mimic clinical efficacy studies. Thirdly, fitting the mechanistic model to the clinical data within a Bayesian framework. We propose that authors present the model both schematically and in equation form and give a detailed description of each parameter, including a biological interpretation of the parameter estimates.
Men, Tran Thanh; Huy, Nguyen Tien; Trang, Dai Thi Xuan; Shuaibu, Mohammed Nasir; Hirayama, Kenji; Kamei, Kaeko
The spread of drug resistance in malaria parasites and the limited number of effective drugs for treatment indicates the need for new anti-malarial compounds. Current assays evaluating drugs against Plasmodium falciparum require expensive materials and equipment, thus limiting the search for new drugs, particularly in developing countries. This study describes an inexpensive procedure that is based on the advantage of a positive correlation between the haemozoin level of infected erythrocytes and parasite load. The relationship between parasitaemia and the haemozoin level of infected erythrocytes was investigated after converting haemozoin into monomeric haem. The 50% inhibitory concentration (IC50) values of chloroquine, quinine, artemisinin, quinidine and clotrimazole against P. falciparum K1 and 9A strains were determined using the novel assay method. The haemozoin of parasites was extracted and converted into monomeric haem, allowing the use of a colorimeter to efficiently and rapidly measure the growth of the parasites. There was a strong and direct linear relationship between the absorbance of haem converted from haemozoin and the percentage of the parasite (R2 = 0.9929). Furthermore, the IC50 values of drugs were within the range of the values previously reported. The haemozoin-based colorimetric assay can be considered as an alternative, simple, robust, inexpensive and convenient method, making it applicable in developing countries.
SENYAWA AKTIF ANTIKANKER PAYUDARA DAN ANTIMALARIA DARI TUMBUHAN DADAP AYAM (ERHYTHRINA VALERIEGATA SECARA IN VITRO (Anti Breast-cancer and anti-malarial Active Compounds of Erithrina Variegata by in Vitro Test
E. variegata used as medicinal folk of anti-cancer and anti-malarial, however haven’t reported yet of bioactive compounds. The purpose of this research was assayed an anti-cancer and anti-malarial compounds toward breast cancer cell-lines T47D and toward Plasmodium falciparum 3D7 (chloroquine sensitive and K1 (chloroquine resistance in vitro from E. variegata. The research was extraction of methanol and fractionation from the leaves and stem bark of E. variegata by using guide-assay in vitro Sulphorhodamine B (SRB method and lactate dehydrogenase (LDH. Furthermore, by using the anti-cancer and anti-malarial activity to follow separation, the active fraction was separated by combination of column chromatography to yield three active compounds (1-3. The chemical structure of active compounds (1-3 were determined on the basis of spectroscopic evidences and comparison with those previously reported and identified as terpenoid pentacyclic glycoside (1, flavonoid, erystagallin A (2 and steroid, (22E-5α,8α-epidioxyergosta-6,22-diene-3β-ol (3. The compound (1 showed anti-malarial activity in vitro against P. falciparum strain 3D7 and K1 with IC50 1.8 and 3.3 µg/mL, respectively. The compounds (2-3 showed anti-cancer activity against of breast cancer cell-lines T47D with IC50 of 3.03and 3.2 µg/ml, respectively. This results strongly suggested that E. variegata is a promising sources of anti-cancer and anti-malarial agents.
Background Maintaining adequate supplies of anti-malarial medicines at the health facility level in rural sub-Saharan Africa is a major barrier to effective management of the disease. Lack of visibility of anti-malarial stock levels at the health facility level is an important contributor to this problem. Methods A 21-week pilot study, 'SMS for Life', was undertaken during 2009-2010 in three districts of rural Tanzania, involving 129 health facilities. Undertaken through a collaborative partnership of public and private institutions, SMS for Life used mobile telephones, SMS messages and electronic mapping technology to facilitate provision of comprehensive and accurate stock counts from all health facilities to each district management team on a weekly basis. The system covered stocks of the four different dosage packs of artemether-lumefantrine (AL) and quinine injectable. Results Stock count data was provided in 95% of cases, on average. A high response rate (≥ 93%) was maintained throughout the pilot. The error rate for composition of SMS responses averaged 7.5% throughout the study; almost all errors were corrected and messages re-sent. Data accuracy, based on surveillance visits to health facilities, was 94%. District stock reports were accessed on average once a day. The proportion of health facilities with no stock of one or more anti-malarial medicine (i.e. any of the four dosages of AL or quinine injectable) fell from 78% at week 1 to 26% at week 21. In Lindi Rural district, stock-outs were eliminated by week 8 with virtually no stock-outs thereafter. During the study, AL stocks increased by 64% and quinine stock increased 36% across the three districts. Conclusions The SMS for Life pilot provided visibility of anti-malarial stock levels to support more efficient stock management using simple and widely available SMS technology, via a public-private partnership model that worked highly effectively. The SMS for Life system has the potential to alleviate
Duah, Nancy O; Matrevi, Sena A; de Souza, Dziedzom K; Binnah, Daniel D; Tamakloe, Mary M; Opoku, Vera S; Onwona, Christiana O; Narh, Charles A; Quashie, Neils B; Abuaku, Benjamin; Duplessis, Christopher; Kronmann, Karl C; Koram, Kwadwo A
With the introduction of artemisinin-based combination therapy (ACT) in 2005, monitoring of anti-malarial drug efficacy, which includes the use of molecular tools to detect known genetic markers of parasite resistance, is important for first-hand information on the changes in parasite susceptibility to drugs in Ghana. This study investigated the Plasmodium falciparum multidrug resistance gene (pfmdr1) copy number, mutations and the chloroquine resistance transporter gene (pfcrt) mutations in Ghanaian isolates collected in seven years to detect the trends in prevalence of mutations. Archived filter paper blood blots collected from children aged below five years with uncomplicated malaria in 2003-2010 at sentinel sites were used. Using quantitative real-time polymerase chain reaction (qRT-PCR), 756 samples were assessed for pfmdr1 gene copy number. PCR and restriction fragment length polymorphism (RFLP) were used to detect alleles of pfmdr1 86 in 1,102 samples, pfmdr1 184, 1034, 1042 and 1246 in 832 samples and pfcrt 76 in 1,063 samples. Merozoite surface protein 2 (msp2) genotyping was done to select monoclonal infections for copy number analysis. The percentage of isolates with increased pfmdr1 copy number were 4, 27, 9, and 18% for 2003-04, 2005-06, 2007-08 and 2010, respectively. Significant increasing trends for prevalence of pfmdr1 N86 (×(2) = 96.31, p resistance has been reported. The decreasing trend in the prevalence of chloroquine resistance markers after change of treatment policy presents the possibility for future introduction of chloroquine as prophylaxis for malaria risk groups such as children and pregnant women in Ghana.
Full Text Available Abstract Background The standard in vitro test to assess anti-malarial activity of chemical compounds is the [3H]hypoxanthine incorporation assay. It is a radioactivity-based method to measure DNA replication of Plasmodium in red blood cells. The method is highly reproducible, however, the handling of radioactive material is costly, hazardous and requires the availability of appropriate technology and trained staff. Several other ways to evaluate in vitro anti-malarial activity do exist, all with their own assets and limitations. Methods The newly developed double-antibody sandwich ELISA described here is based on the properties of a non-overlapping pair of monoclonal antibodies directed against Plasmodium falciparum aldolase. This glycolytic enzyme possesses some unique nucleotide sequences compared to the human isoenzymes and has been highly conserved through evolution. Out of twenty possibilities, the most sensitive antibody pair was selected and used to quantitatively detect parasite aldolase in infected blood lysates. Results A total of 34 compounds with anti-malarial activity were tested side-by-side by ELISA and the [3H]hypoxanthine incorporation assay. The novel ELISA provided IC50s closely paralleling those from the radioactivity-based assay (R = 0.99, p Conclusion The newly developed ELISA presents several advantages over the comparative method, the [3H]hypoxanthine incorporation assay. The assay is highly reproducible, less hazardous (involves no radioactivity and requires little and cheap technical equipment. Relatively unskilled personnel can conduct this user-friendly assay. All this makes it attractive to be employed in resource-poor laboratories.
Shaukat Ayesha M
Full Text Available Abstract Background Distinguishing new from recrudescent infections in post-treatment episodes of malaria is standard in anti-malarial drug efficacy trials. New infections are not considered malaria treatment failures and as a result, the prevention of subsequent episodes of malaria infection is not reported as a study outcome. However, in moderate and high transmission settings, new infections are common and the ability of a short-acting medication to cure an initial infection may be outweighed by its inability to prevent the next imminent infection. The clinical benefit of preventing new infections has never been compared to that of curing the initial infection. Methods Children enrolled in a sulphadoxine-pyrimethamine efficacy study in Blantyre, Malawi from 1998–2004 were prospectively evaluated. Six neutral microsatellites were used to classify new and recrudescent infections in children aged less than 10 years with recurrent malaria infections. Children from the study who did not experience recurrent parasitaemia comprised the baseline group. The odds of fever and anaemia, the rate of haemoglobin recovery and time to recurrence were compared among the groups. Results Fever and anemia were more common among children with parasitaemia compared to those who remained infection-free throughout the study period. When comparing recrudescent vs. new infections, the incidence of fever was not statistically different. However, children with recrudescent infections had a less robust haematological recovery and also experienced recurrence sooner than those whose infection was classified as new. Conclusions The results of this study confirm the paramount importance of providing curative treatment for all malaria infections. Although new and recrudescent infections caused febrile illnesses at a similar rate, recurrence due to recrudescent infection did have a worsened haemological outcome than recurrence due to new infections. Local decision
Karema, Corine; Aregawi, Maru W; Rukundo, Alphonse; Kabayiza, Alain; Mulindahabi, Monique; Fall, Ibrahima S; Gausi, Khoti; Williams, Ryan O; Lynch, Michael; Cibulskis, Richard; Fidele, Ngabo; Nyemazi, Jean-Pierre; Ngamije, Daniel; Umulisa, Irenee; Newman, Robert; Binagwaho, Agnes
To control malaria, the Rwandan government and its partners distributed insecticide-treated nets (ITN) and made artemisinin-based combination therapy (ACT) widely available from 2005 onwards. The impact of these interventions on malaria cases, admissions and deaths was assessed using data from district hospitals and household surveys. District records of ITN and ACT distribution were reviewed. Malaria and non-malaria indictors in 30 district hospitals were ascertained from surveillance records. Trends in cases, admissions and deaths for 2000 to 2010 were assessed by segmented log-linear regression, adjusting the effect size for time trends during the pre-intervention period, 2000-2005. Changes were estimated by comparing trends in post-intervention (2006-2010) with that of pre-intervention (2000-2005) period. All-cause deaths in children under-five in household surveys of 2005 and 2010 were also reviewed to corroborate with the trends of deaths observed in hospitals. The proportion of the population potentially protected by ITN increased from nearly zero in 2005 to 38% in 2006, and 76% in 2010; no major health facility stock-outs of ACT were recorded following their introduction in 2006. In district hospitals, after falling during 2006-2008, confirmed malaria cases increased in 2009 coinciding with decreased potential ITN coverage and declined again in 2010 following an ITN distribution campaign. For all age groups, from the pre-intervention period, microscopically confirmed cases declined by 72%, (95% Confidence Interval [CI], 12-91%) in 2010, slide positivity rate declined 58%, (CI, 47%-68%), malaria inpatient cases declined 76% (CI, 49%-88%); and malaria deaths declined 47% (CI, 47%-81%). In children below five years of age, malaria inpatients decreased 82% (CI, 61%-92%) and malaria hospital deaths decreased 77% (CI, 40%-91%). Concurrently, outpatient cases, admissions and deaths due to non-malaria diseases in all age groups either increased or remained
How sulfadoxine-pyrimethamine (SP was perceived in some rural communities after phasing out chloroquine (CQ as a first-line drug for uncomplicated malaria in Tanzania: lessons to learn towards moving from monotherapy to fixed combination therapy
Nsimba Stephen ED
health workers considered the drug to be good and effective against malaria. Such negative perception towards SP highlights the need to start earlier sensitization and educational campaigns to the rural communities for a new drug program to ensure its success. Messages should clearly state what should be expected from the new drug (Coartem, before its introduction. This is important especially as Tanzania is expected to move towards the expensive but efficacious and effective fixed-combination (Coartem anti-malarial therapy early next year (2006.
Janet M Meredith
Full Text Available Diseases transmitted by mosquitoes have a devastating impact on global health and this is worsening due to difficulties with existing control measures and climate change. Genetically modified mosquitoes that are refractory to disease transmission are seen as having great potential in the delivery of novel control strategies. Historically the genetic modification of insects has relied upon transposable elements which have many limitations despite their successful use. To circumvent these limitations the Streptomyces phage phiC31 integrase system has been successfully adapted for site-specific transgene integration in insects. Here, we present the first site-specific transformation of Anopheles gambiae, the principal vector of human malaria. Mosquitoes were initially engineered to incorporate the phiC31 targeting site at a defined genomic location. A second phase of genetic modification then achieved site-specific integration of Vida3, a synthetic anti-malarial gene. Expression of Vida3, specifically in the midgut of bloodfed females, offered consistent and significant protection against Plasmodium yoelii nigeriensis, reducing average parasite intensity by 85%. Similar protection was observed against Plasmodium falciparum in some experiments, although protection was inconsistent. In the fight against malaria, it is imperative to establish a broad repertoire of both anti-malarial effector genes and tissue-specific promoters for their expression, enabling those offering maximum effect with minimum fitness cost to be identified. In the future, this technology will allow effective comparisons and informed choices to be made, potentially leading to complete transmission blockade.
Duffy, Sandra; Avery, Vicky M
With the increasing occurrence of drug resistance in the malaria parasite, Plasmodium falciparum, there is a great need for new and novel anti-malarial drugs. We have developed a 384-well, high-throughput imaging assay for the detection of new anti-malarial compounds, which was initially validated by screening a marine natural product library, and subsequently used to screen more than 3 million data points from a variety of compound sources. Founded on another fluorescence-based P. falciparum growth inhibition assay, the DNA-intercalating dye 4',6-diamidino-2-phenylindole, was used to monitor changes in parasite number. Fluorescent images were acquired on the PerkinElmer Opera High Throughput confocal imaging system and analyzed with a spot detection algorithm using the Acapella data processing software. Further optimization of this assay sought to increase throughput, assay stability, and compatibility with our high-throughput screening equipment platforms. The assay typically yielded Z'-factor values of 0.5-0.6, with signal-to-noise ratios of 12.
Ahmed, Nafees; Anwar, Sirajudheen; Thet Htar, Thet
The Plasmodium falciparum Lactate Dehydrogenase enzyme (PfLDH) catalyzes inter-conversion of pyruvate to lactate during glycolysis producing the energy required for parasitic growth. The PfLDH has been studied as a potential molecular target for development of anti-malarial agents. In an attempt to find the potent inhibitor of PfLDH, we have used Discovery studio to perform molecular docking in the active binding pocket of PfLDH by CDOCKER, followed by three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of tricyclic guanidine batzelladine compounds, which were previously synthesized in our laboratory. Docking studies showed that there is a very strong correlation between in silico and in vitro results. Based on docking results, a highly predictive 3D-QSAR model was developed with q2 of 0.516. The model has predicted r2 of 0.91 showing that predicted IC50 values are in good agreement with experimental IC50 values. The results obtained from this study revealed the developed model can be used to design new anti-malarial compounds based on tricyclic guanidine derivatives and to predict activities of new inhibitors.
Frausin, Gina; Hidalgo, Ari de Freitas; Lima, Renata Braga Souza; Kinupp, Valdely Ferreira; Ming, Lin Chau; Pohlit, Adrian Martin; Milliken, William
In this article we present the plants used for the treatment of malaria and associated symptoms in Santa Isabel do Rio Negro in the Brazilian Amazon. The region has important biological and cultural diversities including more than twenty indigenous ethnic groups and a strong history in traditional medicine. The aims of this study are to survey information in the Baniwa, Baré, Desana, Piratapuia, Tariana, Tukano, Tuyuca and Yanomami ethnic communities and among caboclos (mixed-ethnicity) on (a) plant species used for the treatment of malaria and associated symptoms, (b) dosage forms and (c) distribution of these anti-malarial plants in the Amazon. Information was obtained through classical ethnobotanical and ethnopharmacological methods from interviews with 146 informants in Santa Isabel municipality on the upper Negro River, Brazil. Fifty-five mainly native neotropical plant species from 34 families were in use. The detailed uses of these plants were documented. The result was 187 records (64.5%) of plants for the specific treatment of malaria, 51 records (17.6%) of plants used in the treatment of liver problems and 29 records (10.0%) of plants used in the control of fevers associated with malaria. Other uses described were blood fortification ('dar sangue'), headache and prophylaxis. Most of the therapeutic preparations were decoctions and infusions based on stem bark, root bark and leaves. These were administered by mouth. In some cases, remedies were prepared with up to three different plant species. Also, plants were used together with other ingredients such as insects, mammals, gunpowder and milk. This is the first study on the anti-malarial plants from this region of the Amazon. Aspidosperma spp. and Ampelozizyphus amazonicus Ducke were the most cited species in the communities surveyed. These species have experimental proof supporting their anti-malarial efficacy. The dosage of the therapeutic preparations depends on the kind of plant, quantity of plant
Full Text Available Abstract Background Presumptive treatment of all febrile patients with anti-malarials leads to massive over-treatment. The aim was to assess the effect of implementing malaria rapid diagnostic tests (mRDTs on prescription of anti-malarials in urban Tanzania. Methods The design was a prospective collection of routine statistics from ledger books and cross-sectional surveys before and after intervention in randomly selected health facilities (HF in Dar es Salaam, Tanzania. The participants were all clinicians and their patients in the above health facilities. The intervention consisted of training and introduction of mRDTs in all three hospitals and in six HF. Three HF without mRDTs were selected as matched controls. The use of routine mRDT and treatment upon result was advised for all patients complaining of fever, including children under five years of age. The main outcome measures were: (1 anti-malarial consumption recorded from routine statistics in ledger books of all HF before and after intervention; (2 anti-malarial prescription recorded during observed consultations in cross-sectional surveys conducted in all HF before and 18 months after mRDT implementation. Results Based on routine statistics, the amount of artemether-lumefantrine blisters used post-intervention was reduced by 68% (95%CI 57-80 in intervention and 32% (9-54 in control HF. For quinine vials, the reduction was 63% (54-72 in intervention and an increase of 2.49 times (1.62-3.35 in control HF. Before-and-after cross-sectional surveys showed a similar decrease from 75% to 20% in the proportion of patients receiving anti-malarial treatment (Risk ratio 0.23, 95%CI 0.20-0.26. The cluster randomized analysis showed a considerable difference of anti-malarial prescription between intervention HF (22% and control HF (60% (Risk ratio 0.30, 95%CI 0.14-0.70. Adherence to test result was excellent since only 7% of negative patients received an anti-malarial. However, antibiotic
Haidara, Mahamane; Haddad, Mohamed; Denou, Adama; Marti, Guillaume; Bourgeade-Delmas, Sandra; Sanogo, Rokia; Bourdy, Geneviève; Aubouy, Agnès
Plasmodium falciparum malaria is still one of the most deadly pathology worldwide. Efficient treatment is jeopardized by parasite resistance to artemisinin and its derivatives, and by poor access to treatment in endemic regions. Anti-malarial traditional remedies still offer new tracks for identifying promising antiplasmodial molecules, and a way to ensure that all people have access to care. The present study aims to validate the traditional use of Terminalia macroptera, a Malian plant used in traditional medicine. Terminalia macroptera was collected in Mali. Leaves (TML) and roots ethanolic extracts (TMR) were prepared and tested at 2000 mg/kg for in vivo acute toxicity in Albino Swiss mice. Antiplasmodial activity of the extracts was assessed against a chloroquine resistant strain P. falciparum (FcB1) in vitro. In vivo, anti-malarial efficacy was assessed by a 4-day suppressive test at 100 mg/kg in two malaria murine models of uncomplicated malaria (Plasmodium chabaudi chabaudi infection) and cerebral malaria (Plasmodium berghei strain ANKA infection). Constituents of TMR were characterized by ultra-high-performance liquid chromatography coupled to high resolution mass spectrometry. Top ranked compounds were putatively identified using plant databases and in silico fragmentation pattern. Lethal dose of TML and TMR were greater than 2000 mg/kg in Albino Swiss mice. According to the OECD's Globally Harmonized System of Classification, both extracts are non-toxic orally. Antiplasmodial activity of T. macroptera extracts was confirmed in vitro against P. falciparum FcB1 strain with IC50 values of 1.2 and 1.6 µg/mL for TML and TMR, respectively. In vivo, oral administration of TML and TMR induced significant reduction of parasitaemia (37.2 and 46.4% respectively) in P. chabaudi chabaudi infected mice at the 7th day of infection compared to untreated mice. In the cerebral malaria experimental model, mice treated with TMR and TML presented respectively 50 and 66
Teboh-Ewungkem, Miranda I; Mohammed-Awel, Jemal; Baliraine, Frederick N; Duke-Sylvester, Scott M
The use of intermittent preventive treatment in pregnant women (IPTp), children (IPTc) and infant (IPTi) is an increasingly popular preventive strategy aimed at reducing malaria risk in these vulnerable groups. Studies to understand how this preventive intervention can affect the spread of anti-malarial drug resistance are important especially when there is human movement between neighbouring low and high transmission areas. Because the same drug is sometimes utilized for IPTi and for symptomatic malaria treatment, distinguishing their individual roles on accelerating the spread of drug resistant malaria, with or without human movement, may be difficult to isolate experimentally or by analysing data. A theoretical framework, as presented here, is thus relevant as the role of IPTi on accelerating the spread of drug resistance can be isolated in individual populations and when the populations are interconnected and interact. A previously published model is expanded to include human movement between neighbouring high and low transmission areas, with focus placed on the malaria parasites. Parasite fitness functions, determined by how many humans the parasites can infect, are used to investigate how fast resistance can spread within the neighbouring communities linked by movement, when the populations are at endemic equilibrium. Model simulations indicate that population movement results in resistance spreading fastest in high transmission areas, and the more complete the anti-malarial resistance the faster the resistant parasite will tend to spread through a population. Moreover, the demography of infection in low transmission areas tends to change to reflect the demography of high transmission areas. Additionally, when regions are strongly connected the rate of spread of partially resistant parasites (R1) relative to drug sensitive parasites (RS), and fully resistant parasites (R2) relative to partially resistant parasites (R1) tend to behave the same in both
Full Text Available Abstract Background There is little existing knowledge about actual quality of drugs provided by different providers in Nigeria and in many sub-Saharan African countries. Such information is important for improving malaria treatment that will help in the development and implementation of actions designed to improve the quality of treatment. The objective of the study was to determine the quality of drugs used for the treatment of malaria in a broad spectrum of public and private healthcare providers. Methods The study was undertaken in six towns (three urban and three rural in Anambra state, south-east Nigeria. Anti-malarials (225 samples, which included artesunate, dihydroartemisinin, sulphadoxine-pyrimethamine (SP, quinine, and chloroquine, were either purchased or collected from randomly selected providers. The quality of these drugs was assessed by laboratory analysis of the dissolution profile using published pharmacopoeial monograms and measuring the amount of active ingredient using high performance liquid chromatography (HPLC. Findings It was found that 60 (37% of the anti-malarials tested did not meet the United States Pharmacopoeia (USP specifications for the amount of active ingredients, with the suspect drugs either lacking the active ingredients or containing suboptimal quantities of the active ingredients. Quinine (46% and SP formulations (39% were among drugs that did not satisfy the tolerance limits published in USP monograms. A total of 78% of the suspect drugs were from private facilities, mostly low-level providers, such as patent medicine dealers (vendors. Conclusion This study found that there was a high prevalence of poor quality drugs. The findings provide areas for public intervention to improve the quality of malaria treatment services. There should be enforced checks and regulation of drug supply management as well as stiffer penalties for people stocking substandard and counterfeit drugs.
Olugbenga O. Oluwagbemi
Full Text Available Malaria is one of the infectious diseases consistently inherent in many Sub-Sahara African countries. Among the issues of concern are the consequences of wrong diagnosis and dosage administration of anti-malarial drugs on sick patients; these have resulted into various degrees of complications ranging from severe headaches, stomach and body discomfort, blurred vision, dizziness, hallucinations, and in extreme cases, death. Many expert systems have been developed to support different infectious disease diagnoses, but not sure of any yet, that have been specifically designed as a voice-based application to diagnose and translate malaria patients’ symptomatic data for pre-laboratory screening and correct prescription of proper dosage of the appropriate medication. We developed Malavefes, (a malaria voice-enabled computational fuzzy expert system for correct dosage prescription of anti-malarial drugs using Visual Basic.NET., and Java programming languages. Data collation for this research was conducted by survey from existing literature and interview from public health experts. The database for this malaria drug informatics system was implemented using Microsoft Access. The Root Sum Square (RSS was implemented as the inference engine of Malavefes to make inferences from rules, while Centre of Gravity (CoG was implemented as the defuzzification engine. The drug recommendation module was voice-enabled. Additional anti-malaria drug expiration validation software was developed using Java programming language. We conducted a user-evaluation of the performance and user-experience of the Malavefes software. Keywords: Informatics, Bioinformatics, Fuzzy, Anti-malaria, Voice computing, Dosage prescription
.9617, or adjusted log mean baseline parasitaemia (p = 0.365. There was no effect of G6PD genotype (p = 0.490 or phenotype (p = 0.391 on the rate of malaria recrudescence, or reinfection (p = 0.134 and p = 0.354, respectively. Conclusions G6PD deficiency is common in African patients with malaria and until a reliable and simple G6PD test is available, the use of 8-aminoquinolines will remain problematic. G6PD status did not impact baseline haemoglobin, parasitaemia or temperature or the outcomes of anti-malarial therapy. Trial registration Clinicaltrials.gov: NCT00344006 and NCT00371735.
Morison, W L
Various adjunctive treatments are now frequently used in combination with PUVA therapy with the aims of limiting adverse effects, improving efficacy and decreasing the cost of treatment. In the management of psoriasis, PUVA plus retinoids, PUVA plus methotrexate and PUVA plus UVB phototherapy are the most frequently used combinations. PUVA plus topical corticosteroids and PUVA plus anthralin are also efficacious but adverse effects and poor acceptance by patients are limiting factors. Combinations of PUVA plus nitrogen mustard and ionizing radiation are used in mycosis fungoides to treat tumors and residual disease in secluded sites. In the management of photodermatoses with PUVA therapy, prednisone is often required to prevent exacerbation of disease. A combination of prednisone and PUVA therapy can also be useful in lichen planus and atopic eczema. The selection of a suitable combination treatment, will depend upon the preferences of the clinician, the disease being treated, and the characteristics of the patient.
Amoa Onguéné, Pascal; Ntie-Kang, Fidele; Lifongo, Lydia Likowo; Ndom, Jean Claude; Sippl, Wolfgang; Mbaze, Luc Meva'a
Traditional medicine caters for about 80% of the health care needs of many rural populations around the world, especially in developing countries. In addition, plant-derived compounds have played key roles in drug discovery. Malaria is currently a public health concern in many countries in the world due to factors such as chemotherapy faced by resistance, poor hygienic conditions, poorly managed vector control programmes and no approved vaccines. In this review, an attempt has been made to assess the value of African medicinal plants for drug discovery by discussing the anti-malarial virtue of the derived phytochemicals that have been tested by in vitro and in vivo assays. This survey was focused on pure compounds derived from African flora which have exhibited anti-malarial properties with activities ranging from "very active" to "weakly active". However, only the compounds which showed anti-malarial activities from "very active" to "moderately active" are discussed in this review. The activity of 278 compounds, mainly alkaloids, terpenoids, flavonoids, coumarines, phenolics, polyacetylenes, xanthones, quinones, steroids, and lignans have been discussed. The first part of this review series covers the activity of 171 compounds belonging to the alkaloid and terpenoid classes. Data available in the literature indicated that African flora hold an enormous potential for the development of phytomedicines for malaria.
Full Text Available In Africa, malaria kills one child each minute. It is also responsible for about one million deaths worldwide each year. Plasmodium falciparum, is the protozoan responsible for the most lethal form of the disease, with resistance developing against the available anti-malarial drugs. Among newly proposed anti-malaria targets, are the P. falciparum cyclin-dependent kinases (PfCDKs. There are involved in different stages of the protozoan growth and development but share high sequence homology with human cyclin-dependent kinases (CDKs. We previously reported the synthesis of CDKs inhibitors that are structurally-related to (R-roscovitine, a 2,6,9-trisubstituted purine, and they showed activity against neuronal diseases and cancers. In this report, we describe the synthesis and the characterization of new CDK inhibitors, active in reducing the in vitro growth of P. falciparum (3D7 and 7G8 strains. Six compounds are more potent inhibitors than roscovitine, and three exhibited IC50 values close to 1 µM for both 3D7 and 7G8 strains. Although, such molecules do inhibit P. falciparum growth, they require further studies to improve their selectivity for PfCDKs.
Nguyen, Thuy-Nhien; Thu, Pham N Huong; Hung, Ngo Trong; Son, Do Hung; Tien, Nguyen Thanh; Van Dung, Nguyen; Quang, Huynh Hong; Seidlein, Lorenz von; Cheah, Phaik Yeong; Dondorp, Arjen M; Day, Nicholas P J; White, Nicholas J; Hien, Tran Tinh
As part of a targeted malaria elimination project, mass drug administrations (MDAs) were conducted in Vietnam. The impact of MDAs on malaria transmission depends largely on the efficacy of the anti-malarial drug regimen, the malaria epidemiology in the site and the population coverage. To explore why some people participate in MDAs and others do not, a quantitative survey of the villagers' perceptions was undertaken in Vietnam. In 2013/2014 MDAs were conducted in a village in Binh Phuoc province and a village in Ninh Thuan province. Within three months of the drug administration, 59 respondents in a village in Binh Phuoc and 79 respondents in a village in Ninh Thuan were randomly selected and interviewed. Comprehension of the purpose of the intervention was of paramount importance for participation in the intervention. Respondents aware that the intervention aims to protect against malaria were significantly more likely to participate than respondents who were unaware of the MDA's purpose. Secondly, how and by whom villagers were informed was critical for participation. There was a strong association between sensitization by an informant such as a member of the local health team with participation in the intervention. The study suggests several approaches to increase participation in mass drug administration campaigns. Training trustworthy informants to sensitize the study population is critical to maximize village participation in this setting. To achieve high coverage the entire community must understand and agree with the intervention.
Full Text Available Abstract Background Drug and multidrug-resistant Plasmodium falciparum malaria has existed in Thailand for several decades. Furthermore, Thailand serves as a sentinel for drug-resistant malaria within the Greater Mekong sub-region. However, the drug resistance situation is highly dynamic, changing quickly over time. Here parasite in vitro drug sensitivity is reported for artemisinin derivatives, mefloquine, chloroquine and quinine, across Thailand. Methods Blood was drawn from patients infected with P. falciparum in seven sentinel provinces along Thai international borders with Cambodia, Myanmar, Laos, and Malaysia. In vitro parasite sensitivity was tested using the World Health Organization’s microtest (mark III (between 1994 and 2002 and the histidine-rich protein-2 (HRP2-based enzyme-linked immunosorbent assay (in 2010. Following World Health Organization protocol, at least 30 isolates were collected for each province and year represented in this study. Where possible, t-tests were used to test for significant differences. Results There appears to be little variation across study sites with regard to parasite sensitivity to chloroquine. Quinine resistance appears to have been rising prior to 1997, but has subsequently decreased. Mefloquine sensitivity appears high across the provinces, especially along the north-western border with Myanmar and the eastern border with Cambodia. Finally, the data suggest that parasite sensitivity to artemisinin and its derivatives is significantly higher in provinces along the north-western border with Myanmar. Conclusions Parasite sensitivity to anti-malarials in Thailand is highly variable over time and largely mirrors official drug use policy. The findings with regard to reduced sensitivity to artemisinin derivatives are supported by recent reports of reduced parasite clearance associated with artemisinin. This trend is alarming since artemisinin is considered the last defence against malaria. Continued
Khatib, Rashid A; Selemani, Majige; Mrisho, Gumi A; Masanja, Irene M; Amuri, Mbaraka; Njozi, Mustafa H; Kajungu, Dan; Kuepfer, Irene; Abdulla, Salim M; de Savigny, Don
Artemisinin-based combination treatment (ACT) has been widely adopted as one of the main malaria control strategies. However, its promise to save thousands of lives in sub-Saharan Africa depends on how effective the use of ACT is within the routine health system. The INESS platform evaluated effective coverage of ACT in several African countries. Timely access within 24 hours to an authorized ACT outlet is one of the determinants of effective coverage and was assessed for artemether-lumefantrine (Alu), in two district health systems in rural Tanzania. From October 2009 to June 2011 we conducted continuous rolling household surveys in the Kilombero-Ulanga and the Rufiji Health and Demographic Surveillance Sites (HDSS). Surveys were linked to the routine HDSS update rounds. Members of randomly pre-selected households that had experienced a fever episode in the previous two weeks were eligible for a structured interview. Data on individual treatment seeking, access to treatment, timing, source of treatment and household costs per episode were collected. Data are presented on timely access from a total of 2,112 interviews in relation to demographics, seasonality, and socio economic status. In Kilombero-Ulanga, 41.8% (CI: 36.6-45.1) and in Rufiji 36.8% (33.7-40.1) of fever cases had access to an authorized ACT provider within 24 hours of fever onset. In neither of the HDSS site was age, sex, socio-economic status or seasonality of malaria found to be significantly correlated with timely access. Timely access to authorized ACT providers is below 50% despite interventions intended to improve access such as social marketing and accreditation of private dispensing outlets. To improve prompt diagnosis and treatment, access remains a major bottle neck and new more innovative interventions are needed to raise effective coverage of malaria treatment in Tanzania.
Full Text Available Abstract Background Regular monitoring of the levels of anti-malarial resistance of Plasmodium falciparum is an essential policy to adapt therapy and improve malaria control. This monitoring can be facilitated by using molecular tools, which are easier to implement than the classical determination of the resistance phenotype. In Cameroon, chloroquine (CQ, previously the first-line therapy for uncomplicated malaria was officially withdrawn in 2002 and replaced initially by amodiaquine (AQ monotherapy. Then, artemisinin-based combination therapy (ACT, notably artesunate-amodiaquine (AS-AQ or artemether-lumefantrine (AL, was gradually introduced in 2004. This situation raised the question of the evolution of P. falciparum resistance molecular markers in Yaoundé, a highly urbanized Cameroonian city. Methods The genotype of pfcrt 72 and 76 and pfmdr1 86 alleles and pfmdr1 copy number were determined using real-time PCR in 447 P. falciparum samples collected between 2005 and 2009. Results This study showed a high prevalence of parasites with mutant pfcrt 76 (83% and pfmdr1 86 (93% codons. On the contrary, no mutations in the pfcrt 72 codon and no samples with duplication of the pfmdr1 gene were observed. Conclusion The high prevalence of mutant pfcrt 76T and pfmdr1 86Y alleles might be due to the choice of alternative drugs (AQ and AS-AQ known to select such genotypes. Mutant pfcrt 72 codon was not detected despite the prolonged use of AQ either as monotherapy or combined with artesunate. The absence of pfmdr1 multicopies suggests that AL would still remain efficient. The limited use of mefloquine or the predominance of mutant pfmdr1 86Y codon could explain the lack of pfmdr1 amplification. Indeed, this mutant codon is rarely associated with duplication of pfmdr1 gene. In Cameroon, the changes of therapeutic strategies and the simultaneous use of several formulations of ACT or other anti-malarials that are not officially recommended result in a
Selemani, Majige; Masanja, Irene M; Kajungu, Dan; Amuri, Mbaraka; Njozi, Mustafa; Khatib, Rashid A; Abdulla, Salim; de Savigny, Don
Improving malaria case management is partially dependent on health worker compliance with clinical guidelines. This study assessed health worker factors associated with correct anti-malarial prescribing practices at two sites in rural Tanzania. Repeated cross-sectional health facility surveys were conducted during high and low malaria transmission seasons in 2010 and collected information on patient consultations and health worker characteristics. Using logistic regression, the study assessed health worker factors associated with correct prescription for uncomplicated malaria defined as prescription of artemisinin-based combination therapy (ACT) for patients with fever and Plasmodium falciparum asexual infection based on blood slide or malaria rapid diagnostic test (RDT) according to national treatment guidelines. The analysis included 685 patients with uncomplicated malaria who were seen in a health facility with ACT in stock, and 71 health workers practicing in 30 health facilities. Overall, 58% of malaria patients were correctly treated with ACT. Health workers with three or more years' work experience were significantly more likely than others to prescribe correctly (adjusted odds ratio (aOR) 2.9; 95% confidence interval (CI) 1.2-7.1; p = 0.019). Clinical officers (aOR 2.2; 95% CI 1.1-4.5; p = 0.037), and nurse aide or lower cadre (aOR 3.1; 95% CI 1.3-7.1; p = 0.009) were more likely to correctly prescribe ACT than medical officers. Training on ACT use, supervision visits, and availability of job aids were not significantly associated with correct prescription. Years of working experience and health worker cadre were associated with correct ACT prescription for uncomplicated malaria. Targeted interventions to improve health worker performance are needed to improve overall malaria case management.
This comprehensive survey of current methods and achievements first takes a look at the two basic therapies, devoting a chapter each to the surgery and radiotherapy of tumors. The principal subjects of the book, however, are the systemic, adjuvant therapy, biological therapies, hyperthermia and various other therapies (as e.g. treatment with ozone, oxygen, or homeopathic means), and psychotherapy. (MG) With 54 figs., 86 tabs [de
Ndong, Ignatius C; Reenen, Mari van; Boakye, Daniel A; Mbacham, Wilfred F; Grobler, Anne F
National malaria treatment policies are devised to guide health professionals and to facilitate diagnosis and case management. Following the recommendations of the WHO, Cameroon changed its malaria treatment policy from monotherapy to artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated malaria. We report an investigation into trends of case management following this change in policy. Data was collected retrospectively, through consultation and perusal of laboratory and prescription registers of the Mbakong Health Centre. Analysis of data was done using SPSS and SAS Statistics. Data presented herein demonstrate that from 2006 to 2012, a total of 2484 (58.7%) of the total prescriptions included an anti-malarial, 1989 (47.0%) included an antibiotic and 1935(45.7%) included an antipyretic. The anti-malarials prescribed were Anti-malaria combination therapy (ACT) - 1216 (47.6%), quinine 1044 (40.8%) or SP 296 (11.6%). Of the 1216 patients prescribed an ACT, 441(36.3%) had a positive malaria parasite confirmation, 746 (61.3%) were negative for plasmodium. Overall, 29 patients (2.4%) were treated either with an ACT without any test performed. Quinine intake was recorded in 566 (54.2%) patients positive for plasmodium. ACT prescription increased from 23% in 2007 to between 44 and 45% in 2008-2009. During this period there was a corresponding drop in the prescription of quinine from 38% in 2007 to 13% in 2009 (r=-0.43, p>0.05). Sulphadoxine-Pyrimethamine (SP) was restrictively prescribed to women of childbearing age (97.0%) after 2008. Antibiotics prescription dropped from 53.7% to 39.3% from 2010 to 2012. The odds of being prescribed an antibiotic was significantly higher in patients with a malaria negative result compared to malaria positive patients (OR=6.12, CI 4.74-7.91, p<0.00001). Overall, there is an over treatment of malaria, thus departing from the WHO guidelines of appropriate treatment. Although there is an overall increase
Accuracy of a Plasmodium falciparum specific histidine-rich protein 2 rapid diagnostic test in the context of the presence of non-malaria fevers, prior anti-malarial use and seasonal malaria transmission
Kiemde, Francois; Bonko, Massa Dit Achille; Tahita, Marc Christian; Lompo, Palpouguini; Rouamba, Toussaint; Tinto, Halidou; Boele van Hensbroek, Michael; Mens, Petra F.; Schallig, Henk D. F. H.
It remains challenging to distinguish malaria from other fever causing infections, as a positive rapid diagnostic test does not always signify a true active malaria infection. This study was designed to determine the influence of other causes of fever, prior anti-malarial treatment, and a possible
Conclusions: CM1 would be effective per se and synergize with PYR in inhibiting growth of murine malaria parasites, possibly by limiting iron supply from plasma transferrin and host PRBC cytoplasm, and chelating catalytic iron cstitutive in parasites’ mitochondrial cytochromes and cytoplasmic ribonucleotide reductase. CM1 would be a promising adjuvant to enhance PYR anti-malarial activity and minimize the drug resistance.
Agnandji Selidji T
Full Text Available Abstract Background Paediatric drug formulations for artemisinin combination therapy (P-ACT have been developed over the past few years and have been shown to improve the therapeutic management of young children with uncomplicated falciparum malaria. This process was however not equally paralleled by a timely adoption of P-ACT in national and international treatment recommendations. National malaria programmes in sub-Saharan Africa have not yet widely embraced this new therapeutic tool. To which extent P-ACT is used in the field in sub-Saharan Africa is not known to date. Methods This snapshot questionnaire survey aimed to provide an overview on the current routine practices for the availability and use of P-ACT as anti-malarial treatment for young children in sub-Saharan Africa. Health care personnel in seven countries in West-, Central, and East-Africa were invited to answer a structured questionnaire assessing use and availability of P-ACT. Results A total of 71 respondents including doctors, nurses and pharmacy personnel responsible for the anti-malarial treatment of young children were interviewed. P-ACT was used by 83% (95% confidence interval: 73-90%; n = 59 as first-line treatment for young children. Use of 15 different P-ACT products was reported among which only two have received WHO prequalification status and approval by a stringent registration authority. Use of a specific P-ACT product was not linked to consumer prices or availability of supporting clinical trial data, but may depend more on the marketing capacity of the manufacturer. Major differences in frequency and dosing of anti-malarial regimens with identical anti-malarial compounds and the marketing of loose combinations were recorded. Conclusion Paediatric ACT is widely used for the treatment of uncomplicated malaria in young children. However, the majority of P-ACT formulations in use do not meet highest international quality standards evoking concerns for patients
Burger, Renée J; Visser, Benjamin J; Grobusch, Martin P; van Vugt, Michèle
Pregnancy has been reported to alter the pharmacokinetic properties of anti-malarial drugs, including the different components of artemisinin-based combination therapy (ACT). However, small sample sizes make it difficult to draw strong conclusions based on individual pharmacokinetic studies. The aim of this review is to summarize the evidence of the influence of pregnancy on the pharmacokinetic properties of different artemisinin-based combinations. A PROSPERO-registered systematic review to identify clinical trials that investigated the influence of pregnancy on the pharmacokinetic properties of different forms of ACT was conducted, following PRISMA guidelines. Without language restrictions, Medline/PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, LILACS, Biosis Previews and the African Index Medicus were searched for studies published up to November 2015. The following components of ACT that are currently recommend by the World Health Organization as first-line treatment of malaria in pregnancy were reviewed: artemisinin, artesunate, dihydroartemisinin, lumefantrine, amodiaquine, mefloquine, sulfadoxine, pyrimethamine, piperaquine, atovaquone and proguanil. The literature search identified 121 reports, 27 original studies were included. 829 pregnant women were included in the analysis. Comparison of the available studies showed lower maximum concentrations (Cmax) and exposure (AUC) of dihydroartemisinin, the active metabolite of all artemisinin derivatives, after oral administration of artemether, artesunate and dihydroartemisinin in pregnant women. Low day 7 concentrations were commonly seen in lumefantrine studies, indicating a low exposure and possibly reduced efficacy. The influence of pregnancy on amodiaquine and piperaquine seemed not to be clinically relevant. Sulfadoxine plasma concentration was significantly reduced and clearance rates were higher in pregnancy, while pyrimethamine and mefloquine need more research as no
Lall Varinder K
Full Text Available Abstract Background Mefloquine is an anti-malarial drug that can have neurological side effects. This study examines how mefloquine (MF influences central nervous control of autonomic and respiratory systems using the arterially perfused working heart brainstem preparation (WHBP of the rat. Recordings of nerve activity were made from the thoracic sympathetic chain and phrenic nerve, while heart rate (HR and perfusion pressure were also monitored in the arterially perfused, decerebrate, rat WHBP. MF was added to the perfusate at 1 μM to examine its effects on baseline parameters as well as baroreceptor and chemoreceptor reflexes. Results MF caused a significant, atropine resistant, bradycardia and increased phrenic nerve discharge frequency. Chemoreceptor mediated sympathoexcitation (elicited by addition of 0.1 ml of 0.03% sodium cyanide to the aortic cannula was significantly attenuated by the application of MF to the perfusate. Furthermore MF significantly decreased rate of return to resting HR following chemoreceptor induced bradycardia. An increase in respiratory frequency and attenuated respiratory-related sympathetic nerve discharge during chemoreceptor stimulation was also elicited with MF compared to control. However, MF did not significantly alter baroreceptor reflex sensitivity. Conclusions These studies indicate that in the WHBP, MF causes profound alterations in autonomic and respiratory control. The possibility that these effects may be mediated through actions on connexin 36 containing gap junctions in central neurones controlling sympathetic nervous outflow is discussed.
antibodies for the drugs used in artemisinin-based combination therapy (ACT.
Montgomery Scott M
Full Text Available Abstract Background The aim of this study was to analyse willingness to pay (WTP and ability to pay (ATP for ACT for children below five years of age in a rural setting in Tanzania before the introduction of artemisinin-based combination therapy (ACT as first-line treatment for uncomplicated malaria. Socio-economic factors associated with WTP and expectations on anti-malaria drugs, including ACT, were also explored. Methods Structured interviews and focus group discussions were held with mothers, household heads, health-care workers and village leaders in Ishozi, Gera and Ishunju wards in north-west Tanzania in 2004. Contingent valuation method (CVM was used with "take-it-or-leave-it" as the eliciting method, expressed as WTP for a full course of ACT for a child and households' opportunity cost of ACT was used to assess ATP. The study included descriptive analyses with multivariate adjustment for potential confounding factors. Results Among 265 mothers and household heads, 244 (92%, CI = 88%–95% were willing to pay Tanzanian Shillings (TSh 500 (US$ 0.46 for a child's dose of ACT, but only 55% (49%–61% were willing to pay more than TSh 500. Mothers were more often willing to pay than male household heads (adjusted odds ratio = 2.1, CI = 1.2–3.6. Socio-economic status had no significant effect on WTP. The median annual non-subsidized ACT cost for clinical malaria episodes in an average household was calculated as US$ 6.0, which would represent 0.9% of the average total consumption expenditures as estimated from official data in 2001. The cost of non-subsidized ACT represented 7.0% of reported total annual expenditure on food and 33.0% of total annual expenditure on health care. "Rapid effect," "no adverse effect" and "inexpensive" were the most desired features of an anti-malarial drug. Conclusion WTP for ACT in this study was less than its real cost and a subsidy is, therefore, needed to enable its equitable affordability. The decision
Full Text Available Abstract Background The aim of this study was to evaluate the clinical outcome after seven-day artesunate monotherapy for uncomplicated Plasmodium falciparum malaria in Yingjiang County along the China-Myanmar border and investigate genetic polymorphisms in the P. falciparum chloroquine-resistance transporter (pfcrt, multidrug resistance 1 (pfmdr1, dihydrofolate reductase (pfdhfr, dihydropteroate synthase (pfdhps and ATPase (pfatp6 genes. Methods Patients ≥ one year of age with fever (axillary temperature ≥37.5°C or history of fever and P. falciparum mono-infection were included. Patients received anti-malarial treatment with artesunate (total dose of 16 mg/kg over seven days by directly observed therapy. After a 28-day follow-up, treatment efficacy and effectiveness were assessed based on clinical and parasitological outcomes. Treatment failure was defined as recrudescence of the original parasite and distinguished with new infection confirmed by PCR. Analysis of gene mutation and amplification were performed by nested polymerase chain reaction. Results Sixty-five patients were enrolled; 10 withdrew from the study, and six were lost to follow-up. All but two patients demonstrated adequate clinical and parasitological response; 12 had detectable parasitaemia on day 3. These two patients were confirmed to be new infection by PCR. The efficacy of artesunate was 95.9%. The pfcrt mutation in codon 76 was found in all isolates (100%, and mutations in codons 71 and 72 were found in 4.8% of parasite isolates. No mutation of pfmdr1 (codons 86 or 1246 was found. Among all samples, 5.1% were wild type for pfdhfr, whereas the other samples had mutations in four codons (51, 59, 108 and 164, and mutations in pfdhps (codons 436, 437, 540 and 581 were found in all isolates. No samples had mutations in pfatp6 codons 623 or 769, but two new mutations (N683K and R756K were found in 4.6% and 9.2% of parasite isolates, respectively. Conclusion Plasmodium
Full Text Available The availability of oral iron chelators and new non-invasive methods for early detection and treatment of iron overload, have significantly improved the life expectancy and quality of life of patients with b thalassemia major. However, monotherapy is not effective in all patients for a variety of reasons. We analyzed the most relevant reports recently published on alternating or combined chelation therapies in thalassemia major with special attention to safety aspects and to their effects in terms of reduction of iron overload in different organs, improvement of complications, and survival. When adverse effects, such as gastrointestinal upset with deferasirox or infusional site reactions with deferoxamine are not tolerable and organ iron is in an acceptable range, alternating use of two chelators (drugs taken sequentially on different days, but not taken on the same day together may be a winning choice. The association deferiprone and deferoxamine should be the first choice in case of heart failure and when dangerously high levels of cardiac iron exist. Further research regarding the safety and efficacy of the most appealing combination treatment, deferiprone and deferasirox, is needed before recommendations for routine clinical practice can be made.
Watsierah, Carren A; Ouma, Collins
Artemisinin-based combination therapy (ACT) has been adopted as the most effective treatment against malaria in many endemic countries like Kenya while quinine has remained the second line. The objective of the current study was to assess access to Kenya's policy recommended anti-malarials, ACT and quinine in the public, private and not-for-profit drug outlets in western Kenya. A cross-sectional survey using purposive sampling of 288 outlets (126 public, 96 private, 66 not-for-profit) was conducted in western Kenya in two regions with varying Plasmodium falciparum endemicities. Information on access (availability, price, affordability) on ACT and quinine was collected using the WHO and Healthcare Associated Infection (HAI) standardized methodologies for availability, prices and affordability of drugs. From a Ministry of Health database, the following were included in the analyses: one (1) main public hospital, followed by random selection of five hospitals under this main facility. Eight other public outlets under each of the hospitals were selected, to a total of 96. Matching number of private outlets (n = 96), all (66) not-for-profit outlets and additional 30 public health facilities were sampled to get the required sample size of 288. More public 111 (88.1%) and not-for-profit 27 (40.9%) outlets stocked subsidized ACT (artemether-lumefantrine, AL). Other artemisinin-based combinations were widely available for both children 93 (96.9%) and adults 82 (85.0%) in private outlets. Frequent stock-outs were in public in 106 (84%), reporting three times or more stock-outs in three months. Subsidized ACT (AL) was sold at median price of USD 0.94 and 0.75 in private and not-for-profit outlets respectively. The costs was higher than recommended price of USD 0.5 and requiring up to 0.20-0.25 days of disposable income for households in lowest economic status. There is low availability of subsidized ACT (AL) and higher frequency of stock-outs in government facilities, while
"Every drug goes to treat its own disease…" - a qualitative study of perceptions and experiences of taking anti-retrovirals concomitantly with anti-malarials among those affected by HIV and malaria in Tanzania
Mangesho, Peter E; Reynolds, Joanna; Lemnge, Martha
and supporting the clinical management and treatment for co-infected individuals. METHODS: A qualitative study was conducted in Tanzania alongside a clinical trial of concomitant treatment for HIV and malaria co-infection. Focus group discussions were held with people receiving treatment for HIV and/or malaria...... to their compromised immune status but saw the disease as unavoidable. For those enrolled in the clinical controlled study, taking anti-malarials together with ARVs was largely seen as unproblematic, with health workers' advice and endorsement of concomitant drug taking influential in reported adherence. However......, perceptions of drug strength appeared to compel some people not enrolled in the clinical study to take the drugs at separate times to avoid anticipated harm to the body. CONCLUSIONS: Management of HIV and malaria concurrently often requires individuals to cross the domains of different disease programmes...
Full Text Available Abstract Background The use of anti-malarial drug combinations with artemisinin or with one of its derivatives is now widely recommended to overcome drug resistance in falciparum as well as vivax malaria. The fixed oral dose artemisinin-naphthoquine combination (ANQ, ARCO™ is a newer artemisinin-based combination (ACT therapy undergoing clinical assessment. A study was undertaken to assess the safety, efficacy and tolerability of ANQ combination in areas of multi-drug resistance to generate preliminary baseline data in adult population of Papua New Guinea. Methods The clinical assessment was an open-labeled, two-arm, randomized study comparing ANQ combination as a single dose regimen and three days regimen (10 mg/kg/day of chloroquine plus single dose sulphadoxine-pyrimethamine (CQ+SP for the treatment of uncomplicated falciparum malaria with 28 days follow-up in an adult population. The primary outcome measures for efficacy were day 1, 2, 3 7, 14 and 28-day cure rates. Secondary outcomes included parasite clearance time, fever clearance time, and gametocyte carriage. The main outcome measures for safety were incidences of post-treatment clinical and laboratory adverse events. Results Between June 2005 and July 2006, 130 patients with confirmed uncomplicated P. falciparum were randomly assigned to receive ANQ and CQ+SP, only 100 patients (51 in ANQ group and 49 in CQ+SP group were evaluated for clinical and parasitological outcomes. All the patients treated with ANQ and CQ+SP showed adequate clinical and parasitological response with 28 days follow-up. The cure rate for ANQ on day 1, 2, 3, 7, 14, and 28 was 47%, 86%, 92%, 94%, 94% and 94%, respectively. Recrudescence account for 6%; all were cleared on day 21. For CQ+SP treated group the cure rates were 24%, 67%, 82%, 82%, 84% and 88%, respectively. Recrudescence accounted for 10%; all were cleared on day 28 except for one patient. Both regimens were well tolerated with no serious adverse
Lin, Lilie L; Hahn, Stephen M
The incidence of cancer among older patients continues to rise. The use of combined modality therapy has improved survival in a variety of malignancies, including rectal, head and neck, and lung cancer; however, the addition of chemotherapy increases substantially the toxicities of treatment. Elderly patients have generally been excluded from prospective clinical trials and as such, there is a lack of evidence-based data with regards to the most appropriate treatment. Age itself should not be used as a criterion for foregoing combined modality therapy in elderly patients. Due to the increased toxicity of therapy, patients must be carefully selected. Any medical intervention should account for life expectancy, performance status, tolerance to therapy, and presence of medical or social conditions that may impact therapy. We encourage a comprehensive geriatric assessment to evaluate functional status, comorbidities, mental status, psychological state, social support, nutritional status, polypharmacy, and geriatric conditions in order to improve a patient's overall functional status during the course of therapy. Fit elderly patients should be considered candidates for combined modality therapy, however, because they are potentially more vulnerable to therapy, careful attention should be paid to hydration and nutritional status with early intervention when necessary. Investigators should be encouraged to expand eligibility to include elderly patients on non age-related clinical trials. Additionally, therapy-related clinical trials directed at the elderly should be developed.
Combined chemotherapy and radiation therapy has been established as standard treatment approach for locally advanced head and neck cancer, esophageal cancer and so on through randomized clinical trials. However, radiation-related morbidity such as acute toxicity also increased as treatment intensity has increased. In underlining mechanism for enhancement of normal tissue reaction in chemo-radiation therapy, chemotherapy enhanced radiosensitivity of normal tissues in addition to cancer cells. Molecular target-based drugs combined with radiation therapy have been expected as promising approach that makes it possible to achieve cancer-specific enhancement of radiosensitivity, and clinical trials using combined modalities have been performed to evaluate the feasibility and efficacy of this approach. In order to obtain maximum radiotherapeutic gain, a detailed understanding of the mechanism underlying the interaction between radiation and Molecular target-based drugs is indispensable. Among molecular target-based drugs, inhibitors targeting epidermal growth factor receptor (EGFR) and its signal transduction pathways have been vigorously investigated, and mechanisms regarding the radiosensitizing effect have been getting clear. In addition, the results of randomized clinical trials demonstrated that radiation therapy combined with cetuximab resulted in improvement of overall and disease-specific survival rate compared with radiation therapy in locally advanced head and neck cancer. In this review, clinical usefulness of chemo-radiation therapy and potential molecular targets for potentiation of radiation-induced cell killing are summarized. (author)
Miura, Satoru; Yamamoto, Nobuyuki
Lung cancer is treated with surgery, radiotherapy and chemotherapy according to histology and clinical stage. Advanced stage lung cancer patients cannot be cured, but early and locally-advanced stage patients can be cured by intensive combined-modality therapy. Combined-modality therapy with surgery plus adjuvant chemotherapy is standard for resectable IB-IIIA non-small cell lung cancer (NSCLC) and stage I small cell lung cancer (SCLC) patients. Chemoradiotherapy is standard for unresectable locally-advanced NSCLC and limited-stage SCLC patients. Recently, several new drugs, molecular targeted drugs, have become available for clinical use and trials. We reviewed standard and new strategy of combined-modality therapy for early and locally-advanced lung cancer patients.
Wu, Lan; Leng, Donglei; Cun, Dongmei
Lung cancer is a complex disease caused by a multitude of genetic and environmental factors. The progression of lung cancer involves dynamic changes in the genome and a complex network of interactions between cancer cells with multiple, distinct cell types that form tumors. Combination therapy......, including small molecule drugs and biopharmaceuticals, which make the optimization of dosing and administration schedule challenging. This article reviews the recent advances in the design and development of combinations of pharmaceuticals for the treatment of lung cancer. Focus is primarily on rationales...... for the selection of specific combination therapies for lung cancer treatment, and state of the art of delivery technologies and dosage regimens for the combinations, tested in preclinical and clinical trials....
Day, Jeremy N.; Chau, Tran T.H.; Wolbers, Marcel; Mai, Pham P.; Dung, Nguyen T.; Mai, Nguyen H.; Phu, Nguyen H.; Nghia, Ho D.; Phong, Nguyen D.; Thai, Cao Q.; Thai, Le H.; Chuong, Ly V.; Sinh, Dinh X.; Duong, Van A.; Hoang, Thu N.
Background\\ud Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days.\\ud Methods\\ud We conducted a randomized, three-group, open-label trial of induction the...
Tsigelny, Igor F
Currently, the development of medicines for complex diseases requires the development of combination drug therapies. It is necessary because in many cases, one drug cannot target all necessary points of intervention. For example, in cancer therapy, a physician often meets a patient having a genomic profile including more than five molecular aberrations. Drug combination therapy has been an area of interest for a while, for example the classical work of Loewe devoted to the synergism of drugs was published in 1928-and it is still used in calculations for optimal drug combinations. More recently, over the past several years, there has been an explosion in the available information related to the properties of drugs and the biomedical parameters of patients. For the drugs, hundreds of 2D and 3D molecular descriptors for medicines are now available, while for patients, large data sets related to genetic/proteomic and metabolomics profiles of the patients are now available, as well as the more traditional data relating to the histology, history of treatments, pretreatment state of the organism, etc. Moreover, during disease progression, the genetic profile can change. Thus, the ability to optimize drug combinations for each patient is rapidly moving beyond the comprehension and capabilities of an individual physician. This is the reason, that biomedical informatics methods have been developed and one of the more promising directions in this field is the application of artificial intelligence (AI). In this review, we discuss several AI methods that have been successfully implemented in several instances of combination drug therapy from HIV, hypertension, infectious diseases to cancer. The data clearly show that the combination of rule-based expert systems with machine learning algorithms may be promising direction in this field. © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: email@example.com.
Background Drug combination therapy is the frontline of malaria treatment. There is an ever-accelerating need for new, efficacious combination therapies active against drug resistant malaria. Proven drugs already in the treatment pipeline, such as the quinolines, are important components of current combination therapy and also present an attractive test bank for rapid development of new concepts. Methods The efficacy of several drug combinations versus chloroquine-sensitive and chloroquine-resistant strains was measured using both cytostatic and cytocidal potency assays. Conclusions These screens identify quinoline and non-quinoline pairs that exhibit synergy, additivity, or antagonism using the fixed-ratio isobologram method and find tafenoquine – methylene blue combination to be the most synergistic. Also, interestingly, for selected pairs, additivity, synergy, or antagonism defined by quantifying IC50 (cytostatic potency) does not necessarily predict similar behaviour when potency is defined by LD50 (cytocidal potency). These data further support an evolving new model for quinoline anti-malarials, wherein haem and haemozoin are the principle target for cytostatic activity, but may not be the only target relevant for cytocidal activity. PMID:24044530
Robert J Allen
Full Text Available Non-healing foot ulcers are the most common cause of non-traumatic amputation and hospitalization amongst diabetics in the developed world. Impaired wound neovascularization perpetuates a cycle of dysfunctional tissue repair and regeneration. Evidence implicates defective mobilization of marrow-derived progenitor cells (PCs as a fundamental cause of impaired diabetic neovascularization. Currently, there are no FDA-approved therapies to address this defect. Here we report an endogenous PC strategy to improve diabetic wound neovascularization and closure through a combination therapy of AMD3100, which mobilizes marrow-derived PCs by competitively binding to the cell surface CXCR4 receptor, and PDGF-BB, which is a protein known to enhance cell growth, progenitor cell migration and angiogenesis.Wounded mice were assigned to 1 of 5 experimental arms (n = 8/arm: saline treated wild-type, saline treated diabetic, AMD3100 treated diabetic, PDGF-BB treated diabetic, and AMD3100/PDGF-BB treated diabetic. Circulating PC number and wound vascularity were analyzed for each group (n = 8/group. Cellular function was assessed in the presence of AMD3100. Using a validated preclinical model of type II diabetic wound healing, we show that AMD3100 therapy (10 mg/kg; i.p. daily alone can rescue diabetes-specific defects in PC mobilization, but cannot restore normal wound neovascularization. Through further investigation, we demonstrate an acquired trafficking-defect within AMD3100-treated diabetic PCs that can be rescued by PDGF-BB (2 μg; topical supplementation within the wound environment. Finally, we determine that combination therapy restores diabetic wound neovascularization and accelerates time to wound closure by 40%.Combination AMD3100 and PDGF-BB therapy synergistically improves BM PC mobilization and trafficking, resulting in significantly improved diabetic wound closure and neovascularization. The success of this endogenous, cell-based strategy to
Narang, Amol K; Terezakis, Stephanie A
The advent of effective combination chemotherapy markedly changed the management of Hodgkin lymphoma, establishing combined modality therapy as the standard of care for most patients with this disease. In response, significant interest has been shown in refining the delivery of radiation in the combined modality setting such that toxicity is minimized while still preserving disease control. An understanding of the way in which radiation treatment fields, prescription dose, and advanced technology have evolved to accomplish these goals is critical. Moreover, fluency in the clinical literature exploring contemporary questions, such as the omission of radiation and response-based treatment, is equally important. Knowledge of these topics will yield both an appreciation of the value of radiation in the combined modality setting and the ability to better customize treatment regimens to individual patients. Copyright © 2015 by the National Comprehensive Cancer Network.
Full Text Available Abstract Meticulous control of blood pressure is required in patients with hypertension to produce the maximum reduction in clinical cardiovascular end points, especially in patients with comorbidities like diabetes mellitus where more aggressive blood pressure lowering might be beneficial. Recent clinical trials suggest that the approach of using monotherapy for the control of hypertension is not likely to be successful in most patients. Combination therapy may be theoretically favored by the fact that multiple factors contribute to hypertension, and achieving control of blood pressure with single agent acting through one particular mechanism may not be possible. Regimens can either be fixed dose combinations or drugs added sequentially one after other. Combining the drugs makes them available in a convenient dosing format, lower the dose of individual component, thus, reducing the side effects and improving compliance. Classes of antihypertensive agents which have been commonly used are angiotensin receptor blockers, thiazide diuretics, beta and alpha blockers, calcium antagonists and angiotensin-converting enzyme inhibitors. Thiazide diuretics and calcium channel blockers are effective, as well as combinations that include renin-angiotensin-aldosterone system blockers, in reducing BP. The majority of currently available fixed-dose combinations are diuretic-based. Combinations may be individualized according to the presence of comorbidities like diabetes mellitus, chronic renal failure, heart failure, thyroid disorders and for special population groups like elderly and pregnant females.
Day, Jeremy N; Chau, Tran T H; Wolbers, Marcel; Mai, Pham P; Dung, Nguyen T; Mai, Nguyen H; Phu, Nguyen H; Nghia, Ho D; Phong, Nguyen D; Thai, Cao Q; Thai, Le H; Chuong, Ly V; Sinh, Dinh X; Duong, Van A; Hoang, Thu N; Diep, Pham T; Campbell, James I; Sieu, Tran P M; Baker, Stephen G; Chau, Nguyen V V; Hien, Tran T; Lalloo, David G; Farrar, Jeremy J
Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days. We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks. A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P=0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P=0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P=0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P=0.13). Amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (-0.42 log10 colony-forming units [CFU] per milliliter per day vs. -0.31 and -0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients
Colombel, Jean Frédéric; Sandborn, William J; Reinisch, Walter
The comparative efficacy and safety of infliximab and azathioprine therapy alone or in combination for Crohn's disease are unknown.......The comparative efficacy and safety of infliximab and azathioprine therapy alone or in combination for Crohn's disease are unknown....
Full Text Available Detectability of early stages of ectopic pregnancies has increased due to improvements in ultrasonographic and biochemical techniques. Since the patients’ future procreative plans must be taken into consideration when commencing treatment, the goal of this work was to compare the effects of treatment methods and their impact on fertility. The study included 91 patients treated surgically for ectopic pregnancy. The choice of treatment depended on patients’ general condition, ultrasonographic evaluation and serum level of beta-hCG. A combination of laparoscopic and conservative systemic treatment was applied in 70% of cases. More rapid beta-hCG reduction was noted when laparoscopy and intra-oviductal injection of hyperosmolar glucose or methotrexate (MTX were combined with intramuscular administration of MTX at a dose of 50 mg/m2. Follow-up examination of 66 patients revealed that the greatest number of spontaneous pregnancies (48% resulted after this combination therapy. We conclude that this combination treatment is safe and provides satisfactory results in terms of future fertility.
de Almeida, Afonso; Arez, Ana Paula; Cravo, Pedro VL; do Rosário, Virgílio E
Background In response to chloroquine (CQ) resistance, the policy for the first-line treatment of uncomplicated malaria in the Democratic Republic of East Timor (DRET) was changed in early 2000. The combination of sulphadoxine-pyrimethamine (SP) was then introduced for the treatment of uncomplicated falciparum malaria. Methods Blood samples were collected in two different periods (2003–2004 and 2004–2005) from individuals attending hospitals or clinics in six districts of the DRET and checked for Plasmodium falciparum infection. 112 PCR-positive samples were inspected for genetic polymorphisms in the pfcrt, pfmdr1, pfdhfr and pfdhps genes. Different alleles were interrogated for potential associations that could be indicative of non-random linkage. Results Overall prevalence of mutations associated with resistance to CQ and SP was extremely high. The mutant form of Pfcrt (76T) was found to be fixed even after five years of alleged CQ removal. There was a significant increase in the prevalence of the pfdhps 437G mutation (X2 = 31.1; p = 0.001) from the first to second survey periods. A non-random association was observed between pfdhfr51/pfdhps437 (p = 0.001) and pfdhfr 59/pfdhps 437 (p = 0.013) alleles. Conclusion Persistence of CQ-resistant mutants even after supposed drug withdrawal suggests one or all of the following: local P. falciparum may still be inadvertently exposed to the drug, that mutant parasites are being "imported" into the country, and/or reduced genetic diversity and low parasite transmission help maintain mutant haplotypes. The association between pfdhfr51/pfdhps437 and pfdhfr 59/pfdhps 437 alleles indicates that these are undergoing concomitant positive selection in the DRET. PMID:19358729
Full Text Available Abstract Background Malaria remains a burden in Sub-Saharan Countries. The strategy proposed by the World Health Organization (WHO is to systematically compare the therapeutic efficacy of antimalarial drugs using as primary outcome for efficacy, a four-category ordered criterion. The objective of the present work was to analyze the treatment effects on this primary outcome taking into account both a center-effect and individual covariates. A three-arm, three-centre trial of Amodiaquine (AQ, sulfadoxine-pyrimethamine (SP and their combination (AQ + SP, conducted by OCEAC-IRD in 2003, in 538 children with uncomplicated Plasmodium falciparum malaria, is used as an illustration. Methods Analyses were based on ordinal regression methods, assuming an underlying continuous latent variable, using either the proportional odds (PO or the proportional hazards (PH models. Different algorithms, corresponding to both frequentist- and bayesian-approaches, were implemented using the freely available softwares R and Winbugs, respectively. The performances of the different methods were evaluated on a simulated data set, and then they were applied on the trial data set. Results Good coverage probability and type-1 error for the treatment effect were achieved. When the methods were applied on the trial data set, results highlighted a significance decrease of SP efficacy when compared to AQ (PO, odds ratio [OR] 0.14, 95% confidence interval [CI] 0.04-0.57; hazard ratio [HR] 0.605, 95% CI 0.42-0.82, and an equal effectiveness between AQ + SP and AQ (PO, odds ratio [OR] 1.70, 95% confidence interval [CI] 0.25-11.44; hazard ratio [HR] 1.40, 95% CI 0.88-2.18. The body temperature was significantly related to the responses. The patient weights were marginally associated to the clinical response. Conclusion The proposed analyses, based on usual statistical packages, appeared adapted to take into account the full information contained in the four categorical outcome in
and tinnitus, a firstname.lastname@example.org. 1 Chloroquine is a 4-aminoquinolone and comes as a number of salts mainly the phosphate and sulphate. Vasodilatation. •. (flushing sensation more obvious in a pale skin). This may be exacerbated by the vasodilatation caused by the malaria itself and so cause postural (orthostatic) ...
Elliott, T.B.; Madonna, G.S.; Ledney, G.D.; Brook, I.
Increased susceptibility to bacterial infection, probably by translocation from the intestinal flora, can be a lethal complication for 2-3 weeks after exposure to ionizing radiation. Antibiotics alone do not provide adequate therapy for induced infections in neutropenic mice. Because some substances that are derived from bacterial cell walls activate macrophages and stimulate nonspecific resistance to infection, such agents might be used to prevent or treat postirradiation infections. In this study, a cell-wall glycolipid, trehalose dimycolate (TDM), was evaluated together with a third-generation cephalosporin, ceftriaxone, for their separate and combined effects on survival of B6D2F1 female mice that were exposed to the sublethal dose of 7.0 Gy Co radiation and challenged s.c. with lethal doses of Klebsiella pneumoniae. A single injection of TDM inoculated i.p. 1 hr postirradiation increased 30-day survival to 80% after a lethal challenge by K. pneumoniae 4 days later. When the challenge dose of K. pneumoniae was increased to 5000 Ld 50/30 on Day 4, all mice died.
Molecular Evidence of Increased Resistance to Anti-Folate Drugs in Plasmodium falciparum in North-East India: A Signal for Potential Failure of Artemisinin Plus Sulphadoxine-Pyrimethamine Combination Therapy
Mohapatra, Pradyumna Kishore; Sarma, Devojit Kumar; Prakash, Anil; Bora, Khukumoni; Ahmed, Md. Atique; Sarma, Bibhas; Goswami, Basanta Kumar; Bhattacharyya, Dibya Ranjan; Mahanta, Jagadish
North-east India, being a corridor to South-east Asia, is believed to play an important role in transmitting drug resistant Plasmodium falciparum malaria to India and South Asia. North-east India was the first place in India to record the emergence of drug resistance to chloroquine as well as sulphadoxine/pyrimethamine. Presently chloroquine resistance is widespread all over the North-east India and resistance to other anti-malarials is increasing. In this study both in vivo therapeutic efficacy and molecular assays were used to screen the spectrum of drug resistance to chloroquine and sulphadoxine/pyrimethamine in the circulating P. falciparum strains. A total of 220 P. falciparum positives subjects were enrolled in the study for therapeutic assessment of chloroquine and sulphadoxine/pyrimethamine and assessment of point mutations conferring resistances to these drugs were carried out by genotyping the isolates following standard methods. Overall clinical failures in sulphadoxine/pyrimethamine and chloroquine were found 12.6 and 69.5% respectively, while overall treatment failures recorded were 13.7 and 81.5% in the two arms. Nearly all (99.0%) the isolates had mutant pfcrt genotype (76T), while 68% had mutant pfmdr-1 genotype (86Y). Mutation in dhps 437 codon was the most prevalent one while dhfr codon 108 showed 100% mutation. A total of 23 unique haplotypes at the dhps locus and 7 at dhfr locus were found while dhps-dhfr combined loci revealed 49 unique haplotypes. Prevalence of double, triple and quadruple mutations were common while 1 haplotype was found with all five mutated codons (F/AGEGS/T) at dhps locus. Detection of quadruple mutants (51I/59R/108N/164L) in the present study, earlier recorded from Car Nicobar Island, India only, indicates the presence of high levels of resistance to sulphadoxine/pyrimethamine in north-east India. Associations between resistant haplotypes and the clinical outcomes and emerging resistance in sulphadoxine/pyrimethamine in
Andersen, Mads Hald; Junker, Niels; Ellebaek, Eva
The clinical efficacy of most therapeutic vaccines against cancer has not yet met its promise. Data are emerging that strongly support the notion that combining immunotherapy with conventional therapies, for example, radiation and chemotherapy may improve efficacy. In particular combination...
Patel, Sagar A; Ryan, David P; Hong, Theodore S
The primary therapy for any potentially curative rectal cancer is surgery. For locally advanced tumors (i.e., T3-4 and/or node positive), the very high rate of local and distant recurrences has necessitated a standard adjuvant regimen of preoperative chemoradiation and postoperative chemotherapy. Several controversies regarding this approach remain, including the technique and fractionation scheme of radiation therapy prior to surgery, the choice of concomitant chemotherapy, and whether all patients require postoperative systemic therapy. Furthermore, in an era of improving staging imaging and surgical techniques, an opportunity for de-escalation of therapy to improve patient morbidity and quality of life may arise. At the same time, advances in radiation and systemic therapy may help facilitate less invasive, sphincter-preserving surgery. This review addresses these questions and others that remain areas of active clinical investigation.
This clinical trial is testing standard therapy (surgery, radiation and temozolomide) plus immunotherapy with pembrolizumab with or without a cancer treatment vaccine for patients with newly diagnosed glioblastoma, a common and deadly type of brain tumor.
Zaderin, V.P.; Polyanichko, M.F.
A scheme of therapy of radiation cystitis is suggested. It was developed on the basis of evaluation of literature data and clinical of 205 patients with radiation injury of the urinary bladder. The method is based on general and local therapy of damaged tissues by antiinflammatory drugs, anesthetics and stimulators of reparative regeneration. Severe ulcerative and incrustation cystites, refractory to conservative therapy, were treated by surgery, using antiseptics and reparation stimulators before, during and after operation. As a result, there were hardly any complications after reconstruction of the bladder with intestinal and peritoneal tissues. 104 patients (96.1%) were cured completely and ability to work was restored in 70 patients (76.9%) [ru
Full Text Available Oncolytic virus (OV therapy utilizes replication-competent viruses to kill cancer cells, leaving non-malignant cells unharmed. With the first U.S. Food and Drug Administration-approved OV, dozens of clinical trials ongoing, and an abundance of translational research in the field, OV therapy is poised to be one of the leading treatments for cancer. A number of recombinant OVs expressing a transgene for p53 (TP53 or another p53 family member (TP63 or TP73 were engineered with the goal of generating more potent OVs that function synergistically with host immunity and/or other therapies to reduce or eliminate tumor burden. Such transgenes have proven effective at improving OV therapies, and basic research has shown mechanisms of p53-mediated enhancement of OV therapy, provided optimized p53 transgenes, explored drug-OV combinational treatments, and challenged canonical roles for p53 in virus-host interactions and tumor suppression. This review summarizes studies combining p53 gene therapy with replication-competent OV therapy, reviews preclinical and clinical studies with replication-deficient gene therapy vectors expressing p53 transgene, examines how wild-type p53 and p53 modifications affect OV replication and anti-tumor effects of OV therapy, and explores future directions for rational design of OV therapy combined with p53 gene therapy.
In this clinical trial, adult patients with any form of advanced Kaposi sarcoma will be treated with liposomal doxorubicin and bevacizumab every 3 weeks for a maximum of six treatments. Patients who respond to this therapy or have stable disease will rec
Hsia, Stephanie L; Myers, Mark G; Chen, Timothy C
Several studies and meta-analyses have demonstrated the efficacy of combination nicotine replacement therapy (NRT) for patients who wish to quit smoking. However, there is limited guidance with respect to initiation and tapering of combination NRT. We attempt to review the evidence and rationale behind combination NRT, present the dosing used in combination NRT studies, and propose a step-down approach for tapering of combination NRT with integration of behavioral strategies. Copyright © 2017. Published by Elsevier Inc.
Miyaguchi, Mamoru; Kubo, Takeshi [Osaka Univ., Suita (Japan). School of Medicine; Takashima, Hitoshi [Kagawa Medical School (Japan)
Post-radiation necrosis of the larynx is a major complication after irradiation and has become rare. Recently, combined chemotherapy and radiation therapy has been introduced for head and neck tumours. The authors report a case of laryngeal necrosis after combination therapy for a patient with cervical lymph node metastases of nasopharyngeal carcinoma and review the literature on late laryngeal necrosis. Although radiation-induced laryngeal necrosis has become a rare complication, the combination of chemotherapy and radiation therapy may increase its incidence. (author).
Full Text Available There is a strong rationale for combining therapies to simultaneously target three of the key pathways implicated in the pathogenesis of pulmonary arterial hypertension (PAH. Evidence to support this strategy is growing, and a number of studies have demonstrated that combination therapy, administered as either a sequential or an initial regimen, can improve long-term outcomes in PAH. Dual combination therapy with a phosphodiesterase-5 inhibitor and an endothelin receptor antagonist is the most widely utilised combination regimen. However, some patients fail to achieve their treatment goals on dual therapy and may benefit from the addition of a third drug. The use of triple therapy in clinical practice was previously reserved for patients with severe disease due to the need for parenteral administration of prostanoids. Although triple therapy with parenteral prostanoids plays a key role in the management of severe PAH, the approval of oral therapies that target the prostacyclin pathway means that all three pathways can now be targeted with oral drugs at an earlier disease stage. Furthermore, there is evidence demonstrating that this approach can delay disease progression. Based on the evidence available, it is becoming increasingly clear that all PAH patients should be offered the benefits of combination therapy.
Ibrahim, Ashraf; Roilides, Emmanuel; Lewis, Russel E.; Lortholary, Olivier; Petrikkos, George; Kontoyiannis, Dimitrios P.; Walsh, Thomas J.
The high mortality rate of mucormycosis with currently available monotherapy, particularly in hematology patients, has stimulated interest in studying novel combinations of antifungal agents to determine whether superior outcomes might be achieved. Combination lipid polyene-echinocandin therapy is the most promising of such regimens based on safety profile, the availability of parenteral formulations of echinocandins, their synergy in murine models of mucormycosis, and observational clinical data that are concordant. Other options include combination lipid polyene plus deferasirox or posaconazole therapy. Definitive, randomized, placebo-controlled phase III clinical trials are needed to determine whether combination therapy with any of these options is superior to monotherapy. Until such studies are conducted, clinicians will continue to be placed in the unacceptable position of not knowing if and when to administer combination therapy. Such a state of confusion may lead to undertreatment if combination therapy is indeed superior but is not used and, conversely, may lead to unacceptable toxicity and cost to patients if combination therapy is not superior but is used. It is critical that sponsors step forward with funding to conduct these clinical trials to determine whether outcomes from these devastating infections can be improved. PMID:22247449
Bismuth, H; Fecteau, A
Hepatocellular carcinoma (HCC) is being diagnosed with increasing frequency in the Western world as a consequence of the hepatitis C epidemia. Multimodal therapy is now the only effective treatment option to offer a chance of complete tumor control in HCC. Liver transplantation and liver resection, including the selection criteria and patient evaluation, are discussed. The benefits and complications of transarterial chemoembolization and cryotherapy are also reviewed. Liver transplantation is now thought to offer the best treatment option in early HCC and should be regarded as the first line of treatment in selected patients.
The original goal of the present study was to determine optimal strategies for combining radiation and antiangiogenic therapies in spontaneous murine tumors and to evaluate the potential of Nuclear Magnetic Resonance (NMR...
Diette, Gregory B; Fuhlbrigge, Anne L; Allen-Ramey, Felicia; Hopper, April; Sajjan, Shiva G; Markson, Leona E
Asthma treatment guidelines recommend medications based on the level of asthma control. To evaluate differences in asthma control between patients who initiated asthma controller monotherapy versus combination therapy. Children (5-16 years; n = 488) and adults (17-80 years; n = 530) with asthma and no controller therapy in the prior 6 months were included. Telephone surveys were conducted within 5 days of filling a new asthma controller prescription with either the caregiver of children or the adult patient. Demographics, asthma control before therapy, and asthma-related resource use were assessed for patients initiating monotherapy (filling one asthma controller prescription) and combination therapy (filling more than one controller medication or a fixed-dose combination). Mean pediatric age was 10 years; 53% were male. Mean adult age was 47 years; 25% were male. There were no significant differences in asthma control score between patients receiving monotherapy and combination therapy. Children on combination therapy did not have more nighttime awakening or short-acting β-agonist use but were more likely to have been hospitalized due to asthma attack (p = .05) and have more unscheduled (p = .0374) and scheduled (p = .009) physician visits. Adults on combination therapy were more likely to have been hospitalized due to asthma attack (p asthma (p asthma control scores in the 4 weeks before index medication suggests that asthma severity during a treatment-free period did not differ significantly for patients initiating controller monotherapy versus combination therapy. From these findings, it appears that although physicians may not focus on asthma control when choosing the intensity of initial controller therapy, the intensity of health-care encounters may be an influence.
It further improves patient compliance and reduces the complexity of treatment and morbidity associated with the disease. Recent studies have shown the combination therapy to serve not only as maintenance but also a reliever therapy with same efficacy as the short acting beta agonists (SABA). Conclusion: This review ...
Tsyba, A.F.; Farshatova, M.N.
Modern notions on combined radiation injuries (CRI) are presented. Characteristic of injurious factors of nuclear explosion and common regularities of the CRI origination is given. The data on the CRI clinical peculiarities, diagnostics and treatment, principles of medical assistance for the injured on the stages of medical evacuation and recommendations on rehabilitation are presented
The role of combination therapy as a treatment strategy for epilepsy is undergoing reevaluation. A growing appreciation that all seizures cannot be controlled by monotherapy and the introduction of over 14 new antiepileptic drugs (AEDs) for the adjunctive treatment in refractory epilepsy in the past twenty years has triggered an renewed interest in combination therapy. However, the experimental and clinical evidence in support of "rational polytherapy" is sparse, with only the combination of sodium valproate and lamotrigine demonstrating synergism. Robust evidence to guide clinicians on how and when to combine AEDs is lacking and current practice recommendations are largely empirical.
Sadanala, Krishna Chaitanya; Chaturvedi, Pankaj Kumar; Seo, You Mi; Kim, Jeung Mo; Jo, Yong Sam; Lee, Yang Koo; Ahn, Woong Shick
Cancer is characterized by the dysregulation of cell signaling pathways at several steps. The majority of current anticancer therapies involve the modulation of a single target. A tumor-targeting drug-delivery system consists of a tumor detection moiety and a cytotoxic material joined directly or through a suitable linker to form a conjugate. Photodynamic therapy has been used for more than 100 years to treat tumors. One of the present goals of photodynamic therapy research is to enhance the selective targeting of tumor cells in order to reduce the risk and extension of unwanted side-effects, caused by normal cell damage. Sonodynamic therapy is a promising new treatment for patients with cancer. It treats cancer with ultrasound and sonosensitive agents. Porphyrin compounds often serve as photosensitive and sonosensitive agents. The combination of these two methods makes cancer treatment more effective. The present review provides an overview of photodynamic therapy, sonodynamic therapy, sono-photodynamic therapy and the four sensitizers which are suitable candidates for combined sono-photodynamic therapy. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
Karachaliou, Niki; Gonzalez-Cao, Maria; Sosa, Aaron; Berenguer, Jordi; Bracht, Jillian Wilhelmina Paulina; Ito, Masaoki; Rosell, Rafael
The therapeutic possibilities for patients with metastatic melanoma have changed due to the development of targeted therapies that inhibit oncogenic signaling pathways as well as immune modulating therapies that unleash the patient antitumor immunity. These therapeutic changes have impressively increased the median overall survival of the patients. Considering the dramatic but transient responses that occur with targeted therapies for a subgroup of patients and the durable responses that can be achieved with immunotherapy in a subset of patients, a lot of effort is ongoing for the clinical development of combinations of these two therapeutic approaches. Herein we discuss the existing preclinical and clinical data for the combination of targeted therapies and immunotherapy focusing mainly on melanoma and non-small cell lung cancer (NSCLC).
Jeon, Minji; Kim, Sunkyu; Park, Sungjoon; Lee, Heewon; Kang, Jaewoo
Drug combination therapy, which is considered as an alternative to single drug therapy, can potentially reduce resistance and toxicity, and have synergistic efficacy. As drug combination therapies are widely used in the clinic for hypertension, asthma, and AIDS, they have also been proposed for the treatment of cancer. However, it is difficult to select and experimentally evaluate effective combinations because not only is the number of cancer drug combinations extremely large but also the effectiveness of drug combinations varies depending on the genetic variation of cancer patients. A computational approach that prioritizes the best drug combinations considering the genetic information of a cancer patient is necessary to reduce the search space. We propose an in-silico method for personalized drug combination therapy discovery. We predict the synergy between two drugs and a cell line using genomic information, targets of drugs, and pharmacological information. We calculate and predict the synergy scores of 583 drug combinations for 31 cancer cell lines. For feature dimension reduction, we select the mutations or expression levels of the genes in cancer-related pathways. We also used various machine learning models. Extremely Randomized Trees (ERT), a tree-based ensemble model, achieved the best performance in the synergy score prediction regression task. The correlation coefficient between the synergy scores predicted by ERT and the actual observations is 0.738. To compare with an existing drug combination synergy classification model, we reformulate the problem as a binary classification problem by thresholding the synergy scores. ERT achieved an F1 score of 0.954 when synergy scores of 20 and -20 were used as the threshold, which is 8.7% higher than that obtained by the state-of-the-art baseline model. Moreover, the model correctly predicts the most synergistic combination, from approximately 100 candidate drug combinations, as the top choice for 15 out of the
Michaelsson, Luba Freja; Medici, Bjarke Borregaard; la Cour, Jeppe Lerche
BACKGROUND: Five to ten percent of patients with hypothyroidism describe persistent symptoms despite being biochemically well regulated on levothyroxine (L-T4). Thyroxine (T4)/triiodothyronine (T3) combination therapy [L-T4/liothyronine (L-T3) or desiccated thyroid] are still regarded as experime......BACKGROUND: Five to ten percent of patients with hypothyroidism describe persistent symptoms despite being biochemically well regulated on levothyroxine (L-T4). Thyroxine (T4)/triiodothyronine (T3) combination therapy [L-T4/liothyronine (L-T3) or desiccated thyroid] are still regarded...... after a patient published a book describing her experiences with hypothyroidism and treatment. OBJECTIVE: To investigate current Danish trends in the use of T4/T3 combination therapy. METHODS: We used an Internet-based questionnaire, distributed as a link via two Danish patient fora. Further...
Jozić Tanja L.
Full Text Available Introduction Rhabdomyolysis is a rare, but serious and potentially fatal adverse reaction of the statin application that may be developed in any time of therapy. It is characterized by massive destruction of muscles associated with the large increase of creatine kinase (CK leading to myoglobinuria and potential acute renal failure. Combined statin-fibrate therapy increases the risk of rhabdomyolysis, especially in elderly and diabetic patients. Case report An 81-year-old male was admitted to Coronary Care Unit of the Emergency Center, Clinical Center of Serbia (CCS with the clinical picture and electrocardiogram of the acute anterior wall myocardial infarction complicated with pulmonary edema. Laboratory tests on admission showed higher elevated values of serum creatinine 179 μmol/L and BUN 9.2 mmol/L (eGFR 32 mL/min/1.73m2, CK 309 U/L (on day 2: 3476 U/L and mixed hyperlipidemia (total cholesterol 10.3 mmol/L, HDL 2.26 mmol/L, TG 4.85 mmol/L. The patient was treated with thrombolysis medication therapy (Alteplase, anticoagulant and dual antiplatelet therapy, diuretics, organic nitrates, angiotensin-converting enzyme (ACE inhibitors, antibiotics, and proton pump inhibitors. During seven days, his therapy included combined pravastatin 20 mg and fenofibrate (160 mg, which was discontinued due to pains and weakness of muscles and significantly elevated CC to 7080 U/L (upper limit 200 U/L, but no significant deterioration of renal function was observed. Discontinuation of therapy resulted in CC level normalization and improvement of clinical condition. Conclusion Combined statin and fibrate therapy requires strict clinical control and monitoring of CK i transaminases. Four-time or higher increase of CK requires discontinuation of therapy. In addition, patients are advised to report immediately any pains in muscles, sensibility, weakness or cramps.
Angeli, Fabio; Reboldi, Gianpaolo; Mazzotta, Giovanni; Garofoli, Marta; Ramundo, Elisa; Poltronieri, Cristina; Verdecchia, Paolo
The goal of antihypertensive therapy is to reduce the risk associated with blood pressure elevation. Although the choice of first-line drug therapy may exert some effects on different long-term cardiovascular endpoints, randomized clinical trials and meta-analyses demonstrated that blood pressure reduction per se is the primary determinant in primary and secondary prevention. Numerous analyses carried out over the last years have repeatedly shown that many patients require the combination of two or more drugs to reach the recommended level of blood pressure control. Within this context, combination therapy with separate agents or fixed-dose combination pills offers an attractive ability to lower blood pressure more quickly, decrease adverse effects and reach blood pressure target. It is not clear whether fixed combinations of antihypertensive agents in a single tablet provide a greater benefit than the corresponding components given separately. In other words, it is not clear if the use of fixed combinations translates into a clearly improved blood pressure control and cardiovascular prevention in clinical practice. Fixed-dose combinations may simplify the treatment regimen by reducing the number of pills and may be attractive for many hypertensive patients. However, single-pill (fixed) drug combinations have some disadvantages: (i) branded fixed combinations may be more expensive than equivalent free combinations; (ii) the duration of action of individual components may not be equivalent, and this may not justify a single daily dosing of the combination; and (iii) the use of fixed combinations implies less flexibility in modifying the doses of individual components and the exposure of patients to unnecessary therapy. Moreover, should a patient develop side effects to one component, the entire combination should be discontinued and replaced by free drugs. The following three types of fixed-dose tablets have been recently proposed to give additional flexibility: (i
Hypothyroidism is currently a condition that can be treated, but not cured. Although levothyroxine reverses stigmata of hypothyroidism in most individuals, some patients feel dissatisfied with 'monotherapy', and this has stimulated interest in 'combination therapy' with both levothyroxine and liothyronine. A search of PubMed was conducted using terms including hypothyroidism, treatment, benefits, risks, and safety. Based on the articles identified, the body of evidence regarding the efficacy of traditional levothyroxine is reviewed. Concerns with levothyroxine therapy including impaired quality of life in treated patients, thyroxine-predominant hormone ratios, and inadvertent iatrogenic thyroid disease are discussed. The trials of combination therapy performed since 1999 were reviewed. The heterogeneity of these trials, both in terms of design and results, is discussed. The potential for new trials to determine whether combination therapy can reverse the dissatisfaction associated with monotherapy, while avoiding non-physiologic hormone ratios, inadvertent thyrotoxicosis, and unacceptable side effects is discussed. Expert commentary: Research regarding which therapy fully reverses hypothyroidism at a tissue and cellular level is ongoing. The field would be advanced by the development of an extended release preparation of liothyronine. In the future regeneration of functional thyroid follicles from stem cells may offer hope for curing hypothyroidism.
Phougat, Neetu; Khatri, Savita; Singh, Anu; Dangi, Mrridula; Kumar, Manish; Dabur, Rajesh; Chhillar, Anil Kumar
Therapeutic options for many infections are extremely limited and at crisis point. We run the risk of entering a second pre-antibiotic era. There had been no miracle drug for the patients infected by resistant microbial pathogens. Most of the very few new drugs under development have problems with their toxicity, or pharmacokinetics and pharmacodynamics. We are already decades behind in the discovery, characterization and development of new antimicrobials. In that scenario, we could not imagine surviving without newer and effective antimicrobial agents. Bacteria have been the champions of evolution and are still evolving continuously, where they pose serious challenges for humans. Along with the crisis of evolving resistance, the condition is made worst by the meager drug pipeline for new antimicrobials. Despite ongoing efforts only 2 new antibiotics (Telavancin in 2009 and Ceftaroline fosamil in 2010) have been approved since 2009 pipeline status report of Infectious Disease Society of America (IDSA). Recent approval of new combination based antiviral drugs such as Stribild (combination of four drugs for HIV treatment) and Menhibrix (combination vaccine to prevent meningococcal disease and Haemophilus influenzae type b in children) proves that combination therapy is still the most promising approach to combat the ever evolving pathogens. Combination therapy involves the drug repurposing and regrouping of the existing antimicrobial agents to provide a synergistic approach for management of infectious diseases. This review article is an effort to highlight the challenges in new drug development and potential of combination drug therapy to deal with them.
Hou,Yongmei; Hu,Peicheng; Zhang,Yongmei; Lu,Qiaoyun; Wang,Dandan; Yin,Ling; Chen,Yaoqi; Zou,Xiaobo
Objective: To explore the effect of cognitive behavioral therapy (CBT) in combination with systemic family therapy (SFT) on mild to moderate postpartum depression and sleep quality. Methods: 249 primiparous women with mild to moderate postpartum depression were recruited and randomly assigned to a control group (n=128), which received conventional postpartum care, or to a psychological intervention group (n=121), which received conventional postpartum care combined with psychological interven...
F. S. Kharlamova
Full Text Available We examined 40 sickly children with recurrent croup (RC — 28 and bronchial obstruction (ROB — 8, (RC + ROB — 4 aged from 18 months till 14 years. We found that high frequency of persistent herpes viruses usually occurs as associations with CMV, EBV and human herpes virus 6 type. We substantiated anti viral and immune corrective therapy in two schemes compared in efficacy: the 1st group was administered monotherapy with Viferon, and the 2nd group received combined therapy Viferon + Arbidol in doses according to the age during three months. We received a more expressed clinical immunologic effect from the therapy with decreased antigenic load and frequency of recurrence of RC and ROB with Viferon application in suppositories in combination with Arbidol per orally in the intermittent scheme during three months.
Glioblastoma is the most malignant brain tumor in adults. Median survival is only about 15 months despite aggressive treatment, consisting of surgery followed by radio- and chemotherapy, stressing the need for new therapies. Development of glioblastoma is thought to be a result of both genetic...... of glioblastoma cells, an effect that is even more pronounced when combined with traditional chemotherapeutic agents. The EGFR and Notch pathways are shown to be of great importance for glioblastoma cell survival and for the formation of new blood vessels, a process known as angiogenesis. Results presented herein...... suggests that targeting redundant signaling pathways can overcome required or initial treatment resistance, thus leading to improved tumor cell elimination. We hypothesize that future therapies will likely be a result of combination therapies for glioblastoma patients based on their molecular tumor profile...
Artemesinin combination therapies (ACTs) are first line antimalarial drugs in malaria endemic regions of the world as recommended by the World Health Organization. ACTs are relatively new in Nigeria and there is little experience with their use. The pharmacovigilance of ACT drugs has been advocated in African countries ...
... combination of alpha adrenergic uroselective blocker (Tamsulosin) and 5 alpha iso-enzyme inhibitor (Dutasteride) is a first option of therapy in the management of BPH especially in those cases that are surgical risks with the category of mild to moderate prostate symptom scores. The Annals of African Surgery, Volume 6, ...
Full Text Available Background: The purpose of observational program of patients with lower urinary tract symptoms (LUTS because of benign prostatic hyperplasia (BPH (LUTS/BPH was to acquire additional pharmaco-epidemiological data on the safety and efficacy of combination therapy with finasteride and tamsulosin.Methods: Observational program of men with BPH was conducted in urological outpatient clinics in Slovenia from April 2004 until November 2005. In open-label, non-interventional program 1173 patients were observed, who had been treated because of LUTS/BPH with combination therapy with finasteride and tamsulosin, in the framework of common treatment. At baseline and after six months of treatment for each patient the International Prostatic Symptom Score (IPSS questionnaire and assessment of quality of life (QL were filled in. In addition, urinary flow rate and prostate volume were determined. Adverse effects of drugs were reported spontaneously. For statistical analysis the Student’s t-test was performed.Results: Combination therapy with finasteride and tamsulosin was well tolerated. 89 (7.6 % patients discontinued with medication because of lack of efficacy or because of adverse effects of drugs. Symptom score, assessment of quality of patients’ lives and volume of prostates were significantly lower (p < 0.0001, while urinary flow rate was significantly higher (p < 0.0001 after six months of treatment with finasteride and tamsulosin.Conclusions: Combination therapy of patients with LUTS/BPH with finasteride and tamsulosin is effective and safe.
Purpose: To explore the outcomes and safety of atorvastatin/trimetazidine combination therapy in patients with chronic cardiac failure. Methods: A total of 144 patients with chronic cardiac failure were divided into test group (n = 72) and control group (n = 72). In addition to conventional anti-heart failure treatment, all patients ...
The current case management and drug policy of malaria in Nigeria recommended by the Federal ministry of health may not be appropriate for all age categories. This suspicion was tested by running a cost effectiveness analysis of two possible and alternative strategies: Artemisinin Combination Therapy (ACT) or ...
Andersen, M.H.; Sorensen, R.B.; Schrama, D.
on the specific chemotherapeutics. Also, chemotherapy represents one of several options available for clearance of CD4(+) Foxp3(+) regulatory T cells. Moreover, therapies based on monoclonal antibodies may have synergistic potential in combination with vaccination, both when used for targeting of tumor cells...
Andersen, Mads Hald; Junker, N.; Ellebaek, E.
The clinical efficacy of most therapeutic vaccines against cancer has not yet met its promise. Data are emerging that strongly support the notion that combining immunotherapy with conventional therapies, for example, radiation and chemotherapy may improve efficacy. In particular combination...... of proteins coupled to intrinsic properties of cancer cells. For example, proteins associated with drug resistance can be targeted, and form ideal target structures for use in combination with chemotherapy for killing of surviving drug resistant cancer cells. Proteins associated with the malignant phenotype...
Andersen, Mads Hald; Junker, Niels; Ellebaek, Eva
The clinical efficacy of most therapeutic vaccines against cancer has not yet met its promise. Data are emerging that strongly support the notion that combining immunotherapy with conventional therapies, for example, radiation and chemotherapy may improve efficacy. In particular combination...... of proteins coupled to intrinsic properties of cancer cells. For example, proteins associated with drug resistance can be targeted, and form ideal target structures for use in combination with chemotherapy for killing of surviving drug resistant cancer cells. Proteins associated with the malignant phenotype...
Perry, Daniel; Sperling, Reisa; Katz, Russell; Berry, Donald; Dilts, David; Hanna, Debra; Salloway, Stephen; Trojanowski, John Q; Bountra, Chas; Krams, Michael; Luthman, Johan; Potkin, Steven; Gribkoff, Val; Temple, Robert; Wang, Yaning; Carrillo, Maria C; Stephenson, Diane; Snyder, Heather; Liu, Enchi; Ware, Tony; McKew, John; Fields, F Owen; Bain, Lisa J; Bens, Cynthia
Combination therapy has proven to be an effective strategy for treating many of the world's most intractable diseases. A growing number of investigators in academia, industry, regulatory agencies, foundations and advocacy organizations are interested in pursuing a combination approach to treating Alzheimer's disease. A meeting co-hosted by the Accelerate Cure/Treatments for Alzheimer's Disease Coalition, the Critical Path Institute and the Alzheimer's Association addressed challenges in designing clinical trials to test multiple treatments in combination and outlined a roadmap for making such trials a reality.
Use of fixed combination of antihypertensive drugs clearly improves compliance to the pharmacological therapy, control of hypertension and prognosis. Based on the current guidelines triple antihypertensive therapy with RAS-blocker, calcium channel blocker (CCB) and diuretic represents the standard and best option. The article introduces first and innovative fixed triple combination of perindopril arginine + indapamide + amlodipine (Triplixam®). This type of therapy is suitable for patients already treated with free combinations of three antihypertensive drugs or in those hypertensives with uncontrolled hypertension on two antihypertensive molecules (approx. 60% of all hypertensive population). Fixed combination of perindopril arginine + indapamid + amlodipin is indicated also in severe hypertension (approx. 30% of pts). Large clinical data from various morbidity-mortality studies related to each of these substances are discussed as well as basic pharmacological characteristics. Based on the results from ADVANCE-CCB study combination of perindopril arginine + indapamide + CCB decreases total mortality in hypertension by 28%. Another discussed study-PIANIST confirmed significant antihypertensive effect of Triplixam® on large sample of patients with various stages of hypertension. Triplixam® in addition to that has very good tolerance with low side effects profile, flexibility of the dosages and large body of evidence of positive impact on prognosis of hypertensive patients. Use of Triplixam® may improve control of hypertension in the Czech Republic.Key words: amlodipine - fixed combination - hypertension - indapamide - perindopril arginine - therapy.
Heng, Desmond; Lee, Sie Huey; Teo, Jeanette; Ng, Wai Kiong; Chan, Hak-Kim; Tan, Reginald B. H.
Combination products play an important role in medicine as they offer improved clinical effectiveness, enhanced patient adherence, and reduced administrative costs. In combination antimicrobial therapy, the desired outcome is to extend the antimicrobial spectrum and to achieve a possible synergistic effect. However, adverse antagonistic species may sometimes emerge from such combinations, leading to treatment failure. Therefore, it is crucial to screen the drug candidates for compatibility and possible antagonistic interactions. This work aims to develop a novel synergistic dry powder inhaler (DPI) formulation for antimicrobial combination therapy via the pulmonary route. Binary and ternary combinations were prepared via spray drying on a BUCHI® Nano Spray Dryer B-90. All powders were within the respirable size range, and were consisted of spherical particles that were slightly corrugated. The powers yielded fine particle fractions (of the loaded dose) of over 40% when dispersed using an Aerolizer® DPI at 60 L/min. Time-kill studies carried out against common respiratory tract pathogenic bacteria Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumonia and Acinetobacter baumannii at 1x the minimum inhibitory concentration (MIC) over 24 hours revealed no antagonistic behavior for both combinations. While the interactions were generally found to be indifferent, a favorable synergistic effect was detected in the binary combination when it was tested against Pseudomonas aeruginosa bacteria.
Bozic, Ivana; Reiter, Johannes G; Allen, Benjamin; Antal, Tibor; Chatterjee, Krishnendu; Shah, Preya; Moon, Yo Sup; Yaqubie, Amin; Kelly, Nicole; Le, Dung T; Lipson, Evan J; Chapman, Paul B; Diaz, Luis A; Vogelstein, Bert; Nowak, Martin A
In solid tumors, targeted treatments can lead to dramatic regressions, but responses are often short-lived because resistant cancer cells arise. The major strategy proposed for overcoming resistance is combination therapy. We present a mathematical model describing the evolutionary dynamics of lesions in response to treatment. We first studied 20 melanoma patients receiving vemurafenib. We then applied our model to an independent set of pancreatic, colorectal, and melanoma cancer patients with metastatic disease. We find that dual therapy results in long-term disease control for most patients, if there are no single mutations that cause cross-resistance to both drugs; in patients with large disease burden, triple therapy is needed. We also find that simultaneous therapy with two drugs is much more effective than sequential therapy. Our results provide realistic expectations for the efficacy of new drug combinations and inform the design of trials for new cancer therapeutics. DOI: http://dx.doi.org/10.7554/eLife.00747.001 PMID:23805382
José Ramón Martínez Pérez
Full Text Available Background: hypertension is one of the main cardiovascular risk factors, so its control improves the life expectancy of patients.Objective: to assess the effects of a treatment combining medication with auricular therapy and phyto-therapy in hypertensive patients assisted at the health area of ”Romárico Oro” Polyclinic, in Puerto Padre, Las Tunas province.Methods: an intervention study was carried out in 68 hypertensive patients of the health area of “Romárico Oro” Polyclinic in Puerto Padre from April, 2013 to April, 2014. The patients were distributed at random into two equal groups; the first received medication combined with auricular therapy and phyto-therapy, while the second one received only medication. The statistical analysis was done by means of Statistic system, t-student and Chi-Square tests were used and p< or =0.05 was considered as level of statistical significance.Results: by the end of the intervention, 73, 53% of the patients of the group with the combination of drug treatment and auricular therapy and phyto-therapy were controlled. In this group, the diastolic filling pressure diminished to 2, 2 mm Hg and the systolic gradient to 3, 66 mm, regarding the group treated only with drugs. Only one patient, representing the 2, 94% showed adverse reaction to the natural and traditional treatment.Conclusions: the combination of medication with auricular therapy and phyto-therapy proved to be effective, corroborated by a significant decrease of quantity of crisis, diastolic and systolic filling pressure values and increase of number of patients with their disease controlled; the report of only one complication shows the innocuousness of the auricular therapy and phyto-therapy treatment.
Matsuno, Teppei; Kuroda, Hiroyuki; Jomen, Wataru; Yoshida, Masahiro; Yamada, Michiko; Sato, Masanori; Abe, Tomoyuki; Sakurai, Tamaki; Fujii, Shigeyuki; Maeda, Masahiro; Fujita, Miri; Nagashima, Kazuo; Nojiri, Shuichi; Arihara, Yohei; Kato, Junji
A 71-year-old man with malaise, anorexia, and weight loss was referred to our hospital from a clinic. Abdominal computed tomography(CT)revealed bilateral adrenal masses. An ultrasound-guided percutaneous needle biopsy of the adrenal grand indicated diffuse large B-cell lymphoma. A rapid adrenocorticotropic hormone(ACTH)test revealed primary adrenal failure. Rituximab-cyclophosphamide/doxorubicin/vincristine/prednisolone(common name, R-CHOP)therapy accompanied by intrathecal treatment was initiated along with steroid replacement therapy. After the fourth courses, a CT scan showed a reduction of the adrenal masses, and there was no[18F]-fluorodeoxyglucose(FDG)uptake in the adrenal masses. The patient has remained in metabolic complete remission. Subsequently, both adrenal lymphomas were irradiated. The patient has been disease-free for 6 months after the diagnosis of primary adrenal lymphoma. The combined modality of chemoradiation therapy plus intrathecal treatment could be effective for primary adrenal lymphoma with a poor prognosis.
Andersen, M.H.; Sorensen, R.B.; Schrama, D.
Harnessing of the immune system by the development of 'therapeutic' vaccines, for the battle against cancer has been the focus of tremendous research efforts over the past two decades. As an illustration of the impressive amounts of data gathered over the past years, numerous antigens expressed...... their escape from cytotoxic therapies represent prime vaccination candidates. The characterization of a high number of tumor antigens allow the concurrent or serial immunological targeting of different proteins associated with such cancer traits. Moreover, while vaccination in itself is a promising new...... approach to fight cancer, the combination with additional therapy could create a number of synergistic effects. Herein we discuss the possibilities and prospects of vaccination when combined with other treatments. In this regard, cell death upon drug exposure may be immunogenic or non-immunogenic depending...
Hobbs, Robert F.; McNutt, Todd; Baechler, Sebastien; He Bin; Esaias, Caroline E.; Frey, Eric C.; Loeb, David M.; Wahl, Richard L.; Shokek, Ori; Sgouros, George
Purpose: Effective cancer treatment generally requires combination therapy. The combination of external beam therapy (XRT) with radiopharmaceutical therapy (RPT) requires accurate three-dimensional dose calculations to avoid toxicity and evaluate efficacy. We have developed and tested a treatment planning method, using the patient-specific three-dimensional dosimetry package 3D-RD, for sequentially combined RPT/XRT therapy designed to limit toxicity to organs at risk. Methods and Materials: The biologic effective dose (BED) was used to translate voxelized RPT absorbed dose (D RPT ) values into a normalized total dose (or equivalent 2-Gy-fraction XRT absorbed dose), NTD RPT map. The BED was calculated numerically using an algorithmic approach, which enabled a more accurate calculation of BED and NTD RPT . A treatment plan from the combined Samarium-153 and external beam was designed that would deliver a tumoricidal dose while delivering no more than 50 Gy of NTD sum to the spinal cord of a patient with a paraspinal tumor. Results: The average voxel NTD RPT to tumor from RPT was 22.6 Gy (range, 1-85 Gy); the maximum spinal cord voxel NTD RPT from RPT was 6.8 Gy. The combined therapy NTD sum to tumor was 71.5 Gy (range, 40-135 Gy) for a maximum voxel spinal cord NTD sum equal to the maximum tolerated dose of 50 Gy. Conclusions: A method that enables real-time treatment planning of combined RPT-XRT has been developed. By implementing a more generalized conversion between the dose values from the two modalities and an activity-based treatment of partial volume effects, the reliability of combination therapy treatment planning has been expanded.
El-Sharkawi, Salah; Vaughton, Keith
Patient. A 65-year old man who had previously undergone surgery for benign prostatic hyperplasia presented with symptoms of recurrent bladder outflow obstruction. Cystoscopy revealed the presence of recurrent tissue. Results. Histology identified a leiomyosarcoma. Several years after further surgery and radiotherapy, the patient presented with secondaries in the lungs and brain, but there was no evidence of local recurrence. Discussion. It is suggested that combined modality therapy (conserva...
Brodin, N Patrik; Guha, Chandan; Tomé, Wolfgang A
Photodynamic therapy (PDT) is a relatively new modality for anticancer treatment and although the interest has increased greatly in the recent years, it is still far from clinical routine. As PDT consists of administering a nontoxic photosensitizing chemical and subsequently illuminating the tumor with visible light, the treatment is not subject to dose-limiting toxicity, which is the case for established anticancer treatments like radiation therapy or chemotherapy. This makes PDT an attractive adjuvant therapy in a combined modality treatment regimen, as PDT provides an antitumor immune response through its ability to elicit the release of damage-associated molecular patterns and tumor antigens, thus providing an increased antitumor efficacy, potentially without increasing the risk of treatment-related toxicity. There is great interest in the elicited immune response after PDT and the potential of combining PDT with other forms of treatment to provide potent antitumor vaccines. This review summarizes recent studies investigating PDT as part of combined modality treatment, hopefully providing an accessible overview of the current knowledge that may act as a basis for new ideas or systematic evaluations of already promising results. © The Author(s) 2014.
Full Text Available BACKGROUND: Cardiovascular disease management and prevention represent the leading cost driver in Italian healthcare expenditure. In order to reach the target blood pressure, a large majority of patients require simultaneous administration of multiple antihypertensive agents.OBJECTIVE: To assess the economic impact of the use of fixed dose combinations of antihypertensive agents, compared to the extemporary combination of the same principles.METHODS: A cost minimization analysis was conducted to determine the pharmaceutical daily cost of five fixed dose combinations (olmesartan 20 mg + amlodipine 5 mg, perindopril 5 mg + amlodipine 5 mg, enalapril 20 mg + lercanidipine 10 mg, felodipine 5 mg + ramipril 5 mg, and delapril 30 mg + manidipine 10 mg compared with extemporary combination of the same principles in the perspective of the Italian NHS. Daily acquisition costs are estimated based on current Italian prices and tariffs.RESULTS: In three cases the use of fixed‑dose combination instead of extemporary combination induces a lower daily cost. Fixed combination treatment with delapril 30 mg + manidipine 10 mg induces greater cost savings for the National Health System (95,47 €/pts/year, as compared to free drugs combination therapy.CONCLUSIONS: Compared with free drug combinations, fixed‑dose combinations of antihypertensive agents are associated with lower daily National Health Service acquisition costs.http://dx.doi.org/10.7175/fe.v14i4.886
Davey, Ryan J; van der Westhuizen, Andre; Bowden, Nikola A
Metastatic melanoma is an aggressive form of cancer characterised by poor prognosis and a complex etiology. Until 2010, the treatment options for metastatic melanoma were very limited. Largely ineffective dacarbazine, temozolamide or fotemustine were the only agents in use for 35 years. In recent years, the development of molecularly targeted inhibitors in parallel with the development of checkpoint inhibition immunotherapies has rapidly improved the outcomes for metastatic melanoma patients. Despite these new therapies showing initial promise; resistance and poor duration of response have limited their effectiveness as monotherapies. Here we provide an overview of the history of melanoma treatment, as well as the current treatments in development. We also discuss the future of melanoma treatment as we go beyond monotherapies to a combinatorial approach. Combining older therapies with the new molecular and immunotherapies will be the most promising way forward for treatment of metastatic melanoma. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Xu, Xiaoyang; Ho, William; Zhang, Xueqing; Bertrand, Nicolas; Farokhzad, Omid
The advent of nanomedicine marks an unparalleled opportunity to advance the treatment of a variety of diseases, including cancer. The unique properties of nanoparticles, such as large surface-to volume ratio, small size, the ability to encapsulate a variety of drugs, and tunable surface chemistry, gives them many advantages over their bulk counterparts. This includes multivalent surface modification with targeting ligands, efficient navigation of the complex in vivo environment, increased intracellular trafficking, and sustained release of drug payload. These advantages make nanoparticles a mode of treatment potentially superior to conventional cancer therapies. This article highlights the most recent developments in cancer treatment using nanoparticles as drug-delivery vehicles, including promising opportunities in targeted and combination therapy. PMID:25656384
Meredith, R.; Okunewick, J.; Shadduck, R.; Raikow, R.; Brozovich, B.; Seeman, P.
Use of total body irradiation (TBI) and/or chemotherapy as a preparation for marrow transplantation in the treatment of leukemia has been only moderately successful in the clinic. Although cyclophosphamide (CY) has shown promise as a marrow ablative agent, leukemia relapses are often found, and optimal therapeutic protocols have not been established. Our transplantation therapy studies of murine leukemia with parental recipients and hybrid donors provide an excellent model for research aimed at improved survival of human transplant patients. Utilizing a murine leukemia induced by a virus, various doses of CY in combination with sub-lethal irradiation were compared to determine the optimal pretreatment for transplantation therapy. Both normal and leukemic mice were engrafted with virus resistant, histocompatible marrow following these preparations, then monitored for survival and long term effects. Leukemic mice were also evaluated for pluripotent as well as myeloid committed stem cells as a measure of the effectiveness of the treatment in elimination of leukemic cells. Leukemic groups were also compared for the percentage and time of leukemia relapse. All CY/X-ray combinations were more effective in elimination of stem cell populations than supralethal TBI alone. However, the best survival was obtained with lethal TBI alone or low dose CY in combination with 550 R
Full Text Available Michael Goyfman,1 Paul Zamudio,2 Kristine Jang,3 Jennifer Chee,3 Catherine Miranda,2 Javed Butler,1 Nand K Wadhwa2 1Division of Cardiology, 2Division of Nephrology, 3Department of Medicine, Stony Brook School of Medicine, Stony Brook, NY, USA Introduction: Acute heart failure (AHF is a leading cause of hospitalization and readmission in the US. The present study evaluated maximum diuresis while minimizing electrolyte imbalances, hemodynamic instability, and kidney dysfunction, to achieve a euvolemic state safely in a shorter period of time.Methods and results: A protocol of combined therapy with furosemide, metolazone, and spironolactone, with or without tolvaptan and acetazolamide, was used in 17 hospitalized patients with AHF. The mean number of days on combination diuretic protocol was 3.8 days. The mean daily fluid balance was 3.0±2.1 L negative. The mean daily urine output (UOP was 4.1±2.0 L (range 1.8–10.5 L. There were minimal fluctuations in serum electrolyte levels and serum creatinine over the duration of diuretic therapy. There was no statistically significant change in patients’ creatinine from immediately prior to therapy to the last day of therapy, with a mean increase in creatinine of 0.14 mg/dL (95% CI −0.03, +0.30, p=0.10.Conclusion: Our strategy of treating AHF by achieving high UOP, while maintaining stable electrolytes and creatinine in a short period to euvolemic state, is safe. Keywords: diuretics, aquaretic, acute heart failure, volume overload
Goto, Takuma; Saito, Hiroya; Yanagawa, Nobuyuki; Fujinaga, Akihiro; Saito, Yoshinori
In this study, we investigated an effective strategy of treatment for unresectable gallbladder cancer (GBC) by the retrospective analysis of prognostic factors and anti-tumor therapies, especially combination therapy of arterial infusion chemotherapy and radiation therapy (AI+PT). Forty-three patients with unresectable GBC were enrolled, and prognostic factors were investigated by multivariate analysis using a proportional hazard model. In addition, we examined the indication and after-therapy by analyzing the each factor cumulative survival rates and anti-tumor effect about the AI + RT group (n=24). AI + RT and the responders to the first-line therapy were significant prognostic factors. In AI + RT group, median survival time, progression-free survival and the 1-year survival rate, the response and disease control rates was 15.5 months, 7.1 months, 62.5%. 54.2% and 95.8%, respectively; which suggested prolonged survival and high anti-tumor effect. Cumulative survival rate was significantly shorter in cases with distant metastasis except liver metastases, and has been tendency to extend in the group who underwent systemic chemotherapy as after-therapy. The treatment strategy, using the Al + RT as first-line with the systemic chemotherapy as after-therapy, suggested contribute to the prolonged survival in locally advanced and liver metastases cases of GBC. (author)
Nyato Daniel J
Full Text Available Abstract Background New malaria treatment guidelines in Tanzania have led to the large-scale deployment of artemether-lumefantrine (Coartem®, popularly known as ALu or dawa mseto. Very little is known about how people in malaria endemic areas interpret policy makers' decision to replace existing anti-malarials, such as sulphadoxine-pyrimethamine (SP with "new" treatment regimens, such as ALu or other formulations of ACT. This study was conducted to examine community level understandings and interpretations of ALu's efficacy and side-effects. The paper specifically examines the perceived efficacy of ALu as articulated by the mothers of young children diagnosed with malaria and prescribed ALu. Methods Participant observation, six focus group discussions in two large villages, followed by interviews with a random sample of 110 mothers of children less than five years of age, who were diagnosed with malaria and prescribed ALu. Additionally, observations were conducted in two village dispensaries involving interactions between mothers/caretakers and health care providers. Results While more than two-thirds of the mothers had an overall negative disposition toward SP, 97.5% of them spoke favourably about ALu, emphasizing it's ability to help their children to rapidly recover from malaria, without undesirable side-effects. 62.5% of the mothers reported that they were spending less money dealing with malaria than previously when their child was treated with SP. 88% of the mothers had waited for 48 hours or more after the onset of fever before taking their child to the dispensary. Mothers' knowledge and reporting of ALu's dosage was, in many cases, inconsistent with the recommended dosage schedule for children. Conclusion Deployment of ALu has significantly changed community level perceptions of anti-malarial treatment. However, mothers continue to delay seeking care before accessing ALu, limiting the impact of highly subsidized rollout of the drug
Full Text Available Abstract Background One of the major complications of Plasmodium falciparum infection is cerebral malaria (CM, which causes one million deaths worldwide each year, results in long-term neurological sequelae and the treatment for which is only partially effective. Statins are recognized to have an immunomodulatory action, attenuate sepsis and have a neuroprotective effect. Atorvastatin (AVA has shown in vitro anti-malarial activity and has improved the activity of mefloquine (MQ and quinine. Methods The efficiency of 40 mg/kg intraperitoneal AVA, alone or in association with MQ, was assessed in an experimental Plasmodium berghei ANKA rodent parasite model of CM and performed according to different therapeutic schemes. The effects on experimental CM were assessed through the evaluation of brain histopathological changes and neuronal apoptosis by TUNEL staining. Results AVA alone in the therapeutic scheme show no effect on survival, but the prophylactic scheme employing AVA associated with MQ, rather than MQ alone, led to a significant delay in mouse death and had an effect on the onset of CM symptoms and on the level of parasitaemia. Histopathological findings show a correlation between brain lesions and CM onset. A neuronal anti-apoptotic effect of AVA in the AVA + MQ combination was not shown. Conclusions The combination of AVA and MQ therapy led to a significant delay in mouse mortality. There were differences in the incidence, time to cerebral malaria and the level of parasitaemia when the drug combination was administered to mice. When used in combination with MQ, AVA had a relevant effect on the in vivo growth inhibition and clinical outcome of P. berghei ANKA-infected mice.
Full Text Available The serotonin syndrome has been described only in rare instances for electroconvulsive therapy combined with an antidepressant medication. We describe a case of serotonin toxicity induced by electroconvulsive therapy in combination with fluoxetine.
Postiglione, Ilaria; Chiaviello, Angela; Palumbo, Giuseppe
Combination therapy is a common practice in many medical disciplines. It is defined as the use of more than one drug to treat the same disease. Sometimes this expression describes the simultaneous use of therapeutic approaches that target different cellular/molecular pathways, increasing the chances of killing the diseased cell. This short review is concerned with therapeutic combinations in which PDT (Photodynamyc Therapy) is the core therapeutic partner. Besides the description of the principal methods used to assess the efficacy attained by combinations in respect to monotherapy, this review describes experimental results in which PDT was combined with conventional drugs in different experimental conditions. This inventory is far from exhaustive, as the number of photosensitizers used in combination with different drugs is very large. Reports cited in this work have been selected because considered representative. The combinations we have reviewed include the association of PDT with anti-oxidants, chemotherapeutics, drugs targeting topoisomerases I and II, antimetabolites and others. Some paragraphs are dedicated to PDT and immuno-modulation, others to associations of PDT with angiogenesis inhibitors, receptor inhibitors, radiotherapy and more. Finally, a look is dedicated to combinations involving the use of natural compounds and, as new entries, drugs that act as proteasome inhibitors
Full Text Available Objective. Olanzapine is proved to be effective for chemotherapy induced nausea and vomiting (CINV. But its efficacy in combination with standard antiemetic therapy is unknown. The purpose of this study is to prove the preventive effect of olanzapine for the prevention of CINV caused by highly emetogenic chemotherapy when used with standard antiemetic therapy. Method. Gynecologic cancer patients receiving cisplatin-based chemotherapy who had grade 2 or 3 nausea in overall phase (0–120 h after chemotherapy despite standard therapy were assigned to this study. From the next cycles to cycles in which patients developed grade 2 or 3 nausea, they received olanzapine with standard therapy. 5 mg oral olanzapine was administered for 7 days from the day before chemotherapy. The effectiveness of preventive administration of olanzapine was evaluated retrospectively. The primary endpoint was nausea control rate (grade 0 or 1 with olanzapine. Results. Fifty patients were evaluable. The nausea control rate with olanzapine was improved from 58% to 98% in acute phase (0–24 h after chemotherapy and 2% to 94% in delayed phase (24–120 h after chemotherapy. In overall phase, the nausea control rate improved from 0% to 92%, and it was statistically significant (P<0.001. Conclusion. Preventive use of olanzapine combined with standard antiemetic therapy showed improvement in control of refractory nausea.
Hara, Eri; Makino, Akira; Kurihara, Kensuke; Ueda, Motoki; Hara, Isao; Kawabe, Takashi; Yamamoto, Fumihiko; Ozeki, Eiichi; Togashi, Kaori; Kimura, Shunsaku
We present here a radionuclide therapy using nanoparticle of 131I-labeled Lactosome (131I-Lactosome) is effective as a tumor therapy when combined with the local therapy of the percutaneous ethanol injection therapy (PEIT). A mixture of 131I-labeled poly( l-lactic acid)30 and amphiphilic block polymer of poly(sarcosine)64- block-poly( l-lactic acid)30 was dispersed in saline to generate polymeric micelles of 131I-Lactosome (the diameter of 46 nm with PDI of 0.057). Mice were transplanted with murine mammary cancer (4T1) cells, and a relatively small amount of ethanol was injected percutaneously to the tumor region, followed by intravenous administration of 131I-Lactosome (2.0 × 102 MBq/kg). At 16 days after the 131I-Lactosome dosage with PEIT, the relative tumor volume (RTV) was suppressed as low as 5.32 ± 1.06, while the RTV values became significant to be 15.9 ± 5.0 with PEIT alone and 17.4 ± 3.9 with 131I-Lactosome alone. Indeed, 131I-accumulation in the transplanted tumor region at 48 h after 131I-Lactosome dosage became three times higher with PEIT than that without PEIT. The nanoparticle-based radionuclide therapy in combination with PEIT was, therefore, effective in suppression of tumor proliferation.
Klysner, René; Bjerg Bendsen, Birgitte; Hansen, Maja Soon
The serotonin syndrome has been described only in rare instances for electroconvulsive therapy combined with an antidepressant medication. We describe a case of serotonin toxicity induced by electroconvulsive therapy in combination with fluoxetine.......The serotonin syndrome has been described only in rare instances for electroconvulsive therapy combined with an antidepressant medication. We describe a case of serotonin toxicity induced by electroconvulsive therapy in combination with fluoxetine....
K. Zoe Tsagaris
Full Text Available Upon its inception, repetitive transcranial magnetic stimulation (rTMS was delivered at rest, without regard to the potential impact of activity occurring during or around the time of stimulation. rTMS was considered an experimental intervention imposed on the brain; therefore, the myriad features that might suppress or enhance its desired effects had not yet been explored. The field of rTMS has since grown substantially and therapeutic benefits have been reported, albeit with modest and inconsistent improvements. Work in this field accelerated following approval of a psychiatric application (depression, and it is now expanding to other applications and disciplines. In the last decade, experimental enquiry has sought new ways to improve the therapeutic benefits of rTMS, intended to enhance underlying brain reorganization and functional recovery by combining it with behavioral therapy. This concept is appealing, but poorly defined and requires clarity. We provide a snapshot of how combined rTMS and behavioral therapy has been delineated in the literature, highlighting the diversity of approaches. We outline a framework for study design and reporting such that the effects of this emerging method can be better understood.
Kuo, Phoebe; Manes, R Peter; Schwam, Zachary G; Judson, Benjamin L
Objective Sinonasal undifferentiated carcinoma is a rare and aggressive malignancy of the nasal cavity and paranasal sinuses. Multi-institutional studies examining outcomes of combined modality treatment versus other treatment modalities have not been performed. The objective of our study was to present outcomes for multimodality therapy through use of the National Cancer Database. Study Design Retrospective cohort study. Setting National Cancer Database. Methods A total of 435 cases of SNUC diagnosed between 2004 and 2012 were identified. Kaplan-Meier analyses were performed to find 5-year cumulative survival rates. Multivariate Cox regression evaluated overall survival based on treatment when adjusting for other prognostic factors (age, primary site, sex, race, comorbidity, insurance, and TNM stage). Within the surgery + chemoradiotherapy group, survival analysis was also performed to compare outcomes for induction and adjuvant chemotherapy. Results The cumulative 5-year survival rate was 41.5%, and 36.1% of patients received surgery with chemoradiotherapy. In multivariate analysis, surgery + chemoradiotherapy was associated with significantly improved overall survival versus surgery + radiotherapy and radiotherapy but not significantly different from chemoradiotherapy. Within the surgery + chemoradiotherapy group, induction and adjuvant chemotherapy groups did not have associated differences in survival. Conclusion Combined modality therapy (chemoradiotherapy or surgery + chemoradiotherapy) is associated with improved survival outcomes versus other treatment modalities in patients with sinonasal undifferentiated carcinoma.
Christopher L. Cubitt
Full Text Available For patients with sarcoma, metastatic disease remains very difficult to cure, and outcomes remain less than optimal. Treatment options have not largely changed, although some promising gains have been made with single agents in specific subtypes with the use of targeted agents. Here, we developed a system to investigate synergy of combinations of targeted and cytotoxic agents in a panel of sarcoma cell lines. Agents were investigated alone and in combination with varying dose ratios. Dose-response curves were analyzed for synergy using methods derived from Chou and Talalay (1984. A promising combination, dasatinib and triciribine, was explored in a murine model using the A673 cell line, and tumors were evaluated by MRI and histology for therapy effect. We found that histone deacetylase inhibitors were synergistic with etoposide, dasatinib, and Akt inhibitors across cell lines. Sorafenib and topotecan demonstrated a mixed response. Our systematic drug screening method allowed us to screen a large number of combinations of sarcoma agents. This method can be easily modified to accommodate other cell line models, and confirmatory assays, such as animal experiments, can provide excellent preclinical data to inform clinical trials for these rare malignancies.
Melisi, Davide; Calvetti, Lorenzo; Frizziero, Melissa; Tortora, Giampaolo
Pancreatic cancer is the only human malignancy for which patients' survival has not improved substantially during the past 30 years. Despite advances in the comprehension of the molecular mechanisms underlying pancreatic carcinogenesis, current systemic treatments offer only a modest benefit in tumor-related symptoms and survival. Over the past decades, gemcitabine and its combination with other standard cytotoxic agents have been the reference treatments for advanced pancreatic cancer patients. The recent introduction of the three-drug combination regimen FOLFIRINOX or the new taxane nab-paclitaxel represent key advances for a better control of the disease. Novel agents targeting molecular mechanisms involved in cancer development and maintenance are currently under clinical investigation. This review describes the most important findings in the field of systemic combination therapies for the treatment of pancreatic cancer. We discuss the emerging evidences for the clinical activity of combination treatments with standard chemotherapy plus novel agents targeting tumor cell-autonomous and tumor microenvironment signaling pathways. We present some of the most important advances in the comprehension of the molecular mechanisms responsible for the chemoresistance of pancreatic cancer and the emerging therapeutic targets to overcome this resistance.
Johnson, Leigh G; Rohan, Kelly J
...), group cognitive-behavioral therapy (CBT), or combination therapy (CBT+LT). Atypical and typical symptoms were assessed using subscales of the Structured Interview Guide for the Hamilton Rating Scale for Depression - SAD Version (SIGH-SAD...
Yang, Bo-shuai; Ye, Ding-wei; Yao, Xu-dong; Peng, Jiang-yan; Zhang, Shi-lin; Dai, Bo; Zhang, Hai-liang; Shen, Yi-jun; Zhu, Yao; Zhu, Yi-ping; Shi, Guo-hai
To explore the effectiveness and significance of whether electrical acupuncture stimulation combining with pelvic floor muscle therapy (PFMT) can improve the recovery of urinary continence. A total of 109 patients took part in the study of novel combination treatment for urinary continence from September 2008 to September 2009. Patients were divided into study group (n = 40) and control group (n = 69). The patients in study group received electrical acupuncture stimulation therapy combined with PFMT one week after removal the catheter. The patients in control group performed PFMT as the only treatment for post prostatectomy incontinence. The patients were followed up closely, with their clinical characteristics recorded, questionnaires of ICI-Q-SF filled up, and all the data for statistical analysis collected. There was a significant difference between the study group and the control group in the urinary control curve (P = 0.029). The difference of continence probability between these two groups became greater from 4 weeks after surgery, and the difference reached the peak at 6 weeks (P = 0.023). Then the difference became smaller, and there was no difference at 16 weeks after surgery. ICI-Q-SF questionnaires showed the same results. Electrical acupuncture stimulation therapy combining with PFMT can improve the recovery of patients' urinary continence after radical prostatectomy.
Rubio-Guerra, Alberto F; Castro-Serna, David; Barrera, Cesar I Elizalde; Ramos-Brizuela, Luz M
Recent guidelines for the management of hypertension recommend target blood pressures hypertensive patients, or hypertensive patients do not reach the recommended treatment targets with monotherapy, making combination therapy necessary to achieve the therapeutic goal. Combination therapy with 2 or more agents is the most effective method for achieving strict blood pressure goals. Fixed-dose combination simplifies treatment, reduces costs, and improves adherence. There are many drug choices for combination therapy, but few data are available about the efficacy and safety of some specific combinations. Combination therapy of calcium antagonists and inhibitors of the renin-angiotensin-aldosterone system (RAAS) are efficacious and safe, and have been considered rational by both the JNC 7 and the 2007 European Society of Hypertension - European Society of Cardiology guidelines for the management of arterial hypertension. The aim of this review is to discuss some relevant issues about the use of combinations with calcium channel blockers and RAAS inhibitors in the treatment of hypertension.
Lavie, Efrat; Shapiro, Michele; Julius, Mona
The aim of this article is to present a new and challenging model of treatment that combines two therapeutic interventions: hydrotherapy and Snoezelen or controlled multisensory stimulation. The combination of the two therapeutic approaches enhances the treatment effect by utilizing the unique characteristics of each approach. We believe that this combined model will further enhance each media to the benefit of the clients and create a new intervention approach. This article relates to a hydrotherapy swimming pool facility that has been established at the Williams Island Therapeutic Swimming and Recreation Center, Beit Issie Shapiro, Raanana in Israel, after acquiring many years of experience and gaining substantial knowledge both in the field of hydrotherapy and Snoezelen intervention. Beit Issie Shapiro is a non-profit community organization providing a range of services for children with developmental disabilities and their families. The organization provides direct services for nearly 6,000 children and adults each year. This article provides an overview of hydrotherapy and Snoezelen and presents a case study, which will demonstrate the new model of treatment and show how this new and innovative form of therapy can be used as a successful intervention. We believe it will open a path to enriching the repertoire of therapists helping people with special needs. This article is also addressed to researchers to provide ideas for further studies in this area.
Dominguez, P A; Dervisis, N G; Cadile, C D; Sarbu, L; Kitchell, B E
Response and adverse reactions to combined gemcitabine (GEM) and carboplatin (CARBO) therapy in dogs with carcinomas are not documented. GEM and CARBO are safe for the treatment of dogs with carcinomas. Thirty-seven dogs with histologically or cytologically confirmed carcinomas. Prospective clinical trial. Dogs were treated with GEM (2 mg/kg, 20-30-minute infusion IV) on Days 1 and 8 and 4 hours later, CARBO (10 mg/kg IV) on Day 1. The cycle was repeated on Day 22. Thirty-seven dogs (29 with measurable tumor) received a median of 2 cycles (range 0.5-6) for a total of 101 cycles administered. Twelve dogs (32%) developed neutropenia (3 Grade 3, and 5 Grade 4) and 9 (24%) thrombocytopenia (2 Grade 3, and 1 Grade 4). Dogs >20 kg were twice as likely to develop thrombocytopenia (P= .023). Twenty-seven dogs (73%) had evidence of gastrointestinal (GI) toxicosis, but most signs were of mild to moderate severity and self-limiting. One dog died of treatment-related complications. Overall tumor response rate was 13%. One dog with metastatic prostatic carcinoma achieved a complete remission and 1 dog with intestinal adenocarcinoma and 1 with tonsillar squamous cell carcinoma achieved partial remission. Twelve dogs achieved stable disease for a median of 72 days. GEM and CARBO combination causes mild to moderate hematologic and GI toxicosis in dogs with carcinoma. Response rate in this study was modest, and optimization of dosing of this combination is required.
Full Text Available Raphael E Steiner, Elisabet E Manasanch Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Abstract: Carfilzomib is a proteasome inhibitor that binds selectively and irreversibly to the 20S proteasome, the proteolytic core particle within the 26S proteasome, resulting in the accumulation of proteasome substrates and ultimately growth arrest and apoptosis of tumor cells. The development and ultimate approval of this medication by regulatory agencies has been an important step toward improving clinical outcomes in multiple myeloma. Although initially approved as a single agent for the treatment of multiply relapsed and/or refractory myeloma, in the USA, it is now widely used in the early relapse setting in combination with lenalidomide and dexamethasone. Carfilzomib has also been studied in combination with second-generation immunomodulatory drugs, histone deacetylase inhibitors, alkylating agents and other novel medications. In this review article, we will discuss the efficacy, safety, tolerability and quality of life of carfilzomib-based combination therapies, as well as novel agents, for relapsed multiple myeloma. Keywords: multiple myeloma, relapsed and refractory myeloma, carfilzomib, novel drugs, salvage chemotherapy
Blonde, Lawrence; San Juan, Zinnia T; Bolton, Peggy
The management of type 2 diabetes mellitus (T2DM) often requires combinations of antihyperglycemic medications with complementary mechanisms of action. Inadequate adherence to combination therapy, possibly related to pill burden (greater number of pills and higher administration frequency) and poor tolerability, may lead to suboptimal clinical outcomes. One potential means of addressing these problems is the use of fixed-dose combinations (FDCs) that simplify the treatment regimen by reducing pill burden compared with the same combination delivered as separate pills. The present study evaluates the efficacy and tolerability of FDCs in the treatment of T2DM patients and provides an overview of dosing, costs, and adherence. A review of FDCs, with particular attention to those that contain metformin extended-release (XR) and allow once-daily dosing. Many FDCs contain metformin as one of the component drugs. However, the standard immediate-release (IR) formulation of metformin requires twice-daily dosing and may have tolerability problems related to adverse gastrointestinal (GI) effects. The XR formulations of metformin can be administered once daily and have been shown to reduce the occurrence of GI effects frequently observed with metformin IR; consequently, they may have significant advantages for inclusion in FDCs. The long-term cost-effectiveness of FDCs remains to be fully determined. For patients taking metformin, FDCs containing metformin XR offer equivalent efficacy with reduced dose frequency and, potentially, fewer GI events compared with standard IR formulation, as well as a reduced number of pills compared with separate-pill regimens. By reducing pill burden and improving tolerability, FDCs may improve adherence.
Matsuda, Tadayoshi; Tanaka, Yoshiaki; Takeshita, Nagayuki; Ishiwata, Junichi; Awane, Yasuyuki
Sixty-eight cases of cancer were treated by combined use of Thermotron RF-8 hyperthermia and radiotherapy, and 16 cases by combined use of hyperthermia and anti-cancer drug. Shallow-seated tumor at a depth of 7 cm or less from the skin surface was present in 43 cases. Most of these were metastatic tumors of lymphnode, chest wall and abdominal wall. The effect of treatment was evaluable in 40 cases, the breakdown being as follows: CR 21 cases 53 %, PR 13 cases 40 %, and NR 3 cases 7 %. The effectiveness ratios (CR + PRa) were as follows: adenocarcinoma 13 cases out of 18, 72 %; squamous cell carcinoma 12 cases out of 15, 80 %. Out of 19 cases of tumor 5.9 cm or smaller, 17 cases obtained CR. Out of 17 cases of tumor 6 cm or larger, there were 5 cases of CR. Cases of larger-sized tumor thus showed a poorer effect of treatment. Nine cases of recurrence after radiotherapy were treated by combined use of hyperthermia and radiotherapy. Irradiation of 20 to 40 Gy was combined with 5 to 10 rounds of hyperthermia. The effectiveness ratio was 78 %, i.e., 7 cases out of 9. Cases of recurrence of radio-resistant tumor after radiotherapy responded well to low-dose irradiation. Twenty-two cases of deep-seated tumor were treated with the combined use of radiation therapy and hyperthermia. They comprised 10 cases of rectal cancer, 3 cases each of gastric cancer and uterine cancer, 2 cases each of lung cancer and sarcoma, and 2 cases involving other reglons. The treatment results were: 3 cases each of CR, 15 cases of PR, and 4 cases of NR. The effectiveness ratio (CR + PRa) was 8 cases out of 22, i.e., 36 %. Systemic administration of anti-cancer drug was combined with hyperthermia, and 16 cases were treated. The treatment results were; one case of CR, 4 cases of PR, 6 cases of MR, 3 cases of NC, and 2 cases of PD. More cases of lymph node tumor showed excellent results. (J.P.N.)
Full Text Available Background: Atrophic acne scars are difficult to treat. The demand for less invasive but highly effective treatment for scars is growing. Objective: To assess the efficacy of combination therapy using subcision, microneedling and 15% trichloroacetic acid (TCA peel in the management of atrophic scars. Materials and Methods: Fifty patients with atrophic acne scars were graded using Goodman and Baron Qualitative grading. After subcision, dermaroller and 15% TCA peel were performed alternatively at 2-weeks interval for a total of 6 sessions of each. Grading of acne scar photographs was done pretreatment and 1 month after last procedure. Patients own evaluation of improvement was assessed. Results: Out of 16 patients with Grade 4 scars, 10 (62.5% patients improved to Grade 2 and 6 (37.5% patients improved to Grade 3 scars. Out of 22 patients with Grade 3 scars, 5 (22.7% patients were left with no scars, 2 (9.1% patients improved to Grade 1and 15 (68.2% patients improved to Grade 2. All 11 (100% patients with Grade 2 scars were left with no scars. There was high level of patient satisfaction. Conclusion: This combination has shown good results in treating not only Grade 2 but also severe Grade 4 and 3 scars.
External beam radiation therapy for recurrent sigmoid colorectal cancer. Retrospective analysis by group comparison between the radiation therapy alone and the radiation therapy combined with other therapies
Churei, Hisahiko; Takeshita, Tsuyoshi; Hiraki, Yoshiyuki; Baba, Yasutaka; Hokotate, Hirohumi; Nakajo, Masayuki; Ohkubo, Kouichi; Miyaji, Noriaki
The purpose of this study is to evaluate retrospectively clinical efficacy of curativeintent external beam radiation therapy for recurrent sigmoid colorectal cancer. As the radiation therapy of higher dose level combined with other therapies might improve pain control, tumor response, and prognosis, the total dose over 60 Gy was delivered except cases that were received surgery for the recurrent tumor. The study population consisted of 25 patients received the radiation therapy alone (RTA) and 24 patients received the radiation therapy combined with other one or two treatment modalities (RTC), which included surgery (tumor resection) in 15 cases, chemotherapy (low dose daily CDDP) in 13 cases, and hyperthermia in 6 cases. They received the radiation therapy from January, 1989 to June, 1996. Data on pain relief and tumor response were compared between the groups of RTA and RTC. The effect on pain relief was not different between the two groups. Tumor response appeared to be high in the patients combined with chemotherapy, but the difference was not statistically significant between the groups. There were no differences in the prognosis by the recurrent tumor size, the pain relief, and the tumor response. There was a statistically significant difference in the prognosis between the groups with and without extrapelvic distant metastases. A more effective treatment modality combined with the external radiation therapy is necessary to improve the clinical efficacy for the recurrent sigmoid colorectal cancer. (author)
Full Text Available Teresa L Kauf1, Keith L Davis2, Stephanie R Earnshaw2, E Anne Davis31Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL, 2RTI Health Solutions, Research Triangle Park, NC, 3Independent consultant, Pittsboro, NC, USAAbstract: The impact of fixed-dose combination (FDC products on adherence to other, non-fixed regimen components has not been examined. We compared adherence to a third antiretroviral (ART component among patients receiving a nucleoside reverse transcriptase inhibitor (NRTI backbone consisting of the FDC Epzicom®, GlaxoSmithKline Inc, Research Triangle Park, NC (abacavir sulfate 600 mg + lamivudine 300 mg; FDC group versus NRTI combinations taken as two separate pills (NRTI Combo group using data from a national sample of 30 health plans covering approximately 38 million lives from 1997 to 2005. Adherence was measured as the medication possession ratio (MPR. Multivariate logistic regression compared treatment groups based on the likelihood of achieving ≥95% adherence, with sensitivity analyses using alternative thresholds. MPR was assessed as a continuous variable using multivariate linear regression. Covariates included age, gender, insurance payer type, year of study drug initiation, presence of mental health and substance abuse disorders, and third agent class. The study sample consisted of 650 FDC and 1947 NRTI Combo patients. Unadjusted mean adherence to the third agent was higher in the FDC group than the NRTI Combo group (0.92 vs 0.85; P < 0.0001. In regression analyses, FDC patients were 48% and 39% more likely to achieve 95% and 90% third agent adherence, respectively (P ≤ 0.03. None of the other MPR specifications achieved comparable results. Among managed care patients, use of an FDC appears to substantially improve adherence to a third regimen component and thus the likelihood of achieving the accepted standard for adherence to HIV therapy of 95%.Keywords
Ishikawa, Youjirou; Nakamura, Tatsuya; Takada, Akinori; Takayama, Kanako; Makita, Chiyoko; Suzuki, Motohisa; Azami, Yusuke; Kikuchi, Yasuhiro; Fuwa, Nobukazu
Between 2009 and 2012, 10 patients with advanced oropharyngeal cancer underwent proton therapy combined with chemotherapy. The initial results of this therapy were 8 complete response (CR) and 2 partial response (PR), local recurrence was detected 1 patient. Proton beam therapy combined with chemotherapy is thought to be an effective treatment for locally advanced oropharyngeal cancer. (author)
Wang, Geoffrey D; Nguyen, Ha T; Chen, Hongmin; Cox, Phillip B; Wang, Lianchun; Nagata, Koichi; Hao, Zhonglin; Wang, Andrew; Li, Zibo; Xie, Jin
Conventional photodynamic therapy (PDT)'s clinical application is limited by depth of penetration by light. To address the issue, we have recently developed X-ray induced photodynamic therapy (X-PDT) which utilizes X-ray as an energy source to activate a PDT process. In addition to breaking the shallow tissue penetration dogma, our studies found more efficient tumor cell killing with X-PDT than with radiotherapy (RT) alone. The mechanisms behind the cytotoxicity, however, have not been elucidated. In the present study, we investigate the mechanisms of action of X-PDT on cancer cells. Our results demonstrate that X-PDT is more than just a PDT derivative but is essentially a PDT and RT combination. The two modalities target different cellular components (cell membrane and DNA, respectively), leading to enhanced therapy effects. As a result, X-PDT not only reduces short-term viability of cancer cells but also their clonogenecity in the long-run. From this perspective, X-PDT can also be viewed as a unique radiosensitizing method, and as such it affords clear advantages over RT in tumor therapy, especially for radioresistant cells. This is demonstrated not only in vitro but also in vivo with H1299 tumors that were either subcutaneously inoculated or implanted into the lung of mice. These findings and advances are of great importance to the developments of X-PDT as a novel treatment modality against cancer.
Intention of this study is to detect in 49 patients suffering from prostate carcinomas, effects and side effects of radiotherapy. According to the present results, there is not any doubt that prostate carcinomas are radiosensitive. In all patients radiotherapy induced a prostate shrinkage and an increasing of consistency. It resulted that a prostate biopsy must be carried out in order to control the success of therapy. The success of the treatment depends upon tumour spreading and on its degree of differentiation. Within the observation period only in four cases metastasation of the prostate carcinoma occurred after radiotherapy. According to literature, the 5-year survival rate with an organ-defined prostate carcinoma ranges between 70 and 80% when radiotherapeutic methods are applied. The same authors indicate a 5-year survival rate between 42 and 48% for scattered carcinomas. Only minor side effects are provoked by radiotherapy. In 75% of the patients pollakisuria and dysuria resulted. After irradiation was finished, the symptoms disappeared and did not cause in any case any late complications. In 12% of the cases proctitic pain occurred during irradiation, which in 6% remained even after the treatment was terminated. We could prove unequivocally on our patients that passage impairments caused by a prostate carcinoma are improved by radiotherapy. Finally it can be said that this treatment is applicable for curing carcinoma which is localised on the prostate. In the case of an undefined, scattered carcinoma radiotherapy combined with hormone therapy is the treatment of choice. With regards to undesired side effects radiotherapy is superior to other therapeutic measures. (orig./MG) [de
Anghel, R M; Gales, L N; Trifanescu, O G
Rationale: Urinary bladder cancer is the fourth most common cancer in men and the eighth in women, being an important public health issue. Methods: : Medical files of 155 patients (132M/ 23F) with urinary bladder cancer treated between 2006 and 2012 were retrospectively analyzed. The median age at diagnosis was 65 years (range: 19-85 years). Disease free survival (DFS) for patients with complete tumor resection receiving adjuvant treatment and progression free survival (PFS) for patients with post-operative residual disease was estimated. Results: The distribution of the stage disease was: 50 patients (32.2%) stage II, 47 (30.3%) stage III, 58 (37.4%) stage IV. Radical cystectomy was performed in 56 patients (36.1%), while 99 patients (63.9%) underwent repeated transurethral resection of the urinary bladder tumor (TURBT). Postoperative treatment included multimodal therapy in 47 patients (30.3%) (chemotherapy and external beam radiation), external beam radiation alone in 57 patients (36.8%) and chemotherapy alone (methotrexate, vinblastine, doxorubicin, and cisplatin-MVAC or gemcitabine+platinum) in 51 patients (32.9%). After a median follow-up of 31 months (range: 3-79 months), 51 patients (32.9%) presented local recurrence, 32 patients (21%) distant recurrence (metastases), 10 patients (6.4%) both local and distant recurrence, and 62 patients (40%) were free of disease. The median duration until progression was 27 months. Discussion: Despite the combined therapy approaches, urinary bladder carcinoma remains an aggressive disease, with a high relapse rate. Earlier diagnosis, aggressive radical surgery in intention to cure (cystectomy), and adjuvant multimodal treatment (radiotherapy and chemotherapy) are needed for survival improvement.
Full Text Available Objective: To explore the effect of cognitive behavioral therapy (CBT in combination with systemic family therapy (SFT on mild to moderate postpartum depression and sleep quality. Methods: 249 primiparous women with mild to moderate postpartum depression were recruited and randomly assigned to a control group (n=128, which received conventional postpartum care, or to a psychological intervention group (n=121, which received conventional postpartum care combined with psychological intervention. The Edinburgh Postnatal Depression Scale (EPDS and Pittsburgh Sleep Quality Index (PSQI were employed to evaluate depression and sleep quality, respectively. Results: 104 patients in the intervention group and 109 in the control group completed the study. After intervention, the EPDS score, PSQI score, sleep quality score, sleep latency score, sleep duration score, habitual sleep efficiency score, sleep disturbance score, and daytime dysfunction score were significantly lower in the intervention group than in the control group. The EPDS and PSQI scores of each group at different time points after intervention were markedly decreased compared with those before intervention, and the reduction in the intervention group was more evident than that in the control group. Conclusion: CBT in combination with SFT can improve depression and sleep quality in patients with mild to moderate postpartum depression.
Robert S. Hanley
Full Text Available Purpose: We evaluated the effectiveness of combining behavioral therapy, pharmacologic therapy and endoscopic hydrodistension for treating painful bladder syndrome / interstitial cystitis (PBS/IC. Materials and Methods: Twenty-five patients with PBS/IC were prospectively enrolled in a pilot multimodal behavioral, pharmacologic and endoscopic treatment protocol. Behavioral modification included diet recommendations, fluid restriction to 64 oz. /day, progressive timed voiding and Kegel exercises. Oral pharmacologic therapy consisted of daily doses of macrodantin 100 mg, hydroxyzine 10-20 mg and urised 4 tablets. Patients underwent endoscopic bladder hydrodistention under anesthesia at least 2 weeks after protocol enrollment. Behavioral and pharmacological treatments were continued after the hydrodistention. O'Leary-Sant questionnaire scores were recorded before starting the protocol, after pharmacologic/behavioral therapy, 2 months post-hydrodistension, and at scheduled follow-up. Results: Eighteen patients (72% completed the pilot multimodal treatment protocol and were followed for a mean of 10.2 months. All patients were female with a median age of 36.3 years and had mean bladder capacity under anesthesia of 836 milliliters. Mean O'Leary-Sant symptom index scores for baseline symptoms, after behavioral/pharmacologic treatment, post-hydrodistension and during follow up were 12.5, 8.6, 7.0, and 6.7 (p < 0.05. Mean O'Leary-Sant problem index scores for baseline, after behavioral/pharmacologic treatment, post-hydrodistention and during follow up were 12.7, 8.9, 6.7, and 7.7 (p < 0.05. Conclusion: Our pilot multimodal protocol of behavioral modification, pharmacologic therapy and endoscopic hydrodistention demonstrated a significant progressive improvement in PBS/IC quality of life scores, compared to a pre-treatment baseline. These results should be validated in a larger, placebo controlled trial.
Huang, Wei; Chen, Liqing; Kang, Lin; Jin, Mingji; Sun, Ping; Xin, Xin; Gao, Zhonggao; Bae, You Han
Anticancer therapy has always been a vital challenge for the development of nanomedicine. Repeated single therapeutic agent may lead to undesirable and severe side effects, unbearable toxicity and multidrug resistance due to complex nature of tumor. Nanomedicine-based combination anticancer therapy can synergistically improve antitumor outcomes through multiple-target therapy, decreasing the dose of each therapeutic agent and reducing side effects. There are versatile combinational anticancer strategies such as chemotherapeutic combination, nucleic acid-based co-delivery, intrinsic sensitive and extrinsic stimulus combinational patterns. Based on these combination strategies, various nanocarriers and drug delivery systems were engineered to carry out the efficient co-delivery of combined therapeutic agents for combination anticancer therapy. This review focused on illustrating nanomedicine-based combination anticancer therapy between nucleic acids and small-molecular drugs for synergistically improving anticancer efficacy. Copyright © 2017 Elsevier B.V. All rights reserved.
Full Text Available Abstract Background To improve access to treatment in the private retail sector a new class of outlets known as accredited drug dispensing outlets (ADDO was created in Tanzania. Tanzania changed its first-line treatment for malaria from sulphadoxine-pyrimethamine (SP to artemether-lumefantrine (ALu in 2007. Subsidized ALu was made available in both health facilities and ADDOs. The effect of these interventions on access to malaria treatment was studied in rural Tanzania. Methods The study was carried out in the villages of Kilombero and Ulanga Demographic Surveillance System (DSS and in Ifakara town. Data collection consisted of: 1 yearly censuses of shops selling drugs; 2 collection of monthly data on availability of anti-malarials in public health facilities; and 3 retail audits to measure anti-malarial sales volumes in all public, mission and private outlets. The data were complemented with DSS population data. Results Between 2004 and 2008 access to malaria treatment greatly improved and the number of anti-malarial treatment doses dispensed increased by 78%. Particular improvements were observed in the availability (from 0.24 shops per 1,000 people in 2004 to 0.39 in 2008 and accessibility (from 71% of households within 5 km of a shop in 2004 to 87% in 2008 of drug shops. Despite no improvements in affordability this resulted in an increase of the market share from 49% of anti-malarial sales 2005 to 59% in 2008. The change of treatment policy from SP to ALu led to severe stock-outs of SP in health facilities in the months leading up to the introduction of ALu (only 40% months in stock, but these were compensated by the wide availability of SP in shops. After the introduction of ALu stock levels of the drug were relatively high in public health facilities (over 80% months in stock, but the drug could only be found in 30% of drug shops and in no general shops. This resulted in a low overall utilization of the drug (19% of all anti-malarial
Gill, Martin R; Falzone, Nadia; Du, Yong; Vallis, Katherine A
Targeted radionuclide therapy (TRT) is a branch of cancer medicine concerned with the use of radioisotopes, radiolabelled molecules, nanoparticles, or microparticles that either naturally accumulate in or are designed to target tumours. TRT combines the specificity of molecular and sometimes physical targeting with the potent cytotoxicity of ionising radiation. Targeting vectors for TRT include antibodies, antibody fragments, proteins, peptides, and small molecules. The diversity of available carrier molecules, together with the large panel of suitable radioisotopes with unique physicochemical properties, allows vector-radionuclide pairings to be matched to the molecular, pathological, and physical characteristics of a tumour. Some pairings are designed for dual therapeutic and diagnostic applications. Use of TRT is increasing with the adoption into practice of radium-223 dichloride for the treatment of bone metastases and with the ongoing clinical development of, among others, 177 Lu-dodecanetetraacetic acid tyrosine-3-octreotate (DOTATATE) for the treatment of neuroendocrine tumours and 90 Y-microspheres for the treatment of hepatic tumours. The increasing use of TRT raises the question of how best to integrate TRT into multimodality protocols. Achievements in this area and the future prospects of TRT are evaluated in this Review. Copyright © 2017 Elsevier Ltd. All rights reserved.
Bader, J; Schöni-Affolter, F; Böni, J; Gorgievski-Hrisoho, M; Martinetti, G; Battegay, M; Klimkait, T
A significant percentage of patients infected with HIV-1 experience only suboptimal CD4 cell recovery while treated with combination therapy (cART). It is still unclear whether viral properties such as cell tropism play a major role in this incomplete immune response. This study therefore intended to follow the tropism evolution of the HIV-1 envelope during periods of suppressive cART. Viruses from two distinct patient groups, one with good and another one with poor CD4 recovery after 5 years of suppressive cART, were genotypically analysed for viral tropism at baseline and at the end of the study period. Patients with CCR5-tropic CC-motif chemokine receptor 5 viruses at baseline tended to maintain this tropism to the study end. Patients who had a CXCR4-tropic CXC-motif chemokine receptor 4 virus at baseline were overrepresented in the poor CD4 recovery group. Overall, however, the majority of patients presented with CCR5-tropic viruses at follow-up. Our data lend support to the hypothesis that tropism determination can be used as a parameter for disease progression even if analysed long before the establishment of a poorer immune response. Moreover, the lasting predominating CCR5-tropism during periods of full viral control suggests the involvement of cellular mechanisms that preferentially reduce CXCR4-tropic viruses during cART. © 2016 British HIV Association.
Ge, Yanxiu; Ma, Yakun; Li, Lingbing
Single drug therapy that leads to the multidrug resistance of cancer cells and severe side-effect is a thing of the past. Combination therapies that affect multiple signaling pathways have been the focus of recent active research. Due to the successful development of prodrug-based nano-drug delivery systems (P-N-DDSs), their use has been extended to combination therapy as drug delivery platforms. In this review, we focus specifically on the P-N-DDSs in the field of combination therapy including the combinations of prodrugs with different chemotherapeutic agents, other therapeutic agents, nucleic acid or the combination of different types of therapy (e.g. chemotherapy and phototherapy). The relevant examples of prodrug-based nanoparticulate drug delivery strategy in combination cancer therapy from the recent literature are discussed to demonstrate the feasibilities of relevant technology. Copyright © 2016 Elsevier B.V. All rights reserved.
Østergaard, Kasper Rud
Selective mutism (SM) is a debilitating childhood anxiety disorder characterized by a persistent lack of speech in certain social settings and is considered hard to treat. Cognitive behavioral therapy (CBT) and pharmacological treatments are the best described treatments in the literature. To test whether there is evidence on treatment based on CBT, medication or a combination of these. Systematic and critical review of the literature on CBT and/or pharmacological treatments of SM. Literature was sought on PubMed, Embase and Psycinfo in March 2017. Of the included studies, six examined CBT, seven pharmacologic treatment and two a combination of these. Using CBT 53/60 children improved symptomatically whilst respectively 55/67 and 6/7 improved using pharmacologic- and combination-treatment. Pharmacologic treatment and especially CBT showed promising results supported by some degree of evidence, which combination treatment lacks. Yet small numbers, few RCTs, heterogeneous study designs, lack of consistent measures, short treatment and follow-up periods, generally limits the evidence. This needs focus in future research.
Mocroft, Amanda; Sterne, Jonathan A C; Egger, Matthias
BACKGROUND: The extent to which mortality differs following individual acquired immunodeficiency syndrome (AIDS)-defining events (ADEs) has not been assessed among patients initiating combination antiretroviral therapy. METHODS: We analyzed data from 31,620 patients with no prior ADEs who started...... combination antiretroviral therapy. Cox proportional hazards models were used to estimate mortality hazard ratios for each ADE that occurred in >50 patients, after stratification by cohort and adjustment for sex, HIV transmission group, number of antiretroviral drugs initiated, regimen, age, date of starting...... combination antiretroviral therapy, and CD4+ cell count and HIV RNA load at initiation of combination antiretroviral therapy. ADEs that occurred in
Artemisinins seem to regulate key factors such as nuclear factor‑kappa B, survivin, NOXA, hypoxia‑inducible factor‑1α, and BMI‑1, involving multiple pathways that may affect drug response, drug interactions, drug resistance, and associated parameters upon normal cells. Newer synthetic artemisinins have been developed ...
of medicine is the emergence of the Peruvian (Cinchona) bark (Rubiaceae) coupled with its pharmacologically active substance, - the quinine. Quinine is a classic ... at optimum humidity for at least three days before being subjected to the experiments (2). All the experiments were carried out in a calm laboratory setting that ...
ABSTRACT. The best way to analyze drug utilization and evaluate impact of an intervention in health care institutions is to study the universal indicators, which are not dependent either on investigator or time of measurement. The aim of this study was to characterize the prescription pattern of public health institutions in ...
Background: Malaria caused by the parasite Plasmodium falciparum is an acute disease which kills an estimated 863,000 people per year according to the WHO report of 2009. The fight against malaria is faced with the occurrence of widespread resistance of P. falciparum. The search for plant-derived antimalarial drugs ...
The best way to analyze drug utilization and evaluate impact of an intervention in health care institutions is to study the universal indicators, which are not dependent either on investigator or time of measurement. The aim of this study was to characterize the prescription pattern of public health institutions in Kano, Nigeria ...
Artemisinin and its derivatives have become antimalarial drugs of choice because they are effective against most stages in the life cycle of plasmodium and are safe for all, including pregnant women. World Health Organisation ... The target compound also had an LD50 of 330 mg/kg in mice by the oral route. A single dose ...
V. B. Grinevich
Full Text Available Background: Chronic pancreatitis is characterized by an imbalance of pro-inflammatory and anti-inflammatory cytokines, reflecting the presence of chronic systemic inflammation. The functional state of microbial-tissue complex of the intestine determines the severity of chronic systemic inflammation. Restoration of normal microbial-tissue complex functioning of the intestine reduces the severity of inflammatory changes in the pancreas.Aim: To study clinical efficacy of combination of chronic pancreatitis through correction of the functional state of intestinal microbial-tissue complex.Materials and methods: The analyzed patient sample included 117 patients with uncomplicated chronic pancreatitis and moderate pain syndrome, moderate exocrine and endocrine, with their mean age of 43.9 ± 11.6 years (men, 40.9 ± 13.5 years and women, 48.6 ± 11.7 years. Patients with chronic pancreatitis were divided into 2 groups, with the Results: After combination therapy of chronic pancreatitis with the agent for correction of the functional state of intestinal microbial-tissue complex, there was a significant (p < 0.05 reduction in the representation of pathogenic and conditionally pathogenic microflora, with a significant increase in the primary intestinal flora, as well as a decrease in cytokines TNF-α (74.32 ± 11.22 ng/ml before treatment, 31.34 ± 8.92 ng/ml after treatment and IL-1β (25.32 ± 4.36 ng/ml before treatment, 10.52 ± 3.52 ng/ml after treatment, a significant decrease in cortisol (456.53 ± 68.99 nmol/ml before treatment, 382.61 ± 60.24 nmol/ml after treatment. The significant improvement of metabolic abnormalities was associated with positive clinical dynamics and improvement of quality of life.Conclusion: Treatment strategies in chronic pancreatitis should include agents restoring the functioning of intestinal microbial-tissue complex and positively affecting metabolic and hormonal milieu.
Kainuma, Satoshi; Nakajima, Kiyokazu; Miyagawa, Shigeru; Fukushima, Satsuki; Saito, Atsuhiro; Harada, Akima; Hirota, Masashi; Miyazaki, Yasuhiro; Sawabata, Noriyoshi; Watabe, Tadashi; Watabe, Hiroshi; Toda, Koichi; Hatazawa, Jun; Okumura, Meinoshin; Sawa, Yoshiki
combination of techniques may provide less-invasive endoscopic intervention and regenerative therapy. © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
Zhang, Rui Xue; Wong, Ho Lun; Xue, Hui Yi; Eoh, June Young; Wu, Xiao Yu
Nanomedicine of synergistic drug combinations has shown increasing significance in cancer therapy due to its promise in providing superior therapeutic benefits to the current drug combination therapy used in clinical practice. In this article, we will examine the rationale, principles, and advantages of applying nanocarriers to improve anticancer drug combination therapy, review the use of nanocarriers for delivery of a variety of combinations of different classes of anticancer agents including small molecule drugs and biologics, and discuss the challenges and future perspectives of the nanocarrier-based combination therapy. The goal of this review is to provide better understanding of this increasingly important new paradigm of cancer treatment and key considerations for rational design of nanomedicine of synergistic drug combinations for cancer therapy. Copyright © 2016 Elsevier B.V. All rights reserved.
Nankar, Rakesh; Prabhakar, P K; Doble, Mukesh
Ferulic acid, an anti-oxidant phytochemical present in several dietary components, is known to produce wide range of pharmacological effects. It is approved for use in food industry as a preservative and in sports food. Previous reports from our lab have shown synergistic interaction of ferulic acid with metformin in cell lines and diabetic rats. The purpose of this review is to compile information about anti-diabetic activity of ferulic acid in in vitro and in vivo models with special emphasis on activity of ferulic acid when combined with metformin. The mechanism of synergistic interaction between ferulic acid and metformin is also proposed after carefully studying effects of these compounds on molecules involved in glucose metabolism. Scientific literature for the purpose of this review was collected using online search engines and databases such as ScienceDirect, Scopus, PubMed and Google scholar. Ferulic acid forms resonance stabilized phenoxyl radical which scavenges free radicals and reduce oxidative stress. It improves glucose and lipid profile in diabetic rats by enhancing activities of antioxidant enzymes, superoxide dismutase and catalase in the pancreatic tissue. Combining ferulic acid with metformin improves both, in vitro glucose uptake activity and in vivo hypoglycemic activity of the latter. It is possible to reduce the dose of metformin by four folds (from 50 to 12.5 mg/kg body weight) by combining it with 10 mg of ferulic acid/kg body weight in diabetic rats. Ferulic acid improves glucose uptake through PI3-K pathway whereas metformin activates AMPK pathway to improve glucose uptake. The synergistic interaction of ferulic acid and metformin is due their action on parallel pathways which are involved in glucose uptake. Due to synergistic nature of their interaction, it is possible to reduce the dose of metformin (by combining with ferulic acid) required to achieve normoglycemia. Since the dose of metformin is reduced, the dose associated side
Nakayama, Toshitake; Ito, Hisao; Hashimoto, Shozo
Anti-tumor activities of direct current (DC) therapy combined with fractionated radiation or cyclophosphamide were studied in mice which were transplanted with murine fibrosarcoma (FSa) in the right thighs. Using TCD 50 assay, DC therapy, given in a single fraction, enhanced the effect of a single dose of radiation with the dose-modifying factor of 1.3. Tumor control rates were more improved by the combination therapy with the smaller doses of radiation than the larger ones. When DC therapy was applied one time immediately after the first radiation of fractionated ones, the combination therapy still showed the enhanced effect. However, both of DC therapy and radiation were divided in three fractions and DC therapy was applied everytime after radiation, tumor growth retardation were not different between the combination therapy and radiation alone. This result suggests that there is a minimum amount of Coulombs to improve the effect of radiation alone. On the other hand, DC therapy combined with cyclophosphamide given in one fraction showed the same enhancement effect as those divided in three fractions. These results suggest that DC therapy combined with radiation or cyclophosphamide is effective to improve tumor control, but the mechanisms to enhance the effect of radiation or cyclophosphamide are different. (author)
Buttar, N. S.; Wang, K. K.; Lutzke, L. S.; Krishnadath, K. K.; Anderson, M. A.
BACKGROUND: Endoscopic mucosal resection (EMR) and photodynamic therapy have been proposed as treatments for early stage cancers. EMR is limited by its focal nature whereas photodynamic therapy is dependent on precise staging. The combination of EMR and photodynamic therapy were studied in the
PAANS, AMJ; SCHIPPERS, JM
To evaluate the possibility of combining proton therapy with Positron Emission Tomography (PET) as a therapy monitor and as a tool for in situ dosimetry during therapy, proton activiation experiments have been performed using a 55 MeV proton beam on two different materials. The 3-D measurements of
Castellini, Giovanni; Lo Sauro, Carolina; Rotella, Carlo M.; Faravelli, Carlo
Objective. Binge eating disorder is a serious, prevalent eating disorder that is associated with overweight. Zonisamide is an antiepileptic drug that can promote weight loss. We evaluated the efficacy and safety of zonisamide as augmentation to individual cognitive behavioral therapy in the treatment of binge eating disorder patients. Design: controlled open study. Participants: Twenty four threshold and subthreshold binge eating disorder patients were enrolled in the cognitive behavioral therapy treatment group, and 28 patients in the cognitive behavioral therapy plus zonisamide group. Measurements: At the beginning (T0), at the end (T1) of treatment, and one year after the end of treatment (T2), body mass index was measured and Eating Disorder Examination-Questionnaire, Binge Eating Scale, Beck Depression Inventory, and State-Trait Anxiety Inventory were administered. Results. At T1 the cognitive behavioral therapy plus zonisamide group showed a higher mean reduction of body mass index, Eating Disorder Examination-Questionnaire, Beck Depression Inventory, and Binge Eating Scale scores. At T2, the cognitive behavior therapy group regained weight, while the cognitive behavioral therapy plus zonisamide group reduced their body mass and showed a higher reduction in binge eating frequency and Binge Eating Scale, Eating Disorder Examination-Questionnaire Restraint, and State and Trait Anxiety Inventory scores. Conclusion. The zonisamide augmentation to individual cognitive behavior therapy can improve the treatment of binge eating disorder patients, reducing body weight and the number of binge eating episodes. These results are maintained one year after the end of treatment. PMID:20049147
Full Text Available Aim: To evaluate the six months follow-up outcome of combined intravitreal triamcinolone acetonide (IVTA and photodynamic therapy (PDT for subfoveal choroidal neovascularization compared to PDT alone. Study design: Prospective interventional pilot study. Materials and Methods: Patients with six months follow-up of IVTA following PDT (Group I, eight eyes and PDT alone (Group II, eight eyes were included. Four mg/ 0.1 ml of IVTA was injected 7-10 days following PDT. The patients were reevaluated every month for the first two months and every three months thereafter in both the groups. Results: Group I: The mean age was 65.8±11.8 years (range: 47-79 years. Five patients were male. The total treatment sessions in six months were 11 (mean: 1.36. At six months, one eye had ³ 10 letters gain and three eyes had > 10 letters loss. Four eyes had stable vision. Two eyes (25% developed increased intraocular pressure (>40 mmHg during follow-up. Group II: The mean age was 58.7±11.7 years (range: 46-76 years. Five patients were male. The total treatment sessions in six months were 17 (mean: 2.13. At six months, six eyes had ³ 10 letters gain and none had > 10 letters loss. Two eyes had stable vision. Conclusion: The mean number of treatment sessions following combination therapy of IVTA (4 mg and PDT appears relatively less (1.36 at six months compared to PDT alone (mean: 2.13. ( P =0.02
Gaskill, C L; Cribb, A E
In a retrospective study, at least 10% of dogs receiving potassium bromide/phenobarbital combination therapy, compared with 0.3% of dogs receiving phenobarbital monotherapy, had probable pancreatitis. Pancreatitis may be a more frequent and more serious adverse effect of potassium bromide/phenobarbital combination therapy than has been reported previously.
Gaskill, C L; Cribb, A E
In a retrospective study, at least 10% of dogs receiving potassium bromide/phenobarbital combination therapy, compared with 0.3% of dogs receiving phenobarbital monotherapy, had probable pancreatitis. Pancreatitis may be a more frequent and more serious adverse effect of potassium bromide/phenobarbital combination therapy than has been reported previously. PMID:10907578
Watarai, Jiro; Itagaki, Takatomo; Akutsu, Thoru; Yamaguchi, Kouichi; Kato, Isao
Larygeal cancer were treated with synergistic combination therapy of Futraful in suppository, vitamin A, cepharanthin and irradiation from April 1981 to June 1982. This combination therapy resulted in high percentage of the tumor regression in the case of the invading laryngeal cancer and negligible complication. (author)
Bomback, Andrew S; Rekhtman, Yelena; Klemmer, Philip J; Canetta, Pietro A; Radhakrishnan, Jai; Appel, Gerald B
Aldosterone levels increase in 30%-40% of patients on angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers over the long term. This "aldosterone breakthrough" may carry important clinical consequences given aldosterone's nonepithelial, pro-fibrotic actions. The renin inhibitor, aliskiren, by suppressing the renin-angiotensin-aldosterone system (RAAS) proximally, may limit breakthrough compared to conventional RAAS blockade. This open-label study (NCT01129557) randomized subjects to aliskiren 300 mg daily (A), valsartan 320 mg daily (V), or aliskiren 150 mg + valsartan 160 mg daily (A+V) for 9 months. Eligible subjects had proteinuria >300 mg/day, estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m(2), and systolic blood pressure (BP) >130 or diastolic BP >80 mm Hg. Serum and 24-hour urine aldosterone (indexed to 24-hour urine Na) were checked before initiation of therapy and at 3, 6, and 9 months. Aldosterone breakthrough was defined as a sustained increase from baseline aldosterone by study end. The study was intended to enroll 120 subjects but was terminated early by the sponsor. We present here the results of 33 subjects who completed the protocol, of which 12 were randomized to A, 11 were randomized to V, and 10 were randomized to A+V. Mean baseline eGFR was 75.5 (±23.3) mL/min/1.73 m(2); baseline proteinuria was 3104 (±2943) mg/day; and baseline BP was 134.7 (±10.5)/84.8 (±8.4) mm Hg. Three (27%) subjects on V, three (25%) subjects on A, and three (30%) subjects on A+V had aldosterone breakthrough. Mean proteinuria reduction was 31% from baseline in all subjects: 30% in subjects with breakthrough vs. 32% in subjects without breakthrough. Mean BP reduction was 11.0/8.8 mm Hg in all subjects: 8.4/6.1 mm Hg in subjects with breakthrough vs. 12.0/9.8 mm Hg in subjects without breakthrough. Aliskiren, alone or in combination with valsartan, did not reduce the incidence of aldosterone breakthrough in subjects with hypertension
Gerard, J P; Benezery, K; Doyen, J; Francois, E
OPTIMIZING THE COST/BENEFIT RATIO OF TREATMENT: Evidence Based The aim of a cancer treatment is always to achieve the maximum of cure rate with a minimum of toxicity and best quality of life at an acceptable cost for the society. It is always a multifactorial challenge depending on the patient, the tumor, the doctor, and the society cultural and financial backgrounds. The goal is to find the best cost/benefit ratio between all possible strategies in agreement with a well-informed patient. In rectal cancer (M0) surgery is the cornerstone of treatment. Combined modality therapies aim at optimizing the cost/benefit ratio of possible strategies and only randomized trials can bring strong evidence regarding their results and recommendations. LESSONS FROM RANDOMIZED TRIALS: quite modest During the past decades many phase III trials have shown that: (1) neoadjuvant treatment even with "TME" surgery was better than adjuvant, (2) chemoradiotherapy (CRT) was better than RT alone, (3) long course CRT was probably more efficient (in terms of ypCR) than short course (25/5), and (4) capecitabine was as efficient as 5 FU but oxaliplatin was not adding benefit. Overall, the gains of nCRT remain modest and it is mainly a reduction in local relapse not exceeding 5 %, but no benefit in survival and neither in sphincter saving surgery has been proven. The way forwards organ preservation in case of CCR. Local control: can probably be improved for T4 tumors by RT dose escalation. Survival: can be increased by innovative medical treatment either before or after surgery. may be reduced by a less aggressive treatment in elderly. Conservative treatment: A new field of clinical research is to achieve "organ preservation" (and not only sphincter saving). To modify the surgical approach and preserve the whole rectum, neoadjuvant treatment must achieve safely a clinical complete response. As rectal adenocarcinoma is a relatively radioresistant tumor endocavitary irradiation (contact X-Ray) is a
El-Kheir, Wael Abo; Gabr, Hala; Awad, Mohamed Reda; Ghannam, Osama; Barakat, Yousef; Farghali, Haithem A M A; El Maadawi, Zeinab M; Ewes, Ibrahim; Sabaawy, Hatem E
Spinal cord injuries (SCI) cause sensory loss and motor paralysis. They are normally treated with physical therapy, but most patients fail to recover due to limited neural regeneration. Here we describe a strategy in which treatment with autologous adherent bone marrow cells is combined with physical therapy to improve motor and sensory functions in early stage chronic SCI patients. In a phase I/II controlled single-blind clinical trial (clinicaltrials.gov identifier: NCT00816803), 70 chronic cervical and thoracic SCI patients with injury durations of at least 12 months were treated with either intrathecal injection(s) of autologous adherent bone marrow cells combined with physical therapy or with physical therapy alone. Patients were evaluated with clinical and neurological examinations using the American Spinal Injury Association (ASIA) Impairment Scale (AIS), electrophysiological somatosensory-evoked potential, magnetic resonance imaging (MRI), and functional independence measurements. Chronic cervical and thoracic SCI patients (15 AIS A and 35 AIS B) treated with autologous adherent bone marrow cells combined with physical therapy showed functional improvements over patients in the control group (10 AIS A and 10 AIS B) treated with physical therapy alone, and there were no long-term cell therapy-related side effects. At 18 months posttreatment, 23 of the 50 cell therapy-treated cases (46%) showed sustained functional improvement. Compared to those patients with cervical injuries, a higher rate of functional improvement was achieved in thoracic SCI patients with shorter durations of injury and smaller cord lesions. Therefore, when combined with physical therapy, autologous adherent bone marrow cell therapy appears to be a safe and promising therapy for patients with chronic SCI of traumatic origin. Randomized controlled multicenter trials are warranted.
Oyarzabal Yera, Ambar; Molina Cuevas, Vivian; Jimenez Despaigne, Sonia
The Polycosanol, a mixture of superior primary aliphatic alcohols obtained from the sugarcane wax (Sacharum officinarum, L.) and the grape seeds extract (Vitis vinifera, L.) produces antioxidant effects experimentally and clinically demonstrated. The aim of present paper was to compare the effects of Polycosanol, the grape seed extract, and its combined therapy on oxidative markers in plasma and liver of rats. The rats were distributed into 4 groups: a control one and three treated with Polycosanol, grape seed extract and its combined therapy, respectively, using a 25 mg/kg dose over 4 weeks. The single-therapies significantly reduced the plasmatic concentrations of malonyldialdehyde and of protein-associated carbonyl groups regarding the control, showing a similar efficacy. Combined therapy reduced in a more effective way (p < 0,001) the malonyldialdehyde concentrations of carbonyl groups, and also decreased (p < 0,01) the concentrations of carbonyl groups, but no more than the single-therapies. Each single-therapy reduced the malonyldialdehyde concentrations generated by spontaneous oxidant system in liver homogenate. The effect of combined therapy was higher (p < 0,05) than the grape seed extract, but no more than that of polycosanol. We concluded that oral single-therapies using polycosanol and grape seed extract, administered during 4 weeks, decreased in a similar way, the lipid peroxidation in plasma and liver of rats. Combined therapy was more effective to inhibits the lipid peroxidation in plasma than each single-therapy, separately
Yeh, Steven; Suhler, Eric B; Smith, Justine R; Bruce, Beau; Fahle, Gary; Bailey, Steven T; Hwang, Thomas S; Stout, J Timothy; Lauer, Andreas K; Wilson, David J; Rosenbaum, James T; Flaxel, Christina J
Acute retinal necrosis (ARN) may lead to severe visual loss because of its rapid progression and high likelihood of retinal detachment (RD). This study investigates whether combination systemic and intravitreal antiviral therapy is superior to systemic antiviral therapy alone. Single-center, interventional, comparative case series of patients with ARN treated with combination systemic antiviral and intravitreal foscarnet injection therapy or systemic antiviral therapy alone. Survival analysis and incidence rates of visual acuity (VA) gain of two lines or greater, severe visual loss of 20/200 or worse, and RD were assessed. Twelve patients received combination therapy and 12 received systemic therapy alone. Patients receiving combination therapy were more likely to gain two or more lines of VA and showed decreased incidences of severe visual loss and RD. Combination oral and intravitreal antiviral therapy may improve the likelihood for VA gain and decrease the risk of RD in patients with ARN. Clinicians should consider administering combination systemic and intravitreal antiviral therapy for patients with the ARN syndrome.
Effectiveness of cognitive behavioral therapy integrated with systematic desensitization, cognitive behavioral therapy combined with eye movement desensitization and reprocessing therapy, and cognitive behavioral therapy combined with virtual reality exposure therapy methods in the treatment of flight anxiety: a randomized trial.
Triscari, Maria Teresa; Faraci, Palmira; Catalisano, Dario; D'Angelo, Valerio; Urso, Viviana
The purpose of the research was to compare the effectiveness of the following treatment methods for fear of flying: cognitive behavioral therapy (CBT) integrated with systematic desensitization, CBT combined with eye movement desensitization and reprocessing therapy, and CBT combined with virtual reality exposure therapy. Overall, our findings have proven the efficacy of all interventions in reducing fear of flying in a pre- to post-treatment comparison. All groups showed a decrease in flight anxiety, suggesting the efficiency of all three treatments in reducing self-report measures of fear of flying. In particular, our results indicated significant improvements for the treated patients using all the treatment programs, as shown not only by test scores but also by participation in the post-treatment flight. Nevertheless, outcome measures maintained a significant effect at a 1-year follow-up. In conclusion, combining CBT with both the application of eye movement desensitization and reprocessing treatment and the virtual stimuli used to expose patients with aerophobia seemed as efficient as traditional cognitive behavioral treatments integrated with systematic desensitization.
Pawełczyk, Agnieszka; Kołodziej-Kowalska, Emilia; Pawełczyk, Tomasz; Rabe-Jabłońska, Jolanta
An analysis of literature shows that there is still little evidence concerning the efficacy of electroconvulsive therapy (ECT) combined with antipsychotic therapy in a group of treatment-resistant schizophrenia patients. More precisely, its influence on cognitive functions is still equivocal. The aim of this study was to assess the influence of ECT combined with antipsychotic therapy on working memory, attention, and executive functions in a group of treatment-refractory schizophrenia patients. Twenty-seven patients completed the study: 14 men and 13 women, aged 21 to 55 years (mean age, 32.8 years), diagnosed with treatment-resistant schizophrenia. Each patient underwent a course of ECT sessions and was treated with antipsychotic medications. Before the ECT and within 3 days after the last ECT session, the participants were assessed with the following neuropsychological tests: Trail Making Test (TMT) and Wisconsin Cart Sorting Test (WCST). There were no significant differences in the TMT and WCST results after combined ECT and antipsychotic therapy in treatment-refractory schizophrenia patients. According to the results of the neuropsychological tests, there was no decline in attention, executive functions, or working memory. The current study shows no significant difference in attention, working memory, or executive functions after treatment with a combination of electroconvulsive and antipsychotic therapy. This suggests that combined electroconvulsive therapy may not have a negative influence on the neuropsychological functioning of patients with treatment resistant schizophrenia.
Navaratnarajah, Manoraj; Siedlecka, Urszula; Ibrahim, Michael; van Doorn, Carin; Soppa, Gopal; Gandhi, Ajay; Shah, Adarsh; Kukadia, Punam; Yacoub, Magdi H.; Terracciano, Cesare M.
Background Clenbuterol (Cl), a β2 agonist, is associated with enhanced myocardial recovery during left ventricular assist device (LVAD) support, and exerts beneficial remodelling effects during mechanical unloading (MU) in rodent heart failure (HF). However, the specific effects of combined Cl+β1 blockade during MU are unknown. Methods and Results We studied the chronic effects (4 weeks) of β2-adrenoceptor (AR) stimulation via Cl (2 mg/kg/day) alone, and in combination with β1-AR blockade using metoprolol ((Met), 250 mg/kg/day), on whole heart/cell structure, function and excitation-contraction (EC) coupling in failing (induced by left coronary artery (LCA) ligation), and unloaded (induced by heterotopic abdominal heart transplantation (HATx)) failing rat hearts. Combined Cl+Met therapy displayed favourable effects in HF: Met enhanced Cl's improvement in ejection fraction (EF) whilst preventing Cl-induced hypertrophy and tachycardia. During MU combined therapy was less beneficial than either mono-therapy. Met, not Cl, prevented MU-induced myocardial atrophy, with increased atrophy occurring during combined therapy. MU-induced recovery of Ca2+ transient amplitude, speed of Ca2+ release and sarcoplasmic reticulum Ca2+ content was enhanced equally by Cl or Met mono-therapy, but these benefits, together with Cl's enhancement of sarcomeric contraction speed, and MU-induced recovery of Ca2+ spark frequency, disappeared during combined therapy. Conclusions Combined Cl+Met therapy shows superior functional effects to mono-therapy in rodent HF, but appears inferior to either mono-therapy in enhancing MU-induced recovery of EC coupling. These results suggest that combined β2-AR simulation +β1-AR blockade therapy is likely to be a safe and beneficial therapeutic HF strategy, but is not as effective as mono-therapy in enhancing myocardial recovery during LVAD support. PMID:25268495
Full Text Available Clenbuterol (Cl, a β2 agonist, is associated with enhanced myocardial recovery during left ventricular assist device (LVAD support, and exerts beneficial remodelling effects during mechanical unloading (MU in rodent heart failure (HF. However, the specific effects of combined Cl+β1 blockade during MU are unknown.We studied the chronic effects (4 weeks of β2-adrenoceptor (AR stimulation via Cl (2 mg/kg/day alone, and in combination with β1-AR blockade using metoprolol ((Met, 250 mg/kg/day, on whole heart/cell structure, function and excitation-contraction (EC coupling in failing (induced by left coronary artery (LCA ligation, and unloaded (induced by heterotopic abdominal heart transplantation (HATx failing rat hearts. Combined Cl+Met therapy displayed favourable effects in HF: Met enhanced Cl's improvement in ejection fraction (EF whilst preventing Cl-induced hypertrophy and tachycardia. During MU combined therapy was less beneficial than either mono-therapy. Met, not Cl, prevented MU-induced myocardial atrophy, with increased atrophy occurring during combined therapy. MU-induced recovery of Ca2+ transient amplitude, speed of Ca2+ release and sarcoplasmic reticulum Ca2+ content was enhanced equally by Cl or Met mono-therapy, but these benefits, together with Cl's enhancement of sarcomeric contraction speed, and MU-induced recovery of Ca2+ spark frequency, disappeared during combined therapy.Combined Cl+Met therapy shows superior functional effects to mono-therapy in rodent HF, but appears inferior to either mono-therapy in enhancing MU-induced recovery of EC coupling. These results suggest that combined β2-AR simulation +β1-AR blockade therapy is likely to be a safe and beneficial therapeutic HF strategy, but is not as effective as mono-therapy in enhancing myocardial recovery during LVAD support.
Kavanaugh, James A. [Department of Physics and Astronomy, Louisiana State University and Agricultural and Mechanical College, 202 Nicholson Hall, Tower Drive, Baton Rouge, Louisiana 70803-4001 (United States); Hogstrom, Kenneth R.; Fontenot, Jonas P.; Henkelmann, Gregory [Department of Physics and Astronomy, Louisiana State University and Agricultural and Mechanical College, 202 Nicholson Hall, Tower Drive, Baton Rouge, Louisiana 70803-4001 and Mary Bird Perkins Cancer Center, 4950 Essen Lane, Baton Rouge, Louisiana 70809 (United States); Chu, Connel; Carver, Robert A. [Mary Bird Perkins Cancer Center, 4950 Essen Lane, Baton Rouge, Louisiana 70809 (United States)
Purpose: The purpose of this study was to demonstrate that a bolus electron conformal therapy (ECT) dose plan and a mixed beam plan, composed of an intensity modulated x-ray therapy (IMXT) dose plan optimized on top of the bolus ECT plan, can be accurately delivered. Methods: Calculated dose distributions were compared with measured dose distributions for parotid and chest wall (CW) bolus ECT and mixed beam plans, each simulated in a cylindrical polystyrene phantom that allowed film dose measurements. Bolus ECT plans were created for both parotid and CW PTVs (planning target volumes) using 20 and 16 MeV beams, respectively, whose 90% dose surface conformed to the PTV. Mixed beam plans consisted of an IMXT dose plan optimized on top of the bolus ECT dose plan. The bolus ECT, IMXT, and mixed beam dose distributions were measured using radiographic films in five transverse and one sagittal planes for a total of 36 measurement conditions. Corrections for film dose response, effects of edge-on photon irradiation, and effects of irregular phantom optical properties on the Cerenkov component of the film signal resulted in high precision measurements. Data set consistency was verified by agreement of depth dose at the intersections of the sagittal plane with the five measured transverse planes. For these same depth doses, results for the mixed beam plan agreed with the sum of the individual depth doses for the bolus ECT and IMXT plans. The six mean measured planar dose distributions were compared with those calculated by the treatment planning system for all modalities. Dose agreement was assessed using the 4% dose difference and 0.2 cm distance to agreement. Results: For the combined high-dose region and low-dose region, pass rates for the parotid and CW plans were 98.7% and 96.2%, respectively, for the bolus ECT plans and 97.9% and 97.4%, respectively, for the mixed beam plans. For the high-dose gradient region, pass rates for the parotid and CW plans were 93.1% and 94
Kavanaugh, James A.; Hogstrom, Kenneth R.; Fontenot, Jonas P.; Henkelmann, Gregory; Chu, Connel; Carver, Robert A.
Purpose: The purpose of this study was to demonstrate that a bolus electron conformal therapy (ECT) dose plan and a mixed beam plan, composed of an intensity modulated x-ray therapy (IMXT) dose plan optimized on top of the bolus ECT plan, can be accurately delivered. Methods: Calculated dose distributions were compared with measured dose distributions for parotid and chest wall (CW) bolus ECT and mixed beam plans, each simulated in a cylindrical polystyrene phantom that allowed film dose measurements. Bolus ECT plans were created for both parotid and CW PTVs (planning target volumes) using 20 and 16 MeV beams, respectively, whose 90% dose surface conformed to the PTV. Mixed beam plans consisted of an IMXT dose plan optimized on top of the bolus ECT dose plan. The bolus ECT, IMXT, and mixed beam dose distributions were measured using radiographic films in five transverse and one sagittal planes for a total of 36 measurement conditions. Corrections for film dose response, effects of edge-on photon irradiation, and effects of irregular phantom optical properties on the Cerenkov component of the film signal resulted in high precision measurements. Data set consistency was verified by agreement of depth dose at the intersections of the sagittal plane with the five measured transverse planes. For these same depth doses, results for the mixed beam plan agreed with the sum of the individual depth doses for the bolus ECT and IMXT plans. The six mean measured planar dose distributions were compared with those calculated by the treatment planning system for all modalities. Dose agreement was assessed using the 4% dose difference and 0.2 cm distance to agreement. Results: For the combined high-dose region and low-dose region, pass rates for the parotid and CW plans were 98.7% and 96.2%, respectively, for the bolus ECT plans and 97.9% and 97.4%, respectively, for the mixed beam plans. For the high-dose gradient region, pass rates for the parotid and CW plans were 93.1% and 94
Kavanaugh, James A; Hogstrom, Kenneth R; Chu, Connel; Carver, Robert A; Fontenot, Jonas P; Henkelmann, Gregory
The purpose of this study was to demonstrate that a bolus electron conformal therapy (ECT) dose plan and a mixed beam plan, composed of an intensity modulated x-ray therapy (IMXT) dose plan optimized on top of the bolus ECT plan, can be accurately delivered. Calculated dose distributions were compared with measured dose distributions for parotid and chest wall (CW) bolus ECT and mixed beam plans, each simulated in a cylindrical polystyrene phantom that allowed film dose measurements. Bolus ECT plans were created for both parotid and CW PTVs (planning target volumes) using 20 and 16 MeV beams, respectively, whose 90% dose surface conformed to the PTV. Mixed beam plans consisted of an IMXT dose plan optimized on top of the bolus ECT dose plan. The bolus ECT, IMXT, and mixed beam dose distributions were measured using radiographic films in five transverse and one sagittal planes for a total of 36 measurement conditions. Corrections for film dose response, effects of edge-on photon irradiation, and effects of irregular phantom optical properties on the Cerenkov component of the film signal resulted in high precision measurements. Data set consistency was verified by agreement of depth dose at the intersections of the sagittal plane with the five measured transverse planes. For these same depth doses, results for the mixed beam plan agreed with the sum of the individual depth doses for the bolus ECT and IMXT plans. The six mean measured planar dose distributions were compared with those calculated by the treatment planning system for all modalities. Dose agreement was assessed using the 4% dose difference and 0.2 cm distance to agreement. For the combined high-dose region and low-dose region, pass rates for the parotid and CW plans were 98.7% and 96.2%, respectively, for the bolus ECT plans and 97.9% and 97.4%, respectively, for the mixed beam plans. For the high-dose gradient region, pass rates for the parotid and CW plans were 93.1% and 94.62%, respectively, for the
with mild to moderate lower urinary symptoms (LUTs). Apart from symptom resolution, these therapies can fur- ther stop the disease progression to acute retention of urine (AUR) or BPH-related surgeries with the attendant complications (9). Alfuzocin and tamsulosin are uro-selective (acts only on α1a and α1d adrenergic ...
Whittington, Richard; Malkowicz, S. Bruce; Machtay, Mitchell; Van Arsdalen, Keith; Barnes, Margaret M.; Broderick, Gregory A.; Wein, Alan J.
Purpose: To determine the rate of tumor response and patterns of relapse following combined hormonal-radiation therapy of adenocarcinoma of the prostate and to measure the survival in a group of men with tumor metastatic to pelvic lymph nodes. Methods and Materials: 66 patients with adenocarcinoma of the prostate with pathologically confirmed pelvic lymph node involvement were treated with combined radiation therapy and hormonal therapy. An additional five patients declined hormonal therapy. The patients treated with combined therapy represented a group with locally advanced disease including 44 patients (67%) with T3 or T4 tumors and 51 patients (80%) had N2 or N3 lymph node metastases. The pelvic lymph nodes were treated to a dose of 45 Gy and the prostate was boosted to a dose of 65 to 71 Gy. Hormonal therapy began up to 2 months before radiation and continued indefinitely. Patients were allowed to select their hormonal therapy and could choose DES (2 patients), orchiectomy (21 patients), LHRH agonist (7 patients) or combined androgen blockade (34 patients). Results: Median follow-up is 49 months (range 12 to 131 months) and 21 patients have been followed for longer than 5 years. There have been 15 recurrences the entire group including three local recurrences in the prostate, seven patients with distant metastases, four patients with biochemical recurrences without clinical evidence of disease, and one patient where the location was unknown. Two of the PSA recurrences occurred in patients who elected to discontinue hormones after less than 3 years of therapy. The overall survival at 5 and 8 years is 94 and 84%, the clinical disease free survival is 85 and 67%, and the biochemical disease-free survival is 78 and 47%. There was no increased toxicity of the combined modality regimen compared to the expected effects of radiation and hormonal therapy. Conclusion: Combined hormonal and radiation therapy represents an effective treatment option for patients with
Full Text Available Schwann cell transplantation and hyperbaric oxygen therapy each promote recovery from spinal cord injury, but it remains unclear whether their combination improves therapeutic results more than monotherapy. To investigate this, we used Schwann cell transplantation via the tail vein, hyperbaric oxygen therapy, or their combination, in rat models of spinal cord contusion injury. The combined treatment was more effective in improving hindlimb motor function than either treatment alone; injured spinal tissue showed a greater number of neurite-like structures in the injured spinal tissue, somatosensory and motor evoked potential latencies were notably shorter, and their amplitudes greater, after combination therapy than after monotherapy. These findings indicate that Schwann cell transplantation combined with hyperbaric oxygen therapy is more effective than either treatment alone in promoting the recovery of spinal cord in rats after injury.
Alberto F Rubio-Guerra
Full Text Available Alberto F Rubio-Guerra1, David Castro-Serna2, Cesar I Elizalde Barrera2, Luz M Ramos-Brizuela21Metabolic and Research Clinic, 2Internal Medicine Department, Hospital General de Ticomán SS DF, MéxicoAbstract: Recent guidelines for the management of hypertension recommend target blood pressures <140/90 mmHg in hypertensive patients, or <130/80 mmHg in subjects with diabetes, chronic kidney disease, or coronary artery disease. Despite the availability and efficacy of antihypertensive drugs, most hypertensive patients do not reach the recommended treatment targets with monotherapy, making combination therapy necessary to achieve the therapeutic goal. Combination therapy with 2 or more agents is the most effective method for achieving strict blood pressure goals. Fixed-dose combination simplifies treatment, reduces costs, and improves adherence. There are many drug choices for combination therapy, but few data are available about the efficacy and safety of some specific combinations. Combination therapy of calcium antagonists and inhibitors of the renin-angiotensin-aldosterone system (RAAS are efficacious and safe, and have been considered rational by both the JNC 7 and the 2007 European Society of Hypertension – European Society of Cardiology guidelines for the management of arterial hypertension. The aim of this review is to discuss some relevant issues about the use of combinations with calcium channel blockers and RAAS inhibitors in the treatment of hypertension.Keywords: hypertension, calcium channel blockers, renin-angiotensin-aldosterone system inhibitors, fixed-dose combination, adherence
Nnennaya Anthony Ajayi
Full Text Available Artemisinin-based combination therapy-resistant malaria is rare in Sub-Saharan Africa. The World Health Organization identifies monitoring and surveillance using day-3 parasitaemia post-treatment as the standard test for identifying suspected artemisinin resistance. We report three cases of early treatment failure due to possible artemisinin-based combination therapy-resistant Plasmodium falciparum malaria. All cases showed adequate clinical and parasitological responses to quinine. This study reveals a need to re-evaluate the quality and efficacy of artemisinin-based combination therapy agents in Nigeria and Sub-Saharan Africa.
Combination antibiotic therapy for Gram-negative sepsis is controversial. The present review provides a brief summary of the existing knowledge on combination therapy for severe infections with multidrug-resistant Pseudomonas spp., Acinetobacter spp., and Enterobacteriaceae. Empirical combination antibiotic therapy is recommended for severe sepsis and septic shock to reduce mortality related to inappropriate antibiotic treatment. Because definitive combination therapy has not been proven superior to monotherapy in meta-analyses, it is generally advised to de-escalate antibiotic therapy when the antibiotic susceptibility profile is known, although it cannot be excluded that some subgroups of patients might still benefit from continued combination therapy. Definitive combination therapy is recommended for carbapenemase-producing Enterobacteriaceae and should also be considered for severe infections with Pseudomonas and Acinetobacter spp. when beta-lactams cannot be used. Because resistance to broad-spectrum beta-lactams is increasing in Gram-negative bacteria and because no new antibiotics are expected to become available in the near future, the antibacterial potential of combination therapy should be further explored. In vitro data suggest that combinations can be effective even if the bacteria are resistant to the individual antibiotics, although existing evidence is insufficient to support the choice of combinations and explain the synergistic effects observed. In vitro models can be used to screen for effective combinations that can later be validated in animal or clinical studies. Further, in the absence of clinical evidence, in vitro data might be useful in supporting therapeutic decisions for severe infections with multidrug-resistant Gram-negative bacteria.
Khaled, Yazan S; Wright, Kathleen; Melcher, Alan; Jayne, David
Oncolytic viral therapy and photodynamic therapy are potential therapies for inoperable or advanced pancreatic cancer. Our aim was to investigate the anti-cancer killing effects of reovirus therapy combined with protoporphyrin IX (PpIX)-mediated photodynamic therapy on a variety of human pancreatic cancer cell lines. Pancreatic cancer cell lines (PsPC-1 and BXPC-3) and a non-cancer control cell line (HEK293) were infected with reovirus serotype 3 strain Dearing (T3D) at 0, 0·1, 1, and 10 plaque-forming units (PFU) per cell for 48 h. Cells were incubated with PpIX pro-drug 5-aminolevulinic acid (5-ALA) at 0, 1, 2, 3, and 4 mM for 4 h. Then, cells were photo-irradiated for 15 min with visible red light-emitting diodes with a light-fluence of 0·54 J/cm(2) of 653 nm (PpIX optimal excitation wavelength). The killing effects of reovirus combined with PpIX-mediated photodynamic therapy were analysed in methylthiazoltetrazolium (MTT) and trypan blue assays. The effect of adding reovirus after photodynamic therapy was also assessed. The statistical significance of the difference between groups was assessed with the two-tailed Student's t test. pphotodynamic therapy resulted in a significantly increased cytotoxic effect compared with reovirus monotherapy and photodynamic therapy (p=0·042) with 100% cell death observed across pancreatic cell lines with 10 PFU per cell combined with 1 and 2 mM 5-ALA. There was no difference in cytotoxicity observed between added reovirus before or after photodynamic therapy. To our knowledge, this is the first in-vitro study to combine reovirus oncolytic viral therapy with PpIX-mediated photodynamic therapy to treat pancreatic cancer. These results show a significant additive effect in cell killing and they provide initial evidence for a novel combined therapeutic intervention. National Institute for Health Research. Copyright © 2015 Elsevier Ltd. All rights reserved.
Clinical isolates of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa strains were exposed to antibacterial agents namely, Gentamicin, Cefuroxime, Ceftriaxone and Norfloxacin singly and also in combination with Rifampicin. Each minimum inhibitory concentration (MIC) as ...
Barker, Christopher A.; Postow, Michael A.
Radiation therapy has long played a role in the management of melanoma. Recent advances have also demonstrated the efficacy of immunotherapy in the treatment of melanoma. Preclinical data suggest a biologic interaction between radiation therapy and immunotherapy. Several clinical studies corroborate these findings. This review will summarize the outcomes of studies reporting on patients with melanoma treated with a combination of radiation therapy and immunotherapy. Vaccine therapies often use irradiated melanoma cells, and may be enhanced by radiation therapy. The cytokines interferon-α and interleukin-2 have been combined with radiation therapy in several small studies, with some evidence suggesting increased toxicity and/or efficacy. Ipilimumab, a monoclonal antibody which blocks cytotoxic T-lymphocyte antigen-4, has been combined with radiation therapy in several notable case studies and series. Finally, pilot studies of adoptive cell transfer have suggested that radiation therapy may improve the efficacy of treatment. The review will demonstrate that the combination of radiation therapy and immunotherapy has been reported in several notable case studies, series and clinical trials. These clinical results suggest interaction and the need for further study
Barker, Christopher A., E-mail: email@example.com [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Postow, Michael A. [Department of Medicine, Melanoma and Sarcoma Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)
Radiation therapy has long played a role in the management of melanoma. Recent advances have also demonstrated the efficacy of immunotherapy in the treatment of melanoma. Preclinical data suggest a biologic interaction between radiation therapy and immunotherapy. Several clinical studies corroborate these findings. This review will summarize the outcomes of studies reporting on patients with melanoma treated with a combination of radiation therapy and immunotherapy. Vaccine therapies often use irradiated melanoma cells, and may be enhanced by radiation therapy. The cytokines interferon-α and interleukin-2 have been combined with radiation therapy in several small studies, with some evidence suggesting increased toxicity and/or efficacy. Ipilimumab, a monoclonal antibody which blocks cytotoxic T-lymphocyte antigen-4, has been combined with radiation therapy in several notable case studies and series. Finally, pilot studies of adoptive cell transfer have suggested that radiation therapy may improve the efficacy of treatment. The review will demonstrate that the combination of radiation therapy and immunotherapy has been reported in several notable case studies, series and clinical trials. These clinical results suggest interaction and the need for further study.
Yasuda, Hiroshi; Kitayama, Yoshiaki
A combined therapy of radiation and hyperthermia is said to be fairly effective when applied to certain malignant tumors. However, the utility of this therapy for the treatment of angiosarcoma has not been well discussed. Recently, we have had a chance to treat a patient with metastatic angiosarcoma of the neck by using this combined therapy. In this paper, the clinical course of this patient and the availability of this combined therapy for angiosarcoma is reported. The patient was a 77-year-old man, having a primary lesion on the head and a metastatic tumor over the left cheek and neck. This combined therapy was used for the treatment of the metastatic tumor which caused severe pain and uncontrollable bleeding. The results were considered good ; the tumor decreased in size, pain disappeared and no further bleeding or severe side effects were observed. Though the patient died of another metastatic lesion which could not be treated with this combined therapy because the area of its localization could not allow placement in our hyperthermal apparatus, it is concluded that the combined therapy of radiation and hyperthermia is useful selectively for the treatment for angiosarcoma. (author)
Wijngaarden, Johannes Willem van
One of the most effective anticancer therapy still remains chemotherapy, however, both used as single agent as in combinational regimens, chemotherapy still encounters the problem of therapeutic resistance. Limitations of chemotherapy have led to the exploration of alternative anti-cancer approaches
Imbernón, Adrián; Agud, José Luis; Cuétara, María Soledad; Casqueiro, José Carlos; Nuñez, Pilar; Domínguez, Alegría R; Bullido, Eusebio; Stchigel, Alberto M
We present a case of rhino-orbitary mucormycosis which progressed despite liposomal amphotericin and early surgical debridement. Combined echinocandin and high dose liposomal amphotericin, repeated debridement, prolonged therapy with hyperbaric oxygen and continued therapy with posaconazole, along with strict diabetic control, allowed cure without disfigurement.
Imbernón, Adrián; Agud, José Luis; Cuétara, María Soledad; Casqueiro, José Carlos; Nuñez, Pilar; Domínguez, Alegría R.; Bullido, Eusebio; Stchigel, Alberto M.
10.1016/j.mmcr.2014.09.004 We present a case of rhino-orbitary mucormycosis which progressed despite liposomal amphotericin and early surgical debridement. Combined echinocandin and high dose liposomal amphotericin, repeated debridement, prolonged therapy with hyperbaric oxygen and continued therapy with posaconazole, along with strict diabetic control, allowed cure without disfigurement.
Full Text Available We present a case of rhino-orbitary mucormycosis which progressed despite liposomal amphotericin and early surgical debridement. Combined echinocandin and high dose liposomal amphotericin, repeated debridement, prolonged therapy with hyperbaric oxygen and continued therapy with posaconazole, along with strict diabetic control, allowed cure without disfigurement.
江原, 英俊; 加藤, 成一; 中根, 慶太; 加藤, 卓; 高田, 俊彦; 小島, 圭太郎; 亀井, 信吾; 萩原, 徳康; 柚原, 一哉; 高橋, 義人; 藤本, 佳則; 藤広, 茂; 蟹本, 雄右; 出口, 隆
We prospectively studied the usefulness of chlormadinone acetate (CMA) as an alternative therapy for prostate cancer relapse after combined androgen blockade (CAB) therapy. Sixteen patients with relapsed prostate cancer after treatment with CAB, including surgical or medical castration and nonsteroidal antiandrogens, 80 mg bicalutamide daily or 375 mg flutamide daily, were enrolled. After discontinuing the antiandrogen for evaluating the patient for the antiandrogen withdrawal syndrome, we ad...
Yamaguchi, Hiroshi; Mochizuki, Kazuo; Ishii, Yoshiaki
We conducted an experimental study, using a combination of coarse crystal cisplatin and radiotherapy for bone tumors, to evaluate the possibility of the clinical application of chemical embolus therapy in the field of orthopedic surgery. Experimental femoral bone tumors were produced, in rabbits, using VX2 carcinoma. The rabbits were allocated to five groups: untreated control, embolus, chemical embolus, irradiation alone, and chemical embolus and irradiation combination. These therapies were evaluated comparatively, in terms of local antitumor effects (including body weight, X-ray findings, angiography, and histopathology) and in terms of inhibition of pulmonary metastasis. Local antitumor effects, as evaluated by all parameters, except for body weight, were significantly greater for the chemical and irradiation combination group than for the chemical embolus, irradiation alone, untreated control, and embolus groups. There was no significant difference in the inhibition of pulmonary metastasis among the chemical embolus and irradiation combination, chemical embolus, and irradiation alone groups. These findings demonstrated the synergistic effect of the combination of chemical embolus therapy and radiotherapy. In this study, however, no significant difference was found between the chemical embolus therapy alone and the combination therapy groups in the inhibitory effect on pulmonary tumor metastasis, suggesting the need to conduct combination therapy repeatedly in the clinical setting. (author)
Craig, Jennifer; Tomlinson, Carey; Stevens, Kristin; Kotagal, Kiran; Fornadley, Judith; Jacobson, Barbara; Garrett, C. Gaelyn; Francis, David O.
Objective This study investigated the role of a specialized physical therapy program for muscle tension dysphonia patients as an adjunct to standard of care voice therapy. Study Design Retrospective Cohort Study Methods Adult MTD patients seen between 2007 and 2012 were identified from the clinical database. They were prescribed voice therapy and, if concomitant neck pain, adjunctive physical therapy. In a pragmatic observational cohort design, patients underwent one of four potential treatment approaches: voice therapy alone (VT), voice therapy and physical therapy (VT+PT), physical therapy alone (PT), or incomplete/no treatment. Voice handicap outcomes were compared between treatment approaches. Results Of 153 patients meeting criteria (Median age 48 years, 68% female, and 30% had fibromyalgia, chronic pain, chronic fatigue, depression, and/or anxiety), there was a similar distribution of patients with moderate or severe pre-treatment VHI scores across treatment groups (VT 45.5%, VT+PT 43.8%, PT 50%, no treatment 59.1%; p=0.45). Patients treated with VT alone had significantly greater median improvement in VHI than those not treated: 10-point vs. 2-point (p=0.02). Interestingly, median VHI improvement in patients with baseline moderate-severe VHI scores was no different between VT (10), VT+PT (8) and PT alone (10; p=0.99). Conclusions Findings show voice therapy to be an effective approach to treating MTD. Importantly, other treatment modalities incorporating physical therapy had a similar, albeit not significant, improvement in VHI. This preliminary study suggests that physical therapy techniques may have a role in the treatment of a subset of MTD patients. Larger, comparative studies are needed to better characterize the role of physical therapy in this population. PMID:26012419
A. Rahimi; F. Shamsaie; M.K. Zarabian; M. Sedehi
Introduction & Objective: Patients with Major depressive are difficult to treat, and the relative efficacy of medications and cognitive therapy in the treatment of depression is still a matter of deabath. The purpose of this study was to compare the efficacies of antidepressant medication, cognitive therapy and combination of cognitive therapy and antidepressant medication. Materials & Methods: In an experimental study, 120 depressive patients were randomly selected and divided in three grou...
Abdulla, Salim; Achan, Jane; Adam, Ishag
Background: Gametocytes are responsible for transmission of malaria from human to mosquito. Artemisinin combination therapy (ACT) reduces post-treatment gametocyte carriage, dependent upon host, parasite and pharmacodynamic factors. The gametocytocidal properties of antimalarial drugs are importa...
Pereira, Luiz Miguel; Vigato-Ferreira, Isabel Cristina; DE Luca, Gabriela; Bronzon DA Costa, Cássia Mariana; Yatsuda, Ana Patrícia
Neospora caninum is an apicomplexan parasite strongly related to reproductive problems in cattle. The neosporosis control is not well established and several fronts are under development, predominantly based on immune protection, immunomodulation and chemotherapy. The use of anti-malarial drugs as therapeutic sources has, in theory, considerable potential for any apicomplexan. Drugs such as methylene blue (MB) and pyrimethamine (Pyr) represent therapeutic options for malaria; thus, their use for neosporosis should be assessed. In this work, we tested the effects of MB and Pyr on N. caninum proliferation and clearance, using LacZ-tagged tachyzoites. The drugs inhibited at nanomolar dosages and its combination demonstrated an antagonistic interaction in proliferation assays, according to the Chou and Talalay method for drug combination index. However, the drug combination significantly improved the parasite in vitro clearance. The repositioning of well-established drugs opens a short-term strategy to obtain low-cost therapeutics approaches against neosporosis.
From 496 case reports of patients with a corpus carcinoma collected between 1970 and 1976, the clinical findings, separation into clinical stages and the various therapy forms were compiled and evaluated. As a mean age of 62.3 years, 56.9 per cent of patients reached an average five-year, recidivation-free survival periods. Metastases occurred in 19.1 per cent of all treated women, vaginal recidivations in 1.8 per cent. Particular attention was given to the side effects of radiation therapy and retarded harmful effects. In this connexion an increase in complications following treatment with newly introduced radiation qualities had to be recorded. 21.9 per cent of all radiation-treated patients differed side-effects, and in 11.7 per cent of all radiation-treated women retarded harmful effects were found. Owing to the experience collected meanwhile in radiotherapy with ultra-hard X-rays and to the use of computerized tomography establishing the adequate quantity of radiation, complications following radiation treatment are expected to occur less frequently in future. (orig./MG) [de
Full Text Available Disinfectant and antibacterial properties of ozone are utilized in the treatment of nonhealing or ischemic wounds. We present here a case of 59 years old woman with compartment syndrome following surgical treatment of stress fracture of proximal tibia with extensively infected wound and exposed tibia to about 4/5 of its extent. The knee joint was also infected with active pus draining from a medial wound. At presentation the patient had already taken treatment for 15 days in the form of repeated wound debridements and parenteral antibiotics, which failed to heal the wound and she was advised amputation. Topical ozone therapy twice daily and ozone autohemotherapy once daily were given to the patient along with daily dressings and parenteral antibiotics. Within 5 days, the wound was healthy enough for spilt thickness skin graft to provide biological dressing to the exposed tibia bone. Topical ozone therapy was continued for further 5 days till the knee wound healed. On the 15th day, implant removal, intramedullary nailing, and latissimus dorsi pedicle flap were performed. Both the bone and the soft tissue healed without further complications and at 20 months follow-up, the patient was walking independently with minimal disability.
van Tubergen, A.; Landewé, R.; van der Heijde, D.; Hidding, A.; Wolter, N.; Asscher, M.; Falkenbach, A.; Genth, E.; Thè, H. G.; van der Linden, S.
To determine the efficacy of combined spa-exercise therapy in addition to standard treatment with drugs and weekly group physical therapy in patients with ankylosing spondylitis (AS). A total of 120 Dutch outpatients with AS were randomly allocated into 3 groups of 40 patients each. Group 1 (mean
Bethell, Delia; Hall, Georgina; Goodman, T Robin; Klein, Nigel; Pollard, Andrew J
Orbitocerebral aspergillosis has a very high fatality rate and cure is unusual. We describe the successful management of a child with cereberal aspergillosis who had a dramatic response to therapy with a combination of liposomal amphotericin and voriconazole with adjunctive cytokine therapy during immunosuppresive chemotherapy for acute lymphoblastic leukaemia.
Wen, Ling; Chen, Ling; Zheng, Shimin; Zeng, Jianfeng; Duan, Guangxin; Wang, Yong; Wang, Guanglin; Chai, Zhifang; Li, Zhen; Gao, Mingyuan
Ultrasmall biocompatible WO3 - x nanodots with an outstanding X-ray radiation sensitization effect are prepared, and demonstrated to be applicable for multi-modality tumor imaging through computed tomography and photoacoustic imaging (PAI), and effective cancer treatment combining both photothermal therapy and radiation therapy. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
K. Pike (Karin)
textabstractSevere combined immunodeficiency (SCID) is a rare class of primary, inherited, immunodeficiency causing infants to suffer from persistent diarrhea, opportunistic infections and a failure to thrive. RAG proteins play a crucial role in the initiation of V(D)J recombination of
Yu, Jin-ming; Meng, Xiang-jiao
Single modality treatment of advanced gastrointestinal cancer has been associated with unfavorable outcomes. Radiotherapy as an important component of the combined modality therapy of gastrointestinal tract tumors may achieve down-staging, increase resection rate while preserving sphincter function, decrease local recurrence rate, and improve survival rate. Precision radiotherapy has better conformity, accuracy, and lower toxicity. Precision radiotherapy will become more and more important in the combined modality therapy of gastrointestinal tract cancer.
Cavalcante, Ludimila; Kelsen, David P; Yu, Kenneth H
Due to its extremely high mortality rates, strong efforts continue to be made to develop new therapies in the treatment of pancreatic adenocarcinoma. The use of combined modality chemoradiotherapy for the treatment of pancreatic adenocarcinoma remains an approach with both promise and controversy. This article reviews the conflicting data with regards to role of combined modality therapy in pancreatic adenocarcinoma and provides an update on current studies in the field.
Ghanbari, Ali; Askarzadeh, Saghar; Petramfar, Peyman; Mohamadi, Marzieh
Migraine is one of the most frequent headaches. Cervical myofascial and trigger point disorders are effective factors on accession of this type of headache. PRT is an indirect technique that treats trigger points. The purpose of this study was to compare the effectiveness of trigger points' management by positional release therapy (PRT) combined with routine medical therapy and routine medical therapy alone in treatment of migraine headache. Forty-four patients with active trigger points in cervical muscles entered to the study. They were randomly assigned to PRT-medical therapy or medical therapy group. Headache frequency, intensity, duration and tablet count were recorded by use of a daily headache diary. The sensitivity of trigger points was assessed by the use of a digital force gauge (Wagner-FDIX). Cervical range of motion was measured by a goniometer. Both groups showed significant reduction in headache intensity, frequency, duration and tablet count after 4 months follow up. The sensitivity of trigger points and all cervical range of motions significantly increased in PRT-medical group after 4 months follow up; however in medication group except cervical right lateral flexion, right and left rotation the other factors showed no change after 4 months follow up. In comparison of the two study groups, there was no significant difference in headache-related variables. Apart from the headache intensity and tablet count, the trends of other factors were significantly different between the two groups (p < 0.05). The combined PRT-medical therapy is more effective than the medical therapy alone. Thus, the combination of PRT and medical therapy is suggested as a treatment choice for patients with migraine headache.
The purpose of this article is to formulate a theoretical conceptualization for utilizing ego state therapy (EST) as an adjunct with cognitive hypnotherapy (CH) for depression. As the relationship between life events and onset of depression is very complex, it is not clear from current literature how stressors cause depressive symptoms. The notion of "wounded self," derived from the work of Wolfe (2005, 2006), is examined as a potential unifying concept for binding the role of risk factors in the precipitation of depression. By incorporating wounded self, the circular feedback model of depression, on which CH for depression is based, is expanded. This revised version provides conceptual and empirical underpinnings for integrating EST with CH in the management of depression.
Ravenhall, Matt; Benavente, Ernest Diez; Mipando, Mwapatsa
BACKGROUND: Malawi experienced prolonged use of sulfadoxine/pyrimethamine (SP) as the front-line anti-malarial drug, with early replacement of chloroquine and delayed introduction of artemisinin-based combination therapy. Extended use of SP, and its continued application in pregnancy is impacting...
Molife, Cliff; Bernauer, Mark J; Farr, Amanda M; Haynes, Virginia S; Kelsey, Doug
Several stimulant and nonstimulant medications are used alone or in combination to treat attention-deficit/hyperactivity disorder (ADHD). Little is known about the current prevalence and predictors of combination therapy. This analysis describes ADHD medication use focusing on combination versus monotherapy. Health insurance claims from the Truven Health MarketScan® Commercial Database and Multi-State Medicaid Database were analyzed for patients with an ADHD diagnosis (International Classification of Diseases, Ninth Revision codes 314.0x). Patients included were aged ≥ 6 years as of January 2010, continuously enrolled from July 2009 through December 2010, and had a claim for an ADHD medication in 2010. Medication use was measured in treatment months during 2010. Baseline demographic and clinical predictors of combination therapy (> 1 ADHD medication class in the same month) involving atomoxetine, long-acting stimulants, and α2-adrenergic agonists were explored using logistic regression, with generalized estimating equations to account for within-patient correlation between months. Commercially insured patients with ADHD (N = 211 226) were primarily aged 6 to 17 years (58.4%) and male (61.5%). Attention-deficit/hyperactivity disorder with hyperactivity was present in 15.8% of these patients. Combination therapy was used in 10.3% of 1 125 119 treatment months. Short-acting stimulants and α2-adrenergic agonists had the highest combination use (45.3% and 54.0%, respectively). Patients with ADHD insured through Medicaid (N = 125 104) were primarily aged 6 to 17 years (94.4%) and male (69.5%). Hyperactivity was present in 39.7% of these patients. Combination therapy was used in 24.0% of 721 986 treatment months. Short-acting stimulants, α2-adrenergic agonists, and intermediate-acting stimulants had the highest combination use (70.0%, 63.8%, and 51.8%, respectively). In multivariate models for both data sources, female patients were less likely to use combination
Grgov, Saša; Stamenković, Perica; Janjić, Dejan
Endoscopic injection therapy of epinephrine is safe and effective in the treatment of bleeding peptic ulcer, but with high risk of rebleeding. The combination therapy of epinephrine and hemoclips could lead to a reduction of rebleeding and a potential reduction in mortality. To investigate the efficacy and safety of epinephrine injection therapy and combination therapy with epinephrine and hemoclips in treating bleeding peptic ulcers. A prospective randomized study included 58 patients with bleeding gastric or duodenal ulcer. In 30 patients endoscopic injection therapy with diluted epinephrine was applied (group I), while in 28 patients combination therapy of epinephrine and hemoclips was applied (group II). RESULTS; Initial haemostasis was achieved in most patients treated with epinephrine injection therapy (93.3%) and patients treated with combination therapy of epinephrine and hemoclips (96.4%). After initial haemostasis was achieved rebleeding was significantly more frequent in the patients treated with epinephrine (28.5%) than in the patients treated with combination therapy (3.7%, p < 0.05). Two patients treated with epinephrine injection therapy were subjected to surgical intervention, whereas no patient treated with combination therapy needed surgery. Lethal ending occurred in one patient treated with epinephrine and in one patient treated with combination therapy. The difference between the two groups of patients in need for surgical intervention and mortality was not statistically significant. Combination therapy with epinephrine and hemoclips is more efficient than epinephrine alone in the treatment of bleeding peptic ulcers.
Full Text Available Introduction. Endoscopic injection therapy of epinephrine is safe and effective in the treatment of bleeding peptic ulcer, but with high risk of rebleeding. The combination therapy of epinephrine and hemoclips could lead to a reduction of rebleeding and a potential reduction in mortality. Objective. To investigate the efficacy and safety of epinephrine injection therapy and combination therapy with epinephrine and hemoclips in treating bleeding peptic ulcers. Methods. A prospective randomized study included 58 patients with bleeding gastric or duodenal ulcer. In 30 patients endoscopic injection therapy with diluted epinephrine was applied (group I, while in 28 patients combination therapy of epinephrine and hemoclips was applied (group II. Results. Initial haemostasis was achieved in most patients treated with epinephrine injection therapy (93.3% and patients treated with combination therapy of epinephrine and hemoclips (96.4%. After initial haemostasis was achieved rebleeding was significantly more frequent in the patients treated with epinephrine (28.5% than in the patients treated with combination therapy (3.7%, p<0.05. Two patients treated with epinephrine injection therapy were subjected to surgical intervention, whereas no patient treated with combination therapy needed surgery. Lethal ending occurred in one patient treated with epinephrine and in one patient treated with combination therapy. The difference between the two groups of patients in need for surgical intervention and mortality was not statistically significant. Conclusion. Combination therapy with epinephrine and hemoclips is more efficient than epinephrine alone in the treatment of bleeding peptic ulcers.
Yoon, Won Sup; Yang, Dae Sik; Kim, Chul Yong
To compare radiation therapy alone to combined modality therapy about survival rate and tolerance of elderly patients (70 = or ≥) with non-small-cell lung cancer (NSCLC). Between 1998 and 2002, 57 patients given radiation therapy due to NSCLC (Stage III) were analysed retrospectively. Radiation therapy alone (RT), concurrent chemoradiation (CRT), and sequential chemoradiation (SCRT) was done to 33, 16 and 8 patients, respectively. Patient's median age was 74 (range 70 ∼ 85). Male and female are 51 patients and 6 patients, respectively. 23 patients were stage IIIa and 34 were stage IIIb. Patients' characteristic distribution of RT and CRT was not significantly different except mass size that RT has a bigger than CRT. The fraction size of radiation therapy was 1.8 Gy in CRT and 1.8 ∼ 3 Gy in other groups. Total radiation dose was 51 ∼ 63 Gy according to the fraction size. If the prescribed total radiation dose was successfully irradiated, we stated that it was completion of radiation therapy. 52 patients was dead. Median period of radiation therapy was as follow: RT, 35 days, CRT, 60.5 days and SCRT, 35 days. Overall median survival time (MST) was 10.1 months. The 1 yr-and 2 yr-overall survival rate was 39.8% and 17.6%, respectively. MST of RT, CRT and SCRT was 8.9, 8.2 and 11.7 months, respectively. The 1 yr survival rate of RT, CRT and SCRT was 38.4%, 37.5% and 50% (not significant). Patients given incomplete radiation therapy were 12 (RT, 5 CRT, 6 SCRT, 1). N stage (ρ = 0.081) and the difference of treatment methods (ρ = 0.079) were the factors affecting incompletion of radiation therapy, but it was not significant. In case of combined-agents chemotherapy, 4 of 8 ceased radiation therapy. T stage (T ≥ 3), mass size (≥ 5 cm), Karnofsky performance scale (≤ 70) and completion of radiation therapy were the prognostic factors in uni-and multi-variate analysis. In elderly patients wit NSCLC, radiation therapy alone was a treatment method with similar
Mizusawa, Hirokazu; Takahashi, Toshio
Twelve cases of carcinoma of the rectum were treated preoperatively by combination therapy with 5-fluorouracil (5-FU) suppository (100 mg twice a day consecutively, a total dose of more than 4,000 mg) and irradiation (300 rad x 3/week, a total dose of 3,000 rad). This group was compared with 34 cases given single preoperative 5-FU therapy and 24 control cases given no preoperative adjuvant modality. The group treated by preoperative combination therapy showed marked antitumor effects macroscopically and histologically. In addition, decrease in local recurrence was expected for this group, compared with the other two groups. (Chiba, N.)
V. L. Filinov
Full Text Available Results of follow-up of patient with melanoma metastases to inguinal lymph nodes (two tumor foci are represented. The patient underwent a course of combined photodynamic therapy and distant gamma-ray therapy. Single intravenous injection of fotosens as photosensitizer at dose of 0.3 mg/kg was administered to the patient. Distant gamma-ray therapy was performed daily during 12 days (single dose of 3 Gy, total dose of 36 Gy, beginning in a day after injection of photosensitizer. Two hours after gamma-ray therapy session contact photodynamic therapy on both metastatic tumors was performed. There were 7 sessions of photodynamic therapy in all, total light dose on each tumor accounted for 1800 J. Three weeks after combined modality treatment the second step of radiotherapy on inguinal region including 12 daily irradiation sessions (single dose of 3 Gy, total dose of 36 Gy was performed. One year after treatment the patient had complete tumor resorption proved in 6 months. There were no additional treatment during this period in this patient. The patient is still under follow-up.
Full Text Available In healthy individuals, immune checkpoint molecules prevent autoimmune responses and limit immune cell-mediated tissue damage. Tumors frequently exploit these molecules to evade eradication by the immune system. Over the past years, immune checkpoint blockade of cytotoxic T lymphocyte antigen-4 (CTLA-4 and programmed death-1 (PD-1 emerged as promising strategies to activate anti-tumor cytotoxic T cell responses. Although complete regression and long-term survival is achieved in some patients, not all patients respond. This review describes promising, novel combination approaches involving immune checkpoint blockade, aimed at increasing response-rates to the single treatments.
Hosseini, Seyed Mojtaba; Farahmandnia, Mohammad; Razi, Zahra; Delavari, Somayeh; Shakibajahromi, Benafsheh; Sarvestani, Fatemeh Sabet; Kazemi, Sepehr; Semsar, Maryam
Brain stroke is the second most important events that lead to disability and morbidity these days. Although, stroke is important, there is no treatment for curing this problem. Nowadays, cell therapy has opened a new window for treating central nervous system disease. In some previous studies the Mesenchymal stem cells and neural stem cells. In this study, we have designed an experiment to assess the combination cell therapy (Mesenchymal and Neural stem cells) effects on brain stroke. The Mesenchymal stem cells were isolated from adult rat bone marrow and the neural stem cells were isolated from ganglion eminence of rat embryo 14 days. The Mesenchymal stem cells were injected 1 day after middle cerebral artery occlusion (MCAO) and the neural stem cells transplanted 7 day after MCAO. After 28 days, the neurological outcomes and brain lesion volumes were evaluated. Also, the activity of Caspase 3 was assessed in different groups. The group which received combination cell therapy had better neurological examination and less brain lesion. Also the combination cell therapy group had the least Caspase 3 activity among the groups. The combination cell therapy is more effective than Mesenchymal stem cell therapy and neural stem cell therapy separately in treating the brain stroke in rats.
Shakeeb, N.; Noor, S.M.; Paracha, M.M.; Ullah, G.
Objective:To compare the efficacy of intense pulse light therapy (IPL) and triple combination cream (TCC) versus intense pulse light therapy and triple combination cream alone in epidermal melasma treatment, downgrading MASI score to more than 10. Study Design:Randomized controlled trial. Place and Duration of Study:Dermatology Department, Lady Reading Hospital, Peshawar, from August 2014 to January 2015. Methodology:Patients of 18-45 years were included in the study with Fitzpatrick skin type II-V. Sample of 96 patients was divided in to three groups of 32 each, through consecutive (non-probability) sampling method. Detailed history was taken, Woods Lamp Examination done, and melasma area and severity index (MASI) score was calculated. TCC had to be applied daily at night for two months by group A patients while group B was consigned for IPL therapy fortnightly, and those in group C were given both for two months. Efficacy was compared by recalculating MASI score at treatment end as well as at follow-up after 4 weeks, using Chi-square test with significance at p < 0.05. Results:Male and female patients were 10 (31.2%) and 22 (68.8%) in group A, 7 (21.9%) and 25 (78.1%) in group B, while in group C were 12 (37.5%) and 20 (62.5%). The average age was 28.70 +8.70 years. MASI score reduction was achieved in 22 (68.8%) patients in group A; whereas, in 20 (62.5%) and 30(93.8%) patients in group B and C, respectively. Efficacy-wise distribution was significant (p=0.009). Conclusion:Intense pulse light therapy and triple combination cream are more efficacious in epidermal melasma treatment than intense pulse light therapy and triple combination cream alone. (author)
Lo, Victor C K; Akens, Margarete K; Wise-Milestone, Lisa; Yee, Albert J M; Wilson, Brian C; Whyne, Cari M
Photodynamic therapy (PDT) has been shown to ablate tumors within vertebral bone and yield short-term improvements in vertebral architecture and biomechanical strength, in particular when combined with bisphosphonate (BP) treatment. Longer-term outcomes of PDT combined with current treatments for skeletal metastases are essential to understand its therapeutic potential. The objective of this study is to evaluate the response of vertebrae to PDT after a longer (6-week) time period, alone and combined with previous BP or radiation treatment (RT). Sixty-three female rnu/rnu rats were randomized to six treatment groups: untreated control, BP-only, RT-only, PDT-only, combined BP + PDT and combined RT + PDT. L2 vertebrae were structurally analyzed through µCT-based analysis, axial compressive load-to-failure testing and histological analysis of morphology, osteoid formation and osteoclast activity. Combined BP + PDT treatment yielded the largest improvements in bone architecture with combined RT + PDT treatment yielding similar findings, but of a lesser magnitude. Mechanically, ultimate force and stress were correlated to stereological parameters that demonstrated a positive structural effect from combinatory treatment. Increased osteoid formation was observed in both combination therapies without any significant differences in osteoclast activity. Overall, multimodality treatment demonstrated a sustained positive effect on vertebral structural integrity, motivating PDT as a minimally-invasive adjuvant treatment for spinal metastases. Copyright © 2013 Orthopaedic Research Society.
using survival methods. Ten age strata were chosen: less than 2, 2-5, 6-12, 13-17, 18-29, 30-39 (reference group), 40-49, 50-54, 55-59 and 60 years or older; those aged 6 years or more were included in multivariable analyses. RESULTS: The four youngest age groups had 223, 184, 219 and 201 individuals...... and the three oldest age groups had 2693, 1656 and 1613 individuals. Precombination antiretroviral therapy CD4 cell counts were highest in young children and declined with age. By 12 months, 53.7% (95% confidence interval: 53.2-54.1%) and 59.2% (58.7-59.6%) had experienced a virological and immunological...... response. The probability of virological response was lower in those aged 6-12 (adjusted hazard ratio: 0.87) and 13-17 (0.78) years, but was higher in those aged 50-54 (1.24), 55-59 (1.24) and at least 60 (1.18) years. The probability of immunological response was higher in children and younger adults...
Zhao Jingguo; Ni Yanjun; Song Xiangfu; Li Yanyi; Yang Wei; Sun Ting; Ma Qingjie; Gao Fengtong
Objective: To explore the anti-tumor effects of Egr-IFNγ gene therapy combined with 125 I-UdR radionuclide therapy in mice bearing H22 hepatocarcinoma and its mechanism. Methods: The recombinant plasmid pcDNAEgr-IFNγ mixed with liposome was injected into tumor. 48 h later, 370 kBq 125 I-UdR was injected into tumor. The tumor growth rates at different times were observed. After 3 d gene-radionuclide therapy, the concentration of IFNγ in cytoplasm of H22 cells and cytotoxic activities of splenic CTL of the mice in different groups were examined. Results: The tumor growth rates of pcDNAEgr-IFNγ + 125 I-UdR group were obviously lower than those of control group, 125 I-UdR group and pcDNAEgr-1 + 125 I-UdR group 6-15 d after gene-radionuclide therapy. IFNγ protein was found in cytoplasm of H22 cells in pcDNAEgr-IFNγ + 125 I-UdR group after 3 d gene-radionuclide therapy. Cytotoxic activity of splenic CTL in pcDNAEgr-IFNγ + 125 I-UdR group was significantly higher than that in the other groups (P 125 I-UdR radionuclide therapy are better than those of 125 I-UdR therapy. (authors)
de Man, R. A.; Schalm, S. W.; Heijtink, R. A.; Berk, L.; den Ouden, J.; ten Kate, F. J.; Chamuleau, R. A.; Reesink, H. W.
For patients with chronic hepatitis B e (HBe)-positive hepatitis, long-term results of pilot studies with lymphoblastoid interferon-alpha, acyclovir, or a combination, and of a randomized controlled trial of interferon/desciclovir combination therapy are presented. HBe seroconversion was observed in
Yu. A. Barsukov
Full Text Available A new combined treatment scheme with short-course chemoradiotherapy and 2 selective radiosensitizers (metronidazole in a polymeric composition and local hyperthermia is investigated in this article.Material and methods. 77 T1–3N0–2M0 rectal cancer patients treatment data was analyzed. All patients received 5 Ч 5 Gy radiotherapy with capecitabine 1300 mg/m2 days 1–5 per os and radiosensitization with local hyperthermia and metronidazole.Results. Investigated treatment scheme has acceptable toxicity and leads to high local control rate (none of the patients experienced local recurrence. 7 (9.1 % patients developed distant metastases. 59 (76.6 % patients had sphincter-sparing surgery. Median followup was 65.6 months. 5-year survival rate was 81.7 %.Conclusion. Developed treatment scheme is safe and leads to high local control rate.
Full Text Available Abstract Recent publications put a serious warning regarding the inefficacy of sulphadoxine-pyrimethamine (SP for the intermittent preventive treatment of malaria in young children (IPTi. Recommendations for other therapies are being made. By using a different and better sulphonamide (sulphamethoxypyrazine, it is possible to manufacture fixed dose combination pills with artesunate and pyrimethamine. This combination permits a full therapy over 24 hours (dosing interval being 12 hours. It is recommended that this combination should be tested in future field studies of IPTi.
Koo, John; Behnam, Shahdad E; Behnam, Shahrad M
Tazarotene (Tazorac, Allergan, Inc.) is the first topical retinoid approved for the treatment of plaque psoriasis. It has a similar onset of action compared to potent topical steroids and has the advantage of a longer remission. The common side effects associated with the drug include skin irritation (including pruritus), erythema and a burning sensation. To overcome some of these shortcomings, it has been used in combination with steroids, calcipotriene and phototherapy. Combination therapy not only results in a decrease in adverse side effects, but also enhanced efficacy. Clinical study data have shown that combination therapy is just as important as tazarotene monotherapy, if not more.
R M Balabanova
Full Text Available Ummary Objective. To reveal J'reguency of accompaning virus infection and possibility to use antivirus therapy together in therapy RA. Material. 40 patients with RA at the age of 17-45 were studied. The duration of disease was not more than 6 months; patients had 2-3 degrees of activity. Every one had a positive rheumatoid factor. Results. 78,2% of the examined patients connected the beginning of the illness with virus infection they have had. The most difficalt variant of RA course and uneffectiveness of basic therapy were registerd among the patients with combination HSV and CMV infection. Inclusion of Cymevene in complex therapy RA has exerted positive influence on clinical-laboratory, signs stregthened effect of basic therapy. Conclusion. The most difficult variant of RA course was registered among the patients with virus infection. Inclusion of antivirus drugs had a positive influence on effectiveness of basic therapy.
Jacobs, David M; Safir, M Courtney; Huang, Dennis; Minhaj, Faisal; Parker, Adam; Rao, Gauri G
The spread of carbapenemase-producing K. pneumoniae (CPKP) has become a significant problem worldwide. Combination therapy for CPKP is encouraging, but polymyxin resistance to many antibiotics is hampering effective treatment. Combination therapy with three or more antibiotics is being increasingly reported, therefore we performed a systematic review of triple combination cases in an effort to evaluate their clinical effectiveness for CPKP infections. The PubMed database was searched to identify all published clinical outcomes of CPKP infections treated with triple combination therapy. Articles were stratified into two tiers depending on the level of clinical detail provided. A tier 1 study included: antibiotic regimen, regimen-specific outcome, patient status at onset of infection, and source of infection. Articles not reaching these criteria were considered tier 2. Thirty-three studies were eligible, 23 tier 1 and ten tier 2. Among tier 1 studies, 53 cases were included in this analysis. The most common infection was pneumonia (31%) followed by primary or catheter-related bacteremia (21%) and urinary tract infection (17%). Different combinations of antibiotic classes were utilized in triple combinations, the most common being a polymyxin (colistin or polymyxin B, 86.8%), tigecycline (73.6%), aminoglycoside (43.4%), or carbapenem (43.4%). Clinical and microbiological failure occurred in 14/39 patients (35.9%) and 22/42 patients (52.4%), respectively. Overall mortality for patients treated with triple combination therapy was 35.8% (19/53 patients). Triple combination therapy is being considered as a treatment option for CPKP. Polymyxin-based therapy is the backbone antibiotic in these regimens, but its effectiveness needs establishing in prospective clinical trials.
Leung, Stephanie; Bulloch, Blake; Young, Christine; Yonker, Marcy; Hostetler, Mark
To compare outcomes of pediatric migraine patients treated in an emergency department (ED) before and after implementation of a standardized combination intravenous therapy regimen aimed toward improving and standardizing abortive migraine therapy. In a pediatric ED, migraines represent 8-18% of all headache visits. Despite this large number, no standard treatment for acute migraine therapy currently exists. The study utilized a retrospective chart review of patients seeking acute migraine treatment at a tertiary care, pediatric ED from August 2006 to March 2010. Inclusion criteria were pediatric migraine patients as defined by International Headache Society guidelines. The comparison population received various migraine therapies based on attending practice preference. After October 2008, patients received standardized intravenous combination therapy involving a normal saline fluid bolus, ketorolac, prochlorperazine, and diphenhydramine. Occasionally, metoclopramide was substituted during prochlorperazine shortages. Reduction in headache pain score was the primary outcome. Secondary outcome measures included length of ED stay, hospital admission rate, and ED readmission rate within 48 hours. The study yielded 87 patients who received standardized combination therapy and 165 comparison patients. No significant difference in patient characteristics existed when evaluating patient demographics, outpatient medication use, and initial headache pain score. When compared with the non-standardized therapy population, the combination therapy patients revealed significant reductions in pain score (decrease of 5.3 vs. 6.9, difference -1.6, 95% confidence interval -2.2 to -0.8, P pediatric migraine therapy in the ED by significantly reducing headache pain scores, length of ED stay, and hospital admission rates. © 2013 American Headache Society.
Boudagov, R.; Oulianova, L.
Radiation accidents of the 5-7 th levels according to IAEA scale lead to life-threatening acute radiation syndrome and many patients will probably suffer from additional thermal burns. These combined injuries (CI) will be among the most difficult to achieve survival. Present therapeutic means need to augment with new approaches to stimulate host defence mechanisms, blood system recovery and to enhance survival. The evaluation of therapeutic properties of human recombinant G-CSF, IL-1,IL-2 and other so called 'biological response modifiers' on survival and blood recovery after CI was the purpose of this work. Experiments carried out with mice CBA x C57BL6 receiving 7 Gy total body irradiation followed by a full-thickness thermal bum of 10% of body surface. It established that G-CSF does not exhibit a positive modifying action on the damage level and on hematopoietic recovery. I.p two-four/fold infusion of IL-2 during the initial 2 days has provided a significant statistically survival increase from 40% (untreated mice with CI) to 86%. Single s.c IL-1 injection resulted in abrupt deterioration of the outcome when dealing with CI; three/fold administration of IL-1 in 2,4 and 6 days after CI did not increase survival. Extracellular yeast polysaccharides resulted only a 15 to 30% increase in survival it given 1 h after CI. The best results obtained when mixture of heat-killed L.acidophilus injected s.c immediately alter CI - survival has increased from 27% (untreated mice) to 80%. Revealed beneficial effects of IL-2 and biological response modifiers did not accompany by a corresponding correction of depressed hematological parameters
Full Text Available 2-Methoxyestradiol (2-ME has potent anti proliferative effects on cancer cells. Its utility alone or in combination with other therapies for treating prostate cancer, however, has not been fully explored. Androgendependent, independent human prostate cancer cells were examined in vivo for their response to combination therapy. Efficacy was assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay, measuring microvessel density (MVD in excised tumors. Animals harboring hormonedependent tumors treated with 2-ME alone, androgen deprivation therapy alone, or the combination of the two had a 3.1-fold, 5.3-fold, 10.1-fold increase in apoptosis, respectively. For hormone-independent tumors, treatment with 2-ME resulted in a 2.43-fold increase in apoptosis, a 73% decrease in MVD. 2-ME was most effective against hormone-dependent tumors in vivo, combination therapy resulted in a significant increase in efficacy compared to no treatment controls, trended toward greater efficacy than either 2-ME or androgen deprivation alone. Combination therapy should be investigated further as an additional therapeutic option for early prostate cancer.
Otieno Dorothy N
Full Text Available Abstract Backgound Sulphadoxine/sulphalene-pyrimethamine (SP was adopted in Kenya as first line therapeutic for uncomplicated malaria in 1998. By the second half of 2003, there was convincing evidence that SP was failing and had to be replaced. Despite several descriptive investigations of policy change and implementation when countries moved from chloroquine to SP, the different constraints of moving to artemisinin-based combination therapy (ACT in Africa are less well documented. Methods A narrative description of the process of anti-malarial drug policy change, financing and implementation in Kenya is assembled from discussions with stakeholders, reports, newspaper articles, minutes of meetings and email correspondence between actors in the policy change process. The narrative has been structured to capture the timing of events, the difficulties and hurdles faced and the resolutions reached to the final implementation of a new treatment policy. Results Following a recognition that SP was failing there was a rapid technical appraisal of available data and replacement options resulting in a decision to adopt artemether-lumefantrine (AL as the recommended first-line therapy in Kenya, announced in April 2004. Funding requirements were approved by the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM and over 60 million US$ were agreed in principle in July 2004 to procure AL and implement the policy change. AL arrived in Kenya in May 2006, distribution to health facilities began in July 2006 coincidental with cascade in-service training in the revised national guidelines. Both training and drug distribution were almost complete by the end of 2006. The article examines why it took over 32 months from announcing a drug policy change to completing early implementation. Reasons included: lack of clarity on sustainable financing of an expensive therapeutic for a common disease, a delay in release of funding, a lack of comparative efficacy data
SA HIV Clinicians Society
Full Text Available This document serves to guide clinicians and programme managers on how to switch from 3 separate antiretroviral (ARV drugs to the new, single, fixed-dose combination (FDC tablet containing tenofovir (TDF, emtricitabine (FTC and efavirenz (EFV. Summary Transitioning from individual drugs to an FDC tablet needs to be managed carefully, particularly regarding stock management, ordering processes, supply-chain integrity and comprehensive patient counselling. Priority groups • Initially, FDC supply will be insufficient to provide for all FDC-suitable patients • Therefore, the National Department of Health (NDoH has recommended that the following patient groups be prioritized for FDC initiation/switch: • Priority group 1: All HIV-positive patients newly initiating ART – adults, adolescents and pregnant women (regardless of CD4 count (amendment to the guidelines for the prevention of mother-to-child transmission of HIV (PMTCT anticipated in April 2013 – and who do not have contra-indications to the FDC component drugs • Priority group 2: HIV-positive pregnant women and breastfeeding mothers currently stable on lamivudine (3TC, TDF and EFV • Priority group 3: Virologically suppressed patients on a stavudine (d4T-based regimen and who have normal renal function • Priority group 4: Stable patients receiving individual TDF, 3TC and EFV and who have tuberculosis (TB co-infection • Priority group 5: Stable patients receiving individual TDF, 3TC and EFV and who have other co-morbidites (e.g. hypertension, diabetes • Priority group 6: Patients receiving individual TDF, 3TC and EFV and who request to switch to the FDC treatment • Priority group 7: Patients receiving individual TDF, 3TC and EFV and who, after counselling, agree to switch to the FDC treatment. Important: Clinic staff must co-ordinate this process and only switch as many patients to the FDC tablet as stock allows. This should avoid patients being switched back and forth
Loh, J.J.K.; Seong, J.S.; Suh, C.O.; Kim, G.E.
Between May 1985 and December 1987, 36 patients with locally advanced (group 1, N = 21) or recurrent cervical carcinoma after curative surgery (group 2, N = 6) or radiation therapy (group 3, N = 9), who were all thought to be refractory to conventional treatment, were treated with combined radiation therapy and hyperthermia. Eight megahertz radio frequency capacitive type of hyperthermia was used. Temperature was measured by inserting a thermocouple through the vaginal fornix, and an attempt was made to maintain 40 0 C or above for 30-50 minutes. External radiation therapy was combined with a total tumor dose of 54-65 Gy in 32 patients, and high-dose-rate intracavitary radiation was added in some cases. Hyperthermia was given twice a week, with a total of four to ten treatments. Chemotherapy was added in two cases, and chemotherapy and hyperthermia without radiation therapy was given in two cases
An, Jingang; Zhang, Dingwei; Wu, Jiawen; Li, Jiong; Teng, Xiu; Gao, Xiaomin; Li, Ruilian; Wang, Xiuying; Xia, Linlin; Xia, Yumin
Both acitretin and methotrexate are effective in ameliorating psoriatic lesion. However, their combination has been seldom reported in the treatment of psoriasis because of the warning regarding the potential hepatotoxicity of the drug interactions. This study was designed to investigate the effectiveness of such combination therapy for psoriasis vulgaris, and the potential benefit as well as side effect during the treatment. Thirty-nine patients with psoriasis vulgaris were treated with acitretin, methotrexate or their combination or as control. Similarly, K14-VEGF transgenic psoriasis-like mice were treated with these drugs. Human primary keratinocytes and hepatic stellate cells were used for analyzing their effect in vitro. The results showed that the combination therapy exhibited higher effectiveness in remitting skin lesion, but did not significantly affect the liver function of both patients and mice. Moreover, the combination groups showed less elevation of profibrotic factors in sera when compared with methotrexate alone groups accordingly. Furthermore, primary keratinocytes expressed more involucrin as well as loricrin and proliferated more slowly on the combined stimulation. Interestingly, such combination treatment induced lower expression of profibrotic factors in hepatic stellate cells. In conclusion, the acitretin-methotrexate combination therapy for psoriasis vulgaris can achieve higher effectiveness and result in less liver fibrosis. Copyright © 2017 Elsevier Ltd. All rights reserved.
Aleksandr Vitalyevich Volkov
Full Text Available Systemic connective tissue diseases, systemic scleroderma in particular, constitute a group of diseases in which vascular disorders underlying diverse clinical manifestations are one of the pathogenetic components. Raynaud 's syndrome and ulceration are the most common symptoms of these diseases, which influence quality of life in patients and require constant drug therapy. The paper discusses the authors' clinical experience with intravenous iloprost used in the combination therapy of the vascular manifestations of systemic scleroderma and systemic lupus erythematosus.
Hay, Jodie F; Lappin, Katrina; Liberante, Fabio; Kettyle, Laura M; Matchett, Kyle B; Thompson, Alexander; Mills, Ken I
Several histone deacetylase inhibitors including Vorinostat have received FDA approval for the treatment of haematological malignancies. However, data from these trials indicate that Vorinostat has limited efficacy as a monotherapy, prompting the need for rational design of combination therapies. A number of epi-sensitised pathways, including sonic hedgehog (SHH), were identified in AML cells by integration of global patterns of histone H3 lysine 9 (H3K9) acetylation with transcriptomic analysis following Vorinostat-treatment. Direct targeting of the SHH pathway with SANT-1, following Vorinostat induced epi-sensitisation, resulted in synergistic cell death of AML cells. In addition, xenograft studies demonstrated that combination therapy induced a marked reduction in leukemic burden compared to control or single agents. Together, the data supports epi-sensitisation as a potential component of the strategy for the rational development of combination therapies in AML.
Pandit, Aridaman; de Boer, Rob J
Highly active antiretroviral therapy (ART) has successfully turned Human immunodeficiency virus type 1 (HIV-1) from a deadly pathogen into a manageable chronic infection. ART is a lifelong therapy which is both expensive and toxic, and HIV can become resistant to it. An alternative to lifelong ART is gene therapy that targets the CCR5 co-receptor and creates a population of genetically modified host cells that are less susceptible to viral infection. With generic mathematical models we show that gene therapy that only targets the CCR5 co-receptor fails to suppress HIV-1 (which is in agreement with current data). We predict that the same gene therapy can be markedly improved if it is combined with a suicide gene that is only expressed upon HIV-1 infection.
Full Text Available NF-κB signaling plays an important role in tumor cell proliferation, cell survival, angiogenesis, invasion, metastasis and drug/radiation resistance. Combination therapy involving NF-κB pathway inhibition is an attractive strategy for the treatment of advanced forms of thyroid cancer. This study was designed to test the efficacy of NF-κB pathway inhibition in combination with cytotoxic chemotherapy, using docetaxel and ionizing radiation in in vitro models of thyroid cancer. We found that while both docetaxel and ionizing radiation activated NF-κB signaling in thyroid cancer cells, there was no synergistic effect on cell proliferation and/or programmed cell death with either genetic (transduction of a dominant negative mutant form of IκBα or pharmacologic (proteasome inhibitor bortezomib and IKKβ inhibitor GO-Y030 inhibition of the NF-κB pathway in thyroid cancer cell lines BCPAP, 8505C, THJ16T and SW1736. Docetaxel plus bortezomib synergistically decreased in vitro invasion of 8505C cells, but not in the other cell lines. Screening of a panel of clinically relevant targeted therapies for synergy with genetic NF-κB inhibition in a proliferation/cytotoxicity assay identified the histone deacetylase (HDAC inhibitor suberoylanilide hydroxamic acid (SAHA as a potential candidate. However, the synergistic effect was confirmed only in the BCPAP cells. These results indicate that NF-κB inhibitors are unlikely to be beneficial as combination therapy with taxane cytotoxic chemotherapy, external radiation therapy or radioiodine therapy. There may be unique circumstances where NF-κB inhibitors may be considered in combination with docetaxel to reduce tumor invasion or in combination with HDAC inhibitors to reduce tumor growth, but this does not appear to be a combination therapy that could be broadly applied to patients with advanced thyroid cancer. Further research may identify which subsets of patients/tumors may respond to this therapeutic
Mayanja-Kizza, H; Oishi, K; Mitarai, S; Yamashita, H; Nalongo, K; Watanabe, K; Izumi, T; Ococi-Jungala; Augustine, K; Mugerwa, R; Nagatake, T; Matsumoto, K
We performed a randomized trial in which combination therapy with fluconazole and short-term flucytosine was compared with fluconazole monotherapy in 58 patients with AIDS-associated cryptococcal meningitis (CM). Thirty of these patients were randomized to receive combination therapy with fluconazole, 200 mg once a day for 2 months, and flucytosine, 150 mg/(kg.d) for the first 2 weeks, and 28 were randomized to receive monotherapy with fluconazole at the same dose for 2 months. Patients in both groups who survived for 2 months received fluconazole as maintenance therapy at a dose of 200 mg three times per week for 4 months. The combination therapy prevented death within 2 weeks and significantly increased the survival rate among these patients (32%) at 6 months over that among patients receiving monotherapy (12%) (P = .022). The combination therapy also resulted in a significant decrease in the severity of headache after 1 month of treatment, compared with monotherapy (P = .005). No serious adverse reactions were observed in patients receiving either regimen. These data indicate that treatment with fluconazole and short-term flucytosine is a cost-effective and safe regimen that improves the quality of life for patients with AIDS-associated CM in developing countries where human immunodeficiency virus is endemic.
Wei Daoyan; Dai Bingbing; Wang Zhonghe; Chen Shishu
Objective: To investigate the synergistic antitumor effects of adenovirus-mediated IL-12 gene therapy in combination with radiotherapy in mice bearing liver cancer. Methods: Balb/c mice bearing liver cancer received the treatment at day 1 with tumor local irradiation (TLI) of 20 Gy or mask irradiation when tumor size reached 0.6-1.0 cm. Within 1 hour after irradiation, adenovirus containing IL-12 gene or PBS was intra-tumor injected once a week. Forty-eight hours after the second injection, IFN-γ levels in sera and the supernatant of cultured spleen cells were assayed by ELISA, CTL activity of spleen cells was measured by 3 H-TdR release assay, and phenotypes of tumor-infiltrating lymphocytes were analysed by immunohistochemical staining. Results: The growth of tumors in animals treated with a combination of IL-12 gene therapy and TLI was inhibited more significantly than those with either single treatment (P + and CD8 + lymphocyte infiltration and tumor-specific cytolytic activities, and the levels of IFN-γ in sera were higher in IL-12 gene therapy and IL-12 gene therapy combined with TLI groups. Conclusion: These results suggest that IL-12 gene therapy combined with radiotherapy is more effective than both single treatment modalities and can induce specific antitumor immuno-response greatly
Lock, James; Fitzpatrick, Kathleen Kara; Agras, William S; Weinbach, Noam; Jo, Booil
Adolescents with anorexia nervosa who have obsessive-compulsive (OC) features respond poorly to family-based treatment (FBT). This study evaluated the feasibility of combining FBT with either cognitive remediation therapy (CRT) or art therapy (AT) to improve treatment response in this at-risk group. Thirty adolescents with anorexia nervosa and OC features were randomized to 15 sessions of FBT + CRT or AT. Recruitment rate was 1 per month, and treatment attrition was 16.6% with no differences between groups. Suitability, expectancy and therapeutic relationships were acceptable for both combinations. Correlations between changes in OC traits and changes in cognitive inefficiencies were found for both combinations. Moderate changes in cognitive inefficiencies were found in both groups but were larger in the FBT + AT combination. This study suggests that an RCT for poor responders to FBT because of OC traits combining FBT with either CRT or AT is feasible to conduct. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.
Li, Xiaosong; Du, Nan; Li, Haijun; Long, Shan; Chen, Dianjun; Zhou, Feifan; Xu, Yuanyuan; Wang, Fuli; Chen, Wei R.
To evaluate the efficacy and safety of photothermal with dinitrophenyl hapten (DNP) for patients with malignant melanoma (MM), Patients with pathology confirmed stage III or IV MM were enrolled. Seventy-two patients were randomized into two groups, DNP alone group (n=36) and DNP plus photothermal therapy group (n=36). The results showed that the patients in the combination treatment group had longer median progression-free survival time (19.0m vs. 12.0m, p=0.007). No severe adverse events were observed in both groups. Thus, the combination of photothermal therapy and DNP maybe a new therapeutic strategy for patients with advanced MM.
Williams, Derek J; Edwards, Kathryn M; Self, Wesley H; Zhu, Yuwei; Arnold, Sandra R; McCullers, Jonathan A; Ampofo, Krow; Pavia, Andrew T; Anderson, Evan J; Hicks, Lauri A; Bramley, Anna M; Jain, Seema; Grijalva, Carlos G
β-Lactam monotherapy and β-lactam plus macrolide combination therapy are both common empirical treatment strategies for children hospitalized with pneumonia, but few studies have evaluated the effectiveness of these 2 treatment approaches. To compare the effectiveness of β-lactam monotherapy vs β-lactam plus macrolide combination therapy among a cohort of children hospitalized with pneumonia. We analyzed data from the Etiology of Pneumonia in the Community Study, a multicenter, prospective, population-based study of community-acquired pneumonia hospitalizations conducted from January 1, 2010, to June 30, 2012, in 3 children's hospitals in Nashville, Tennessee; Memphis, Tennessee; and Salt Lake City, Utah. The study included all children (up to 18 years of age) who were hospitalized with radiographically confirmed pneumonia and who received β-lactam monotherapy or β-lactam plus macrolide combination therapy. Data analysis was completed in April 2017. We defined the referent as β-lactam monotherapy, including exclusive use of an oral or parenteral second- or third-generation cephalosporin, penicillin, ampicillin, ampicillin-sulbactam, amoxicillin, or amoxicillin-clavulanate. Use of a β-lactam plus an oral or parenteral macrolide (azithromycin or clarithromycin) served as the comparison group. We modeled the association between these groups and patients' length of stay using multivariable Cox proportional hazards regression. Covariates included demographic, clinical, and radiographic variables. We further evaluated length of stay in a cohort matched by propensity to receive combination therapy. Logistic regression was used to evaluate secondary outcomes in the unmatched cohort, including intensive care admission, rehospitalizations, and self-reported recovery at follow-up. Our study included 1418 children (693 girls and 725 boys) with a median age of 27 months (interquartile range, 12-69 months). This cohort was 60.1% of the 2358 children enrolled in the
Vestergaard, Martin; Paulander, Wilhelm; Marvig, Rasmus L; Clasen, Julie; Jochumsen, Nicholas; Molin, Søren; Jelsbak, Lars; Ingmer, Hanne; Folkesson, Anders
Combination therapy with several antibiotics is one strategy that has been applied in order to limit the spread of antimicrobial resistance. We compared the de novo evolution of resistance during combination therapy with the β-lactam ceftazidime and the fluoroquinolone ciprofloxacin with the resistance evolved after single-drug exposure. Combination therapy selected for mutants that displayed broad-spectrum resistance, and a major resistance mechanism was mutational inactivation of the repressor gene mexR that regulates the multidrug efflux operon mexAB-oprM. Deregulation of this operon led to a broad-spectrum resistance phenotype that decreased susceptibility to the combination of drugs applied during selection as well as to unrelated antibiotic classes. Mutants isolated after single-drug exposure displayed narrow-spectrum resistance and carried mutations in the MexCD-OprJ efflux pump regulator gene nfxB conferring ciprofloxacin resistance, or in the gene encoding the non-essential penicillin-binding protein DacB conferring ceftazidime resistance. Reconstruction of resistance mutations by allelic replacement and in vitro fitness assays revealed that in contrast to single antibiotic use, combination therapy consistently selected for mutants with enhanced fitness expressing broad-spectrum resistance mechanisms. Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
Maruyama, Yukio; Yokoyama, Keitaro; Nakayama, Masaaki; Higuchi, Chieko; Sanaka, Tsutomu; Tanaka, Yoshihide; Sakai, Ken; Mizuiri, Sonoo; Otsuka, Yasushi; Kuriyama, Satoru; Maeba, Teruhiko; Iwasawa, Hideaki; Nakao, Toshiyuki; Hosoya, Tatsuo
Combining peritoneal dialysis (PD) and hemodialysis (HD) has been common treatment option in Japan. In this retrospective, multicenter, observational study, the clinical characteristics and outcomes of 104 patients (57 ± 11 years, males 72%) who had switched from PD alone to combined therapy with PD and HD were studied. Clinical parameters were measured at baseline and after 3 months of combined therapy. At baseline, urine volume, dialysate-to-plasma ratio of creatinine (D/P Cr), and total Kt/V were 150 ml/day (range: 0-2,000 ml/day), 0.67 ± 0.11, and 1.8 ± 0.4, respectively. During the first 3 months of combined therapy, body weight, urine volume, serum creatinine level, and D/P Cr decreased, whereas hemoglobin levels increased. In patients where PD does not result in acceptable outcomes, combined therapy with PD and HD may have potential benefits in terms of dialysis adequacy and hydration status. Video Journal Club “Cappuccino with Claudio Ronco” at http://www.karger.com/?doi=368389 © 2014 S. Karger AG, Basel.
Full Text Available Aspirin and clopidogrel are usually used individually to prevent adverse cardiovascular events and stroke. They are used in stabilizing the blood pressure in patients of myocardial infarction while combination therapy of aspirin and Clopidogrel (dual anti-platelet therapy is used for preventing adverse cardiovascular events in myocardial infarction patients. A cross-sectional observational study is conducted through a structured questionnaire from 110 patients of K.I.H.D (Karachi Institute of Heart Disease hospital, Karachi, Pakistan. Indoor/admitted patients with diagnosis of acute coronary syndrome (ACS, non-ST elevation myocardial infarction (NSTE-MI, ST elevation myocardial infarction (STE-MI, supra ventricular tachycardia (SVT were included along with those with previous or current onset of angina pectoris or heart attack. Information from the test reports of these patients was included in the data. Patients without proper test reports were excluded from the study. Combination therapy duration is considered as key tool for evaluation. Out of 100 patients (after exclusion criteria applied almost 18% patients were using the combination therapy for 10 to 25 years while 52% of patients were using the combination therapy for 1 to 10 years. Platelet count of 88% patients was found to be in between 1,50,000–3,50,000/µl. Remaining patients had less than 1,50,000 µl to more than 3,50,000 to 4,50,000 µl. Most frequently reported side effects were chest pain, respiratory issues, headache and depression. On the basis of our data analysis it is concluded that long duration dual anti-platelet therapy will not harm platelet count in human blood but it can create drug dependency in patients. Hypertension is not completely cured with this therapy but can help in stabilizing blood pressure.
Rans, Tonya S; England, Ronald
To review the evolution of gene therapy in infants with X-linked severe combined immunodeficiency (XL-SCID) and to evaluate the current challenges facing this evolving field. The MEDLINE, OVID, CINAHL, and HealthSTAR databases were searched to identify pertinent articles using the following keywords: gene therapy, XL-SCID, bone marrow transplant, and viral vectors. Journal articles were selected for their relevance to human gene therapy in patients with XL-SCID. Gene therapy with a retrovirus-derived vector has been used to treat 20 patients with XL-SCID internationally. Although most patients derived improvements in T- and B-cell immune numbers and function, severe adverse effects have occurred. After gene therapy, 5 of the 20 patients developed leukemia. This outcome has been associated with insertion of the corrected gene near the T-cell proto-oncogene LMO2. One of the 5 patients subsequently died. Within the past decade, effective improvements in vectorology and cell culture conditions have resulted in clinical success in some infants with SCID and have revived interest after many years of setbacks. However, clinical success and significant adverse events have been reported in patients with XL-SCID who have undergone gene therapy using a retroviral vector. As extensive research into improving safety through vector development and monitoring of gene therapy continues, further progress in gene therapy development can be anticipated.
Full Text Available Interferon (IFN and ribavirin (RBV combination therapy was previously the standard of care for treatment of hepatitis C virus (HCV genotype 2 infection. But, it often induced hemolytic anemia. In 2014, sofosbuvir (SOF was approved for the treatment of chronic HCV genotype 2 in Japan. SOF/RBV therapy is more effective against genotype 2 than IFN/RBV therapy. We report a case of a 74-year-old woman with chronic HCV genotype 2b infection. She received five treatments including RBV and IFN therapy before SOF was approved and all of them were ineffective. Therapies that included RBV induced severe anemia and led to discontinuation of treatment. With pegylated IFN/RBV therapy, the maximum change in hemoglobin (Hb from baseline was −3.7 g/dL. However, SOF/RBV therapy was effective and she achieved sustained virologic response (SVR with a maximum change in Hb from baseline of only −1.2 g/dL. We also found reticulocyte count was very low during treatment in this case and speculate it was one of the reasons that she developed hemolytic anemia with RBV. In conclusion, SOF/RBV therapy is effective and allowed the patient to achieve SVR. An SOF/RBV regimen is safe and effective for patients who have or are at risk of anemia induced by RBV.
Combination of nitric oxide therapy, anti-oxidative therapy, low level laser therapy, plasma rich platelet therapy and stem cell therapy as a novel therapeutic application to manage the pain and treat many clinical conditions
Halasa, Salaheldin; Dickinson, Eva
From hypertension to diabetes, cancer to HIV, stroke to memory loss and learning disorders to septic shock, male impotence to tuberculosis, there is probably no pathological condition where nitric oxide does not play an important role. Nitric oxide is an analgesic, immune-modulator, vasodilator, anti-apoptotic, growth modulator, angiogenetic, anti-thrombotic, anti-inflammatory and neuro-modulator. Because of the above actions of nitric oxide, many clinical conditions associated with abnormal Nitric oxide (NO) production and bioavailability. Our novel therapeutic approach is to restore the homeostasis of nitric oxide and replace the lost cells by combining nitric oxide therapy, anti-oxidative therapy, low level laser therapy, plasma rich platelet therapy and stem cell therapy.
Min Li; Jing Zhou; Weifeng Jin; Xiaohong Li; Yuyan Zhang
Background: Hemorrhagic transformation, neurotoxicity, short treatment time windows, and other defects are considered as the major limitations for the thrombolytic therapy. This study is devoted to figure out whether Danhong injection (DHI) combined with tissue-plasminogen activator (t-PA) could extend the treatment time windows and ameliorate brain injury, hemorrhagic complication and BBB disruption after focal embolic stroke.Methods:In vitro, the combined concentrations of DHI and t-PA were...
McClintock, Shawn M.; Brandon, Anna R.; Husain, Mustafa M.; Jarrett, Robin B.
Objective Electroconvulsive therapy (ECT) is one of the most effective treatments for severe Major Depressive Disorder (MDD). However, after acute phase treatment and initial remission, relapse rates are significant. Strategies to prolong remission include continuation phase ECT, pharmacotherapy, psychotherapy, or their combinations. This systematic review synthesizes extant data regarding the combined use of psychotherapy with ECT for the treatment of patients with severe MDD and offers the hypothesis that augmenting ECT with depression-specific psychotherapy represents a promising strategy for future investigation. Methods The authors performed two independent searches in PsychInfo (1806 – 2009) and MEDLINE (1948 – 2009) using combinations of the following search terms: Electroconvulsive Therapy (including ECT, ECT therapy, electroshock therapy, EST, shock therapy) and Psychotherapy (including cognitive behavioral, interpersonal, group, psychodynamic, psychoanalytic, individual, eclectic, and supportive). We included in this review a total of six articles (English language) that mentioned ECT and psychotherapy in the abstract, and provided a case report, series, or clinical trial. We examined the articles for data related to ECT and psychotherapy treatment characteristics, cohort characteristics, and therapeutic outcome. Results Although research over the past seven decades documenting the combined use of ECT and psychotherapy is limited, the available evidence suggests that testing this combination has promise and may confer additional, positive functional outcomes. Conclusions Significant methodological variability in ECT and psychotherapy procedures, heterogeneous patient cohorts, and inconsistent outcome measures prevent strong conclusions; however, existing research supports the need for future investigations of combined ECT and psychotherapy in well-designed, controlled clinical studies. Depression-specific psychotherapy approaches may need special
Lee, Jong Bin; Choi, Seong Jun
We analyzed the effectiveness of combination therapy (CT) for idiopathic sudden sensorineural hearing loss (ISSNHL) and the utility of intratympanic dexamethasone injection (ITDI) reapplication as salvage treatment for ISSNHL refractory to CT. Case series with chart review. Academic university hospital. We reviewed 229 patients with ISSNHL and divided these patients into 2 groups according to treatment: systemic steroid therapy (SST) and CT groups. The SST group received prednisolone therapy. The CT group also received ITDI daily. Patients who demonstrated no recovery (Hearing recovery rates were 77.8% (77/99) in the CT group and 60.8% (79/130) in the SST group. The difference was statistically significant (P = .011). Initial pure-tone audiometry and vertigo were affective factors on hearing recovery rates in the CT group. After salvage therapy, hearing improvement of 10 dB or greater was noted in 6 of the 22 (27.3%) patients in the CT group and 16 of the 51 (31.4%) patients in the SST group. The difference in efficacy of salvage therapy between the CT and SST groups was simply not significant (P = .612). Combination therapy was more effective for ISSNHL in achieving hearing gain than SST alone. Furthermore, ITDI reapplication for ISSNHL refractory to CT was as effective as salvage ITDI for ISSNHL refractory to SST. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.
Noguchi, Masato; Murata, Rumi; Sagoh, Tadashi
The results of intraarterial chemotherapy (IA-CT) combined with definitive radiation therapy for 23 advanced and bulky carcinomas of uterine cervix are reported. IA-CT with cisplatin 50 mg and doxorubicin 30 mg was administered by one shot method in bilateral internal iliac arteries. The protocol consisted of one to three treatment sessions every 3 weeks. Nine of eleven patients with clinical stage III achieved a complete local response (82%), and the 3- and 5-year survival in these cases were 72% and 72%, respectively. These results were superior to the response (58%), 3- and 5-year survivals (68%, 58%) obtained in 19 patients treated mainly with radiation therapy alone. The side effect of grade 2 and 3 for the intestine, such as ileus and hemorrhagic colitis, was noted in 3 patients (15%). In addition, 3 of 8 patients with radical surgery and postoperative radiation therapy after IA-CT developed insufficient fracture of pelvic bone. These complications accompanied by IA-CT combined with radiation therapy and/or surgery increased slightly, compared with that by the previous therapy without IA-CT, but were not critical. The results suggest that IA-CT following radiation therapy is effective to improve the prognosis of patients with stage III cervical cancer. (author)
Wairagkar, Maitreyee; McCrindle, Rachel; Robson, Holly; Meteyard, Lotte; Sperrin, Malcom; Smith, Andy; Pugh, Moyra
The functional connectivity and structural proximity of elements of the language and motor systems result in frequent co-morbidity post brain injury. Although rehabilitation services are becoming increasingly multidisciplinary and "integrated", treatment for language and motor functions often occurs in isolation. Thus, behavioural therapies which promote neural reorganisation do not reflect the high intersystem connectivity of the neurologically intact brain. As such, there is a pressing need for rehabilitation tools which better reflect and target the impaired cognitive networks. The objective of this research is to develop a combined high dosage therapy tool for language and motor rehabilitation. The rehabilitation therapy tool developed, MaLT (Motor and Language Therapy), comprises a suite of computer games targeting both language and motor therapy that use the Kinect sensor as an interaction device. The games developed are intended for use in the home environment over prolonged periods of time. In order to track patients' engagement with the games and their rehabilitation progress, the game records patient performance data for the therapist to interrogate. MaLT incorporates Kinect-based games, a database of objects and language parameters, and a reporting tool for therapists. Games have been developed that target four major language therapy tasks involving single word comprehension, initial phoneme identification, rhyme identification and a naming task. These tasks have 8 levels each increasing in difficulty. A database of 750 objects is used to programmatically generate appropriate questions for the game, providing both targeted therapy and unique gameplay every time. The design of the games has been informed by therapists and by discussions with a Public Patient Involvement (PPI) group. Pilot MaLT trials have been conducted with three stroke survivors for the duration of 6 to 8 weeks. Patients' performance is monitored through MaLT's reporting facility
Bohlius, Julia; Schmidlin, Kurt; Costagliola, Dominique
OBJECTIVE: We examined survival and prognostic factors of patients who developed HIV-associated non-Hodgkin lymphoma (NHL) in the era of combination antiretroviral therapy (cART). DESIGN AND SETTING: Multicohort collaboration of 33 European cohorts. METHODS: We included all cART-naive patients en...
Verschuren, L.; Radonjic, M.; Wielinga, P.Y.; Kelder, T.; Kooistra, T.; Ommen, B. van; Kleemann, R.
AIMS: Combination-drug therapy takes advantage of the complementary action of their individual components, thereby potentiating its therapeutic effect. Potential disadvantages include side effects that are not foreseen on basis of the data available from drug monotherapy. Here, we used a systems
Phillips, A. N.; Gilson, R.; Easterbrook, P.; Fisher, M.; Gazzard, B.; Johnson, M.; Walsh, J.; Leen, C.; Orkin, C.; Anderson, J.; Pillay, D.; Delpech, V.; Schwenk, A.; Dunn, D.; Gompels, M.; Hill, T.; Porter, K.; Babiker, A.; Sabin, C.; Waters, A.; Crates, D.; Mohamed-Saad, S.; Perry, N.; Pullin, A.; Churchill, D.; Harris, W.; Nelson, M.; Asboe, D.; Bulbeck, S.; Mandalia, S.; Clarke, J.; Dodds, J.; Rider, A.; Youle, M.; Lampe, F.; Smith, C.; Gumley, H.; Chaloner, C.; Ismajani, D.; Weber, J.; Cashin, S.; Kemble, C.; Mackie, N.; Thomas, R.; Jones, K.; Gann, S.; Wilson, A.; Ainsworth, J.; de Wolf, F.; Bezemer, D. O.; Gras, L. A. J.; Kesselring, A. M.; van Sighem, A. I.; Smit, C.; Zhang, S.; Zaheri, S.; Prins, J. M.; Bos, J. C.; Eeftinck-Schattenkerk, J. K. M.; Geerlings, S. E.; Godfried, M. H.; Lange, J. M. A.; van der Meer, J. T. M.; Nellen, F. J. B.; Olszyna, D. P.; van der Poll, M.; Reiss, P.; Sankatsing, S. U. C.; Steingrover, R.; van der Valk, M.; Vermeulen, J. N.; Vrouenraets, S. M. E.; van Vugt, M.; Wit, F. W. M. N.; Schreij, G.; van der Geest, S.; Oude Lashof, A.; Lowe, S.; Verbon, A.; Kuijpers, T. W.; Pajkrt, D.; Scherpbier, H. J.; van der Ende, M. E.; Bax, H.; van der Feltz, M.; Gelinck, L. B. S.; Nouwen, J. L.; Rijnders, B. J. A.; de Ruiter, E. D.; Slobbe, L.; Schurink, C. A. M.; de Vries, T. E. M. S.; Driessen, G.; van der Flier, M.; Hartwig, N. G.; Branger, J.; Kauffmann, R. H.; Schippers, E. F.; Groeneveld, P. H. P.; Alleman, M. A.; ten Kate, R. W.; Soetekouw, R.; Kroon, F. P.; Arend, S. M.; de Boer, M. G. J.; van den Broek, P. J.; van Dissel, J. T.; van Nieuwkoop, C.; den Hollander, J. G.; Bronsveld, W.; Vriesendorp, R.; Jeurissen, F. J. F.; Leyten, E. M. S.; van Houte, D.; Polée, M. B.; ten Napel, C. H. H.; Kootstra, G. J.; Brinkman, K.; van den Berk, G. E. L.; Blok, W. L.; Frissen, P. H. J.; Schouten, W. E. M.; van Eeden, A.; Verhagen, D. W. M.; Mulder, J. W.; van Gorp, E. C. M.; Mairuhu, A. T. A.; Wagenaar, J.; Juttmann, J. R.; van Kasteren, M. E. E.; Veenstra, J.; Vasmel, W. L. E.; Koopmans, P. P.; Brouwer, A. M.; Dofferhoff, A. S. M.; de Groot, R.; ter Hofstede, H. J. M.; Keuter, M.; van der Ven, A. J. A. M.; Sprenger, H. G.; van Assen, S.; van Leeuwen, J. T. M.; Stek, C. J.; Doedens, R.; Scholvinck, E. H.; Hoepelman, I. M.; Schneider, M. M. E.; Bonten, M. J. M.; Ellerbroek, P. M.; Jaspers, C. A. J. J.; Maarschalk-Ellerbroek, L. J.; Oosterheert, J. J.; Peters, E. J. G.; Mudrikova, T.; Wassenberg, M. W. M.; Weijer, S.; Geelen, S. P. M.; Wolfs, T. F. W.; Danner, S. A.; van Agtmael, M. A.; Bierman, W. F. W.; Claessen, F. A. P.; Hillebrand, M. E.; de Jong, E. V.; Kortmann, W.; Perenboom, R. M.; bij de Vaate, E. A.; Richter, C.; van der Berg, J.; Gisolf, E. H.; Tanis, A. A.; Duits, A. J.; Winkel, K.; Elisabeth, S. T.; Abgrall, S.; Barin, F.; Bentata, M.; Billaud, E.; Boué, F.; Burty, C.; Cabié, A.; Costagliola, D.; Cotte, L.; de Truchis, P.; Duval, X.; Duvivier, C.; Enel, P.; Fredouille-Heripret, L.; Gasnault, J.; Gaud, C.; Gilquin, J.; Grabar, S.; Katlama, C.; Khuong, M. A.; Lang, J. M.; Lascaux, A. S.; Launay, O.; Mahamat, A.; Mary-Krause, M.; Matheron, S.; Meynard, J. L.; Pavie, J.; Pialoux, G.; Pilorgé, F.; Poizot-Martin, I.; Pradier, C.; Reynes, J.; Rouveix, E.; Simon, A.; Tattevin, P.; Tissot-Dupont, H.; Viard, J. P.; Viget, N.; Salomon, Valérie; Jacquemet, N.; Guiguet, M.; Lanoy, E.; Liévre, L.; Selinger-Leneman, H.; Lacombe, J. M.; Potard, V.; Bricaire, F.; Herson, S.; Desplanque, N.; Girard, P. M.; Meyohas, M. C.; Picard, O.; Cadranel, J.; Mayaud, C.; Clauvel, J. P.; Decazes, J. M.; Gerard, L.; Molina, J. M.; Diemer, M.; Sellier, P.; Honoré, P.; Jeantils, V.; Tassi, S.; Mechali, D.; Taverne, B.; Berthé, H.; Dupont, C.; Chandemerle, C.; Mortier, E.; Tisne-Dessus, D.; Weiss, L.; Salmon, D.; Auperin, I.; Roudière, L.; Fior, R.; Delfraissy, J. F.; Goujard, C.; Jung, C.; Lesprit, P. H.; Vittecoq, D.; Fraisse, P.; Rey, D.; Beck-Wirth, G.; Stahl, J. P.; Lecercq, P.; Gourdon, F.; Laurichesse, H.; Fresard, A.; Lucht, F.; Bazin, C.; Verdon, R.; Chavanet, P.; Arvieux, C.; Michelet, C.; Choutet, P.; Goudeau, A.; Maître, M. F.; Hoen, B.; Eglinger, P.; Faller, J. P.; Borsa-Lebas, F.; Caron, F.; Daures, J. P.; May, T.; Rabaud, C.; Berger, J. L.; Rémy, G.; Arlet-Suau, E.; Cuzin, L.; Massip, P.; Legrand, M. F. Thiercelin; Pontonnier, G.; Yasdanpanah, Y.; Dellamonica, P.; Pugliese, P.; Aleksandrowicz, K.; Quinsat, D.; Ravaux, I.; Delmont, J. P.; Moreau, J.; Gastaut, J. A.; Retornaz, F.; Soubeyrand, J.; Galinier, A.; Ruiz, J. M.; Allegre, T.; Blanc, P. A.; Bonnet-Montchardon, D.; Lepeu, G.; Granet-Brunello, P.; Esterni, J. P.; Pelissier, L.; Cohen-Valensi, R.; Nezri, M.; Chadapaud, S.; Laffeuillade, A.; Raffi, F.; Boibieux, A.; Peyramond, D.; Livrozet, J. M.; Touraine, J. L.; Trepo, C.; Strobel, M.; Bissuel, F.; Pradinaud, R.; Sobesky, M.; Contant, M.; Aebi, C.; Battegay, M.; Bernasconi, E.; Böni, J.; Brazzola, P.; Bucher, H. C.; Bürgisser, P. H.; Calmy, A.; Cattacin, S.; Cavassini, M.; Cheseaux, J.-J.; Drack, G.; Dubs, R.; Egger, M.; Elzi, L.; Fischer, M.; Flepp, M.; Fontana, A.; Francioli, P.; Furrer, H. J.; Fux, C.; Gayet-Ageron, A.; Gerber, S.; Gorgievski, M.; Günthard, H.; Gyr, T. H.; Hirsch, H.; Hirschel, B.; Hösli, I.; Hüsler, M.; Kaiser, L.; Kahlert, C. H.; Karrer, U.; Kind, C.; Klimkait, T. H.; Ledergerber, B.; Martinetti, G.; Martinez, B.; Müller, N.; Nadal, D.; Paccaud, F.; Pantaleo, G.; Raio, L.; Rauch, A.; Regenass, S.; Rickenbach, M.; Rudin, C.; Schmid, P.; Schultze, D.; Schüpbach, J.; Speck, R.; Taffé, P.; Telenti, A.; Trkola, A.; Vernazza, P.; Weber, R.; Wyler, C.-A.; Yerly, S.; Casabona, J.; Miró, J. M.; Alquézar, A.; Isern, V.; Esteve, A.; Podzamczer, D.; Murillas, J.; Gatell, J. M.; Agüero, F.; Tural, C.; Clotet, B.; Ferrer, E.; Riera, M.; Segura, F.; Navarro, G.; Force, L.; Vilaró, J.; Masabeu, A.; García, I.; Guadarrama, M.; Romero, A.; Agustí, C.; Montoliu, A.; Ortega, N.; Lazzari, E.; Puchol, E.; Sanchez, M.; Blanco, J. L.; Garcia-Alcaide, F.; Martínez, E.; López-Dieguez, M.; García-Goez, J. F.; Sirera, G.; Romeu, J.; Jou, A.; Negredo, E.; Miranda, C.; Capitan, M. C.; Olmo, M.; Barragan, P.; Saumoy, M.; Bolao, F.; Cabellos, C.; Peña, C.; Sala, M.; Cervantes, M.; Amengual, M. J.; Navarro, M.; Penelo, E.; Berenguer, J.; del Amo, J.; García, F.; Gutiérrez, F.; Labarga, P.; Moreno, S.; Muñoz, M. A.; Caro-Murillo, A. M.; Sobrino, P.; Jarrín, I.; Sirvent, J. L. Gómez; Rodríguez, P.; Alemán, M. R.; Alonso, M. M.; López, A. M.; Hernández, M. I.; Soriano, V.; Barreiro, P.; Medrano, J.; Rivas, P.; Herrero, D.; Blanco, F.; Vispo, M. E.; Martín, L.; Ramírez, G.; de Diego, M.; Rubio, R.; Pulido, F.; Moreno, V.; Cepeda, C.; Hervás, R. I.; Iribarren, J. A.; Arrizabalaga, J.; Aramburu, M. J.; Camino, X.; Rodríguez-Arrondo, F.; von Wichmann, M. A.; Pascual, L.; Goenaga, M. A.; Masiá, M.; Ramos, J. M.; Padilla, S.; Sánchez-Hellín, V.; Bernal, E.; Escolano, C.; Montolio, F.; Peral, Y.; López, J. C.; Miralles, P.; Cosín, J.; Sánchez, M.; Gutiérrez, I.; Ramírez, M.; Padilla, B.; Vidal, F.; Sanjuan, M.; Peraire, J.; Veloso, S.; Viladés, C.; López-Dupla, M.; Olona, M.; Vargas, M.; Aldeguer, J. L.; Blanes, M.; Lacruz, J.; Salavert, M.; Montero, M.; Cuéllar, S.; de los Santos, I.; Sanz, J.; Oteo, J. A.; Blanco, J. R.; Ibarra, V.; Metola, L.; Sanz, M.; Pérez-Martínez, L.; Sola, J.; Uriz, J.; Castiello, J.; Reparaz, J.; Arriaza, M. J.; Irigoyen, C.; Antela, A.; Casado, J. L.; Dronda, F.; Moreno, A.; Pérez, M. J.; López, D.; Gutiérrez, C.; Hernández, B.; Pumares, M.; Martí, P.; García, L.; Page, C.; Hernández, J.; Peña, A.; Muñoz, L.; Parra, J.; Viciana, P.; Leal, M.; López-Cortés, L. F.; Trastoy, M.; Mata, R.; Justice, A. C.; Fiellin, D. A.; Rimland, D.; Jones-Taylor, C.; Oursler, K. A.; Titanji, R.; Brown, S.; Garrison, S.; Rodriguez-Barradas, M.; Masozera, N.; Goetz, M.; Leaf, D.; Simberkoff, M.; Blumenthal, D.; Leung, J.; Butt, A.; Hoffman, E.; Gibert, C.; Peck, R.; Mattocks, K.; Braithwaite, S.; Brandt, C.; Bryant, K.; Cook, R.; Conigliaro, J.; Crothers, K.; Chang, J.; Crystal, S.; Day, N.; Erdos, J.; Freiberg, M.; Kozal, M.; Gandhi, N.; Gaziano, M.; Gerschenson, M.; Good, B.; Gordon, A.; Goulet, J. L.; Hernán, M. A.; Kraemer, K.; Lim, J.; Maisto, S.; Miller, P.; Mole, L.; O'Connor, P.; Papas, R.; Robins, J. M.; Rinaldo, C.; Roberts, M.; Samet, J.; Tierney, B.; Whittle, J.; Phillips, A.; Brettle, R.; Darbyshire, J.; Fidler, S.; Goldberg, D.; Hawkins, D.; Jaffe, H.; McLean, K.; Porter, Kholoud; Cursley, Adam; Ewings, Fiona; Fairbrother, Keith; Gnatiuc, Louisa; Lodi, Sara; Murphy, Brendan; Douglas, G.; Kennedy, N.; Pritchard, J.; Andrady, U.; Gwynedd, Ysbyty; Rajda, N.; Maw, R.; McKernan, S.; Drake, S.; Gilleran, G.; White, D.; Ross, J.; Toomer, S.; Hewart, R.; Wilding, H.; Woodward, R.; Dean, G.; Heald, L.; Horner, P.; Glover, S.; Bansaal, D.; Eduards, S.; Carne, C.; Browing, M.; Das, R.; Stanley, B.; Estreich, S.; Magdy, A.; O'Mahony, C.; Fraser, P.; Hayman, B.; Jebakumar, S. P. R.; Joshi, U.; Ralph, S.; Wade, A.; Mette, R.; Lalik, J.; Summerfield, H.; El-Dalil, A.; France, A. J.; White, C.; Robertson, R.; Gordon, S.; McMillan, S.; Morris, S.; Lean, C.; Vithayathil, K.; McLean, L.; Winter, A.; Gale, D.; Jacobs, S.; Tayal, S.; Short, L.; Green, S.; Williams, G.; Sivakumar, K.; Bhattacharyya, D. N.; Monteiro, E.; Minton, J.; Dhar, J.; Nye, F.; DeSouza, C. B.; Isaksen, A.; McDonald, L.; Franca, A.; William, L.; Jendrulek, I.; Shaunak, S.; El-Gadi, S.; Easterbrook, P. J.; Mazhude, C.; Johnstone, R.; Fakoya, A.; Mchale, J.; Kegg, S.; Mitchell, S.; Byrne, P.; Rice, P.; Mullaney, S. A.; McCormack, S.; David, D.; Melville, R.; Phillip, K.; Balachandran, T.; Mabey-Puttock, S.; Sukthankar, A.; Murphy, C.; Wilkins, E.; Ahmad, S.; Haynes, J.; Evans, E.; Ong, E.; Grey, R.; Meaden, J.; Bignell, C.; Loay, D.; Peacock, K.; Girgis, M. R.; Morgan, B.; Palfreeman, A.; Wilcox, J.; Tobin, J.; Tucker, L.; Saeed, A. M.; Chen, F.; Deheragada, A.; Williams, O.; Lacey, H.; Herman, S.; Kinghorn, D.; Devendra, S. V.; Wither, J.; Dawson, S.; Rowen, D.; Harvey, J.; Bridgwood, A.; Singh, G.; Chauhan, M.; Kellock, D.; Young, S.; Dannino, S.; Kathir, Y.; Rooney, G.; Currie, J.; Fitzgerald, M.; Devendra, S.; Keane, F.; Booth, G.; Green, T.; Arumainayyagam, J.; Chandramani, S.; Rajamanoharan, S.; Robinson, T.; Curless, E.; Gokhale, R.; Tariq, A.; Luzzi, G.; Fairley, I.; Wallis, F.; Smit, E.; Ward, F.; Morlat, P.; Bonarek, M.; Bonnet, F.; Nouts, C.; Louis, J.; Reliquet, V.; Sauser, F.; Biron, C.; Mounoury, O.; Hue, H.; Brosseau, D.; Ghosn, J.; Rannou, M. T.; Bergmann, J. F.; Badsi, E.; Rami, A.; Parrinello, M.; Samanon-Bollens, D.; Campa, P.; Tourneur, M.; Desplanques, N.; Jeanblanc, F.; Chiarello, P.; Makhloufi, D.; Blanc, A. P.; Allègre, T.; Baillat, V.; Lemoing, V.; de Boever, C. Merle; Tramoni, C.; Sobesky, G.; Abel, S.; Beaujolais, V.; Slama, L.; Chakvetadze, C.; Berrebi, V.; Yeni, P.; Bouvet, E.; Fournier, I.; Gerbe, J.; Koffi, K.; Augustin-Normand, C.; Miailhes, P.; Thoirain, V.; Brochier, C.; Souala, F.; Ratajczak, M.; Beytoux, J.; Jacomet, C.; Morelon, S.; Olivier, C.; Lortholary, O.; Dupont, B.; Maignan, A.; Ragnaud, J. M.; Raymond, I.; Leport, C.; Jadand, C.; Jestin, C.; Longuet, P.; Boucherit, S.; Sereni, D.; Lascoux, C.; Prevoteau, F.; Sobel, A.; Levy, Y.; Lelièvre, J. D.; Dominguez, S.; Dumont, C.; Aumaître, H.; Delmas, B.; Saada, M.; Medus, M.; Guillevin, L.; Tahi, T.; Yazdanpanah, Y.; Pavel, S.; Marien, M. C.; Drenou, B.; Beck, C.; Benomar, M.; Tubiana, R.; Mohand, H. Ait; Chermak, A.; Abdallah, S. Ben; Touam, F.; Drobacheff, C.; Folzer, A.; Obadia, M.; Prudhomme, L.; Bonnet, E.; Balzarin, F.; Pichard, E.; Chennebault, J. M.; Fialaire, P.; Loison, J.; Galanaud, P.; Bornarel, D.; Six, M.; Ferret, P.; Batisse, D.; Gonzales-Canali, G.; Devidas, A.; Chevojon, P.; Turpault, I.; Lafeuillade, A.; Cheret, A.; Philip, G.; Morel, P.; Timsit, J.; Amirat, N.; Brancion, C.; Cabane, J.; Tredup, J.; Stein, A.; Ravault, I.; Chavanet, C.; Buisson, M.; Treuvetot, S.; Nau, P.; Bastides, F.; Boyer, L.; Wassoumbou, S.; Oksenhendeler, E.; Gérard, L.; Bernard, L.; Domart, Y.; Merrien, D.; Belan, A. Greder; Gayraud, M.; Bodard, L.; Meudec, A.; Beuscart, C.; Daniel, C.; Pape, E.; Vinceneux, P.; Simonpoli, A. M.; Zeng, A.; Fournier, L.; Fuzibet, J. G.; Sohn, C.; Rosenthal, E.; Quaranta, M.; Chaillou, S.; Sabah, M.; Audhuy, B.; Schieber, A.; Moreau, P.; Niault, M.; Vaillant, O.; Huchon, G.; Compagnucci, A.; Szmania, I. De Lacroix; Richier, L.; Lamaury, I.; Saint-Dizier, F.; Garipuy, D.; Drogoul, M. P.; Martin, I. Poizot; Fabre, G.; de Cursay, G. Lambert; Abraham, B.; Perino, C.; Lagarde, P.; David, F.; Roche-Sicot, J.; Saraux, J. L.; Leprêtre, A.; Fampin, B.; Uludag, A.; Morin, A. S.; Bletry, O.; Zucman, D.; Regnier, A.; Girard, J. J.; Quinsat, D. T.; Heripret, L.; Grihon, F.; Houlbert, D.; Ruel, M.; Chemlal, K.; Debab, Y.; Tremollieres, F.; Perronne, V.; Slama, B.; Perré, P.; Miodovski, C.; Guermonprez, G.; Dulioust, A.; Boudon, P.; Malbec, D.; Patey, O.; Semaille, C.; Deville, J.; Remy, G.; Béguinot, I.; Boue, F.; Chambrin, V.; Pignon, C.; Estocq, G. A.; Levy, A.; Duracinsky, M.; Le Bras, P.; Ngussan, M. S.; Peretti, D.; Medintzeff, N.; Lambert, T.; Segeral, O.; Lezeau, P.; Laurian, Y.; Piketty, C.; Karmochkine, M.; Eliaszewitch, M.; Jayle, D.; Tisne- Dessus, D.; Kazatchkine, M.; Colasante, U.; Nouaouia, W.; Vilde, J. L.; Bollens, D.; Binet, D.; Diallo, B.; Fonquernie, L.; Lagneau, J. L.; Pietrie, M. P.; Sicard, D.; Stieltjes, N.; Michot, J.; Bourdillon, F.; Lelievre, J. D.; Obenga, G.; Escaut, L.; Bolliot, C.; Schneider, L.; Iguertsira, M.; Tomei, C.; Dhiver, C.; Dupont, H. Tissot; Vallon, A.; Gallais, J.; Gallais, H.; Durant, J.; Mondain, V.; Perbost, I.; Cassuto, J. P.; Karsenti, J. M.; Venti, H.; Ceppi, C.; Krivitsky, J. A.; Bouchaud, O.; Honore, P.; Delgado, J.; Rouzioux, C.; Burgard, M.; Boufassa, L.; Peynet, J.; Hoyos, S. Pérez; Ferreros, I.; Hurtado, I.; González, C.; Caro, A. M.; Muga, R.; Sanvicens, A.; Tor, J.; del Romero, J.; Raposo, P.; Rodríguez, C.; García, Soledad; Alastrue, I.; Belda, J.; Trullen, P.; Fernández, E.; Santos, C.; Tasa, T.; Zafra, T.; Guerrero, R.; Marco, A.; Quintana, M.; Ruiz, I.; Nuñez, R.; Pérez, R.; Castilla, J.; Guevara, M.; de Mendoza, C.; Zahonero, N.
OBJECTIVE: To estimate the effect of combined antiretroviral therapy (cART) on mortality among HIV-infected individuals after appropriate adjustment for time-varying confounding by indication. DESIGN: A collaboration of 12 prospective cohort studies from Europe and the United States (the HIV-CAUSAL
Lodi, Sara; Del Amo, Julia; Moreno, Santiago; Bucher, Heiner C.; Furrer, Hansjakob; Logan, Roger; Sterne, Jonathan; Pérez-Hoyos, Santiago; Jarrín, Inma; Phillips, Andrew; Olson, Ashley; Van Sighem, Ard; Reiss, Peter; Sabin, Caroline; Jose, Sophie; Justice, Amy; Goulet, Joseph; Miró, José M.; Ferrer, Elena; Meyer, Laurence; Seng, Rémonie; Vourli, Georgia; Antoniadou, Anastasia; Dabis, Francois; Vandenhede, Mari-Anne; Costagliola, Dominique; Abgrall, Sophie; Hernán, Miguel A.; Hernan, Miguel; Bansi, L.; Hill, T.; Sabin, C.; Dunn, D.; Porter, K.; Glabay, A.; Orkin, C.; Thomas, R.; Jones, K.; Fisher, M.; Perry, N.; Pullin, A.; Churchill, D.; Gazzard, B.; Nelson, M.; Asboe, D.; Bulbeck, S.; Mandalia, S.; Clarke, J.; Delpech, V.; Anderson, J.; Munshi, S.; Post, F.; Easterbrook, P.; Khan, Y.; Patel, P.; Karim, F.; Duffell, S.; Gilson, R.; Man, S.-L.; Williams, I.; Gompels, M.; Dooley, D.; Schwenk, A.; Ainsworth, J.; Johnson, M.; Youle, M.; Lampe, F.; Smith, C.; Grabowska, H.; Chaloner, C.; Ismajani Puradiredja, D.; Bansi, L.; Hill, T.; Phillips, A.; Sabin, C.; Walsh, J.; Weber, J.; Kemble, C.; Mackie, N.; Winston, A.; Leen, C.; Wilson, A.; Bezemer, D.O.; Gras, L.A.J.; Kesselring, A.M.; Van Sighem, A.I.; Zaheri, S.; Van Twillert, G.; Kortmann, W.; Branger, J.; Prins, J.M.; Kuijpers, T.W.; Scherpbier, H.J.; Van Der Meer, J.T.M.; Wit, F.W.M.N.; Godfried, M.H.; Reiss, P.; Van Der Poll, T.; Nellen, F.J.B.; Lange, J.M.A.; Geerlings, S.E.; Van Vugt, M.; Pajkrt, D.; Bos, J.C.; van der Valk, M.; Grijsen, M.L.; Wiersinga, W.J.; Brinkman, K.; Blok, W.L.; Frissen, P.H.J.; Schouten, W.E.M.; Van Den Berk, G.E.L.; Veenstra, J.; Lettinga, K.D.; Mulder, J.W.; Vrouenraets, S.M.E.; Lauw, F.N.; Van Eeden, A.; Verhagen, D.W.M.; Van Agtmael, M.A.; Perenboom, R.M.; Claessen, F.A.P.; Bomers, M.; Peters, E.J.G.; Richter, C.; Van Der Berg, J.P.; Gisolf, E.H.; Schippers, E.F.; Van Nieuwkoop, C.; Van Elzakker, E.P.; Leyten, E.M.S.; Gelinck, L.B.S.; Pronk, M.J.H.; Bravenboer, B.; Kootstra, G.J.; Delsing, C.E.; Sprenger, H.G.; Doedens, R.; Scholvinck, E.H.; Van Assen, S.; Bierman, W.F.W.; Soetekouw, R.; Ten Kate, R.W.; Van Vonderen, M.G.A.; Van Houte, D.P.F.; Kroon, F.P.; Van Dissel, J.T.; Arend, S.M.; De Boer, M.G.J.; Jolink, H.; Ter Vollaard, H.J.M.; Bauer, M.P.; Weijer, S.; El Moussaoui, R.; Lowe, S.; Schreij, G.; Oude Lashof, A.; Posthouwer, D.; Koopmans, P.P.; Keuter, M.; Van Der Ven, A.J.A.M.; Ter Hofstede, H.J.M.; Dofferhoff, A.S.M.; Warris, A.; Van Crevel, R.; van der Ende, Marchina E.; De Vries-Sluijs, T.E.M.S.; Schurink, C.A.M.; Nouwen, J.L.; Nispen Tot Pannerden, M.H.; Verbon, A.; Rijnders, B.J.A.; Van Gorp, E.C.M.; Hassing, R.J.; Smeulders, A.W.M.; Hartwig, N.G.; Driessen, G.J.A.; Den Hollander, J.G.; Pogany, K.; Juttmann, J.R.; Van Kasteren, M.E.E.; Hoepelman, A.I.M.; Mudrikova, T.; Schneider, M.M.E.; Jaspers, C.A.J.J.; Ellerbroek, P.M.; Oosterheert, J.J.; Arends, J.E.; Wassenberg, M.W.M.; Barth, R.E.; Geelen, S.P.M.; Wolfs, T.F.W.; Bont, L.J.; Van Den Berge, M.; Stegeman, A.; Groeneveld, P.H.P.; Alleman, M.A.; Bouwhuis, J.W.; Barin, F.; Burty, C.; Duvivier, C.; Enel, P.; Fredouille-Heripret, L.; Gasnault, J.; Khuong, M.A.; Mahamat, A.; Pilorgé, F.; Tattevin, P.; Salomon, Valérie; Jacquemet, N.; Abgrall, S.; Costagliola, D.; Grabar, S.; Guiguet, M.; Lanoy, E.; Lièvre, L.; Mary-Krause, M.; Selinger-Leneman, H.; Lacombe, J.M.; Potard, V.; Bricaire, F.; Herson, S.; Katlama, C.; Simon, A.; Desplanque, N.; Girard, P.M.; Meynard, J.L.; Meyohas, M.C.; Picard, O.; Cadranel, J.; Mayaud, C.; Pialoux, G.; Clauvel, J.P.; Decazes, J.M.; Gerard, L.; Molina, J.M.; Diemer, M.; Sellier, P.; Bentata, M.; Honoré, P.; Jeantils, V.; Tassi, S.; Mechali, D.; Taverne, B.; Bouvet, E.; Crickx, B.; Ecobichon, J.L.; Matheron, S.; Picard-Dahan, C.; Yeni, P.; Berthé, H.; Dupont, C.; Chandemerle, C.; Mortier, E.; De Truchis, P.; Tisne-Dessus, D.; Weiss, L.; Salmon, D.; Auperin, I.; Gilquin, J.; Roudière, L.; Viard, J.P.; Boué, F.; Fior, R.; Delfraissy, J.F.; Goujard, C.; Jung, C.; Lesprit, Ph.; Vittecoq, D.; Fraisse, P.; Lang, J.M.; Rey, D.; Beck-Wirth, G.; Stahl, J.P.; Lecercq, P.; Gourdon, F.; Laurichesse, H.; Fresard, A.; Lucht, F.; Bazin, C.; Verdon, R.; Chavanet, P.; Arvieux, C.; Michelet, C.; Choutet, P.; Goudeau, A.; Maître, M.F.; Hoen, B.; Eglinger, P.; Faller, J.P.; Borsa-Lebas, F.; Caron, F.; Reynes, J.; Daures, J.P.; May, T.; Rabaud, C.; Berger, J.L.; Rémy, G.; Arlet-Suau, E.; Cuzin, L.; Massip, P.; Thiercelin Legrand, M.F.; Pontonnier, G.; Viget, N.; Yasdanpanah, Y.; Dellamonica, P.; Pradier, C.; Pugliese, P.; Aleksandrowicz, K.; Quinsat, D.; Ravaux, I.; Tissot-Dupont, H.; Delmont, J.P.; Moreau, J.; Gastaut, J.A.; Poizot-Martin, I.; Retornaz, F.; Soubeyrand, J.; Galinier, A.; Ruiz, J.M.; Allegre, T.; Blanc, P.A.; Bonnet-Montchardon, D.; Lepeu, G.; Granet-Brunello, P.; Esterni, J.P.; Pelissier, L.; Cohen-Valensi, R.; Nezri, M.; Chadapaud, S.; Laffeuillade, A.; Billaud, E.; Raffi, F.; Boibieux, A.; Peyramond, D.; Livrozet, J.M.; Touraine, J.L.; Cotte, L.; Trepo, C.; Strobel, M.; Bissuel, F.; Pradinaud, R.; Sobesky, M.; Cabié, A.; Gaud, C.; Contant, M.; Aubert, V.; Barth, J.; Battegay, M.; Bernasconi, E.; Böni, J.; Bucher, H.C.; Burton-Jeangros, C.; Calmy, A.; Cavassini, M.; Egger, M.; Elzi, L.; Fehr, J.; Fellay, J.; Furrer, H.; Haerry, D.; Fux, C.A.; Gorgievski, M.; Günthard, H.; Hasse, B.; Hirsch, H.H.; Hösli, I.; Kahlert, C.; Kaiser, L.; Keiser, O.; Klimkait, T.; Kovari, H.; Ledergerber, B.; Martinetti, G.; Martinez De Tejada, B.; Metzner, K.; Müller, N.; Nadal, D.; Pantaleo, G.; Rauch, A.; Regenass, S.; Rickenbach, M.; Rudin, C.; Schmid, P.; Schultze, D.; Schöni-Affolter, F.; Schüpbach, J.; Speck, R.; Taffé, P.; Tarr, P.; Telenti, A.; Trkola, A.; Vernazza, P.; Weber, R.; Yerly, S.; Casabona, J.; Gallois, A.; Esteve, A.; Podzamczer, D.; Murillas, J.; Gatell, J.M.; Manzardo, C.; Tural, C.; Clotet, B.; Ferrer, E.; Riera, M.; Segura, F.; Navarro, G.; Force, L.; Vilaró, J.; Masabeu, A.; García, I.; Guadarrama, M.; Cifuentes, C.; Dalmau, D.; Jaen, À.; Agustí, C.; Montoliu, A.; Pérez, I.; Gargoulas, Freyra; Blanco, J.L.; Garcia-Alcaide, F.; Martínez, E.; Mallolas, J.; López-Dieguez, M.; García-Goez, J.F.; Sirera, G.; Romeu, J.; Jou, A.; Negredo, E.; Miranda, C.; Capitan, M.C.; Saumoy, M.; Imaz, A.; Tiraboschi, J.M.; Murillo, O.; Bolao, F.; Peña, C.; Cabellos, C.; Masó, M.; Vila, A.; Sala, M.; Cervantes, M.; Jose Amengual, Ma.; Navarro, M.; Penelo, E.; Barrufet, P.; Bejarano, G.; Molina, J.; Guadarrama, M.; Alvaro, M.; Mercadal, J.; Fernandez, Juanse; Ospina, Jesus E.; Muñoz, M.A.; Caro-Murillo, A.M.; Sobrino, P.; Jarrín, I.; Gomez Sirvent, J.L.; Rodríguez, P.; Aleman, M.R.; Alonso, M.M.; Lopez, A.M.; Hernandez, M.I.; Soriano, V.; Labarga, P.; Barreiro, P.; Medrano, J.; Rivas, P.; Herrero, D.; Blanco, F.; Vispo, M.E.; Martín, L.; Ramírez, G.; De Diego, M.; Rubio, R.; Pulido, F.; Moreno, V.; Cepeda, C.; Hervás, Rl.; Iribarren, J.A.; Arrizabalaga, J.; Aramburu, M.J.; Camino, X.; Rodrí-guez-Arrondo, F.; Von Wichmann, M.A.; Pascual, L.; Goenaga, M.A.; Gutierrez, F.; Masia, M.; Ramos, J.M.; Padilla, S.; Sanchez-Hellín, V.; Bernal, E.; Escolano, C.; Montolio, F.; Peral, Y.; Berenguer, J.; Lopez, J.C.; Miralles, P.; Cosín, J.; Sanchez, M.; Gutierrez, I.; Ramírez, M.; Padilla, B.; Vidal, F.; Sanjuan, M.; Peraire, J.; Veloso, S.; Vilades, C.; Lopez-Dupla, M.; Olona, M.; Vargas, M.; Aldeguer, J.L.; Blanes, M.; Lacruz, J.; Salavert, M.; Montero, M.; Cuéllar, S.; De Los Santos, I.; Sanz, J.; Oteo, J.A.; Blanco, J.R.; Ibarra, V.; Metola, L.; Sanz, M.; Pérez-Martínez, L.; Sola, J.; Uriz, J.; Castiello, J.; Reparaz, J.; Arriaza, M.J.; Irigoyen, C.; Moreno, S.; Antela, A.; Casado, J.L.; Dronda, F.; Moreno, A.; Pérez, M.J.; López, D.; Gutiérrez, C.; Hernández, B.; Pumares, M.; Martí, P.; García, L.; Page, C.; García, F.; Hernández, J.; Peña, A.; Muñoz, L.; Parra, J.; Viciana, P.; Leal, M.; López-Cortés, L.F.; Trastoy, M.; Mata, R.; Justice, A.C.; Fiellin, D.A.; Rimland, D.; Jones-Taylor, C.; Oursler, K.A.; Titanji, R.; Brown, S.; Garrison, S.; Rodriguez-Barradas, M.; Masozera, N.; Goetz, M.; Leaf, D.; Simberkoff, M.; Blumenthal, D.; Leung, J.; Butt, A.; Hoffman, E.; Gibert, C.; Peck, R.; Mattocks, K.; Braithwaite, S.; Brandt, C.; Bryant, K.; Cook, R.; Conigliaro, J.; Crothers, K.; Chang, J.; Crystal, S.; Day, N.; Erdos, J.; Freiberg, M.; Kozal, M.; Gandhi, N.; Gaziano, M.; Gerschenson, M.; Good, B.; Gordon, A.; Goulet, J.L.; Hernán, M.A.; Kraemer, K.; Lim, J.; Maisto, S.; Miller, P.; Mole, L.; O'Connor, P.; Papas, R.; Robins, J.M.; Rinaldo, C.; Roberts, M.; Samet, J.; Tierney, B.; Whittle, J.; Babiker, A.; Brettle, R.; Darbyshire, J.; Gilson, R.; Goldberg, D.; Hawkins, D.; Jaffe, H.; Johnson, A.; McLean, K.; Pillay, D.; Cursley, Adam; Ewings, Fiona; Fairbrother, Keith; Louisa Gnatiuc, S.L.; Murphy, Brendan; Douglas, G.; Kennedy, N.; Pritchard, J.; Andrady, U.; Rajda, N.; Maw, R.; McKernan, S.; Drake, S.; Gilleran, G.; White, D.; Ross, J.; Toomer, S.; Hewart, R.; Wilding, H.; Woodward, R.; Dean, G.; Heald, L.; Horner, P.; Glover, S.; Bansaal, D.; Eduards, S.; Carne, C.; Browing, M.; Das, R.; Stanley, B.; Estreich, S.; Magdy, A.; O'Mahony, C.; Fraser, P.; Hayman, B.; Jebakumar, S.P.R.; Joshi, U.; Ralph, S.; Wade, A.; Mette, R.; Lalik, J.; Summerfield, H.; El-Dalil, A.; France, J.A.; White, C.; Robertson, R.; Gordon, S.; McMillan, S.; Morris, S.; Lean, C.; Vithayathil, K.; McLean, L.; Winter, A.; Gale, D.; Jacobs, S.; Tayal, S.; Short, L.; Roberts, M.; Green, S.; Williams, G.; Sivakumar, K.; Bhattacharyya, N.D.; Monteiro, E.; Minton, J.; Dhar, J.; Nye, F.; De Souza, C.B.; Isaksen, A.; McDonald, L.; McLean, K.; Franca, A.; Hawkins, D.; William, L.; Jendrulek, I.; Peters, B.; Shaunak, S.; El-Gadi, S.; Easterbrook, P.J.; Mazhude, C.; Gilson, R.; Johnstone, R.; Fakoya, A.; McHale, J.; Waters, A.; Kegg, S.; Mitchell, S.; Byrne, P.; Johnson, M.; Rice, P.; Fidler, S.; Mullaney, S.A.; McCormack, S.; David, D.; Melville, R.; Phillip, K.; Balachandran, T.; Mabey-Puttock, S.; Sukthankar, A.; Murphy, C.; Wilkins, E.; Ahmad, S.; Tayal, S.; Haynes, J.; Evans, E.; Ong, E.; Das, R.; Grey, R.; Meaden, J.; Bignell, C.; Loay, D.; Peacock, K.; Girgis, M.R.; Morgan, B.; Palfreeman, A.; Wilcox, J.; Tobin, J.; Tucker, L.; Saeed, A.M.; Chen, F.; Deheragada, A.; Williams, O.; Lacey, H.; Herman, S.; Kinghorn, D.; Devendra, V.S.; Wither, J.; Dawson, S.; Rowen, D.; Harvey, J.; Wilkins, E.; Bridgwood, A.; Singh, G.; Chauhan, M.; Kellock, D.; Young, S.; Dannino, S.; Kathir, Y.; Rooney, G.; Currie, J.; Fitzgerald, M.; Devendra, S.; Keane, F.; Booth, G.; Green, T.; Arumainayyagam, J.; Chandramani, S.; Rajamanoharan, S.; Robinson, T.; Curless, E.; Gokhale, R.; Tariq, A.; Roberts, M.; Williams, O.; Luzzi, G.; FitzGerald, M.; Fairley, I.; Wallis, F.; Smit, E.; Ward, F.; Molina, J.M.; Loze, B.; Morlat, P.; Bonarek, M.; Bonnet, F.; Nouts, C.; Louis, I.; Raffi, F.; Reliquet, V.; Sauser, F.; Biron, C.; Mounoury, O.; Hue, H.; Brosseau, D.; Delfraissy, J.F.; Goujard, C.; Ghosn, J.; Rannou, M.T.; Bergmann, J.F.; Badsi, E.; Rami, A.; Diemer, M.; Parrinello, M.; Girard, P.M.; Samanon-Bollens, D.; Campa, P.; Tourneur, M.; Desplanques, N.; Livrozet, J.M.; Jeanblanc, F.; Chiarello, P.; Makhloufi, D.; Blanc, A.P.; Allègre, T.; Reynes, J.; Baillat, V.; Lemoing, V.; Merle De Boever, C.; Tramoni, C.; Cabié, A.; Sobesky, G.; Abel, S.; Beaujolais, V.; Pialoux, G.; Slama, L.; Chakvetadze, C.; Berrebi, V.; Yeni, P.; Bouvet, E.; Fournier, I.; Gerbe, J.; Trepo, C.; Koffi, K.; Augustin-Normand, C.; Miailhes, P.; Thoirain, V.; Brochier, C.; Thomas, R.; Souala, F.; Ratajczak, M.; Beytoux, J.; Jacomet, C.; Gourdon, F.; Rouveix, E.; Morelon, S.; Dupont, C.; Olivier, C.; Lortholary, O.; Dupont, B.; Viard, J.P.; Maignan, A.; Ragnaud, J.M.; Raymond, I.; Leport, C.; Jadand, C.; Jestin, C.; Longuet, P.; Boucherit, S.; Sereni, D.; Lascoux, C.; Prevoteau, F.; Sobel, A.; Levy, Y.; Lelièvre, J.D.; Lascaux, A.S.; Dominguez, S.; Dumont, C.; Aumâitre, H.; Delmas, B.; Saada, M.; Medus, M.; Guillevin, L.; Salmon, D.; Tahi, T.; Yazdanpanah, Y.; Pavel, S.; Marien, M.C.; Drenou, B.; Beck-Wirth, G.; Beck, C.; Benomar, M.; Katlama, C.; Tubiana, R.; Ait Mohand, H.; Chermak, A.; Ben Abdallah, S.; Bentata, M.; Touam, F.; Hoen, B.; Drobacheff, C.; Folzer, A.; Massip, P.; Obadia, M.; Prudhomme, L.; Bonnet, E.; Balzarin, F.; Pichard, E.; Chennebault, J.M.; Fialaire, P.; Loison, J.; Galanaud, P.; Boué, F.; Bornarel, D.; Verdon, R.; Bazin, C.; Six, M.; Ferret, P.; Weiss, L.; Batisse, D.; Gonzales-Canali, G.; Tisne-Dessus, D.; Devidas, A.; Chevojon, P.; Turpault, I.; Lafeuillade, A.; Cheret, A.; Philip, G.; Morel, P.; Timsit, J.; Herson, S.; Amirat, N.; Simon, A.; Brancion, C.; Cabane, J.; Picard, O.; Tredup, J.; Stein, A.; Ravault, I.; Chavanet, C.; Buisson, M.; Treuvetot, S.; Choutet, P.; Nau, P.; Bastides, F.; May, T.; Boyer, L.; Wassoumbou, S.; Oksenhendeler, E.; Gérard, L.; Bernard, L.; De Truchis, P.; Berthé, H.; Domart, Y.; Merrien, D.; Greder Belan, A.; Gayraud, M.; Bodard, L.; Meudec, A.; Beuscart, C.; Daniel, C.; Pape, E.; Vinceneux, P.; Simonpoli, A.M.; Zeng, A.; Fournier, L.; Fuzibet, J.G.; Sohn, C.; Rosenthal, E.; Quaranta, M.; Dellamonica, P.; Chaillou, S.; Sabah, M.; Audhuy, B.; Schieber, A.; Moreau, P.; Niault, M.; Vaillant, O.; Huchon, G.; Compagnucci, A.; De Lacroix Szmania, I.; Richier, L.; Lamaury, I.; Saint-Dizier, F.; Garipuy, D.; Gastaut, J.A.; Drogoul, M.P.; Poizot Martin, I.; Fabre, G.; Lambert De Cursay, G.; Abraham, B.; Perino, C.; Lagarde, P.; David, F.; Roche-Sicot, J.; Saraux, J.L.; Leprêtre, A.; Fampin, B.; Uludag, A.; Morin, A.S.; Bletry, O.; Zucman, D.; Regnier, A.; Girard, J.J.; Quinsat, D.T.; Heripret, L.; Grihon, F.; Houlbert, D.; Ruel, M.; Chemlal, K.; Caron, F.; Debab, Y.; Tremollieres, F.; Perronne, V.; Lepeu, G.; Slama, B.; Perré, P.; Miodovski, C.; Guermonprez, G.; Dulioust, A.; Boudon, P.; Malbec, D.; Patey, O.; Semaille, C.; Deville, J.; Remy, G.; Béguinot, I.; Galanaud, P.; Boue, F.; Chambrin, V.; Pignon, C.; Estocq, G.A.; Levy, A.; Delfraissy, J.F.; Goujard, C.; Duracinsky, M.; Le Bras, P.; Ngussan, M.S.; Peretti, D.; Medintzeff, N.; Lambert, T.; Segeral, O.; Lezeau, P.; Laurian, Y.; Weiss, L.; Buisson, M.; Piketty, C.; Karmochkine, M.; Batisse, D.; Eliaszewitch, M.; Jayle, D.; Tisne-Dessus, D.; Kazatchkine, M.; Leport, C.; Colasante, U.; Jadand, C.; Jestin, C.; Duval, X.; Nouaouia, W.; Boucherit, S.; Vilde, J.L.; Girard, P.M.; Bollens, D.; Binet, D.; Diallo, B.; Meyohas, M.C.; Fonquernie, L.; Lagneau, J.L.; Salmon, D.; Guillevin, L.; Tahi, T.; Launay, O.; Pietrie, M.P.; Sicard, D.; Stieltjes, N.; Michot, J.; Sobel, A.; Levy, Y.; Bourdillon, F.; Lascaux, A.S.; Lelievre, J.D.; Dumont, C.; Dupont, B.; Obenga, G.; Viard, J.P.; Maignan, A.; Vittecoq, D.; Escaut, L.; Bolliot, C.; Bricaire, F.; Katlama, C.; Schneider, L.; Herson, S.; Simon, A.; Iguertsira, M.; Stein, A.; Tomei, C.; Ravaux, I.; Dhiver, C.; Tissot Dupont, H.; Vallon, A.; Gallais, J.; Gallais, H.; Gastaut, J.A.; Drogoul, M.P.; Fabre, G.; Dellamonica, P.; Durant, J.; Mondain, V.; Perbost, I.; Cassuto, J.P.; Karsenti, J.M.; Venti, H.; Fuzibet, J.G.; Rosenthal, E.; Ceppi, C.; Quaranta, M.; Krivitsky, J.A.; Bentata, M.; Bouchaud, O.; Honore, P.; Sereni, D.; Lascoux, C.; Delgado, J.; Rouzioux, C.; Burgard, M.; Boufassa, L.; Peynet, J.; Pérez-Hoyos, S.; Del Amo, J.; Alvarez, D.; Monge, S.; Muga, R.; Sanvisens, A.; Clotet, B.; Tor, J.; Bolao, F.; Rivas, I.; Vallecillo, G.; Del Romero, J.; Raposo, P.; Rodríguez, C.; Vera, M.; Hurtado, I.; Belda, J.; Fernandez, E.; Alastrue, I.; Santos, C.; Tasa, T.; Juan, A.; Trullen, J.; Garcia De Olalla, P.; Cayla, J.; Masdeu, E.; Knobel, H.; Mirò, J.M.; Sambeat, M.A.; Guerrero, R.; Rivera, E.; Guerrero, R.; Marco, A.; Quintana, M.; Gonzalez, C.; Castilla, J.; Guevara, M.; De Mendoza, C.; Zahonero, N.; Ortíz, M.; Paraskevis, D.; Touloumi, G.; Pantazis, N.; Bakoyannis, G.; Gioukari, V.; Antoniadou, A.; Papadopoulos, A.; Petrikkos, G.; Daikos, G.; Psichogiou, M.; Gargalianos-Kakolyris, P.; Xylomenos, G.; Katsarou, O.; Kouramba, A.; Ioannidou, P.; Kordossis, T.; Kontos, A.; Lazanas, M.; Chini, M.; Tsogas, N.; Panos, G.; Paparizos, V.; Leuow, K.; Kourkounti, S.; Sambatakou, H.; Mariolis, I.; Skoutelis, A.; Papastamopoulos, V.; Baraboutis, I.
Background: There is little information on the incidence of AIDS-defining events which have been reported in the literature to be associated with immune reconstitution inflammatory syndrome (IRIS) after combined antiretroviral therapy (cART) initiation. These events include tuberculosis,
Garcez, Aguinaldo S.; Ribeiro, Martha S.; Tegos, George P.; Núñez, Silvia C.; Jorge, Antonio O.C.; Hamblin, Michael R.
Background and Objective To compare the effectiveness of antimicrobial photodynamic therapy (PDT), standard endodontic treatment and the combined treatment to eliminate bacterial biofilms present in infected root canals. Study Design/Materials and Methods Ten single-rooted freshly extracted human teeth were inoculated with stable bioluminescent Gram-negative bacteria, Proteus mirabilis and Pseudomonas aeruginosa to form 3-day biofilms in prepared root canals. Bioluminescence imaging was used to serially quantify bacterial burdens. PDT employed a conjugate between polyethylenimine and chlorin(e6) as the photosensitizer (PS) and 660-nm diode laser light delivered into the root canal via a 200-µ fiber, and this was compared and combined with standard endodontic treatment using mechanical debridement and antiseptic irrigation. Results Endodontic therapy alone reduced bacterial bioluminescence by 90% while PDT alone reduced bioluminescence by 95%. The combination reduced bioluminescence by >98%, and importantly the bacterial regrowth observed 24 hours after treatment was much less for the combination (Pendodontic therapy. Antimicrobial PDT may have a role to play in optimized endodontic therapy. PMID:17066481
Bannister, WP; Ruiz, L; Loveday, C
BACKGROUND: Combination antiretroviral therapy (cART) may vary in ability to suppress viral load and increase CD4+ T-cell count in people infected with different HIV-1 subtypes, possibly due to differences in resistance development. Antiretroviral drugs have predominantly been developed in Western...
Ghani, Azra C.; Ferguson, Neil M.; Fraser, Christophe; Donnelly, Christl A.; Danner, Sven; Reiss, Peter; Lange, Joep; Goudsmit, Jaap; Anderson, Roy M.; de Wolf, Frank
A mathematical model of the interaction among CD4(+) T-cells, HIV-1, and antiretroviral drugs was fitted to the viral load decline following initiation of combination therapy to estimate differences in the residual reproductive capacity of virus (R-0) in the average patient in each group. Four
Wang, Huanan; Zhang, Lingling; Yang, Xu; Jin, Yipeng; Pei, Shimin; Zhang, Di; Zhang, Hong; Zhou, Bin; Zhang, Yingjie; Lin, Degui
Colon cancer is the third most common cancer in humans which has a high mortality rate, and 5-Fluorouracil (5-FU) is one of the most widely used drugs in colon cancer therapy. However, acquired chemoresistance is becoming the major challenges for patients, and the molecular mechanism underlying the development of 5-FU resistance is still poorly understood. In this study, a newly designed therapy in combination with 5-FU and NVP-BEZ235 in colon cancer cells (HCT-116 and RKO) was established, to investigate the mechanism of 5-FU resistance and optimize drug therapy to improve outcome for patients. Our results show 5-FU induced cell apoptosis through p53/PUMA pathway, with aberrant Akt activation, which may well explain the mechanism of 5-FU resistance. NVP-BEZ235 effectively up-regulated PUMA expression, mainly through inactivation of PI3K/Akt and activation of FOXO3a, leading to cell apoptosis even in the p53−/− HCT-116 cells. Combination treatment of 5-FU and NVP-BEZ235 further increased cell apoptosis in a PUMA/Bax dependent manner. Moreover, significantly enhanced anti-tumor effects were observed in combination treatment in vivo. Together, these results demonstrated that the combination treatment of 5-FU and NVP-BEZ235 caused PUMA-dependent tumor suppression both in vitro and in vivo, which may promise a more effective strategy for colon cancer therapy. PMID:25965911
Abbaraju, Prasanna Lakshmi; Yang, Yannan; Yu, Meihua; Fu, Jianye; Xu, Chun; Yu, Chengzhong
Multifunctional core-shell-structured dendritic mesoporous silica nanoparticles with a fullerene-doped silica core, a dendritic silica shell and large pores have been prepared. The combination of photodynamic therapy and antibody therapeutics significantly inhibits the cancer cell growth by effectively reducing the level of anti-apoptotic proteins. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Rönsholt, Frederikke F; Ostrowski, Sisse Rye; Katzenstein, Terese Lea
Immune activation is decreased by combination antiretroviral therapy (cART) in patients infected with human immunodeficiency virus (HIV), but residual activation remains and has been proposed as a cause of premature aging and death, but data are lacking. We analyzed the relationship between T...
Kuncírová, V.; Poništ, S.; Mihalová, D.; Dráfi, F.; Nosáľ, R.; Acquaviva, A.; Gardi, C.; Harmatha, Juraj; Hrádková, I.; Bauerová, K.
Roč. 28, č. 6 (2014), s. 616-626 ISSN 0767-3981 Institutional support: RVO:61388963 Keywords : arthritis * inflammation * oxidative stress * combination therapy * methotrexate * N-feruloylserotonin Subject RIV: FR - Pharmacology ; Medidal Chemistry Impact factor: 2.121, year: 2014
Evaluation of the 3-drug combination, Rifater, versus 4-drug therapy in the ambulatory treatment of tuberculosis in Cape Town. ... The rates of inadequate compliance and of side-effects were siInilar in the two groups. Drug sensitivity testing of bacteria cultured from pre-treatment sputum specimens revealed an overall ...
Baker, David G
A captive adult male Bengal tiger (Panthera tigris tigris) was treated for chronic footpad ulcers associated with pacing on concrete cage surfaces. Combination therapy of oral fluoxetine and acepromazine administration to diminate pacing behavior, daily application of moisturizing ointment, and oral vitamin E supplementation resulted in complete resolution of all footpad lesions. Subsequent clinical episodes completely resolved with similar treatments.
Yang, Qun-ying; Shen, Dong; Sai, Ke; Jiang, Xiao-bing; Ke, Chao; Zhang, Xiang-heng; Mou, Yong-gao; Chen, Zhong-ping
To explore the survival of newly diagnosed malignant gliomas patients on combined modality therapy of surgery, radiotherapy and chemotherapy. The data of 122 newly diagnosed malignant glioma patients on combined modality therapy at our center between 2000 and 2010 were retrospectively reviewed and analyzed. The median age was 40 years old (range: 5 - 75) and median Karnofsky performance status score (KPS) 80 (range: 60 - 100). Combined modality therapy consisted of surgery (maximal safety tumor resection), followed by fractionated focal irradiation for a total dose of 54 - 60 Gy and then 4 - 6 cycles of adjuvant chemotherapy including temozolomide or nitrosourea-based regimens or other ones without temozolomide and nitrosourea. The overall and progression-free survivals were analyzed by the Kaplan-Meier method and the influencing factors screened by Cox proportional hazard model. There were grade IV (n = 70) and grade III (n = 52). The median survival periods were 17.0 months for grade IV patients and 36.0 months for grade III ones. The 2, 3, 4 and 5-year survival rates were 32.0% vs 64.8%, 19.6% vs 47.8%, 11.8% vs 32.0% and 5.9% vs 25.4% (P Combined modality therapy of surgery, adjuvant radiotherapy and chemotherapy may improve the survival of patients with malignant gliomas.
Hill-Kayser, Christine E.; Plastaras, John P.; Tochner, Zelig; Glatstein, Eli
Results of the Hodgkin's Disease.6 trial are critically examined in light of the advances in radiation therapy techniques that have occurred since it was initiated. The ultimate findings of the HD.6 trial do not close the case for combined-modality treatment of limited-stage Hodgkin's disease.
Tokuchi, Ryo; Hishikawa, Nozomi; Matsuzono, Kosuke; Takao, Yoshiki; Wakutani, Yosuke; Sato, Kota; Kono, Syoichiro; Ohta, Yasuyuki; Deguchi, Kentaro; Yamashita, Toru; Abe, Koji
The aim of the present study was to compare the effects of a galantamine only therapy and a combination therapy with galantamine plus ambulatory cognitive rehabilitation for Alzheimer's disease patients. For this retrospective cohort study, we enrolled 86 patients with Alzheimer's disease, dividing them into two groups - a galantamine only group (group G, n = 45) and a combination with galantamine plus ambulatory rehabilitation group (group G + R, n = 41). The present cognitive rehabilitation included a set of physical therapy, occupational therapy and speech therapy for 1-2 h once or twice a week. We compared the Mini-Mental State Examination and Frontal Assessment Battery for cognitive assessment, and Geriatric Depression Scale, Apathy Scale, and Abe's Behavioral and Psychological Symptoms of Dementia score for affective assessment in two groups over 6 months. The baseline Mini-Mental State Examination score was 20.2 and 18.7 in groups G and G + R, respectively. Other baseline data (Frontal Assessment Battery, Geriatric Depression Scale, Apathy Scale, and Abe's Behavioral and Psychological Symptoms of Dementia) were not different between the two groups. Although group G kept all the scores stable until 6 months of the treatment, the Apathy Scale score showed a significant improvement in group G + R as early as 3 months, followed by the Mini-Mental State Examination and Frontal Assessment Battery improvements at 6 months (*P = 0.04 and *P = 0.02, respectively). The Geriatric Depression Scale and Abe's Behavioral and Psychological Symptoms of Dementia did not show any changes. The combination therapy of galantamine plus ambulatory cognitive rehabilitation showed a superior benefit both on cognitive and affective functions than galantamine only therapy in Alzheimer's disease patients. © 2015 Japan Geriatrics Society.
Wang, Xiao-Hui; Zhang, Wen
To compare clinical therapeutic effects of acupuncture combined with magnetic therapy and simple magnetic therapy on temple-jaw joint dysfunction. Eighty-two cases were randomly divided into an observation group (n = 52) and a control group (n = 30). The observation group was treated with acupuncture at Xiaguan (ST 7), Jiache (ST 6), Hegu (LI 4), etc. and AL-2 low frequency electromagnetic comprehensive treatment instrument; the control group was treated with AL-2 low frequency electromagnetic comprehensive treatment instrument. The cured and markedly effective rate of 90.4% in the observation group was significantly better than 66.7% in the control group (P magnetic therapy is significantly better than that of the simple magnetic therapy on temple-jaw joint dysfunction.
Wakasaki, Takahiro; Gotoh, Seiji; Tomonobe, Eri; Mihara, Takenao; Fukushima, Junichi
Posterior reversible encephalopathy syndrome (PRES) is a rare and acute disease with central nervous system symptoms. Without appropriate therapy, patients may exhibit a poor prognosis. PRES should be recognized as a possible problem during therapy for head and neck squamous cell carcinoma (HNSCC). A 56-year-old female developed PRES during combined modality therapy for HNSCC. On the fourth day after surgery and following chemoradiotherapy, PRES developed with a sudden visual disorder, followed by headache located at the back of the head and convulsions accompanied by impaired consciousness. We diagnosed PRES based on the clinical manifestations and magnetic resonance imaging data. The patient recovered from PRES by appropriate treatment. This is the first case report of PRES developed during treatment for HNSCC. Masked by other cerebrovascular disorders, more cases of PRES could exist than usually expected; therefore, we should consider PRES as a differential diagnosis for central nervous system disorders developing during high-intensity therapy. © The Author(s) 2016.
Full Text Available Masumi G Asahi,1 Andrew T Chon,1 Esmeralda Gallemore,1 Ron P Gallemore1,2 1Clinical Research Department, Retina Macula Institute, Torrance, CA, USA; 2Jules Stein Eye Institute, University of California, Los Angeles, CA, USA Purpose: To determine whether combination photodynamic therapy (PDT and antivascular endothelial growth factor (VEGF therapy is effective in the management of chronic central serous chorioretinopathy (CSC recalcitrant to conventional therapy. Methods: This was a retrospective analysis of eight patients with chronic CSC unresponsive to topical nonsteroidal anti-inflammatory drugs, focal photocoagulation, anti-VEGF alone, or PDT alone. All patients were evaluated with a full ophthalmic examination, spectral-domain optical coherence tomography (OCT, fluorescein angiography (FA, and most with indocyanine green angiography (ICGA followed by treatment with half-fluence PDT and intravitreal anti-VEGF injection (seven bevacizumab, one aflibercept. Patients were seen in follow-up 1 month after treatment. Results: All eight patients achieved complete resolution in subretinal fluid following combination treatment. Average duration of CSC prior to initiation of combination therapy was 7.5 months. Mean central macular thickness on OCT decreased significantly from 401.2±52.7 µm to 297.9±18.2 µm (p=0.0010 by 4 months after treatment (1.63±1.18 months. Seven of eight patients were followed up for an average of 13 months with no recurrence during that time. One case recurred at 8 months and was treated with repeat combination at that time. Frank choroidal neovascularization (CNV was not identified in these cases on FA or ICGA studies. Eight of eight patients showed significant improvement in vision from a logMAR of 0.1125±0.099 to 0.0125±0.064 (p=0.019. Conclusion: Combination PDT and anti-VEGF is effective for chronic CSC which has failed conventional therapy. Associated CNV and/or inflammation may be reasons for greater success in
Sheeja M Krishnan
Full Text Available The current standard of care for hepatitis C virus (HCV infection - combination therapy with pegylated interferon and ribavirin - elicits sustained responses in only ∼50% of the patients treated. No alternatives exist for patients who do not respond to combination therapy. Addition of ribavirin substantially improves response rates to interferon and lowers relapse rates following the cessation of therapy, suggesting that increasing ribavirin exposure may further improve treatment response. A key limitation, however, is the toxic side-effect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus requires striking a balance between the antiviral and hemolytic activities of ribavirin. Current models of viral kinetics describe the enhancement of treatment response due to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and precludes rational optimization of combination therapy. Here, we develop a new mathematical model of the population dynamics of erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients. Based on the assumption that ribavirin accumulation decreases erythrocyte lifespan in a dose-dependent manner, model predictions capture several independent experimental observations of the accumulation of ribavirin in erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy, estimate the reduced erythrocyte lifespan during therapy, and describe inter-patient variations in the severity of ribavirin-induced anemia. Further, model predictions estimate the threshold ribavirin exposure beyond which anemia becomes intolerable and suggest guidelines for the usage of growth hormones, such as erythropoietin, that stimulate erythrocyte production and avert the reduction of ribavirin dosage, thereby improving treatment response. Our model thus facilitates, in
Full Text Available Objective: To explore the mechanism of Smilax China (Chinese spelling: Jingangteng Capsules and Azithromycin combined therapy for chronic annexitis, and offer help to patients with chronic annexitis on relevant clinical therapies. Methods: A total of 170 cases of patients with chronic annexitis were selected from the gynecological department in our hospital, and randomly divided to be the combination therapy group and the control group by digital table, 85 cases for each group. Patients in control group were treated with Azithromycin. Patients in combination therapy group were treated by giving Smilax China capsules based on the Azithromycin treatment. Relevant indexes of lymphocyte subsets (CD3+ , CD4+ , CD8+ and CD4+ /CD8+ , cytokines (TNF-α, IL-2, IL-6 and IL-10 and hemorheology (blood viscosity, plasma viscosity, hematocrit, red blood cell aggregation index in patients of the two groups were detected before and after treatment. Results: Before treatment, no statistical significance found on the differences of lymphocyte subsets, cytokines and hemorheology between the two groups of patients (P>0.05; After treatment received on the two groups of patients, indexes of CD3+ , CD4+ and CD4+ /CD8+ were dramatically increased, CD8+ , cytokines (TNF-α, IL-2, IL-6 and IL-10 and hemorheology in the combination therapy group were significantly decreased compared with patients in the control group; Statistical significance existed in differences between the two groups (P<0.05. Conclusions: Patients who received Azithromycin therapy added with Smilax China capsules concurrently could be significantly improved levels of lymphocyte subsets, cytokines and hemorheology index. It is of clinical importance for treatment of patients with chronic annexitis.
Lee, Sung Uk; Cho, Kwan Ho
Locally advanced prostate cancer (LAPC) is defined as histologically proven T3–4 prostatic adenocarcinoma. In this review, we define the individual roles of radiotherapy (RT), short-term (ST-) and long-term (LT-) androgen deprivation therapy (ADT), and their combination in multimodal therapy for LAPC. Despite limitations in comparing the clinical outcomes among published papers, in the present study, a trend of 10-year clinical outcomes was roughly estimated by calculating the average rates weighted by the cohort number. With RT alone, the following rates were estimated: 87% biochemical failure, 34% local failure (LF), 48% distant metastasis (DM), 38% overall survival (OS), and 27% disease-specific mortality (DSM). Those associated with ADT alone were 74% BCF, 54% OS, and 25% DSM, which appeared to be better than those of RT alone. The addition of ADT to RT produced a notable local and systemic effect, regardless of ST- or LT-ADT. The LF rate decreased from 34% with RT alone to 21% with ST-ADT and further to 15% with LT-ADT. The DM and DSM rates also showed a similar trend among RT alone, RT+ST-ADT, and RT+LT-ADT. The combination of RT+LT-ADT resulted in the best long-term clinical outcomes, indicating that both RT and ADT are important parts of multimodal therapy
Lee, Sung Uk; Cho, Kwan Ho [The Proton Therapy Center, Research Institute and Hospital, National Cancer Center, Goyang (Korea, Republic of)
Locally advanced prostate cancer (LAPC) is defined as histologically proven T3–4 prostatic adenocarcinoma. In this review, we define the individual roles of radiotherapy (RT), short-term (ST-) and long-term (LT-) androgen deprivation therapy (ADT), and their combination in multimodal therapy for LAPC. Despite limitations in comparing the clinical outcomes among published papers, in the present study, a trend of 10-year clinical outcomes was roughly estimated by calculating the average rates weighted by the cohort number. With RT alone, the following rates were estimated: 87% biochemical failure, 34% local failure (LF), 48% distant metastasis (DM), 38% overall survival (OS), and 27% disease-specific mortality (DSM). Those associated with ADT alone were 74% BCF, 54% OS, and 25% DSM, which appeared to be better than those of RT alone. The addition of ADT to RT produced a notable local and systemic effect, regardless of ST- or LT-ADT. The LF rate decreased from 34% with RT alone to 21% with ST-ADT and further to 15% with LT-ADT. The DM and DSM rates also showed a similar trend among RT alone, RT+ST-ADT, and RT+LT-ADT. The combination of RT+LT-ADT resulted in the best long-term clinical outcomes, indicating that both RT and ADT are important parts of multimodal therapy.
Full Text Available Susanne Roas,1 Felix Bernhart,2 Michael Schwarz,3 Walter Kaiser,4 Georg Noll5 1Department of Internal Medicine, University Hospital, Zurich, 2Private Practice, Biberist, 3Ambulatorium Wiesendamm, Basel, 4Healthworld (Schweiz AG, Steinhausen, 5HerzKlinik Hirslanden, Zurich, Switzerland Background: Most hypertensive patients need more than one substance to reach their target blood pressure (BP. Several clinical studies indicate the high efficacy of antihypertensive combinations, and recent guidelines recommend them in some situations even as initial therapies. In general practice they seem widespread, but only limited data are available on their effectiveness under the conditions of everyday life. The objectives of this survey among Swiss primary care physicians treating hypertensive patients were: to know the frequency of application of different treatment modalities (monotherapies, free individual combinations, single-pill combinations; to see whether there are relationships between prescribed treatment modalities and patient characteristics, especially age, treatment duration, and comorbidities; and to determine the response rate (percentage of patients reaching target BP of different treatment modalities under the conditions of daily practice. Methods: This cross-sectional, observational survey among 228 randomly chosen Swiss primary care physicians analyzed data for 3,888 consecutive hypertensive patients collected at one single consultation. Results: In this survey, 31.9% of patients received monotherapy, 41.2% two substances, 20.9% three substances, and 4.7% more than three substances. By combination mode, 34.9% took free individual combinations and 30.0% took fixed-dose single-pill combinations. Combinations were more frequently given to older patients with a long history of hypertension and/or comorbidities. In total, 67.8% of patients achieved their BP target according to their physician's judgment. When compared, single
Xing Yueming; Zhao Xinping; Song Xiang; Wu Wei; Huang Bai
Objective: To probe the therapeutic effectiveness of combination of Gamma Knife and cobalt-60 radiotherapy. Methods: 80 Hypophysoma patients who have been randomly grouped into two groups. Combination of Gamma Knife and cobalt-60 radiotherapy group and single Gamma knife group. Results: The therapeutic effectiveness of combination of Gamma Knife and cobalt-60 radiation therapy group was higher than that of single Gamma Knife group. Conclusion: The hospital that treat Hypophysoma with single Gamma Knife should add cobalt-60 radiotherapy in order to increase the local Hypophysoma dose
Greenberger, J.S.; Come, S.E.; Weichselbaum, R.R.
In this article, the issues of controversy in radiation therapy and combined (radiation and chemotherapy) modality treatment in patients with Hodgkin's disease are discussed. These issues included the technical considerations in the radiation therapy of pathological stage IA and IIA Hodgkin's disease; the approach to the patient with clinical stages I or II disease and B symptoms; the management of stage IIIA disease; the approach to the use of combined modality treatment; the management of stages IIIB and IV disease; the management of relapse after radiation or combined modality treatment; the role of staging laparotomy and its relationship to clinical stage and therapeutic approach. It was concluded that improvements in the treatment of Hodgkin's disease permit approximately half of patients to achieve prolonged disease-free survival. However, since there is no stage of the disease for which therapy is invariably successful, new clinical trials, based on prior therapeutic results and patterns of relapse, are justified. While combinations of radiation and chemotherapy may prove more effective than either modality alone, the short- and long-term treatment complications in combined modality approaches must be considered. Further, it appears that significant numbers of patients can be permanently salvaged following relapse from initial treatment. (author)
Full Text Available In advanced nonsmall cell lung cancer (NSCLC patients, platinum-based combination chemotherapy is standard treatment in the first-line setting; however, the large majority of patients ultimately progress. For more than a decade, single-agent therapy with docetaxel, pemetrexed or erlotinib has been the standard of care after failure with platinum salts, showing some benefit over best supportive care. Nonetheless, prognosis remains poor and new second-line strategies are urgently needed. Combinations of cytotoxic agents, including rechallenge with platinum salts, do not offer clear benefit over single-agent therapy for the majority of patients. In patients without a known tumoural oncogenic driver mutation, regimens based on combinations of targeted agents have shown promising results; however, a clear role in therapeutic management is yet to be established. Some success has been reported in recent research combining a cytotoxic agent with targeted therapies. In this review, we summarise published data for the various strategies evaluated over the past decade in second-line treatment of NSCLC patients without a known driver mutation. We focus on combination treatments and consider future perspectives, including the need to identify predictive markers to support personalised therapeutic strategies.
Full Text Available Piotr Milecki1,2, Piotr Martenka1, Andrzej Antczak3, Zbigniew Kwias31Department of Radiotherapy, Greater Poland Cancer Center, Poznan, Poland; 2Department of Electroradiology, Medical University, Poznan, Poland; 3Chair of Urology, Medical University, Poznan, PolandAbstract: Androgen-deprivation therapy (ADT is used routinely in combination with definitive external beam radiation therapy (EBRT in patients with high-risk clinically localized or locally advanced disease. The combined treatment (ADT–EBRT also seems to play a significant role in improving treatment results in the intermediate-risk group of prostate cancer patients. On the other hand, there is a growing body of evidence that treatment with ADT can be associated with serious and lifelong adverse events including osteoporosis, cardiovascular disease, diabetes, and many others. Almost all ADT adverse events are time dependant and tend to increase in severity with prolongation of hormonal manipulation. Therefore, it is crucial to clearly state the optimal schedule for ADT in combination with EBRT, that maintaining the positive effect on treatment efficacy would keep the adverse events risk at reasonable level. To achieve this goal, treatment schedule may have to be highly individualized on the basis of the patient-specific potential vulnerability to adverse events. In this study, the concise and evidence-based review of current literature concerning the general rationales for combining radiotherapy and hormonal therapy, its mechanism, treatment results, and toxicity profile is presented.Keywords: prostate cancer, radiotherapy, androgen deprivation, combined treatment
Kota, Sunil Kumar; Meher, Lalit Kumar; Rao, Epari Sanjeeva; Jammula, Sruti; Modi, Kirtikumar D
Adequate control of hyperlipidemia is of paramount importance for prevention of vascular events. Statins and fibrates are well established treatments for hyperlipidemia. Combination therapy with a statin and fibrate offers significant therapeutic advantage for the treatment of severe or refractory mixed hyperlipidemia. Although such a combination does increase the risk of myopathy, with an incidence of approximately 0.12%, this small risk of myopathy rarely outweighs the established morbidity and mortality benefits of achieving lipid goals. Nevertheless, a higher incidence of myopathy has been reported with statin monotherapy. Statin+fibrate therapy should be considered if monotherapy or adding other drugs (e.g. cholesterol absorption inhibitors, omega-3 fatty acids or nicotinic acid) did not achieve lipid targets or is impractical. The current article focuses on recent studies highlighting the beneficial effects of this combination. Copyright © 2012 Diabetes India. Published by Elsevier Ltd. All rights reserved.
Bellino, Silvio; Zizza, Monica; Rinaldi, Camilla; Bogetto, Filippo
The combination of antidepressants and brief psychotherapies has been proven more efficacious in treating major depression and is particularly recommended in patients with concomitant personality disorders. We compare the effects of 2 combined therapies, fluoxetine and interpersonal therapy (IPT) or fluoxetine and cognitive therapy (CT), on major depression in patients with borderline personality disorder (BPD). Thirty-five consecutive outpatients with a diagnosis of BPD and a major depressive episode (not bipolar and not psychotic) were enrolled. They were randomly assigned to 1 of the 2 combined treatments and treated for 24 weeks. Assessment included a semistructured interview, Clinical Global Impression (CGI) scale, Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), Beck Depression Inventory-II (BDI-II), Social and Occupational Functioning Assessment Scale (SOFAS), Satisfaction Profile (SAT-P) for quality of life (QOL), and Inventory of Interpersonal Problems (IIP-64). Statistical analysis was performed using the univariate General Linear Model to calculate the effects of duration and type of treatment. No significant differences between treatments were found at CGI, HDRS, BDI-II, and SOFAS score. Combined treatment with CT had greater effects on HARS score and on psychological functioning factor of SAT-P. Combined treatment with IPT was more effective on social functioning factor of SAT-P and on domains domineering or controlling and intrusive or needy of IIP-64. Both combined therapies are efficacious in treating major depression in patients with BPD. Differences between CT and IPT concern specific features of subjective QOL and interpersonal problems. These findings lack reliable comparisons and need to be replicated.
Hershon, Kenneth S
To update clinicians with an overview of empagliflozin for the treatment of type 2 diabetes mellitus (T2DM), with focus on use in combination regimens. Keyword searches were conducted in the Medline database to identify literature reporting clinical trials of at least 12 weeks' duration using empagliflozin treatment in patients with T2DM. When given as monotherapy or in combination therapy (as add-on or single-pill therapy) with metformin, pioglitazone, sulfonylurea, linagliptin, and insulin, empagliflozin produced clinically meaningful reductions in glycated hemoglobin levels, plasma glucose concentrations, bodyweight, and blood pressure. These changes were sustained during long-term treatment. In a dedicated cardiovascular event trial, empagliflozin on top of standard of care demonstrated a significant reduction in the risk of cardiovascular mortality and all-cause mortality. Across the clinical trials, empagliflozin combination therapies were well tolerated, and empagliflozin used alone was not associated with increased risk of hypoglycemia versus placebo. Indeed, the combination of empagliflozin and metformin had a significantly reduced rate of hypoglycemia compared with the combination of metformin and a sulfonylurea. On the other hand, empagliflozin treatment did have increased risk of genital infections compared with placebo. In clinical trials to date, diabetic ketoacidosis was not seen more frequently with empagliflozin than with placebo, but physicians should be alert to the possibility of this rare event. Empagliflozin has the potential to make an important contribution to the treatment of patients with T2DM. In some patients, empagliflozin may be used as monotherapy, but it is most likely to be used in combination with other therapies. Given the reduced risk of mortality seen when empagliflozin was added to standard care in patients at high cardiovascular risk, as well as the lack of alternative options for patients at lower cardiovascular risk
Full Text Available Abstract Introduction Clinical evidence indicates that certain types of movement disorders are due to psychosomatic factors. Patients with myoclonic movements are usually treated by a variety of therapeutic agents. Autogenic training (AT, a recognized form of psychosomatic therapies, is suitable for certain types of neurological diseases. We describe a patient with myoclonus who failed to respond to conventional medical therapy. His symptoms were exaggerated by psychogenic factors, especially anger. Case presentation A 42-year-old man was admitted to our hospital, Preventive Welfare Clinic, for severe paroxysmal axial myoclonus of the left shoulder and abdominal muscles. The initial diagnosis was "combination of spinal segmental myoclonus and propriospinal myoclonus". The myoclonic movements did not occur during sleep but were aggravated by bathing, alcohol drinking, and anger. Psychological examination indicated hostile attribution. Although considered not to be a case of psychogenic myoclonus, a "psychogenic factor" was definitely involved in the induction of the organic myoclonus. The final diagnosis was "combination of spinal segmental myoclonus and propriospinal myoclonus accompanied by features of psychosomatic disorders". The patient underwent psychosomatic therapy including AT and surface electromyography (EMG-biofeedback therapy and treatment with clonazepam and carbamazepine. Results AT and EMG-biofeedback resulted in shortening the duration and reducing the amplitude and frequency of the myoclonic discharges. Conclusion Psychosomatic therapy with AT and surface EMG-biofeedback produced excellent improvement of myoclonic movements and allowed the reduction of the dosage of conventional medications.
Bharathiraja, Subramaniyan; Manivasagan, Panchanathan; Moorthy, Madhappan Santha; Bui, Nhat Quang; Lee, Kang Dae; Oh, Junghwan
The photo-based therapeutic approaches have attracted tremendous attention in recent years especially in treatment and management of tumors. Photodynamic and photothermal are two major therapeutic modalities which are being applied in clinical therapy. The development of nanomaterials for photodynamic combined with photothermal therapy has gained significant attention for its treatment efficacy. In the present study, we designed chlorin e6 (Ce6) conjugated copper sulfide (CuS) nanoparticles (CuS-Ce6 NPs) through amine functionalization and the synthesized nanoparticles act as a dual-model agent for photodynamic therapy and photothermal therapy. CuS-Ce6 NPs showed enhanced photodynamic effect through generation of singlet oxygen upon 670nm laser illumination. The same nanoparticles exerted thermal response under an 808nm laser at 2W/cm 2 . The fabricated nanoparticles did not show any cytotoxic effect toward breast cancer cells in the absence of light. In vitro cell viability assay showed a potent cytotoxicity in photothermal and photodynamic treatment. Rather than singular treatment, the photodynamic combined photothermal treatment showed an enhanced cytotoxic effect on treated cells. In addition, the CuS-Ce6 NPs exert a photoacoustic signal for non-invasive imaging of treated cells in tissue-mimicking phantom. In conclusion the CuS-Ce6 NPs act as multimodal agent for photo based imaging and therapy. Copyright © 2017 Elsevier B.V. All rights reserved.
Horsman, Michael Robert; Siemann, D.W.
A functional vascular supply is critical for the continued growth and development of solid tumors. It also plays a major role in metastatic spread of tumor cells. This importance has led to the concept of targeting the vasculature of the tumor as a form of cancer therapy. Two major types of vascu...... on the tumor response to more conventional therapies. This review aims to discuss the pathophysiologic changes induced by VTAs and the implications of these effects on the potential use of VTAs in combined modality therapy....... successful in the clinic they will need to be combined with more conventional therapies. However, by affecting the tumor vascular supply, these VTAs should induce pathophysiologic changes in variables, such as blood flow, pH, and oxygenation. Such changes could have negative or positive influences......A functional vascular supply is critical for the continued growth and development of solid tumors. It also plays a major role in metastatic spread of tumor cells. This importance has led to the concept of targeting the vasculature of the tumor as a form of cancer therapy. Two major types...
Parchem, N L; Bauer, K A; Cook, C H; Mangino, J E; Jones, C D; Porter, K; Murphy, C V
Currently, in vitro synergy with colistin has not translated into improved clinical outcomes. This study aimed to compare colistin combination therapy to colistin monotherapy in critically ill patients with multi-drug resistant gram-negative (MDR-GN) pneumonia. This was a retrospective analysis of critically ill adult patients receiving intravenous colistin for MDR-GN pneumonia comparing colistin combination therapy to colistin monotherapy with a primary endpoint of clinical cure. Combination therapy was defined by administration of another antibiotic to which the MDR-GN pathogen was reported as susceptible or intermediate. Ninety patients were included for evaluation (41 combination therapy and 49 monotherapy). Baseline characteristics were similar between groups. No difference in clinical cure was observed between combination therapy and monotherapy in univariate analysis, nor when adjusted for APACHE II score and time to appropriate antibiotic therapy (57.1 vs. 63.4 %, adjusted OR 1.15, p = 0.78). Microbiological cure was significantly higher for combination therapy (87 vs. 35.5 %, p Colistin combination therapy was associated with a significant improvement in microbiological cure, without improvement in clinical cure. Based on the in vitro synergy and improvement in microbiological clearance, colistin combination therapy should be prescribed for MDR-GN pneumonia. Further research is warranted to determine if in vitro synergy with colistin translates into improved clinical outcomes.
Hosseinzadeh, Reza; Khorsandi, Khatereh; Jahanshiri, Maryam
The objective of this study was to evaluate the effects of combination therapy with methylene blue (MB) assisted photodynamic therapy (PDT) and salicylic acid (SA) as chemo-therapy anticancer agent. The binding of salicylic acid to methylene blue was studied using spectrophotometric method. The results show the 1:2 complex formation between SA and MB. The binding constants and related Gibbs free energies o are obtained (Kb1 = 183.74, Kb2 = 38.13 and ∆ Gb1° = 12.92 kJ·mol- 1, ∆ Gb2° =9.02 kJ·mol- 1). The spectrophotometric results show the improvement in solubilization and reduction prevention for SA and MB in the complex form. These results are in agreements with cellular experiments. The dark toxicity measurements represent the improve efficacy of chemotherapy using combination of SA and MB. The photodynamic therapy results (using red LED as light source (630 nm; power density: 30 mW cm- 2)) show that the cancer cell killing efficiency of MB increases in the combination with SA due to reduction prevention and stabilization of monomeric form of MB.
Cuevas, José Manuel; Torres-Puente, Manuela; Jiménez-Hernández, Nuria; Bracho, María Alma; García-Robles, Inmaculada; Wrobel, Boris; Carnicer, Fernando; del Olmo, Juan; Ortega, Enrique; Moya, Andrés; González-Candelas, Fernando
We present an analysis of the selective forces acting on two hepatitis C virus genome regions previously postulated to be involved in the viral response to combined antiviral therapy. One includes the three hypervariable regions in the envelope E2 glycoprotein, and the other encompasses the PKR binding domain and the V3 domain in the NS5A region. We used a cohort of 22 non-responder patients to combined therapy (interferon alpha-2a plus ribavirin) for which samples were obtained before initiation of therapy and after 6 or/and 12 months of treatment. A range of 25-100 clones per patient, genome region and time sample were sequenced. These were used to detect general patterns of adaptation, to identify particular adaptation mechanisms and to analyze the patterns of evolutionary change in both genome regions. These analyses failed to detect a common adaptive mechanism for the lack of response to antiviral treatment in these patients. On the contrary, a wide range of situations were observed, from patients showing no positively selected sites to others with many, and with completely different topologies in the reconstructed phylogenetic trees. Altogether, these results suggest that viral strategies to evade selection pressure from the immune system and antiviral therapies do not result from a single mechanism and they are likely based on a range of different alternatives, in which several different changes, or their combination, along the HCV genome confer viruses the ability to overcome strong selective pressures.
José Manuel Cuevas
Full Text Available We present an analysis of the selective forces acting on two hepatitis C virus genome regions previously postulated to be involved in the viral response to combined antiviral therapy. One includes the three hypervariable regions in the envelope E2 glycoprotein, and the other encompasses the PKR binding domain and the V3 domain in the NS5A region. We used a cohort of 22 non-responder patients to combined therapy (interferon alpha-2a plus ribavirin for which samples were obtained before initiation of therapy and after 6 or/and 12 months of treatment. A range of 25-100 clones per patient, genome region and time sample were sequenced. These were used to detect general patterns of adaptation, to identify particular adaptation mechanisms and to analyze the patterns of evolutionary change in both genome regions. These analyses failed to detect a common adaptive mechanism for the lack of response to antiviral treatment in these patients. On the contrary, a wide range of situations were observed, from patients showing no positively selected sites to others with many, and with completely different topologies in the reconstructed phylogenetic trees. Altogether, these results suggest that viral strategies to evade selection pressure from the immune system and antiviral therapies do not result from a single mechanism and they are likely based on a range of different alternatives, in which several different changes, or their combination, along the HCV genome confer viruses the ability to overcome strong selective pressures.
Fujita, Kinichi; Kuwano, Hiroyuki; Asao, Takayuki
The combined effects of preoperative hyperthermia and radiation therapy were evaluated histopathologically for 60 patients with advanced rectal carcinoma located in the lower part of the rectum. Thirty-four patients were treated by preoperative radiation therapy without hyperthermia (Group A). The remaining 26 patients were treated by preoperative radiation therapy combined with hyperthermia (Group B). The total dose of radiation was 30.6 Gy. Hyperthermia was performed twice, immediately after irradiation, at one-week intervals. Effects of the preoperative treatment were assessed by histopathological findings of the resected specimens using a semiquantitative scoring system (Grade 0-3). The local recurrence rates were 17.6 and 15.4 percent in Groups A and B, respectively. No difference in the postoperative survival rates was observed between the two groups. However, regarding the pathological findings of the resected tumor, the percentage of patients with an ineffective change in the resected specimens (Grade 0) was significantly lower in Group B than it was in Group A (p=0.035). Hence, the combination of hyperthermia and preoperative radiation therapy may enhance the radiation effects on a rectal tumor and may be useful as a preoperative therapeutic strategy for rectal carcinoma. (author)
Xia Jiahui; Xia Kun; Feng Yong
Nasopharyngeal carcinoma (NPC) is very common in Southern China and Southeast Asian countries. To explore a novel and more effective approach to NPC therapy, a combined strategy of suicide genes and radiation was designed in this study. Five suicide gene expression cassettes, yeast cytosine deaminase (CD), yeast CD/uracil phosphoribosyl-transferase (UPRT), and yeast CDglyTK gene controlled by CMV, and Egr-1 and a synthetic CMV-enhanced Egr-1 promoter (CE) were constructed in an expression vector p11MS. The expression of suicide genes in NPC CNE-2 cells were detected by reverse transcription polymerase chain reaction (RT-PCR) and Western blot. The cytotoxicity of suicide gene therapy and radiation were analyzed by MTT assay. An animal study in which yeast CD/UPRT-expressing CNE-2 tumors in nude mice were treated with 5-fluorocytosine (5-FC) and radiation was also developed. Our results revealed that p11MSCEyCD/UPRT and p11MSCEyCDglyTK are superior over three other constructs in the killing of NPC cells in vitro. We combined suicide gene-expressing tumors, 5-FC treatment, and radiation in vivo and found that the tumors greatly regressed, some disappeared completely in 3 nude mice in the yCD/UPRT group, and a significant difference of tumor volumes was observed between this group and the other four groups (p<0.05). Our results indicated that suicide gene therapy and radiation have a synergic effect on NPC therapy, and the combined strategy of radiogene therapy is of great potential as a substitute for the traditional method, radiation alone, in NPC therapies. (author)
Osterman, Mark T; Sandborn, William J; Colombel, Jean-Frederic; Robinson, Anne M; Lau, Winnie; Huang, Bidan; Pollack, Paul F; Thakkar, Roopal B; Lewis, James D
Few studies have assessed the risk of malignancy from anti-tumor necrosis factor monotherapy or combination therapy for Crohn's disease (CD). We determined the relative risk of malignancy in patients with CD who received adalimumab monotherapy, compared with the general population. We also compared the risk of malignancy associated with combination adalimumab and immunomodulator therapy with that of adalimumab monotherapy. We performed a pooled analysis of data from 1594 patients with CD who participated in clinical trials of adalimumab (CLASSIC I and II, CHARM, GAIN, EXTEND, and ADHERE studies; 3050 patient-years of exposure). We calculated rates of malignancy among patients; the expected rates of malignancy, based on the general population, were derived from the Surveillance, Epidemiology, and End Results registry and National Cancer Institute survey. Compared with the general population, patients receiving adalimumab monotherapy did not have a greater than expected incidence of nonmelanoma skin cancer (NMSC) or other cancers, whereas those receiving combination therapy had a greater than expected incidence of malignancies other than NMSC (standardized incidence ratio, 3.04; 95% confidence interval [CI], 1.66-5.10) and of NMSC (standardized incidence ratio, 4.59; 95% CI, 2.51-7.70). Compared with patients receiving adalimumab monotherapy, those patients receiving combination therapy had an increased risk of malignancy other than NMSC (relative risk, 2.82; 95% CI, 1.07-7.44) and of NMSC (relative risk, 3.46; 95% CI, 1.08-11.06). In patients with CD, the incidence of malignancy with adalimumab monotherapy was not greater than that of the general population. Co-administration of immunomodulator therapy and adalimumab was associated with an increased risk of NMSC and other cancers. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
Ozdemir, Ismail; Bozkurt, Ozan; Demir, Omer; Aslan, Guven; Esen, Adil A
To compare the efficacy and safety of a combination therapy, doxazosin plus tenoxicam, and doxazosin alone for lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH), as various combination therapies increase the efficacy of medical therapy. Alpha blocker agents have been widely used for the treatment of LUTS secondary to BPH. Fifty-seven patients complaining of LUTS secondary to BPH were enrolled in this clinical trial. Patients were randomly assigned to receive doxazosin 4 mg or doxazosin 4 mg plus tenoxicam 20 mg treatment. Patients were evaluated for BPH according to the European Association of Urology and American Urological Association clinical guidelines. In addition, patients were assessed with Overactive Bladder Symptom Score (OABSS) and International Index of Erectile Function (IIEF). Patients were reevaluated after a 6-week treatment course. The International Prostatic Symptom Score (IPSS), IPSS-Quality of Life (IPSS-QoL), maximal urinary flow rates (Q(max)), and average urinary flow rates (AFR) were determined at baseline and again at 6 weeks as efficacy parameters. The total IPSS, IPSS-QoL, and OABSS decreased significantly in both tenoxicam plus doxazosin group and doxazosin alone group compared with baseline (P < .01). Also, Q(max) and AFR significantly improved in both groups (P < .01). The improvements in IPSS, IPSS-QoL, and OABSS were significantly better in patients treated with combination therapy (P < .05). COX-2 inhibitors in combination with an alpha blocker may increase the effectiveness of the therapy for LUTS secondary to BPH without significant effects on side effect profile.
Full Text Available Objective: To investigate the effectiveness and significance of the Psychological intervention combined with music therapy in abdominal MRI examination. Methods: 230 cases who underwent abdominal MRI examination between 2010 January and 2012 December were collected. They were divided into three groups randomly: routine nursing group, Psychological intervention group and music therapy group. Differences in age, gender, educational level, blood pressure and heart rate were compared between the three groups; To analyze the changes of vital signs after MRI examination, MRI examination results , psychological reaction before and after MRI examination of the three groups. Results: (1There was no significant difference in the general information (P>0.05; (2The heart rate, respiration and blood pressure after MRI examination of patients with routine nursing increased significantly than the other two groups. And psychological nursing group was higher than the music therapy group to some extent;The MRI detection time of routine nursing group was significantly longer than the other two groups (P <0.05; (3The one-time completion rate of the last two groups was significantly higher than the routine nursing group (P <0.05, and music therapy group was significantly higher than that of the psychological intervention group.The adverse psychological reaction in Psychological intervention group was significantly decreased compared with routine nursing group; and music therapy group decreased significantly compared with the psychological intervention group (P <0.05; (4Although the anxiety / depression score of psychological intervention group increased slightly ,but it significantly lower than the usual care group (P <0.05; The anxiety / depression scores of music therapy group were significantly decreased, significantly lower than the other two groups (P <0.05. Conclusion: Psychological nursing combined with music therapy is a good way to eliminate the
Vaduganathan, Muthiah; Mentz, Robert J; Greene, Stephen J; Senni, Michele; Sato, Naoki; Nodari, Savina; Butler, Javed; Gheorghiade, Mihai
Congestion is the most common reason for admissions and readmissions for heart failure (HF). The vast majority of hospitalized HF patients appear to respond readily to loop diuretics, but available data suggest that a significant proportion are being discharged with persistent evidence of congestion. Although novel therapies targeting congestion should continue to be developed, currently available agents may be utilized more optimally to facilitate complete decongestion. The combination of loop diuretics, natriuretic doses of mineralocorticoid receptor antagonists and vasopressin antagonists represents a regimen of currently available therapies that affects early and persistent decongestion, while limiting the associated risks of electrolyte disturbances, hemodynamic fluctuations, renal dysfunction and mortality.
Bowles, Daniel W; Deutsch, Eric; Raben, David
The paradigms for treating head and neck squamous cell carcinoma are changing as new subgroups are defined. The technical successes of improved radiation therapy are many; however, the success of novel combined therapies are few. With the emergence of human papillomavirus and the development of immunooncology agents, such as checkpoint inhibitors, are we ready to reevaluate how we use radiation and chemotherapy for locally advanced and metastatic disease-will we remain the fire or become the fire starter? Copyright © 2016. Published by Elsevier Inc.
I. M. Sokolov
Full Text Available The high prevalence of arterial hypertension in association with high and very high cardiovascular risk requires widespread use of combined therapy. Current approaches to selection of combination components of antihypertensive drugs are based the efficacy of these drugs proven in multicenter randomized clinical trials. The triple combination of calcium antagonist, angiotensin II receptor blocker and thiazide diuretic is regarded as the best option for combined therapy in patients with arterial hypertension and ischemic heart disease to reduce cardiovascular risk.
Elphick, Heather E; Scott, Alison
Choice of antibiotic, and the use of single or combined therapy are controversial areas in the treatment of respiratory infection due to Pseudomonas aeruginosa in cystic fibrosis (CF). Advantages of combination therapy include wider range of modes of action, possible synergy and reduction of resistant organisms; advantages of monotherapy include lower cost, ease of administration and reduction of drug-related toxicity. Current evidence does not provide a clear answer and the use of intravenous antibiotic therapy in cystic fibrosis requires further evaluation. This is an update of a previously published review. To assess the effectiveness of single compared to combination intravenous anti-pseudomonal antibiotic therapy for treating people with cystic fibrosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search of the Group's Trials Register: 14 October 2016. Randomised controlled trials (RCTs) comparing a single intravenous anti-pseudomonal antibiotic with a combination of that antibiotic plus a second anti-pseudomonal antibiotic in people with CF. Two authors independently assessed trial quality and extracted data. We identified 45 trials, of which eight trials (356 participants) comparing a single anti-pseudomonal agent to a combination of the same antibiotic and one other, were included.There was a wide variation in the individual antibiotics used in each trial. In total, the trials included seven comparisons of a beta-lactam antibiotic (penicillin-related or third generation cephalosporin) with a beta-lactam-aminoglycoside combination and three comparisons of an aminoglycoside with a beta-lactam-aminoglycoside combination. These two groups of trials were analysed as separate subgroups.There was considerable heterogeneity amongst these trials
Tonra, James R; Corcoran, Erik; Deevi, Dhanvanthri S; Steiner, Philipp; Kearney, Jessica; Li, Huiling; Ludwig, Dale L; Zhu, Zhenping; Witte, Larry; Surguladze, David; Hicklin, Daniel J
Rational strategies utilizing anticancer efficacy and biological principles are needed for the prioritization of specific combination targeted therapy approaches for clinical development, from among the many with experimental support. Antibodies targeting epidermal growth factor receptor (EGFR) (cetuximab), insulin-like growth factor-1 receptor (IGF-IR) (IMC-A12) or vascular endothelial growth factor receptor 2 (VEGFR2) (DC101), were dosed alone or in combination, in 11 human tumor xenograft models established in mice. Efficacy readouts included the tumor burden and incidence of metastasis, as well as tumor active hypoxia inducible factor-1 (HIF-1), human VEGF and blood vessel density. Cetuximab and DC101 contributed potent and non-overlapping benefits to the combination approach. Moreover, DC101 prevented escape from IMC-A12 + cetuximab in a colorectal cancer model and cetuximab prevented escape from DC101 therapy in a pancreatic cancer model. Targeting VEGFR2 + EGFR was prioritized over other treatment strategies utilizing EGFR, IGF-IR and VEGFR2 antibodies. The criteria that proved to be valuable were a non-overlapping spectrum of anticancer activity and the prevention of resistance to another therapy in the combination.
Due to inflammatory/immune responses elicited by photodynamic therapy (PDT), this modality is particularly suitable in combination with various forms of immunotherapy for an improved therapeutic gain. A wide variety of approaches that may be applicable in this context include those focusing on amplifying the activity of particular immune cell types (neutrophils, macrophages, dendritic cells, natural killer cells, helper or cytotoxic T lymphocytes). Another type of approach is to focus on a specific phase of immune response development, which comprises the activation of non-specific inflammatory immune effectors, immune recognition, immune memory, immune rejection, or blocking of immune suppression. These different strategies call for a variety of immunotherapeutic protocols to be employed in combination with PDT. These include treatments such as: (1) non-specific immunoactivators (e.g. bacterial vaccines), (2) specific immune agents (cytokines, or other activating factors), (3) adoptive immunotherapy treatments (transfer of dendritic cells, tumor-sensitized T lymphocytes or natural killer cells), or (4) their combinations. Techniques of gene therapy employed in some of these protocols offer novel opportunities for securing a potent and persistent immune activity. Using PDT and immunotherapy represents an attractive combination for cancer therapy that is capable of eradicating both localized and disseminated malignant lesions.
George L Drusano
Full Text Available Tuberculosis remains a worldwide problem, particularly with the advent of multi-drug resistance. Shortening therapy duration for Mycobacterium tuberculosis is a major goal, requiring generation of optimal kill rate and resistance-suppression. Combination therapy is required to attain the goal of shorter therapy.Our objective was to identify a method for identifying optimal combination chemotherapy. We developed a mathematical model for attaining this end. This is accomplished by identifying drug effect interaction (synergy, additivity, antagonism for susceptible organisms and subpopulations resistant to each drug in the combination.We studied the combination of linezolid plus rifampin in our hollow fiber infection model. We generated a fully parametric drug effect interaction mathematical model. The results were subjected to Monte Carlo simulation to extend the findings to a population of patients by accounting for between-patient variability in drug pharmacokinetics.All monotherapy allowed emergence of resistance over the first two weeks of the experiment. In combination, the interaction was additive for each population (susceptible and resistant. For a 600 mg/600 mg daily regimen of linezolid plus rifampin, we demonstrated that >50% of simulated subjects had eradicated the susceptible population by day 27 with the remaining organisms resistant to one or the other drug. Only 4% of patients had complete organism eradication by experiment end.These data strongly suggest that in order to achieve the goal of shortening therapy, the original regimen may need to be changed at one month to a regimen of two completely new agents with resistance mechanisms independent of the initial regimen. This hypothesis which arose from the analysis is immediately testable in a clinical trial.
Kajhøj, Tine Qvistgaard; Duch, Mogens R.; Pedersen, Finn Skou
Background: Therapies for muscular dystrophies remain a major challenge in spite of advanced strategies using either cell or gene therapy. We here propose a combined approach of cell and gene therapy. As gene delivery vehicles with specific homing potential we have chosen mesoangioblasts which...
Zhou, Ping; Qin, Jiaqi; Li, Yuan; Li, Guoxia; Wang, Yinsong; Zhang, Ning; Chen, Peng; Li, Chunyu
Metastatic malignant melanoma is one of the most aggressive malignancies and its treatment remains challenging. Recent studies demonstrate that the melanoma metastasis has correlations with the heightened activations of protein kinase C ζ (PKCζ) and cyclooxygenase-2 (COX-2) signaling pathways. Targeted inhibitions for PKCζ and COX-2 have been considered as the promising strategies for the treatment of melanoma metastasis. Thus, the PKCζ inhibitor J-4 and COX-2 inhibitor Celecoxib were combined to treat melanoma metastasis in this study. The Transwell assay, Wound-healing assay and Adhesion assay were used to evaluate the inhibition of combined therapy of J-4 and Celecoxib on melanoma cells invasion, migration and adhesion in vitro, respectively. The impaired actin polymerization was observed by confocal microscope and inactivated signal pathways about PKCζ and COX-2 were confirmed by the Western blotting assay. The B16-F10/C57BL mouse melanoma model was used to test the inhibition of combined therapy of J-4 and Celecoxib on melanoma metastasis in vivo. The in vitro results showed that the combination of J-4 and Celecoxib exerted synergistic inhibitory effects on the migration, invasion and adhesion of melanoma B16-F10 and A375 cells with combination index less than 1. The actin polymerization and phosphorylation of Cofilin required in cell migration were severely impaired, which is due to the inactivation of PKCζ related signal pathways and the decrease of COX-2. The combined inhibition of PKCζ and COX-2 induced Mesenchymal-Epithelial Transition (MET) in melanoma cells with the expression of E-Cadherin increasing and Vimentin decreasing. The secretion of MMP-2/MMP-9 also significantly decreased after the combination treatment. In C57BL/6 mice intravenously injected with B16-F10 cells (5 × 10 4 cells/mouse), co-treatment of J-4 and Celecoxib also severely suppressed melanoma lung metastasis. The body weight monitoring and HE staining results indicated the
Yamamoto, Chika; Yoshikawa, Hiromasa; Fukumoto, Shunsuke; Higuchi, Takashi; Yoshida, Masanori; Yasumori, Koutarou; Horinouchi, Yasufumi; Uehara, Satoru
Combination therapy with S-1, superselective intra-arterial infusion of carboplatin (CBDCA) and radiation therapy has been used to treat patients with oral cancer since 2005. In this study, the histopathological effects and toxicities following concurrent chemoradiotherapy were examined. The subjects consisted of 15 patients (10 men and 5 women) who were treated with S-1 (60-80 mg/day, 4 weeks), superselective intra-arterial infusion of CBDCA (300 mg/body) and radiation therapy (total dose 30-36 Gy) in our department from 2005 to 2009. Nine patients, showed T2 disease, 3 showed T3 disease, and another 3 showed T4 diseases. The primary cancer sites were the tongue (6 cases), buccal mucosa (4 cases), mandible gingival (3 cases), maxillary gingival (1 case), and the floor of the mouth (1 case). The histopathological effects were evaluated according to Oboshi-Shimosato classification. Grade IV was shown in 10 cases (66.7%), grade III in 1 case (6.7%), II bin 3 cases (20.0%), and II a in 1 case (6.7%). All patients completed the treatment. The pathological response of the resected tumor was grade IIb or higher in 14 cases (93.3%). While good histological effects were noted, there was one patient for whom viable tumor cells remained in the central part of the tumor. The present study indicates that further investigation is needed to determine the best dosing and dosing schedule. (author)
Full Text Available Kenneth S Hershon1,2 1North Shore Diabetes and Endocrine Associates, New Hyde Park, 2Department of Medicine, Hofstra Northwell School of Medicine, Hempstead, NY, USA Objective: To update clinicians with an overview of empagliflozin for the treatment of type 2 diabetes mellitus (T2DM, with focus on use in combination regimens. Methods: Keyword searches were conducted in the Medline database to identify literature reporting clinical trials of at least 12 weeks' duration using empagliflozin treatment in patients with T2DM. Results: When given as monotherapy or in combination therapy (as add-on or single-pill therapy with metformin, pioglitazone, sulfonylurea, linagliptin, and insulin, empagliflozin produced clinically meaningful reductions in glycated hemoglobin levels, plasma glucose concentrations, bodyweight, and blood pressure. These changes were sustained during long-term treatment. In a dedicated cardiovascular event trial, empagliflozin on top of standard of care demonstrated a significant reduction in the risk of cardiovascular mortality and all-cause mortality. Across the clinical trials, empagliflozin combination therapies were well tolerated, and empagliflozin used alone was not associated with increased risk of hypoglycemia versus placebo. Indeed, the combination of empagliflozin and metformin had a significantly reduced rate of hypoglycemia compared with the combination of metformin and a sulfonylurea. On the other hand, empagliflozin treatment did have increased risk of genital infections compared with placebo. In clinical trials to date, diabetic ketoacidosis was not seen more frequently with empagliflozin than with placebo, but physicians should be alert to the possibility of this rare event. Conclusion: Empagliflozin has the potential to make an important contribution to the treatment of patients with T2DM. In some patients, empagliflozin may be used as monotherapy, but it is most likely to be used in combination with other
Full Text Available To construct and validate a prediction model for individual combined benefit and harm outcomes (stroke with no major bleeding, major bleeding with no stroke, neither event, or both in patients with atrial fibrillation (AF with and without warfarin therapy.Using the Kaiser Permanente Colorado databases, we included patients newly diagnosed with AF between January 1, 2005 and December 31, 2012 for model construction and validation. The primary outcome was a prediction model of composite of stroke or major bleeding using polytomous logistic regression (PLR modelling. The secondary outcome was a prediction model of all-cause mortality using the Cox regression modelling.We included 9074 patients with 4537 and 4537 warfarin users and non-users, respectively. In the derivation cohort (n = 4632, there were 136 strokes (2.94%, 280 major bleedings (6.04% and 1194 deaths (25.78% occurred. In the prediction models, warfarin use was not significantly associated with risk of stroke, but increased the risk of major bleeding and decreased the risk of death. Both the PLR and Cox models were robust, internally and externally validated, and with acceptable model performances.In this study, we introduce a new methodology for predicting individual combined benefit and harm outcomes associated with warfarin therapy for patients with AF. Should this approach be validated in other patient populations, it has potential advantages over existing risk stratification approaches as a patient-physician aid for shared decision-making.
Full Text Available Photodynamic therapy (PDT has emerged as one of the important therapeutic options in the management of cancer and other diseases. PDT involves a tumor-localized photosensitizer (PS, which when appropriately illuminated by visible light converts oxygen into cytotoxic reactive oxygen species (ROS, that attack key structural entities within the targeted cells, ultimately resulting in necrosis or apoptosis. Though PDT is a selective modality, it can be further enhanced by combining other targeted therapeutic strategies that include the use of synthetic peptides and nanoparticles for selective delivery of photosensitizers. Another potentially promising strategy is the application of targeted therapeutics that exploit a myriad of critical pathways involved in tumorigenesis and metastasis. Vascular disrupting agents that eradicate tumor vasculature during PDT and anti-angiogenic agents that targets specific molecular pathways and prevent the formation of new blood vessels are novel therapeutic approaches that have been shown to improve treatment outcome. In addition to the well-documented mechanisms of direct cell killing and damage to the tumor vasculature, PDT can also activate the body’s immune response against tumors. Numerous pre-clinical studies and clinical observations have demonstrated the immuno-stimulatory capability of PDT. Herein, we aim to integrate the most important findings with regard to the combination of PDT and other novel targeted therapy approaches, detailing its potential in cancer photomedicine.
Di Corato, Riccardo; Béalle, Gaëlle; Kolosnjaj-Tabi, Jelena; Espinosa, Ana; Clément, Olivier; Silva, Amanda K A; Ménager, Christine; Wilhelm, Claire
The ongoing nanotech revolution has the potential to transform diagnostic and therapeutic methods. Stimuli-triggered nanotherapies based on remotely activated agents have become attractive alternatives to conventional chemotherapy. Herein, we designed an optimized smart nanoplatform based on dually loaded hybrid liposomes to achieve enhanced tumor therapy. The aqueous core was highly loaded with iron oxide nanoparticles, while the lipid bilayer was supplied with a photosensitizer payload. The double cargo translated into double functionality: generation of singlet oxygen under laser excitation and heat production under alternating magnetic field stimulation, coupling photodynamic therapy (PDT) to magnetic hyperthermia (MHT). These liposomes address both therapeutic agents within tumor cells, and the combined PDT/MHT therapy resulted in complete cancer cell death in vitro while total solid-tumor ablation was achieved in an in vivo rodent model.
Punanov, Iu A; Gafton, G I; Gudz', Iu V; Nabokov, V V; Ivanova, T V; Safonova, S A; Levchenko, E V; Kupatadze, D D; Novik, V I; Lazareva, Iu R; Krzhivitskiĭ, P I; Petrov, V G
An analyzed cohort consists of 50 pediatric patients with osteosarcoma receiving combined therapy in N. N. Petrov Research Institute for Oncology (1999-2010). Thirty nine of them had localized disease, 11 patients had distant metastases. The treatment scheme included neoadjuvant therapy with cisplatin and doxorubicin, surgical treatment and adjuvant therapy depended on initial response and could include cisplatin, doxorubicin, high-dose methotrexate, ifosfamide, etoposide. Four-year overall and relapse-free survival in children with localized disease was 74.3% and 69.2% accordingly. In 62% of patients were performed organ-preserving surgical interventions, in 22 patients was performed endoprosthetics, in 4 patients the defect was replaced by a bone autograft on a vascular bundle. The effectiveness of initial treatment and secondary endoprosthetics were analyzed. Six patients with lung metastases received normotermic lung chemoperfusion, 4 of them are alive and disease-free for 8 to 24 months.
Dionigi, Alberto; Gremigni, Paola
To test whether a combined intervention of art therapy and clown visits could enhance the efficacy of oral medication in reducing children's anxiety at parental separation prior to induction of anaesthesia. Approximately 50% of children undergoing surgery report high anxiety at anaesthesia induction. Complementary therapies have been used to decrease children's anxiety, but no study has evaluated the efficacy of a combination of such therapies. This is an observational study, which involved allocating different interventions to two groups and measuring their anxiety at two time points. This study assigned 78 children (aged 3-11 years) undergoing general anaesthesia for surgery to two conditions. The control group underwent general anaesthesia following standard practice, and the intervention group received an intervention of integrated art therapy and clown visits upon their arrival at the hospital and throughout their time in the preoperating room. Each child in both groups received 0·5 mg/kg oral midazolam 30 minutes before surgery and had a parent present throughout their time in the preoperating room. Each child's anxiety was evaluated twice using the Modified Yale Preoperative Anxiety Scale: at baseline and at separation from parents. Repeated measures anova was used to test for differences between the time points and the two groups. Children in the intervention group showed a significant (p art therapy and clown visits enhanced the effect of midazolam in reducing children's anxiety at preoperative separation from parents. Paediatric staffs may consider using such a combination of strategies in preparing children for anaesthesia induction. © 2016 John Wiley & Sons Ltd.
Full Text Available Introduction: The aim of this study was to evaluate the efficacy of combined intratympanic and systemic steroid therapy compared with systemic steroid therapy alone in idiopathic sudden sensorineural hearing loss (ISSNHL patients with poor prognostic factors. Materials and Methods: Seventy-seven patients with sudden sensorineural hearing loss (SSNHL who had at least one poor prognostic factor (age greater than 40 years, hearing loss more than 70 db, or greater than a 2-week delay between the onset of hearing loss and initiation of therapy were included in this study. Patients were randomized to the intervention group (combined intratympanic and systemic steroid therapy or the control group (systemic steroid therapy alone. All patients received oral treatment with systemic prednisolone (1 mg/kg/day for 10 days, acyclovir (2 g/day for 10 days, divided into four doses, triamterene H (daily, and omeprazole (daily, during steroid treatment, and were advised to follow a low salt diet. The intervention group also received intratympanic dexamethasone injections (0.4 ml of 4 mg/ml dexamethasone two times a week for two consecutive weeks (four injections in total. A significant hearing improvement was defined as at least a 15-db decrease in pure tone average (PTA. Results: Among all participants, 44 patients (57.14% showed significant improvement in hearing evaluation. More patients showed hearing improvement in the intervention group than in the control group (27 patients (75% versus 17 patients (41.4%, respectively; P = 0.001. Conclusion: The combination of intratympanic dexamethasone and systemic prednisolone is more effective than systemic prednisolone alone in the treatment of poor-prognosis SSNHL.
Pezzi, Todd A; Schwartz, David L; Mohamed, Abdallah S R; Welsh, James W; Komaki, Ritsuko U; Hahn, Stephen M; Sepesi, Boris; Pezzi, Christopher M; Fuller, Clifton D; Chun, Stephen G
Combined-modality therapy with chemotherapy and radiation therapy plays a crucial role in the upfront treatment of patients with limited-stage small-cell lung cancer (SCLC), but there may be barriers to utilization in the United States. To estimate utilization rates and factors associated with chemotherapy and radiation therapy delivery for limited-stage SCLC using the National Cancer Database. Analysis of initial management of all limited-stage SCLC cases from 2004 through 2013 in the National Cancer Database. Utilization rates of chemotherapy and radiation therapy at time of initial treatment. Multivariable analysis identified independent clinical and socioeconomic factors associated with utilization and overall survival. A total of 70 247 cases met inclusion criteria (55.3% female; median age, 68 y [range, 19-90 y]). Initial treatment was 55.5% chemotherapy and radiation therapy, 20.5% chemotherapy alone, 3.5% radiation therapy alone, and 20.0% neither (0.5% not reported). Median survival was 18.2 (95% CI, 17.9-18.4), 10.5 (95% CI, 10.3-10.7), 8.3 (95% CI, 7.7-8.8), and 3.7 (95% CI, 3.5-3.8) months, respectively. Being uninsured was associated with a lower likelihood of both chemotherapy (odds ratio [OR], 0.65; 95% CI, 0.56-0.75; P therapy (OR, 0.75; 95% CI, 0.67-0.85; P therapy delivery. Lack of health insurance (HR, 1.19; 95% CI, 1.13-1.26; P therapy (HR, 0.62; 95% CI, 0.60-0.63; P therapy or chemotherapy as part of initial treatment for limited-stage SCLC, which, in turn, was associated with poor survival. Lack of radiation therapy delivery was uniquely associated with government insurance coverage, suggesting a need for targeted access improvement in this population. Additional work will be necessary to conclusively define exact population patterns, specific treatment deficiencies, and causative factors leading to heterogeneous care delivery.
Wang, Saina; Sheng, Feng; Pan, Yunhua; Xu, Feng; Wang, Zhichao; Cheng, Lei
To compare the clinical efficacy on cervical spondylotic radiculopathy between the combined therapy of massage and magnetic-sticking at the auricular points and the simple massage therapy, and conduct the health economics evaluation. Seventy-two patients of cervical spondylotic radiculopathy were randomized into a combined therapy group, and a simple massage group, 36 cases in each one. Finally, 35 cases and 34 cases were met the inclusive criteria in the corresponding groups separately. In the combined therapy group, the massage therapy and the magnetic sticking therapy at auricular points were combined in the treatment. Massage therapy was mainly applied to Fengchi (GB 20), Jianjing (GB 21), Jianwaishu (SI 14), Jianyu (LI 15) and Quchi (LI 11). The main auricular points for magnetic sticking pressure were Jingzhui (AH13), Gan (On12) Shen (CO10), Shenmen (TF4), Pizhixia (AT4). In the simple massage group, the simple massage therapy was given, the massage parts and methods were the same as those in the combined therapy group. The treatment was given once every two days, three times a week, for 4 weeks totally. The cervical spondylosis effect scale and the simplified McGill pain questionnaire were adopted to observe the improvements in the clinical symptoms, clinical examination, daily life movement, superficial muscular pain in the neck and the health economics cost in the patients of the two groups. The effect was evaluated in the two groups. The effective rate and the clinical curative rate in the combined therapy group were better than those in the control group [100. 0% (35/35) vs 85. 3% (29/34), 42. 9% (15/35) vs 17. 6% (6/34), both P<0. 05]. The scores of the spontaneous symptoms, clinical examnation, daily life movement and superficialmuscular pain in the neck were improved apparently after treatment as compared with those before treatment in the patients of the two groups (all P<0. 001). In terms of the improvements in the spontaneous symptoms, clinical
N. S. Maksimchuk-Kolobova
Full Text Available Aim. To evaluate the economic effectiveness of the combined two-drug antihypertensive therapy in patients with arterial hypertension (HT and high cardiovascular risk by Markov’s modeling.Material and methods. Patients (n= 65; 19 males and 46 females with essential HT accompanied by metabolic disorders, history of previous ineffective antihypertensive therapy were included into the study. Patients were randomized into 2 groups. Group V/A was treated with valsartan and amlodipine in fixed-dose combinations of 160/5 and 160/10 mg depending on blood pressure (BP level. Patients of group L/A were treated with losartan 100 mg and amlodipine 5 or 10 mg daily. Treatment duration was 24 weeks. Changes in BP level, and left ventricular hypertrophy (LVH regression were assessed. Economic evaluation was performed on the basis of modeling with specialized software Decision Tree 4.xla.Results. Effect of the two variants of combination therapy on LVH was used to estimate treatment effectiveness and to build the model. Patients were distributed according to the left ventricular mass (LVM at baseline and after 24 weeks of therapy. Significant decrease in LVM was observed in V/A group: from 225.1±71.7 to 186.3±44.5 g (p<0.05. There was no LVM dynamics in L/A group. The model took into account economic and frequency factors for 10 years forecast. V/A therapy is able to prevent 94 deaths, 22 strokes, and 64 myocardial infarction per 1000 patients. Absence of need in treatment of these prevented events can save about 5.5 million RUR for every 1000 patients. It would reduce the total costs per patient during 10 years. V/A therapy is able to save maximal number of quality adjusted life years (QALY due to LVM regression (5.016 years. L/A combination is the most economical variant of pharmacotherapy due to low cost of treatment (16.491.25 RUR per 1 QALY. It would take 286.698.7 RUR additionally for one additional QALY in the treatment with V/A, and it is
G. P. Martynova
Full Text Available The paper presents the results of the research on effectiveness of combined antiviral therapy conducted with pegylated interferon alpha 2b of prolonged action (Peginterferon alpha 2b at a dose of 60 mcg/m2 per week and Rebetol (Ribavirin at a dose of 15 mg/kg per day in 26 children with chronic viral hepatitis C aged from 3 to 17, who underwent regular medical check-ups in City Clinical Hospital № 20 named after I.S. Berzon in Krasnoyarsk. Evaluation of effectiveness of combined antiviral therapy revealed that patients with genotype 1 had an immediate virologic response in 78,5% of cases, 83,3% of patients with genotype 2, 3 had a stable virologic response.
Full Text Available Introduction: Atypical odontalgia (AO is a subgroup of persistent idiopathic facial pain. We introduced a combination therapy of fluoxetine and clonazepam to treat AO. Case Report: A 30-year-old female with the chief complaint of severe pain (#8 based on Visual Analogue Scale( VAS in the site of extracted tooth #3 since 2 months ago was referred to the Department of Oral Medicine. The pain was of sharp quality continuing all day long and radiated to cervical muscles, forehead, and mandible of the ipsilateral side and contra lateral structures. The patient was treated with fluoxetine 20 mg/d and clonazepam 0.5 mg/d. The pain intensity was reported almost #0 when the patient was re evaluated 1 month after the first visit. An 8-month follow up revealed no sign of pain and discomfort on the affected site. Discussion: Combination therapy with clonazepam and fluoxetine has a positive effect in the treatment of AO.
Ali, Amany; Sayed, Heba; Farrag, Ahmed; El-Sayed, Mohamed
We conducted a retrospective analysis to investigate the clinical outcome of combined-modality therapy using multiagent chemotherapy and involved-field radiotherapy in treatment of children with Hodgkin's lymphoma. Fifty eight cases with newly diagnosed Hodgkin's lymphoma were analyzed. The median follow-up duration was 46 months (range 3-72 months). The 4-year overall and event-free survival rates were 91.5% and 69.7% respectively. High-risk disease (stage IIIB and IV), presence of B symptoms, lymphocyte depletion subtype, bulky disease and late response to chemotherapy were poor prognostic factors. Stage-adapted combined-modality therapy resulted in satisfactory outcome in treatment of pediatric Hodgkin's lymphoma. Copyright © 2010 Elsevier Ltd. All rights reserved.
Full Text Available Lumbar intervertebral disc herniation is a kind of syndrome caused by stimulation or pressure of nerve root and cauda equina due to intervertebral disc disorder, fibrous ring rupture, and pulpiform nucleus protrusion. Application of traditional Chinese medicine (TCM including acupuncture therapy and cupping therapy is unique and effective treatment for lumbar intervertebral disc herniation in China. Hence, we try to investigate the combined clinical efficacy of modified Taiyi miraculous moxa roll and cupping therapy on patients with lumbar intervertebral disc herniation. Seventy patients were randomly assigned into combined treatment group (n=35 and control group (n=35. The treatment group received combined therapy of modified Taiyi miraculous moxa roll and cupping therapy, while control group received acupuncture therapy alone. Diagnostic criteria of TCM syndrome, Japanese Orthopedic Association (JOA score, and simplified McGill pain questionnaire (MPQ were used to evaluate the therapy. 11 and 13 out of 35 subjects in the combined treatment group had improvement > 75% and between 50% and 75%, respectively. The corresponding number was 2 and 22 of 35 subjects in the acupuncture group. There was significant difference in the clinical efficacy between the treatment group and control group (P=0.036. The scores of JOA and MPQ detected in the patients of the two groups (P<0.05 also showed statistically significant differences. Moreover, no serious adverse events occurred in the patients, who received cupping therapy or acupuncture. The combined or alone therapies can effectively improve the treatment efficacy in the patients with lumbar intervertebral disc herniation, while the combined therapies show more comparative effectiveness. Furthermore, the combined therapies are potentially safe and cost-effective and also benefit the improvement of short-term pain. Therefore, the combined therapies of the two ancient TCM deserve further clinical
Leone, Sebastiano; Noviello, Silvana; Esposito, Silvano
Enterococci are common causes of infective endocarditis (IE) in both health care and community-based setting. Enterococcal IE requires bactericidal therapy for an optimal outcome. For decades, cell-wall-active antimicrobial agents (penicillins or vancomycin) in combination with aminoglycosides were the cornerstone of the treatment; however, the emergence of antibiotic resistance has significantly reduced the efficacy of these regimens. Data for this review were identified by searches of MEDLINE and references from relevant articles on antibiotic combination regimens for the treatment of enterococcal IE. Abstracts presented in scientific conferences were not searched for. New effective and safe combination treatments, including double-β-lactam and daptomycin/β-lactam combination, are proving useful for the management of IE due to enterococci.
Full Text Available Studies have shown that topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT can be used successfully for the treatment of oral verrucous hyperplasia (OVH. Studies have also demonstrated that cryotherapy could be used as a treatment modality for OVH lesions. In this case report, we tested the efficacy of topical ALA-PDT, combined with cryogun cryotherapy, for an extensive OVH lesion on the right buccal mucosa of a 65-year-old male areca quid chewer. The tumor was cleared after six treatments of combined topical ALA-PDT and cryogun cryotherapy. No recurrence of the lesion was found after a follow-up period of 18 months. We suggest that our combined treatment protocol may be effective in treating OVH lesions. The treatment course may be slightly shortened with this combined protocol and was well tolerated by the patient.
Parhi, Priyambada; Mohanty, Chandana; Sahoo, Sanjeeb Kumar
Combination therapy for the treatment of cancer is becoming more popular because it generates synergistic anticancer effects, reduces individual drug-related toxicity and suppresses multi-drug resistance through different mechanisms of action. In recent years, nanotechnology-based combination drug delivery to tumor tissues has emerged as an effective strategy by overcoming many biological, biophysical and biomedical barriers that the body stages against successful delivery of anticancer drugs. The sustained, controlled and targeted delivery of chemotherapeutic drugs in a combination approach enhanced therapeutic anticancer effects with reduced drug-associated side effects. In this article, we have reviewed the scope of various nanotechnology-based combination drug delivery approaches and also summarized the current perspective and challenges facing the successful treatment of cancer. Copyright © 2012 Elsevier Ltd. All rights reserved.
Min Kyong Moon
Full Text Available The Korean Diabetes Association (KDA recently updated the Clinical Practice Guidelines on antihyperglycemic agent therapy for adult patients with type 2 diabetes mellitus (T2DM. In combination therapy of oral hypoglycemic agents (OHAs, general recommendations were not changed from those of the 2015 KDA guidelines. The Committee on Clinical Practice Guidelines of the KDA has extensively reviewed and discussed the results of meta-analyses and systematic reviews of effectiveness and safety of OHAs and many clinical trials on Korean patients with T2DM for the update of guidelines. All OHAs were effective when added to metformin or metformin and sulfonylurea, although the effects of each agent on body weight and hypoglycemia were different. Therefore, selection of a second agent as a metformin add-on therapy or third agent as a metformin and sulfonylurea add-on therapy should be based on the patient's clinical characteristics and the efficacy, side effects, mechanism of action, risk of hypoglycemia, effect on body weight, patient preference, and combined comorbidity. In this review, we address the results of meta-analyses and systematic reviews, comparing the effectiveness and safety among OHAs. It will help to choose the appropriate drug for an individual patient with T2DM.
Claudia A Montiel-Equihua
Full Text Available Claudia A Montiel-Equihua, Adrian J Thrasher, H Bobby GasparCentre for Immunodeficiency, Molecular Immunology Unit, UCL Institute of Child Health, London, UKAbstract: The history of stem cell gene therapy is strongly linked to the development of gene therapy for severe combined immunodeficiencies (SCID and especially adenosine deaminase (ADA-deficient SCID. Here we discuss the developments achieved in over two decades of clinical and laboratory research that led to the establishment of a protocol for the autologous transplant of retroviral vector-mediated gene-modified hematopoietic stem cells, which has proved to be both successful and, to date, safe. Patients in trials in three different countries have shown long-term immunological and metabolic correction. Nevertheless, improvements to the safety profile of viral vectors are underway and will undoubtedly reinforce the position of stem cell gene therapy as a treatment option for ADA-SCID.Keywords: adenosine deaminase, severe combined immunodeficiency, gene therapy, hematopoietic stem cell, retrovirus, clinical trial
Tamura, Masaru; Zama, Akira; Kunimine, Hideo; Tamaki, Yoshio; Niibe, Hideo
Rat glioma model was used to evaluate the effect of hyperthermia with and without radiation therapy. The animal model was induced by left frontal burr hole opening and inoculation of a small piece of G-XII glioma tissue to 6- to 8-week-old rats. The therapeutical experiments were given 10 - 14 days after inoculation of the tumor. Interstitial heating at 44 and 45 deg C at the surface of the inserting probe using 2450 MHz microwave was delivered for 30 minutes. Deep X-ray whole head irradiation of 800 R using Stabilipan 2 (Siemens) was given just after the hyperthermia therapy. The survival of treated animals of hyperthermia, radiation, and combination of hyperthermia and radiation was significantly superior to that of non-treated control group. There was no significant difference of survival among the treated groups, though median survival was longest in the group of combination therapy of hyperthermia and radiation. Large tumors developed at the time of death in all the control and the treated animals. Histological examination showed some tendencies of macrophage infiltration in tumor tissue of hyperthermia therapy. (author)
Lecaros, Rumwald Leo G.; Huang, Leaf; Hsu, Yih-Chih
Vascular endothelial growth factor A (VEGF-A), commonly known as VEGF, is one of the primary factors that affect tumor angiogenesis. It was found to be expressed in cancer cell lines including oral squamous cell carcinoma. Photodynamic therapy (PDT) is a novel therapeutic modality to treat cancer by using a photosensitizer which is activated by a light source to produce reactive oxygen species and mediates oxygen-independent hypoxic conditions to tumor. Another emerging treatment to cure cancer is the use of interference RNA (e.g. siRNA) to silence a specific mRNA sequence. VEGF-A was found to be expressed in oral squamous cell carcinoma and overexpressed after 24 hour post-PDT by Western blot analysis. Cell viability was found to decrease at 25 nM of transfected VEGF-A siRNA. In vitro combined therapy of PDT and VEGF-A siRNA showed better response as compared with PDT and gene therapy alone. The results suggest that PDT combined with targeted gene therapy has a potential mean to achieve better therapeutic outcome.
T. B. Minasov
Full Text Available Osteoporosis is one of the most dangerous diseases occurred in elderly persons. Results of application of strontium ranelate in combination with calcium for treatment a women with a postmenopausal osteoporosis are resulted. The influence of this complex therapy on dynamics of mineral density indexes of a bone tissue and the level of bone metabolism were studied. Strontium ranelate both at monotherapy, and in combination with calcium promotes the augmentation of mineral density of bone tissue in an axial skeleton. The taking Strontium ranelate doesn’t cause serious side effect.
Hirschberg, Henry; Trinidad, Anthony; Christie, Catherine E.; Peng, Qian; Kwon, Young J.; Madsen, Steen
Macrophages loaded with gold nanoshells (AuNS), that convert near infrared light to heat, can be used as transport vectors for photothermal hyperthermia of tumors. The purpose of this study was to investigate the effects of combined macrophage mediated photothermal therapy (PTT) and PDT on head and neck squamous cell carcinoma (HNSCC). The results provide proof of concept for the use of macrophages as a delivery vector of AuNS for photothermal enhancement of the effects of PDT on squamous cell carcinoma. A significant synergy was demonstrated with combined PDT and PTT compared to each modality applied separately.
Borghi, Alessandro; Minghetti, Sara; Toni, Giulia; Virgili, Annarosa; Corazza, Monica
Abstrract Purpose: To assess efficacy and safety profile of combining a potent corticosteroid with a retinoid in the treatment of vulvar lichen sclerosus (VLS). We retrospectively compared 21 VLS patients treated with tretinoin (T) in short-contact therapy and mometasone furoate (MMF) (group A) and 20 treated with cold cream (CC) and MMF (group B) for 5 consecutive days/week for 12 weeks. The efficacy parameters were the response rate, the percentage of patients achieving an improvement from baseline of ≥75% in subjective and objective scores and the mean reduction in subjective and objective scores. Thirteen patients (75.2%) were considered as responders in group A and 15 (78.9%) in group B; 50% and 61.1% of patients in group A and 100% and 63.1% in group B achieved an improvement of at least 75% in subjective and objective scores, respectively. The scheme combining MMF and CC was better tolerated than the combination of MMF and T. The combination with a topical retinoid did not enhance the effectiveness of a potent corticosteroid in the treatment of VLS. Either the scarce efficacy of the short-contact therapy regimen or a less favorable safety profile of such combination may account for these findings.
Miyoshi, Norio; Idehara, Toshitaka; Khutoryan, Eduard; Fukunaga, Yukihiro; Bibin, Andriana Bintang; Ito, Shinji; Sabchevski, Svilen Petrov
In this paper, we present results of a hyperthermia treatment of malignant tumors using a gyrotron as a radiation source for heating of the cancerous tissue. They clearly demonstrate the efficiency of the irradiation by sub-THz waves, which leads to steady decrease of the volume of the tumor and finally to its disappearance. A combination of hyperthermia and photodynamic therapy (PDT) that utilizes a novel multifunctional photosensitizer has also been explored. In the latter case, the results are even more convincing and promising. In particular, while after a hyperthermia treatment sometimes a regrowth of the tumor is being observed, in the case of combined hyperthermia and PDT such regrowth has never been noticed. Another combined therapy is based on a preheating of the tumor by gyrotron radiation to temperatures lower than the hyperthermia temperature of 43 °C and followed then by PDT. The results show that such combination significantly increases the efficiency of the treatment. We consider this phenomenon as a synergy effect since it is absent when hyperthermia and PDT are applied separately, and manifests itself only when both methods are combined.
Full Text Available Ceramide (CE-based combination therapy (CE combination as a novel therapeutic strategy has attracted great attention in the field of anti-cancer therapy. The principal purposes of this study were to investigate the synergistic effect of CE in combination with docetaxel (DTX (CE + DTX and to explore the synergy mechanisms of CE + DTX. The 3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT and combination index (CI assay showed that simultaneous administration of CE and DTX with a molar ratio of 0.5:1 could generate the optimal synergistic effect on murine malignant melanoma cell (B16, CI = 0.31 and human breast carcinoma cell (MCF-7, CI = 0.48. The apoptosis, cell cycle, and cytoskeleton destruction study demonstrated that CE could target and destruct the microfilament actin, subsequently activate Caspase-3 and induce apoptosis. Meanwhile, DTX could target and disrupt the microtubules cytoskeleton, leading to a high proportion of cancer cells in G2/M-phase arrest. Moreover, CE plus DTX could cause a synergistic destruction of cytoskeleton, which resulted in a significantly higher apoptosis and a significantly higher arrest in G2/M arrest comparing with either agent alone (p < 0.01. The in vivo antitumor study evaluated in B16 tumor-bearing mice also validated the synergistic effects. All these results suggested that CE could enhance the antitumor activity of DTX in a synergistic manner, which suggest promising application prospects of CE + DTX combination treatment.
Krysiak, Robert; Marek, Bogdan; Okopień, Bogusław
Both overt and subclinical hypothyroidism are often accompanied by sexual dysfunction. Despite improving male sexual functioning, levothyroxine treatment does not always restore all its aspects. The aim of this study was to compare male sexual function-ing and depressive symptoms between men with hypothyroidism receiving levothyroxine/liothyronine combination therapy and men receiving levothyroxine alone. The study population consisted of 21 young levothyroxine-treated men with clinical symptoms of hypothyroid-ism, in whom serum thyrotropin and thyroid hormone levels were within the normal limits. In 11 of these patients, levothyroxine was replaced with levothyroxine/liothyronine combination therapy, while the remaining ones (n = 10) continued levothyroxine treatment. Beyond measuring serum levels of thyrotropin, free thyroxine, free triiodothyronine, and prolactin, before the beginning of the study and six months later, all enrolled patients completed questionnaires evaluating male sexual function (International Index of Erectile Func-tion-15: IIEF-15) and assessing the presence and severity of depressive symptoms (Beck Depression Inventory-Second Edition - BDI-II). The study included 10 patients from each group. At baseline, erectile function, intercourse satisfaction, orgasmic function, sexual desire and overall satisfaction, as well as the total BDI-II score did not differ between both groups. With the exception of an improvement in sexual desire, replacing levothyroxine with levothyroxine/liothyronine combination therapy did not affect sexual functioning and depressive symptoms. The obtained results suggest that levothyroxine/liothyronine combination therapy has a relatively mild effect on sexual functioning in levothyroxine-treated men with normal thyrotropin and thyroid hormone levels experiencing clinical symptoms of hypo-thyroidism.
Jones, Graeme; Panova, Elena; Day, Richard
Graeme Jones,1 Elena Panova,1 Richard Day2 1Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia; 2University of New South Wales, Medicine, St Vincent’s Hospital, Sydney, NSW, Australia Abstract: The aim of this review was to summarize the evidence for combination therapy to achieve serum urate (SUA) target levels in gout. Within this overarching aim, a second aim was to evaluate the evidence for a new uricosuric agent lesinurad, which inhibits ur...
Barter, Philip; Ginsberg, Henry N.
Combination therapy for the treatment of dyslipidemia and reduction of cardiovascular risk has been demonstrated to beneficially modify the lipid profile in multiple randomized clinical trials. As reported in the updated National Cholesterol Education Program Adult Treatment Panel III guidelines, low-density lipoprotein (LDL) cholesterol remains the primary treatment target, although the comprehensive management of dyslipidemia in high-risk patients includes the modification of secondary lipi...
Grady, E.D.; McLaren, J.; Auda, S.P.; McGinley, P.H.
Sixteen patients were treated for liver cancer (primary and metastatic) by a combination of internal radiation therapy with intra-arterial yttrium 90 microspheres and regional hyperthermia with electromagnetic radiation. Four patients have their liver disease apparently controlled; two had a partial regression of more than 50%; and two had a partial regression of less than 50%. The complications consisted of one case of radiation hepatitis and one of peptic ulcer.
Matsuo, N; Yokoyama, K; Maruyama, Y; Ueda, Y; Yoshida, H; Tanno, Y; Yamamoto, R; Terawaki, H; Ikeda, M; Hanaoka, K; Yamamoto, H; Ogura, M; Watanabe, S; Kimura, Y; Hosoya, T
Although peritoneal dialysis (PD) is recommended as the first-line treatment for end-stage renal disease, limitations exist to achieving good clinical status when the residual renal function (RRF) has declined. Combined therapy with PD and hemodialysis (HD) is the treatment of choice for patients who cannot control body fluid status and/or cannot obtain adequate solute removal by PD alone. The aim of this study was to evaluate the clinical efficacy of this combined therapy. In this retrospective study, 53 patients on PD and diagnosed with underdialysis and/or overhydration with declining RRF were recruited. Parameters of volume control, uremic solute removal, anemia, and predictors for encapsulating peritoneal sclerosis (EPS) were compared before and 1 year after combined therapy. The patients' hydration status improved significantly with reductions in atrial natriuretic peptide and blood pressure. Serum creatinine and beta2 microglobulin also decreased significantly. The hemoglobin level increased remarkably from 8.2 ± 1.6 to 10.7 ± 1.2 g/dl (p < 0.01) and the reticulocyte count also increased significantly, even though at the same time the dose of recombinant human erythropoietin decreased significantly. The dialysate to plasma creatinine ratio obtained from the fast peritoneal equilibration test (PET) decreased significantly from 0.65 ± 0.11 to 0.59 ± 0.13, and the level of interleukin 6 in PET drainage also significantly decreased. Furthermore, serum C-reactive protein and fibrinogen decreased significantly. Combined therapy with PD and HD is an effective way to control fluid status and to correct inadequate solute removal, leading to improvement in inflammation, peritoneal function and anemia.
Sielska-Badurek, Ewelina; Osuch-Wójcikiewicz, Ewa; Sobol, Maria; Kazanecka, Ewa; Rzepakowska, Anna; Niemczyk, Kazimierz
The purpose of this study was to evaluate vocal tract function and the voice quality in singers with muscle tension dysphonia (MTD) after undergoing combined functional voice therapy of the singing voice. This is a prospective, randomized study. Forty singers (29 females and 11 males, mean age: 24.6 ± 8.8 years) with MTD were enrolled in the study. The study group consisted of 20 singers who underwent combined functional voice therapy (10-15 individual sessions, 30-40 minutes each). Singers who did not opt for vocal rehabilitation consisted of the control group. Effects of rehabilitation were assessed with videolaryngostroboscopy, palpation of the vocal tract structures, flexible fiberoptic evaluation of the pharynx and the larynx, perceptual speaking and singing voice assessment, acoustic analysis, maximal phonation time, and the Voice Handicap Index. After combined functional voice therapy in the study group, great improvement was noticed in palpation of the vocal tract structures (P < 0.001), perceptual voice assessment (P < 0.001), phonetograms (P = 0.002), and singing range obtained from acoustic analysis of glissando (P < 0.001). In the control group, no statistically significant differences were found between the first and the second assessments. Combined functional voice therapy proved to be an efficacious treatment method in singers with MTD in singing. Development of palpation and perceptual singing voice examination protocols enables one to compare results before and after rehabilitation in clinics. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.
Shah, Swapnil R; Kadage, Shahajahan; Sinn, John
To compare the effectiveness of music, oral sucrose, and combination therapy for pain relief in neonates undergoing a heel prick procedure. This randomized, controlled, blinded crossover clinical trial included stable neonates >32 weeks of postmenstrual age. Each neonate crossed over to all 3 interventions in random order during consecutive heel pricks. A video camera on mute mode recorded facial expressions, starting 2 minutes before until 7 minutes after the heel prick. The videos were later analyzed using the Premature Infant Pain Profile-Revised (PIPP-R) scale once per minute by 2 independent assessors, blinded to the intervention. The PIPP-R scores were compared between treatment groups using Friedman test. For the 35 participants, the postmenstrual age was 35 weeks (SD, 2.3) with an average weight of 2210 g (SD, 710). The overall median PIPP-R scores following heel prick over 6 minutes were 4 (IQR 0-6), 3 (IQR 0-6), and 1 (IQR 0-3) for the music, sucrose, and combination therapy interventions, respectively. The PIPP-R scores were significantly lower at all time points after combination therapy compared with the groups given music or sucrose alone. There was no difference in PIPP-R scores between the music and sucrose groups. In relatively stable and mature neonates, the combination of music therapy with sucrose provided better pain relief during heel prick than when sucrose or music was used alone. Recorded music in isolation had a similar effect to the current gold standard of oral sucrose. www.anzctr.org.au ACTRN12615000271505. Copyright © 2017 Elsevier Inc. All rights reserved.
Hamed Mortazavi; Maryam Baharvand; Amin Khodadoustan; Zahra Mansouri
Introduction: Atypical odontalgia (AO) is a subgroup of persistent idiopathic facial pain. We introduced a combination therapy of fluoxetine and clonazepam to treat AO. Case Report: A 30-year-old female with the chief complaint of severe pain (#8 based on Visual Analogue Scale( VAS)) in the site of extracted tooth #3 since 2 months ago was referred to the Department of Oral Medicine. The pain was of sharp quality continuing all day long and radiated to cervical muscles, forehead, and mandible...
Sharabi, Andrew B; Tran, Phuoc T; Lim, Michael; Drake, Charles G; Deweese, Theodore L
Stereotactic radiosurgery and stereotactic body radiation therapy are two contemporary radiation modalities that can treat tumors in any area of the body using highly focused radiation. Recently, immunotherapy has established itself as a viable and powerful anticancer treatment. In this review we detail the rationale supporting a combination of immunotherapy and stereotactic radiation. Additionally, we discuss the evidence for the immune stimulatory effects of focused radiation and the role that radiation may play in enhancing the systemic treatment effects of immunotherapy.
Full Text Available Abstract Background Photodynamic therapy (PDT is a promising cancer treatment modality that involves the interaction of the photosensitizer, molecular oxygen and light of specific wavelength to destroy tumor cells. Treatment induced hypoxia is one of the main side effects of PDT and efforts are underway to optimize PDT protocols for improved efficacy. The aim of this study was to investigate the anti-tumor effects of PDT plus Erbitux, an angiogenesis inhibitor that targets epidermal growth factor receptor (EGFR, on human bladder cancer model. Tumor-bearing nude mice were assigned to four groups that included control, PDT, Erbitux and PDT plus Erbitux and tumor volume was charted over 90-day period. Results Our results demonstrate that combination of Erbitux with PDT strongly inhibits tumor growth in the bladder tumor xenograft model when compared to the other groups. Downregulation of EGFR was detected using immunohistochemistry, immunofluorescence and western blotting. Increased apoptosis was associated with tumor inhibition in the combination therapy group. In addition, we identified the dephosphorylation of ErbB4 at tyrosine 1284 site to play a major role in tumor inhibition. Also, at the RNA level downregulation of EGFR target genes cyclin D1 and c-myc was observed in tumors treated with PDT plus Erbitux. Conclusion The combination therapy of PDT and Erbitux effectively inhibits tumor growth and is a promising therapeutic approach in the treatment of bladder tumors.
Luan, X-R; Li, W-H; Lou, F-L
To analyze and evaluate the effects of humanized nursing combined with wet healing therapy to treat the stage II and III bedsores in hospitalized patients. From March 2013 to July 2014 we enrolled fifty patients with stage II and III bedsores. They were randomly divided into control group and experimental group, with 25 cases in each group. For the control group, we adopted a traditional method of treatment for pressure ulcer treatment, while the experimental group was treated with humanized nursing in combination with wet healing therapy. After 28 days, the treatment results in both groups were evaluated. The improvement rate for patients in the experimental group was significantly higher than that of the control group. In the experimental group, the improvement rates for patients suffering from stage II and III pressure ulcers were significantly higher than those of the control group. The Branden score and the area of pressure ulcer were significantly decreased in the experimental group. The frequency of dressing change, the dressing time and the average cost of hospitalization in the experimental group were significantly lower. The effect of wet healing therapy combined with humanized nursing in preventing and treating the bedsore is promising, and it is worthy of clinical promotion.
Salehi, Samie; Saljooghi, Amir Sh.; Badiee, Somayeh; Moqadam, Mojtaba Mashmool
Thallium and its compounds are a class of highly toxic chemicals that cause wide-ranging symptoms such as gastrointestinal disturbances; polyneuritis; encephalopathy; tachycardia; skin eruptions; hepatic, renal, cardiac, and neurological toxicities; and have mutagenic and genotoxic effects. The present research aimed to evaluate the efficacy of the chelating agents deferasirox (DFX) and deferiprone (L1) in reducing serum and tissue thallium levels after the administration of thallium (III), according to two different dosing regimens, to several groups of Wistar rats for 60 days. It was hypothesized that the two chelators might be more efficient as a combined therapy than as monotherapies in removing thallium (III) from the rats’ organs. The chelators were administered orally as either single or combined therapies for a period of 14 days. Serum and tissue thallium (III) and iron concentrations were determined by flame atomic absorption spectroscopy. Serum and tissue thallium (III) levels were significantly reduced by combined therapy with DFX and L1. Additionally, iron concentrations returned to normal levels and symptoms of toxicity decreased. PMID:29071014
Full Text Available Background: There are several million new cases of peptic disease annually. The disease has a various range of presentations. Gram negative helicobacter pylori bacilli is considered as an etiologic factor in this disease. Goal of treatment in peptic disease is eradication of the helicobacter pylori (HP. Combination therapy has been implemented in the treatment of this disease. Different modalities have been recommended up to now. In order to lower adverse effects, cost and drug resistance, researchers have introduced a new combination therapy in which honey is substituted for metronidazole. Methods: A step II of clinical trial was designed. The sample size was 15 children. Diagnosis of HP infection was confirmed with histopathology. Treatment regimen consisted of omeprazole, amoxicillin, bismuth and honey. After a 3-4 week follow- up, eradication was evaluated. Results: 15 children completed the follow- up period. Mean age of patients was 9.4 years. Treatment effectiveness was 80 percent. Conclusion: Combination therapy with 3 drugs along with honey has significant effectiveness on HP eradication.
Xu, Wujun; Thapa, Rinez; Liu, Dongfei; Nissinen, Tuomo; Granroth, Sari; Närvänen, Ale; Suvanto, Mika; Santos, Hélder A; Lehto, Vesa-Pekka
In spite of the advances in drug delivery, the preparation of smart nanocomposites capable of precisely controlled release of multiple drugs for sequential combination therapy is still challenging. Here, a novel drug delivery nanocomposite was prepared by coating porous silicon (PSi) nanoparticles with poly(beta-amino ester) (PAE) and Pluronic F-127, respectively. Two anticancer drugs, doxorubicin (DOX) and paclitaxel (PTX), were separately loaded into the core of PSi and the shell of F127. The nanocomposite displayed enhanced colloidal stability and good cytocompatibility. Moreover, a spatiotemporal drug release was achieved for sequential combination therapy by precisely controlling the release kinetics of the two tested drugs. The release of PTX and DOX occurred in a time-staggered manner; PTX was released much faster and earlier than DOX at pH 7.0. The grafted PAE on the external surface of PSi acted as a pH-responsive nanovalve for the site-specific release of DOX. In vitro cytotoxicity tests demonstrated that the DOX and PTX coloaded nanoparticles exhibited a better synergistic effect than the free drugs in inducing cellular apoptosis. Therefore, the present study demonstrates a promising strategy to enhance the efficiency of combination cancer therapies by precisely controlling the release kinetics of different drugs.
Chico, R Matthew; Chandramohan, Daniel
Introduction: The first-line therapy for the intermittent preventive treatment of malaria in pregnancy (IPTp) is sulphadoxine-pyrimethamine (SP). There is an urgent need to identify safe, well-tolerated and efficacious alternatives to SP due to widespread Plasmodium falciparum resistance. Combination therapy using azithromycin and chloroquine is one possibility that has demonstrated adequate parasitological response > 95% in clinical trials of non-pregnant adults in sub-Saharan Africa and where IPTp is a government policy in 33 countries. Areas covered: Key safety, tolerability and efficacy data are presented for azithromycin and chloroquine, alone and/or in combination, when used to prevent and/or treat P. falciparum, P. vivax, and several curable sexually transmitted and reproductive tract infections (STI/RTI). Pharmacokinetic evidence from pregnant women is also summarized for both compounds. Expert opinion: The azithromycin-chloroquine regimen that has demonstrated consistent efficacy in non-pregnant adults has been a 3-day course containing daily doses of 1 g of azithromycin and 600 mg base of chloroquine. The pharmacokinetic evidence of these compounds individually suggests that dose adjustments may not be necessary when used in combination for treatment efficacy against P. falciparum, P. vivax, as well as several curable STI/ RTI among pregnant women, although clinical confirmation will be necessary. Mass trachoma-treatment campaigns have shown that azithromycin selects for macrolide resistance in the pneumococcus, which reverses following the completion of therapy. Most importantly, no evidence to date suggests that azithromycin induces pneumococcal resistance to penicillin. PMID:21736423
Carlos M Ferrario
Full Text Available Carlos M Ferrario, Ronald D SmithWake Forest University School of Medicine, Winston-Salem, North Carolina, USAAbstract: Angiotensin receptor blockers have emerged as a first-line therapy in the management of hypertension and hypertension-related comorbidities. Since national and international guidelines have stressed the need to control blood pressure to <140/90 mmHg in uncomplicated hypertension and <130/80 mmHg in those with associated comorbidities such as diabetes or chronic kidney disease, these goal blood pressures can only be achieved through combination therapy. Of several drugs that can be effectively combined to attain the recommended blood pressure goals, fixed-dose combinations of angiotensin receptor blockers and the calcium channel blocker amlodipine provide additive antihypertensive effects associated with a safe profile and increased adherence to therapy. In this article, we review the evidence regarding the beneficial effects of renin–angiotensin system blockade with olmesartan medoxomil and amlodipine in terms of blood pressure control and improvement of vascular function and target organ damage.Keywords: amlodipine, angiotensin receptor blockers, angiotensin-converting enzyme 2, hypertension, renin–angiotensin system
Salehi, Samie; Saljooghi, Amir Sh; Badiee, Somayeh; Moqadam, Mojtaba Mashmool
Thallium and its compounds are a class of highly toxic chemicals that cause wide-ranging symptoms such as gastrointestinal disturbances; polyneuritis; encephalopathy; tachycardia; skin eruptions; hepatic, renal, cardiac, and neurological toxicities; and have mutagenic and genotoxic effects. The present research aimed to evaluate the efficacy of the chelating agents deferasirox (DFX) and deferiprone (L1) in reducing serum and tissue thallium levels after the administration of thallium (III), according to two different dosing regimens, to several groups of Wistar rats for 60 days. It was hypothesized that the two chelators might be more efficient as a combined therapy than as monotherapies in removing thallium (III) from the rats' organs. The chelators were administered orally as either single or combined therapies for a period of 14 days. Serum and tissue thallium (III) and iron concentrations were determined by flame atomic absorption spectroscopy. Serum and tissue thallium (III) levels were significantly reduced by combined therapy with DFX and L1. Additionally, iron concentrations returned to normal levels and symptoms of toxicity decreased.
Paulo Cesar Fagundes Neves
Full Text Available OBJECTIVES: The purpose is to study the effects of hyperbaric oxygen therapy and autologous platelet concentrates in healing the fibula bone of rabbits after induced fractures. METHODS: A total of 128 male New Zealand albino rabbits, between 6-8 months old, were subjected to a total osteotomy of the proximal portion of the right fibula. After surgery, the animals were divided into four groups (n = 32 each: control group, in which animals were subjected to osteotomy; autologous platelet concentrate group, in which animals were subjected to osteotomy and autologous platelet concentrate applied at the fracture site; hyperbaric oxygen group, in which animals were subjected to osteotomy and 9 consecutive daily hyperbaric oxygen therapy sessions; and autologous platelet concentrate and hyperbaric oxygen group, in which animals were subjected to osteotomy, autologous platelet concentrate applied at the fracture site, and 9 consecutive daily hyperbaric oxygen therapy sessions. Each group was divided into 4 subgroups according to a pre-determined euthanasia time points: 2, 4, 6, and 8 weeks postoperative. After euthanasia at a specific time point, the fibula containing the osseous callus was prepared histologically and stained with hematoxylin and eosin or picrosirius red. RESULTS: Autologous platelet concentrates and hyperbaric oxygen therapy, applied together or separately, increased the rate of bone healing compared with the control group. CONCLUSION: Hyperbaric oxygen therapy and autologous platelet concentrate combined increased the rate of bone healing in this experimental model.
Dewi D. Agustini
Full Text Available Treatment of breast cancer with combination chemotherapy Florouracil, doxorubicin, and Cyclofosfamide (FAC lead to differences in the quality of life of patients is important to know because it can support the effectiveness of patient treatment. The aim of the study was to measure the difference and know the dimensions that affect the quality of life of breast cancer patients from each cycle of chemotherapy in Hasan Sadikin Hospital. This research is an observational analytic cross sectional approach. A sample of 200 breast cancer patients who were selected purposively and separated based on cycles of therapy. Assessment of quality of life of patients is done using a multidimensional instrument EORTC QLQ (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and BR23. Data analysis was calculated using independent t test and linear regression. The results showed that there are differences in quality of life is very significant between QLQ-C30 functioning scale baseline with treatment 5, the QLQ-C30 symptom scale baseline therapy 5th, QLQ-BR23 function scale baseline with therapy 1st, 2nd, 3rd, 4th, and 5th, QLQ-BR23 symptoms scale baseline with therapy 4th, then a significant difference between scale symptoms of QLQ-BR23 baseline therapy with the 1st, 3rd, and 5th. Dimensions have a significant effect on quality of life is a social function, nausea and vomiting, dyspnea, sleep disorders and financial difficulties.
Neves, Paulo César Fagundes; Abib, Simone de Campos Vieira; Neves, Rogério Fagundes; Pircchio, Oronzo; Saad, Karen Ruggeri; Saad, Paulo Fernandes; Simões, Ricardo Santos; Moreira, Marcia Bento; Laurino, Cristiano Frota de Souza
The purpose is to study the effects of hyperbaric oxygen therapy and autologous platelet concentrates in healing the fibula bone of rabbits after induced fractures. A total of 128 male New Zealand albino rabbits, between 6-8 months old, were subjected to a total osteotomy of the proximal portion of the right fibula. After surgery, the animals were divided into four groups (n = 32 each): control group, in which animals were subjected to osteotomy; autologous platelet concentrate group, in which animals were subjected to osteotomy and autologous platelet concentrate applied at the fracture site; hyperbaric oxygen group, in which animals were subjected to osteotomy and 9 consecutive daily hyperbaric oxygen therapy sessions; and autologous platelet concentrate and hyperbaric oxygen group, in which animals were subjected to osteotomy, autologous platelet concentrate applied at the fracture site, and 9 consecutive daily hyperbaric oxygen therapy sessions. Each group was divided into 4 subgroups according to a pre-determined euthanasia time points: 2, 4, 6, and 8 weeks postoperative. After euthanasia at a specific time point, the fibula containing the osseous callus was prepared histologically and stained with hematoxylin and eosin or picrosirius red. Autologous platelet concentrates and hyperbaric oxygen therapy, applied together or separately, increased the rate of bone healing compared with the control group. Hyperbaric oxygen therapy and autologous platelet concentrate combined increased the rate of bone healing in this experimental model.
Hacein-Bey-Abina, Salima; Hauer, Julia; Lim, Annick; Picard, Capucine; Wang, Gary P; Berry, Charles C; Martinache, Chantal; Rieux-Laucat, Frédéric; Latour, Sylvain; Belohradsky, Bernd H; Leiva, Lily; Sorensen, Ricardo; Debré, Marianne; Casanova, Jean Laurent; Blanche, Stephane; Durandy, Anne; Bushman, Frederic D; Fischer, Alain; Cavazzana-Calvo, Marina
The outcomes of gene therapy to correct congenital immunodeficiencies are unknown. We reviewed long-term outcomes after gene therapy in nine patients with X-linked severe combined immunodeficiency (SCID-X1), which is characterized by the absence of the cytokine receptor common gamma chain. The nine patients, who lacked an HLA-identical donor, underwent ex vivo retrovirus-mediated transfer of gamma chain to autologous CD34+ bone marrow cells between 1999 and 2002. We assessed clinical events and immune function on long-term follow-up. Eight patients were alive after a median follow-up period of 9 years (range, 8 to 11). Gene therapy was initially successful at correcting immune dysfunction in eight of the nine patients. However, acute leukemia developed in four patients, and one died. Transduced T cells were detected for up to 10.7 years after gene therapy. Seven patients, including the three survivors of leukemia, had sustained immune reconstitution; three patients required immunoglobulin-replacement therapy. Sustained thymopoiesis was established by the persistent presence of naive T cells, even after chemotherapy in three patients. The T-cell-receptor repertoire was diverse in all patients. Transduced B cells were not detected. Correction of the immunodeficiency improved the patients' health. After nearly 10 years of follow-up, gene therapy was shown to have corrected the immunodeficiency associated with SCID-X1. Gene therapy may be an option for patients who do not have an HLA-identical donor for hematopoietic stem-cell transplantation and for whom the risks are deemed acceptable. This treatment is associated with a risk of acute leukemia. (Funded by INSERM and others.) 2010 Massachusetts Medical Society
Oh, Sug; Choi, Jong Tae; Jung, Kyoon Soon; Jung, Seung Hye [Jeil Women' s Hospital, Seoul (Korea, Republic of)
As the use of hormone replacement therapy for the menopausal women increases, some caution is advised, since there is an increased risk of breast cancer. Accordingly, the importance of regular mammography has been addressed. This cross-setional study analyzed the effects of different hormone therapies on mammographic density. Sixty-seven postemenopausal women who had completed one year of hormone therapy and had undergone follow-up mammography, were divided into two groups : Group I : continuous conjugated equine estrogen, 0.625mg, plus continuous medroxyprogesterone acetate, 2.5mg (n=48), Group II : continuous conjugated equine estrogen 0.625mg (n=19). The mammograms were read by two radiologists. With regard to the radiologists involved, interobserver reliabillity (kappa) was 0.70 and intraobserver reliability (kappa) was 0.51 and 0.67. Before hormone therapy, factors related to decreased mammographic density were age and number of full term pregnancies (p<0.05). After one year of hormone therapy, body fat showed a significant increase (p<0.05), but in spite of this, increased mammographic density induced by hormone therapy remained significantly high (p<0.05). Compared with Group II, Group I showed a significant increase in mammographic density (p<0.05). In Group I, mammographic density increased from P2 to DY pattern in two cases, but there was no such change in Group II. The increase of mammographic density seen in Group II was much more significant statistically than that seen in Group I. The mammograms of women who have undergone continuous combined hormone therapy should therefore be interpreted very cautiously.
Flaxel, Christina J; Yeh, Steven; Lauer, Andreas K
To compare the outcomes of combination systemic and intravitreal antiviral therapy vs systemic antiviral therapy alone for treating acute retinal necrosis syndrome (ARN). We hypothesize that combination therapy might result in superior visual acuity (VA) and retinal detachment (RD) outcomes vs traditional systemic antiviral therapy alone. A retrospective, interventional, comparative single-center study of patients with ARN. We reviewed demographic data, herpesvirus diagnoses, polymerase chain reaction (PCR) results, VA, RD, and the use of systemic and intravitreal antiviral therapy. Outcome measures included VA improvement by 2 or more lines, severe visual loss, VA ≤20/200, and RD. We studied 29 eyes of 24 patients, treated from 1987 through 2009. Mean age was 42.6 years and mean follow-up was 44.0 months. Twelve patients (14 eyes) were treated with combined systemic and intravitreal antiviral therapy and 12 patients (15 eyes) with systemic therapy alone. Kaplan-Meier survival analysis revealed that patients receiving combination intravitreal and systemic antiviral therapy were more likely to have VA improved by 2 lines or greater (P=.006). Patients receiving combination therapy also showed a decreased incidence of progression to severe visual loss (0.13/patient-years [PY]) compared to patients receiving systemic therapy alone (0.54/PY, P=.02) and had decreased incidence of RD (0.29/PY vs 0.74/PY, P=.03). Combination oral and intravitreal antiviral therapy may improve visual and functional outcomes in patients with ARN. Clinicians should consider prompt administration of combination systemic and intravitreal antiviral therapy as first-line treatment for patients with clinical features of ARN.
Margalit, Danielle N; Mamon, Harvey J; Ancukiewicz, Marek; Kobayashi, Wendy; Ryan, David P; Blaszkowsky, Lawrence S; Clark, Jeffrey; Willett, Christopher G; Hong, Theodore S
To determine the rate of treatment deviations during combined modality therapy for rectal cancer in elderly patients aged 75 years and older. We reviewed the records of consecutively treated patients with rectal cancer aged 75 years and older treated with combined modality therapy at Massachusetts General Hospital and Brigham & Women's Hospital from 2002 to 2007. The primary endpoint was the rate of treatment deviation, defined as a treatment break, dose reduction, early discontinuation of therapy, or hospitalization during combined modality therapy. Patient comorbidity was rated using the validated Adult Comorbidity Evaluation 27 Test (ACE-27) comorbidity index. Fisher's exact test and the Mantel-Haenszel trend test were used to identify predictors of treatment tolerability. Thirty-six eligible patients had a median age of 79.0 years (range, 75-87 years); 53% (19/36) had no or mild comorbidity and 47% (17/36) had moderate or severe comorbidity. In all, 58% of patients (21/36) were treated with preoperative chemoradiotherapy (CRT) and 33% (12/36) with postoperative CRT. Although 92% patients (33/36) completed the planned radiotherapy (RT) dose, 25% (9/36) required an RT-treatment break, 11% (4/36) were hospitalized, and 33% (12/36) had a dose reduction, break, or discontinuation of concurrent chemotherapy. In all, 39% of patients (14/36) completed≥4 months of adjuvant chemotherapy, and 17% (6/36) completed therapy without a treatment deviation. More patients with no to mild comorbidity completed treatment than did patients with moderate to severe comorbidity (21% vs. 12%, p=0.66). The rate of deviation did not differ between patients who had preoperative or postoperative CRT (19% vs. 17%, p=1.0). The majority of elderly patients with rectal cancer in this series required early termination of treatment, treatment interruptions, or dose reductions. These data suggest that further intensification of combined modality therapy for rectal cancer should be performed
Full Text Available Background: Hemorrhagic transformation, neurotoxicity, short treatment time windows, and other defects are considered as the major limitations for the thrombolytic therapy. This study is devoted to figure out whether Danhong injection (DHI combined with tissue-plasminogen activator (t-PA could extend the treatment time windows and ameliorate brain injury, hemorrhagic complication and BBB disruption after focal embolic stroke.Methods:In vitro, the combined concentrations of DHI and t-PA were added to wells reacted with plasminogen and D-Val-Leu-Lys-AMC. The optimum ratio of the combination of DHI plus t-PA was explored by detecting relative fluorescent. In vivo experiments, we firstly investigated the optimal dose of t-PA and Danhong injection for focal embolic stroke. The neurological deficit score, infarct volume and brain edema were assessed. Secondly, we proved that the combination group extended the thrombolytic window for treatment of focal embolic stroke. The neurological deficit score, infarct volume, brain edema and hemorrhagic complication were assessed, while levels of BAX, Bcl-2 and caspase-3 in brain tissue were analyzed by real-time polymerase chain reaction. Finally, to ask whether combination therapy with DHI plus t-PA protected the blood–brain barrier in a rat model of focal embolic stroke, neurological deficit score, ELISA, RT-PCR, western blot and fluorescence were used to detect the indicators of blood–brain barrier, such as tight junction protein, blood–brain barrier permeability and related gene expression.Results:In vitro, plasmin activity assays showed that the combination of t-PA with DHI at about 1:1.6 w/v ratio increased by almost 1.4-fold the plasmin-generating capability of t-PA. In vivo experiments, the results showed that the combination of Danhong injection (4 mL/kg and t-PA (2.5 mg/kg could extend the t-PA treatment time windows to 4.5 h. And the combination t-PA (2.5 mg/kg with DHI (4 mL/kg ameliorated
Khatib Rashid A
Full Text Available Abstract Background Artemisinin-based combination therapy (ACT has been promoted as a means to reduce malaria transmission due to their ability to kill both asexual blood stages of malaria parasites, which sustain infections over long periods and the immature derived sexual stages responsible for infecting mosquitoes and onward transmission. Early studies reported a temporal association between ACT introduction and reduced malaria transmission in a number of ecological settings. However, these reports have come from areas with low to moderate malaria transmission, been confounded by the presence of other interventions or environmental changes that may have reduced malaria transmission, and have not included a comparison group without ACT. This report presents results from the first large-scale observational study to assess the impact of case management with ACT on population-level measures of malaria endemicity in an area with intense transmission where the benefits of effective infection clearance might be compromised by frequent and repeated re-infection. Methods A pre-post observational study with a non-randomized comparison group was conducted at two sites in Tanzania. Both sites used sulphadoxine-pyrimethamine (SP monotherapy as a first-line anti-malarial from mid-2001 through 2002. In 2003, the ACT, artesunate (AS co-administered with SP (AS + SP, was introduced in all fixed health facilities in the intervention site, including both public and registered non-governmental facilities. Population-level prevalence of Plasmodium falciparum asexual parasitaemia and gametocytaemia were assessed using light microscopy from samples collected during representative household surveys in 2001, 2002, 2004, 2005 and 2006. Findings Among 37,309 observations included in the analysis, annual asexual parasitaemia prevalence in persons of all ages ranged from 11% to 28% and gametocytaemia prevalence ranged from Interpretation The introduction of ACT at
Zhang, Zhenxian; Cai, Zhixing; Yu, Yonghui; Wu, Lili; Zhang, Ye
To observe the clinical effects of the Lixujieyu recipe combined with Five Elements music therapy on chronic fatigue syndrome (CFS) identified as the symptom patterns of liver stagnation and spleen deficiency in terms of Traditional Chinese Medicine. Patients with CFS were randomly divided into treatment group 1 (Lixujieyu recipe combined with Gong-Tune, n = 15); treatment group 2 (Lixujieyu recipe combined with Jiao-Tune, n = 15); treatment group 3 (Lixujieyu recipe combined with Yu-Tune, n = 15); treatment group 4 (Lixujieyu recipe combined with Shang-Tune, n = 15); treatment group 5 (Lixuiievu recipe combined with Zhi-Tune, n = 15); and the control group (Lixujieyu recipe alone, n = 15). Chinese medicine was given twice daily, and music was listened to for 45 minutes daily, 5 days a week. All patients were treated for 4 weeks. Patients were assessed via the Fatigue Scale, the Hamilton Depression Rating Scale, and the Hamilton Anxiety Rating Scale before and after treatment. Treatment groups 1 and 2 had better effects on relieving the symptoms of physical fatigue related to anxiety and depression than the control group (P < 0.05). Lixujieyu recipe combined with Gong-Tune or Jiao-Tune significantly relieved the symptoms of CFS.
Full Text Available Abstract Background Combinations of disease-modifying anti-rheumatic drugs (DMARDs are increasingly used to control active rheumatoid arthritis (RA; however there is little information about patients’ perspectives, their expectations, concerns and experiences of this intensive treatment. Method We interviewed a quota sample of 18 patients from a single tertiary outpatient clinic, stratified by gender, ethnicity and age, based on the outpatient clinic population. Patients with early RA (2 years received combined conventional DMARDs or DMARDs with biologics. Results Four main themes emerged from the analytical framework: (i patients’ expectations about the combined treatment focuses mainly on physical symptoms; (ii the impact of the treatment on quality of life varied with the new medication in both groups (iii concerns about new interventions concentrated mainly on potential side effects; and (iv combination therapy can be self-managed in close collaboration with clinic staff, but this requires individualised management approaches. These themes resonate with von Korff’s collaborative management of chronic illness model. Conclusion To our knowledge this is the first qualitative study that examined systematically in patients with early and established RA their expectations, impact on quality of life, concerns about side effects and the management of the treatment when taking combined medication with DMARDs or DMARDs and biologics. Patients have generally positive views of combination DMARDs. Within routine practice settings, achieving medication concordance with complex combined DMARD regimens is challenging, and the concerns vary between patients; careful individual assessments are essential to successfully deliver such intensive treatment.
Full Text Available Shazia Bano,1–3,* Samina Nazir,2,* Saeeda Munir,3 Mohamed Fahad AlAjmi,4 Muhammad Afzal,1 Kehkashan Mazhar3 1Department of Physics, The Islamia University of Bahawalpur, 2Nanosciences and Technology Department, National Centre for Physics, Islamabad, 3Institute of Biomedical and Genetic Engineering, Islamabad, Pakistan; 4College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia *These authors contributed equally to this work Abstract: We report “smart” nickel oxide nanoparticles (NOPs as multimodal cancer therapy agent. Water-dispersible and light-sensitive NiO core was synthesized with folic acid (FA connected bovine serum albumin (BSA shell on entrapped doxorubicin (DOX. The entrapped drug from NOP-DOX@BSA-FA was released in a sustained way (64 hours, pH=5.5, dark conditions while a robust release was found under red light exposure (in 1/2 hour under λmax=655 nm, 50 mW/cm2, at pH=5.5. The cell viability, thiobarbituric acid reactive substances and diphenylisobenzofuran assays conducted under light and dark conditions revealed a high photodynamic therapy potential of our construct. Furthermore, we found that the combined effect of DOX and NOPs from NOP-DOX@BSA-FA resulted in cell death approximately eightfold high compared to free DOX. We propose that NOP-DOX@BSA-FA is a potential photodynamic therapy agent and a collective drug delivery system for the systemic administration of cancer chemotherapeutics resulting in combination therapy. Keywords: light-triggered drug release, cancer, bovine serum albumin, multi-model therapy
Donaldson, S.S.; Moskowitz, P.S.; Canty, E.L.; Fajardo, L.F.
The normal tissue effects of radiation-adriamycin combination therapy were studied in the renoprival weanling mouse in an attempt to determine whether compensatory renal growth inhibition from radiation and chemotherapy could be associated with structural or functional abnormalities. Weanling BLc/sub Fl/ mice underwent unilateral nephrectomy, then single fraction renal irradiation, LD 1/21 doses of adriamycin in 5 daily doses, or combination therapy with radiation and adriamycin. Animals were sacrificed at 3, 12, and 24 weeks. Compensatory renal growth, body growth, serum blood urea nitrogen (BUN), and renal morphology by light microscopy were evaluated. Significant compensatory renal growth inhibition from radiation-adriamycin therapy exceeded that produced by adriamycin alone and radiation alone, at all time periods (p < 0.005). Body growth inhibition from radiation-adriamycin therapy or adriamycin alone significantly exceeded that produced by radiation alone (p < 0.005). Kidney and body growth inhibition from radiation-adriamycin therapy was proportionately severe. Kidney growth inhibition proportionately exceeded body growth inhibition with radiation alone; body growth inhibition proportionately exceeded kidney growth inhibition with adriamycin alone. Comparable azotemia developed by 24 weeks in both the radiation alone (p < .005) and radiation-adriamycin animals (p < 0.005), but not in the adriamycin only animals. Morphologic alterations consisting of increased glomerular density, tubular atrophy, and stromal fibrosis occurred with greater severity in the radiation-adriamycin animals than in the radiation only animals by 24 weeks; no alterations were seen in the adriamycin only animals. Using histologic criteria 750 rad plus adriamycin produced comparable injury as seen with 1000 rad alone, thus adriamycin produced an apparent dose-modifying factor of 1.33