Towards subsidized malaria rapid diagnostic tests. Lessons learned from programmes to subsidise artemisinin-based combination therapies in the private sector: a review.

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Lussiana, Cristina

2016-09-01

The idea of a private sector subsidy programme of artemisinin-based combination therapies (ACTs) was first proposed in 2004. Since then, several countries around the world have hosted pilot projects or programmes on subsidized ACTs and/or the Affordable Medicines Facility-malaria programme (AMFm). Overall the private sector subsidy programmes of ACTs have been effective in increasing availability of ACTs in the private sector and driving down average prices but struggled to crowd out antimalarial monotherapies. The results obtained from this ambitious strategy should inform policy makers in the designing of future interventions aimed to control malaria morbidity and mortality. Among the interventions recently proposed, a subsidy of rapid diagnostic tests (RDTs) in the private sector has been recommended by governments and international donors to cope with over-treatment with ACTs and to delay the emergence of resistance to artemisinin. In order to improve the cost-effectiveness of co-paid RDTs, we should build on the lessons we learned from almost 10 years of private sector subsidy programmes of ACTs in malaria-endemic countries. © The Author 2015. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.

Repeated Artemisinin-Based Combination Therapies in a Malaria Hyperendemic Area of Mali: Efficacy, Safety, and Public Health Impact

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Sagara, Issaka; Fofana, Bakary; Gaudart, Jean; Sidibe, Bakary; Togo, Amadou; Toure, Sekou; Sanogo, Kassim; Dembele, Demba; Dicko, Alassane; Giorgi, Roch; Doumbo, Ogobara K.; Djimde, Abdoulaye A.

2012-01-01

Artemisinin-based combination therapies (ACTs) are the first-line treatment of uncomplicated malaria. The public health benefit and safety of repeated administration of a given ACT are poorly studied. We conducted a randomized trial comparing artemether-lumefantrine, artesunate plus amodiaquine (AS+AQ) and artesunate plus sulfadoxine-pyrimethamine (AS+SP) in patients 6 months of age and older with uncomplicated malaria in Mali from July 2005 to July 2007. The patient received the same initial treatment of each subsequent uncomplicated malaria episode except for treatment failures where quinine was used. Overall, 780 patients were included. Patients in the AS+AQ and AS+SP arms had significantly less risk of having malaria episodes; risk ratio (RR) = 0.84 (P = 0.002) and RR = 0.80 (P = 0.001), respectively. The treatment efficacy was similar and above 95% in all arms. Although all drugs were highly efficacious and well tolerated, AS+AQ and AS+SP were associated with less episodes of malaria. PMID:22764291

Approaches and Recent Developments for the Commercial Production of Semi-synthetic Artemisinin.

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Kung, Stephanie H; Lund, Sean; Murarka, Abhishek; McPhee, Derek; Paddon, Chris J

2018-01-01

The antimalarial drug artemisinin is a natural product produced by the plant Artemisia annua . Extracts of A. annua have been used in Chinese herbal medicine for over two millennia. Following the re-discovery of A. annua extract as an effective antimalarial, and the isolation and structural elucidation of artemisinin as the active agent, it was recommended as the first-line treatment for uncomplicated malaria in combination with another effective antimalarial drug (Artemisinin Combination Therapy) by the World Health Organization (WHO) in 2002. Following the WHO recommendation, the availability and price of artemisinin fluctuated greatly, ranging from supply shortfalls in some years to oversupply in others. To alleviate these supply and price issues, a second source of artemisinin was sought, resulting in an effort to produce artemisinic acid, a late-stage chemical precursor of artemisinin, by yeast fermentation, followed by chemical conversion to artemisinin (i.e., semi-synthesis). Engineering to enable production of artemisinic acid in yeast relied on the discovery of A. annua genes encoding artemisinic acid biosynthetic enzymes, and synthetic biology to engineer yeast metabolism. The progress of this effort, which resulted in semi-synthetic artemisinin entering commercial production in 2013, is reviewed with an emphasis on recent publications and opportunities for further development. Aspects of both the biology of artemisinin production in A. annua , and yeast strain engineering are discussed, as are recent developments in the chemical conversion of artemisinic acid to artemisinin.

Treatment of malaria from monotherapy to artemisinin-based combination therapy by health professionals in urban health facilities in Yaoundé, central province, Cameroon

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Bley Daniel

2009-07-01

Full Text Available Abstract Background After adoption of artesunate-amodiaquine (AS/AQ as first-line therapy for the treatment of uncomplicated malaria by the malaria control programme, this study was designed to assess the availability of anti-malarial drugs, treatment practices and acceptability of the new protocol by health professionals, in the urban health facilities and drugstores of Yaoundé city, Cameroon. Methods Between April and August 2005, retrospective and current information was collected by consulting registers and interviewing health practitioners in urban health facilities using a structured questionnaire. Results In 2005, twenty-seven trade-named drugs have been identified in drugstores; quinine tablets (300 mg were the most affordable anti-malarial drugs. Chloroquine was restricted to food market places and no generic artemisinin derivative was available in public health centres. In public health facilities, 13.6% of health professionals were informed about the new guidelines; 73.5% supported the use of AS-AQ as first-line therapy. However, 38.6% apprehended its use due to adverse events attributed to amodiaquine. Malaria treatment was mainly based on the diagnosis of fever. Quinine (300 mg tablets was the most commonly prescribed first-line anti-malarial drug in adults (44.5% and pregnant women (52.5%. Artequin® was the most cited artemsinin-based combination therapy (ACT (9.9%. Medical sales representatives were the main sources of information on anti-malarials. Conclusion The use of AS/AQ was not implemented in 2005 in Yaoundé, despite the wide range of anti-malarials and trade-named artemisinin derivatives available. Nevertheless, medical practitioners will support the use of this combination, when it is available in a paediatric formulation, at an affordable price. Training, information and participation of health professionals in decision-making is one of the key elements to improve adherence to new protocol guidelines. This baseline

Selection and Clonal Propagation of High Artemisinin Genotypes of Artemisia annua

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Wetzstein, Hazel Y.; Porter, Justin A.; Janick, Jules; Ferreira, Jorge F. S.; Mutui, Theophilus M.

2018-01-01

Artemisinin, produced in the glandular trichomes of Artemisia annua L. is a vital antimalarial drug effective against Plasmodium falciparum resistant to quinine-derived medicines. Although work has progressed on the semi-synthetic production of artemisinin, field production of A. annua remains the principal commercial source of the compound. Crop production of artemisia must be increased to meet the growing worldwide demand for artemisinin combination therapies (ACTs) to treat malaria. Grower artemisinin yields rely on plants generated from seeds from open-pollinated parents. Although selection has considerably increased plant artemisinin concentration in the past 15 years, seed-generated plants have highly variable artemisinin content that lowers artemisinin yield per hectare. Breeding efforts to produce improved F1 hybrids have been hampered by the inability to produce inbred lines due to self-incompatibility. An approach combining conventional hybridization and selection with clonal propagation of superior genotypes is proposed as a means to enhance crop yield and artemisinin production. Typical seed-propagated artemisia plants produce less than 1% (dry weight) artemisinin with yields below 25 kg/ha. Genotypes were identified producing high artemisinin levels of over 2% and possessing improved agronomic characteristics such as high leaf area and shoot biomass production. Field studies of clonally-propagated high-artemisinin plants verified enhanced plant uniformity and an estimated gross primary productivity of up to 70 kg/ha artemisinin, with a crop density of one plant m-2. Tissue culture and cutting protocols for the mass clonal propagation of A. annua were developed for shoot regeneration, rooting, acclimatization, and field cultivation. Proof of concept studies showed that both tissue culture-regenerated plants and rooted cutting performed better than plants derived from seed in terms of uniformity, yield, and consistently high artemisinin content. Use of

Artemisinin-resistant malaria: research challenges, opportunities, and public health implications.

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Fairhurst, Rick M; Nayyar, Gaurvika M L; Breman, Joel G; Hallett, Rachel; Vennerstrom, Jonathan L; Duong, Socheat; Ringwald, Pascal; Wellems, Thomas E; Plowe, Christopher V; Dondorp, Arjen M

2012-08-01

Artemisinin-based combination therapies are the most effective drugs to treat Plasmodium falciparum malaria. Reduced sensitivity to artemisinin monotherapy, coupled with the emergence of parasite resistance to all partner drugs, threaten to place millions of patients at risk of inadequate treatment of malaria. Recognizing the significance and immediacy of this possibility, the Fogarty International Center and the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health convened a conference in November 2010 to bring together the diverse array of stakeholders responding to the growing threat of artemisinin resistance, including scientists from malarious countries in peril. This conference encouraged and enabled experts to share their recent unpublished data from studies that may improve our understanding of artemisinin resistance. Conference sessions addressed research priorities to forestall artemisinin resistance and fostered collaborations between field- and laboratory-based researchers and international programs, with the aim of translating new scientific evidence into public health solutions. Inspired by this conference, this review summarizes novel findings and perspectives on artemisinin resistance, approaches for translating research data into relevant public health information, and opportunities for interdisciplinary collaboration to combat artemisinin resistance.

Putting the genie back in the bottle? Availability and presentation of oral artemisinin compounds at retail pharmacies in urban Dar-es-Salaam

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Black Carolyn

2006-03-01

Full Text Available Abstract Background Recently global health advocates have called for the introduction of artemisinin-containing antimalarial combination therapies to help curb the impact of drug-resistant malaria in Africa. Retail trade in artemisinin monotherapies could undermine efforts to restrict this class of medicines to more theoretically sound combination treatments. Methods This paper describes a systematic search for artemisinin-containing products at a random sample of licensed pharmacies in Dar-es-Salaam, Tanzania in July 2005. Results Nineteen different artemisinin-containing oral pharmaceutical products, including one co-formulated product, one co-packaged product, and 17 monotherapies were identified. All but one of the products were legally registered and samples of each product were obtained without a prescription. Packaging and labeling of the products seldom included local language or illustrated instructions for low-literate clients. Packaging and inserts compared reasonably well with standards recommended by the national regulatory authority with some important exceptions. Dosing instructions were inconsistent, and most recommended inadequate doses based on international standards. None of the monotherapy products mentioned potential benefits of combining the treatment with another antimalarial drug. Conclusion The findings confirm the widespread availability of artemisinin monotherapies that led the World Health Organization to call for the voluntary withdrawal of these drugs in malaria-endemic countries. As the global public health community gathers resources to deploy artemisinin-containing combination therapies in Africa, planners should be mindful that these drugs will coexist with artemisinin monotherapies in an already well-established market place. In particular, regulatory authorities should be incorporated urgently into the process of planning for rational deployment of artemisinin-containing antimalarial combination therapies.

Do anti-malarials in Africa meet quality standards? The market penetration of non quality-assured artemisinin combination therapy in eight African countries.

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Newton, Paul N; Hanson, Kara; Goodman, Catherine

2017-05-25

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

Cost of increasing access to artemisinin combination therapy: the Cambodian experience

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Socheat Duong

2008-05-01

Full Text Available Abstract Background Malaria-endemic countries are switching antimalarial drug policy from cheap ineffective monotherapies to artemisinin combination therapies (ACTs for the treatment of Plasmodium falciparum malaria and the global community are considering setting up a global subsidy to fund their purchase. However, in order to ensure that ACTs are correctly used and are accessible to the poor and remote communities who need them, specific interventions will be necessary and the additional costs need to be considered. Methods This paper presents an incremental cost analysis of some of these interventions in Cambodia, the first country to change national antimalarial drug policy to an ACT of artesunate and mefloquine. These costs include the cost of rapid diagnostic tests (RDTs, the cost of blister-packaging the drugs locally and the costs of increasing access to diagnosis and treatment to remote communities through malaria outreach teams (MOTs and Village Malaria Workers (VMW. Results At optimum productive capacity, the cost of blister-packaging cost under $0.20 per package but in reality was significantly more than this because of the low rate of production. The annual fixed cost (exclusive of RDTs and drugs per capita of the MOT and VMW schemes was $0.44 and $0.69 respectively. However because the VMW scheme achieved a higher rate of coverage than the MOT scheme, the cost per patient treated was substantially lower at $5.14 compared to $12.74 per falciparum malaria patient treated. The annual cost inclusive of the RDTs and drugs was $19.31 for the MOT scheme and $11.28 for the VMW scheme given similar RDT positivity rates of around 22% and good provider compliance to test results. Conclusion In addition to the cost of ACTs themselves, substantial additional investments are required in order to ensure that they reach the targeted population via appropriate delivery systems and to ensure that they are used appropriately. In addition, differences

Subsidising artemisinin-based combination therapy in the private retail sector

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Opiyo, Newton; Yamey, Gavin; Garner, Paul

2016-01-01

Background Malaria causes ill health and death in Africa. Treating illness promptly with artemisinin-based combination therapy (ACT) is likely to cure people and avoid the disease progressing to more severe forms and death. In many countries, ACT use remains low. Part of the problem is that most people seek treatment from the retail sector where ACTs are expensive; this expense is a barrier to their use. The Global Fund and other international organisations are subsidising the cost of ACTs for private retail providers to improve access to ACTs. The subsidy was initially organised through a stand-alone initiative, called the Affordable Medicines Facility-malaria (AMFm), but has since been integrated into the Global Fund core grant management and financial processes. Objectives To assess the effect of programmes that include ACT price subsidies for private retailers on ACT use, availability, price and market share. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 1, The Cochrane Library, including the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register); MEDLINE (OvidSP), EMBASE (OvidSP), CINAHL (EbscoHost), EconLit (ProQuest), Global Health (OvidSP), Regional Indexes (Global Health Library, WHO), LILACS (Global Health Library, WHO), Science Citation Index and Social Sciences Citation Index (ISI Web of Science) and Health Management (ProQuest). All databases were searched February 2015, except for Health Management which was searched November 2013, without any date, language or publication status restrictions. We also searched the International Clinical Trials Registry Platform (ICTRP; WHO), ClinicalTrials.gov (NIH) and various grey literature sources. We also conducted a cited reference search for all included studies in ISI Web of Knowledge, checked references of identified articles and contacted authors to identify additional studies. Selection criteria Randomised trials, non

Safety and Tolerability Profile of Artemisinin-Based Antimalarial ...

African Journals Online (AJOL)

The WHO in 2001 advocated artemisinin- based antimalarial combination therapy (ACT), which was adopted by Nigeria in 2005. The objective of this study was to characterize the safety and tolerability profile of the ACTs in adult patients with uncomplicated malaria. A descriptive longitudinal study was conducted in the ...

Treatment of Febrile illness with artemisinin combination therapy: prevalence and predictors in five African household surveys.

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Vialle-Valentin, Catherine E; LeCates, Robert F; Zhang, Fang; Ross-Degnan, Dennis

2015-01-01

To evaluate the determinants of compliance with national policies recommending Artemisinin Combination Therapy (ACT) for the treatment of uncomplicated malaria in the community. We used data from Gambia, Ghana, Kenya, Nigeria, and Uganda national household surveys that were conducted with a standardized World Health Organization (WHO) methodology to measure access to and use of medicines. We analyzed all episodes of acute fever reported in the five surveys. We used logistic regression models accounting for the clustered design of the surveys to identify determinants of seeking care in public healthcare facilities, of being treated with antimalarials, and of receiving ACT. Overall, 92% of individuals with a febrile episode sought care outside the home, 96% received medicines, 67% were treated with antimalarials, and 16% received ACT. The choice of provider was influenced by perceptions about medicines availability and affordability. In addition, seeking care in a public healthcare facility was the single most important predictor of treatment with ACT [odds ratio (OR): 4.64, 95% confidence intervals (CI): 2.98-7.22, P policies recommending ACT for the treatment of uncomplicated malaria depends not only on restricting ACT to confirmed malaria cases, but also on ensuring that ACT is available and affordable for those who need it.

A threshold analysis of the cost-effectiveness of artemisinin-based combination therapies in sub-saharan Africa.

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Coleman, Paul G; Morel, Chantal; Shillcutt, Sam; Goodman, Catherine; Mills, Anne J

2004-08-01

Artemisinin-based combination therapies (ACTs) are generally regarded as vital in addressing the growing problem posed by the development of antimalarial resistance across sub-Saharan Africa. However, the costs of the new ACTs are likely to be significantly higher than current therapies. Therefore, it is important to examine formally the cost-effectiveness of the more effective yet more expensive ACTs before advocating a switch in policy. Importantly, any such economic evaluation must consider the temporal dynamics of drug resistance, and not just focus on the static question of whether switching today would be cost-effective at current levels of resistance, particularly since the development of new antimalarials in the future is so uncertain. However, predicting the future changes in drug resistance is a major difficulty in accurately quantifying the relative costs and health outcomes associated with different drug therapies over time. Here, we use a simple decision tree model to estimate the incremental cost-effectiveness of using ACTs, compared with persisting with current therapies, over 5-, 10-, and 15-year periods. We describe the dynamics of drug resistance using a general logistic growth function, in which the starting frequency of resistance and maximum growth may be altered. However, rather than make assumptions about the absolute rate at which resistance to ACTs will progress, we allow the ratio of the growth rate of resistance to ACTs relative to that of current therapies to vary. Defining the growth rate of ACT resistance in this manner allows us to calculate the threshold ratio at which ACTs would no longer appear cost-effective, for any starting conditions of resistance to current therapies and ACTs, and over any time period. The influence of uncertainty in other decision tree parameters on the threshold ratio values is also quantified, using Monte Carlo simulation techniques. This analysis shows that ACTs are more than 95% likely to be cost

Flavonoids from Artemisia annua L. as Antioxidants and Their Potential Synergism with Artemisinin against Malaria and Cancer

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Jorge F.S. Ferreira

2010-04-01

Full Text Available Artemisia annua is currently the only commercial source of the sesquiterpene lactone artemisinin.Since artemisinin was discovered as the active component of A. annua in early 1970s, hundreds of papers have focused on the anti-parasitic effects of artemisinin and its semi-synthetic analogs dihydroartemisinin, artemether, arteether, and artesunate. Artemisinin per se has not been used in mainstream clinical practice due to its poor bioavailability when compared to its analogs. In the past decade, the work with artemisinin-based compounds has expanded to their anti-cancer properties. Although artemisinin is a major bioactive component present in the traditional Chinese herbal preparations (tea, leaf flavonoids, also present in the tea, have shown a variety of biological activities and may synergize the effects of artemisinin against malaria and cancer. However, only a few studies have focused on the potential synergistic effects between flavonoids and artemisinin. The resurgent idea that multi-component drug therapy might be better than monotherapy is illustrated by the recent resolution of the World Health Organization to support artemisinin-based combination therapies (ACT, instead of the previously used monotherapy with artemisinins. In this critical review we will discuss the possibility that artemisinin and its semi-synthetic analogs might become more effective to treat parasitic diseases (such as malaria and cancer if simultaneously delivered with flavonoids. The flavonoids present in A. annua leaves have been linked to suppression of CYP450 enzymes responsible for altering the absorption and metabolism of artemisinin in the body, but also have been linked to a beneficial immunomodulatory activity in subjects afflicted with parasitic and chronic diseases.

Molecular monitoring of Plasmodium falciparum resistance to artemisinin in Tanzania

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Genton Blaise

2006-12-01

Full Text Available Abstract Artemisinin-based combination therapies (ACTs are recommended for use against uncomplicated malaria in areas of multi-drug resistant malaria, such as sub-Saharan Africa. However, their long-term usefulness in these high transmission areas remains unclear. It has been suggested that documentation of the S769N PfATPase6 mutations may indicate an emergence of artemisinin resistance of Plasmodium falciparum in the field. The present study assessed PfATPase6 mutations (S769N and A623E in 615 asymptomatic P. falciparum infections in Tanzania but no mutant genotype was detected. This observation suggests that resistance to artemisinin has not yet been selected in Tanzania, supporting the Ministry of Health's decision to adopt artemether+lumefantrine as first-line malaria treatment. The findings recommend further studies to assess PfATPase6 mutations in sentinel sites and verify their usefulness in monitoring emergency of ACT resistance.

High-level semi-synthetic production of the potent antimalarial artemisinin.

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Paddon, C J; Westfall, P J; Pitera, D J; Benjamin, K; Fisher, K; McPhee, D; Leavell, M D; Tai, A; Main, A; Eng, D; Polichuk, D R; Teoh, K H; Reed, D W; Treynor, T; Lenihan, J; Fleck, M; Bajad, S; Dang, G; Dengrove, D; Diola, D; Dorin, G; Ellens, K W; Fickes, S; Galazzo, J; Gaucher, S P; Geistlinger, T; Henry, R; Hepp, M; Horning, T; Iqbal, T; Jiang, H; Kizer, L; Lieu, B; Melis, D; Moss, N; Regentin, R; Secrest, S; Tsuruta, H; Vazquez, R; Westblade, L F; Xu, L; Yu, M; Zhang, Y; Zhao, L; Lievense, J; Covello, P S; Keasling, J D; Reiling, K K; Renninger, N S; Newman, J D

2013-04-25

In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers. A stable source of affordable artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker's yeast) for high-yielding biological production of artemisinic acid, a precursor of artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price.

ISOLASI DAN IDENTIFIKASI ARTEMISININ DARI HERBA Artemisia annua L .

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Sukmayati Alegantina

2012-07-01

Full Text Available Abstract. Malaria is still a major problem in Indonesia, because mortality in patients with severe malaria remains high. Many cases are occurs in endemic areas (e.g. Papua,Kalimantan, Bali and Sulawesi. Chloroquin is the most common antimalarial drug which is widely used since 1934. Plasmodium falciparum resistant to chloroquine was reported in some countries (e.g. Thailand, Vietnam, Indonesia, and Bangladesh. To delay the development of resistance, WHO recommended antimalarial combination therapy. Artemisinin and its derivatives (artesunate, artemether, dihydroartemisin produce rapid clearance of parasitemia and rapid resolution of symptoms compare with chloroquine. Artemisinin is obtained from Artemisia annua L. Even though there are some research produced a chemical synthetic of artemisinin, but it is not efficient and notstable. Our purposes are to conduct a preliminary research to obtain a method of isolation and identification of artemisinin which is the first step to develop a raw material of artemisinin as antimalarial drug in Indonesia.The first step of isolation is extraction from herb Artemisia annua L with n-hexane thatproduced n-hexane extract, this process is well-known as soxhletation. The second step isidentification of chemical substances from n-hexane extract. The third step is to obtain isolate from n-hexane extract by fractionation with acetonitril and separation with column chromatography. The last step is chemical and physical identification of isolateby TLC (Thin Layer (Chromatography and FT-IR.The result from n-hexane extract measurement is 4.33 % and from acetonitril fraction is2. 40 %. Chemical identification of n-hexan extract found there are terpenoid, phenol, flavonoid, fatty acid, atsiri oil and saponin. Organoleptic identification of isolate is white crystal, monosubstrate, odorless and bitter. Identification of isolate with TLC and FT-IR confirmed that the isolate is artemisinin.Keywords: artemisinin, Artemisia

Study on effect of artemisinin combined with 60Co γ-ray on DNA damage in HeLa and SiHa cells

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Feng Yang; Zhou Yuanyuan; Yang Wei; Chen Qiu; Li Ming; Zhang Shuyu; Zhu Wei; Cao Jianping; Zhang Xuguang

2011-01-01

Objective: To investigate the effect of Artemisinin combined with 60 Co γ-ray on DNA damage in HeLa and SiHa cells of human cervical cancer. Methods: Cell growth kinetics was evaluated by MTT assay to determine the most appropriate drug concentration. Effects of Artemisinin combined with 60 Co γ-ray on DNA damage in HeLa and SiHa cells were detected by single cell gel electrophoresis. Results: With the concentration increased during the effect of Artemisinin, the HeLa and SiHa cells had higher inhibition on cell proliferation. The SCGE showed that:the comet cell analysis indexes (the comet cells ratio, Tail Length, Olive Tail Moment and Tail DNA%) there was no statistic difference in between the artemisinin group and the control group (P>0.05). With radiation in the same dose, the comet cell analysis indexes of Hela cells treated with both artermisinin and exposed to radiation were higher than that only exposed to radiation group(P 0.05). Conclusion: Artemisinin can not induce DNA damage in both HeLa and SiHa cells, but it can make irradiated HeLa cells DNA damage to be aggravated and enhance HeLa cells' radiation sensitivity. However, Artemisinin has no radiosensitizing effect on SiHa cells. (authors)

Optimising strategies for Plasmodium falciparum malaria elimination in Cambodia: primaquine, mass drug administration and artemisinin resistance.

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Richard J Maude

Full Text Available Malaria elimination requires a variety of approaches individually optimized for different transmission settings. A recent field study in an area of low seasonal transmission in South West Cambodia demonstrated dramatic reductions in malaria parasite prevalence following both mass drug administration (MDA and high treatment coverage of symptomatic patients with artemisinin-piperaquine plus primaquine. This study employed multiple combined strategies and it was unclear what contribution each made to the reductions in malaria.A mathematical model fitted to the trial results was used to assess the effects of the various components of these interventions, design optimal elimination strategies, and explore their interactions with artemisinin resistance, which has recently been discovered in Western Cambodia. The modelling indicated that most of the initial reduction of P. falciparum malaria resulted from MDA with artemisinin-piperaquine. The subsequent continued decline and near elimination resulted mainly from high coverage with artemisinin-piperaquine treatment. Both these strategies were more effective with the addition of primaquine. MDA with artemisinin combination therapy (ACT increased the proportion of artemisinin resistant infections, although much less than treatment of symptomatic cases with ACT, and this increase was slowed by adding primaquine. Artemisinin resistance reduced the effectiveness of interventions using ACT when the prevalence of resistance was very high. The main results were robust to assumptions about primaquine action, and immunity.The key messages of these modelling results for policy makers were: high coverage with ACT treatment can produce a long-term reduction in malaria whereas the impact of MDA is generally only short-term; primaquine enhances the effect of ACT in eliminating malaria and reduces the increase in proportion of artemisinin resistant infections; parasite prevalence is a better surveillance measure for

Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: A review

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Olliaro P

2004-01-01

Full Text Available The emergence and spread of drug resistant malaria represents a considerable challenge to controlling malaria. To date, malaria control has relied heavily on a comparatively small number of chemically related drugs, belonging to either the quinoline or the antifolate groups. Only recently have the artemisinin derivatives been used but mostly in south east Asia. Experience has shown that resistance eventually curtails the life-span of antimalarial drugs. Controlling resistance is key to ensuring that the investment put into developing new antimalarial drugs is not wasted. Current efforts focus on research into new compounds with novel mechanisms of action, and on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and costly ventures. Antimalarial drug development has traditionally been slow but now various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial development pipeline is looking reasonably healthy. Most development relies on the quinoline, antifolate and artemisinin compounds. There is a pressing need to have effective, easy to use, affordable drugs that will last a long time. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance. Most research work has focused on the use of artesunate combined with currently used standard drugs, namely, mefloquine, amodiaquine, sulfadoxine/pyrimethamine, and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and depend on the level of resistance of the standard drug. From these studies, further work is underway to produce fixed dose combinations that will be packaged in blister packs. This review will summarise current antimalarial drug developments and outline recent

Willingness and ability to pay for artemisinin-based combination therapy in rural Tanzania.

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Saulo, Eleonor C; Forsberg, Birger C; Premji, Zul; Montgomery, Scott M; Björkman, Anders

2008-10-31

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. 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. 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. 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 taken in Tanzania to subsidize Coartem fully at governmental health

Antimalarial activity of Garcinia mangostana L rind and its synergistic effect with artemisinin in vitro.

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Tjahjani, Susy

2017-02-28

Malaria especially falciparum malaria still causes high morbidity and mortality in tropical countries. Several factors have been linked to this situation and the most important one is the rapid spread of parasite resistance to the currently available antimalarials, including artemisinin. Artemisinin is the main component of the currently recommended antimalarial, artemisinin based combination therapy (ACT), and it is a free radical generating antimalarial. Garcinia mangostana L (mangosteen) rind contain a lot of xanthone compounds acting as an antioxidant and exhibited antimalarial activity. The aim of this study was to evaluate the antimalarial activity of mangosteen rind extract and its fractions and their interaction with artemisinin against the 3D7 clone of Plasmodium falciparum in vitro. Dry ripe mangosteen rind was extracted with ethanol followed by fractionation with hexane, ethylacetate, buthanol, and water consecutively to get ethanol extract, hexane, athylacetate, buthanol, and water fractions. Each of these substances was diluted in DMSO and examined for antimalarial activity either singly or in combination with artemisinin in vitro against Plasmodium falciparum 3D7 clone. Synergism between these substances with artemisinin was evaluated according to certain formula to get the sum of fractional inhibitory concentration 50 (∑FIC 50 ). Analysis of the parasite growth in vitro indicated that IC 50 of these mangosteen rind extract, hexane, ethylacetate, buthanol, and water fraction ranged from 0.41 to > 100 μg/mL. All of the ∑FIC50 were antimalarial activity of the extract and fractions of G.mangostana L rind and its synergistic effect with artemisinin. Further study using lead compound(s) isolated from extract and fractions should be performed to identify more accurately their mechanism of antimalarial activities.

Knowledge, access and utilization of bed-nets among stable and seasonal migrants in an artemisinin resistance containment area of Myanmar

OpenAIRE

Phyo Than, Wint; Oo, Tin; Wai, Khin Thet; Thi, Aung; Owiti, Philip; Kumar, Binay; Deepak Shewade, Hemant; Zachariah, Rony

2017-01-01

Background Myanmar lies in the Greater Mekong sub-region of South-East Asia faced with the challenge of emerging resistance to artemisinin combination therapies (ACT). Migrant populations are more likely than others to spread ACT resistance. A vital intervention to reduce malaria transmission, resistance spread and eliminate malaria is the use of bed nets. Among seasonal and stable migrants in an artemisinin resistance containment region of Myanmar, we compared a) their household characterist...

Radical chemistry of artemisinin

Energy Technology Data Exchange (ETDEWEB)

Denisov, Evgenii T; Solodova, S L; Denisova, Taisa G [Institute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka, Moscow Region (Russian Federation)

2011-12-29

The review summarizes physicochemical characteristics of the natural sesquiterpene peroxide artemisinin. The kinetic schemes of transformations of artemisinin radicals under anaerobic conditions are presented and analyzed. The sequence of radical reactions of artemisinin in the presence of oxygen is considered in detail. Special emphasis is given to the intramolecular chain oxidation resulting in the transformation of artemisinin into polyatomic hydroperoxide. The kinetic characteristics of elementary reaction steps involving alkyl, alkoxyl, and peroxyl radicals generated from artemisinin are discussed. The results of testing of artemisinin and its derivatives for the antimalarial activity and the scheme of the biochemical synthesis of artemisinin in nature are considered.

Radical chemistry of artemisinin

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Denisov, Evgenii T.; Solodova, S. L.; Denisova, Taisa G.

2010-12-01

The review summarizes physicochemical characteristics of the natural sesquiterpene peroxide artemisinin. The kinetic schemes of transformations of artemisinin radicals under anaerobic conditions are presented and analyzed. The sequence of radical reactions of artemisinin in the presence of oxygen is considered in detail. Special emphasis is given to the intramolecular chain oxidation resulting in the transformation of artemisinin into polyatomic hydroperoxide. The kinetic characteristics of elementary reaction steps involving alkyl, alkoxyl, and peroxyl radicals generated from artemisinin are discussed. The results of testing of artemisinin and its derivatives for the antimalarial activity and the scheme of the biochemical synthesis of artemisinin in nature are considered.

Radical chemistry of artemisinin

International Nuclear Information System (INIS)

Denisov, Evgenii T; Solodova, S L; Denisova, Taisa G

2010-01-01

The review summarizes physicochemical characteristics of the natural sesquiterpene peroxide artemisinin. The kinetic schemes of transformations of artemisinin radicals under anaerobic conditions are presented and analyzed. The sequence of radical reactions of artemisinin in the presence of oxygen is considered in detail. Special emphasis is given to the intramolecular chain oxidation resulting in the transformation of artemisinin into polyatomic hydroperoxide. The kinetic characteristics of elementary reaction steps involving alkyl, alkoxyl, and peroxyl radicals generated from artemisinin are discussed. The results of testing of artemisinin and its derivatives for the antimalarial activity and the scheme of the biochemical synthesis of artemisinin in nature are considered.

Radical chemistry of artemisinin

Energy Technology Data Exchange (ETDEWEB)

Denisov, Evgenii T; Solodova, S L; Denisova, Taisa G [Institute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka, Moscow Region (Russian Federation)

2010-12-29

The review summarizes physicochemical characteristics of the natural sesquiterpene peroxide artemisinin. The kinetic schemes of transformations of artemisinin radicals under anaerobic conditions are presented and analyzed. The sequence of radical reactions of artemisinin in the presence of oxygen is considered in detail. Special emphasis is given to the intramolecular chain oxidation resulting in the transformation of artemisinin into polyatomic hydroperoxide. The kinetic characteristics of elementary reaction steps involving alkyl, alkoxyl, and peroxyl radicals generated from artemisinin are discussed. The results of testing of artemisinin and its derivatives for the antimalarial activity and the scheme of the biochemical synthesis of artemisinin in nature are considered.

Willingness and ability to pay for artemisinin-based combination therapy in rural Tanzania

Directory of Open Access Journals (Sweden)

Montgomery Scott M

2008-10-01

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

Artemisinin Resistance-Associated Polymorphisms at the K13-Propeller Locus Are Absent in Plasmodium falciparum Isolates from Haiti

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Carter, Tamar E.; Boulter, Alexis; Existe, Alexandre; Romain, Jean R.; St. Victor, Jean Yves; Mulligan, Connie J.; Okech, Bernard A.

2015-01-01

Antimalarial drugs are a key tool in malaria elimination programs. With the emergence of artemisinin resistance in southeast Asia, an effort to identify molecular markers for surveillance of resistant malaria parasites is underway. Non-synonymous mutations in the kelch propeller domain (K13-propeller) in Plasmodium falciparum have been associated with artemisinin resistance in samples from southeast Asia, but additional studies are needed to characterize this locus in other P. falciparum populations with different levels of artemisinin use. Here, we sequenced the K13-propeller locus in 82 samples from Haiti, where limited government oversight of non-governmental organizations may have resulted in low-level use of artemisinin-based combination therapies. We detected a single-nucleotide polymorphism (SNP) at nucleotide 1,359 in a single isolate. Our results contribute to our understanding of the global genomic diversity of the K13-propeller locus in P. falciparum populations. PMID:25646258

Development of the protocol for purification of artemisinin based on combination of commercial and computationally designed adsorbents.

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Piletska, Elena V; Karim, Kal; Cutler, Malcolm; Piletsky, Sergey A

2013-01-01

A polymeric adsorbent for extraction of the antimalarial drug artemisinin from Artemisia annua L. was computationally designed. This polymer demonstrated a high capacity for artemisinin (120 mg g(-1) ), quantitative recovery (87%) and was found to be an effective material for purification of artemisinin from complex plant matrix. The artemisinin quantification was conducted using an optimised HPLC-MS protocol, which was characterised by high precision and linearity in the concentration range between 0.05 and 2 μg mL(-1) . Optimisation of the purification protocol also involved screening of commercial adsorbents for the removal of waxes and other interfering natural compounds, which inhibit the crystallisation of artemisinin. As a result of a two step-purification protocol crystals of artemisinin were obtained, and artemisinin purity was evaluated as 75%. By performing the second stage of purification twice, the purity of artemisinin can be further improved to 99%. The developed protocol produced high-purity artemisinin using only a few purification steps that makes it suitable for large scale industrial manufacturing process. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

ANALYSIS OF ARTEMISININ AND RELATED SESQUITERPENOIDS FROM ARTEMISIA-ANNUA L BY COMBINED GAS-CHROMATOGRAPHY MASS-SPECTROMETRY

NARCIS (Netherlands)

WOERDENBAG, HJ; PRAS, N; BOS, R; VISSER, JF; HENDRIKS, H; MALINGRE, TM

1991-01-01

The sesquiterpenoid artemisinin (3) and its biosynthetic precursors arteannuic acid (1), arteannuin B (2) and artemisitene (4) can be separated and identified by combined gas chromatography/mass spectrometry both as a mixture of reference standards as well as in extracts of Artemisia annua L. From

Holotransferrin enhances selective anticancer activity of artemisinin against human hepatocellular carcinoma cells.

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Deng, Xiao-rong; Liu, Zhao-xia; Liu, Feng; Pan, Lei; Yu, He-ping; Jiang, Jin-ping; Zhang, Jian-jun; Liu, Li; Yu, Jun

2013-12-01

Artemisinin, also termed qinghaosu, is extracted from the traditional Chinese medicine artemesia annua L. (the blue-green herb) in the early 1970s, which has been confirmed for effectively treating malaria. Additionally, emerging data prove that artemisinin exhibits anti-cancer effects against many types of cancers such as leukemia, melanoma, etc. Artemisinin becomes cytotoxic in the presence of ferrous iron. Since iron influx is high in cancer cells, artemisinin and its analogs selectively kill cancer cells with increased intracellular iron concentrations. This study is aimed to investigate the selective inhibitory effects of artemisinin on SMMC-7721 cells in vitro and determine the effect of holotransferrin, which increases the concentration of ferrous iron in cancer cells, combined with artemisinin on the anticancer activity. MTT assay was used for assessing the proliferation of SMMC-7721 cells treated with artemisinin. The induction of apoptosis and inhibition of colony formation in SMMC-7721 cells treated with artemisinin were determined by TdT-mediated dUTP nick end labeling (TUNEL) and colony formation assay, respectively. The results showed that artemisinin at various concentrations significantly inhibited growth, colony formation and cell viability of SMMC-7721 cells (P<0.05), likely due to induction of apoptosis of SMMC-7721 cells. Of interest, it was found that incubation of artemisinin combined with holotransferrin sensitized the growth inhibitory effect of artemisinin on SMMC-7721 cells (P<0.01). Our data suggest that treatment with artemisinin leads to inhibition of viability and proliferation, and apoptosis of SMMC-7721 cells. Furthermore, we observed that holotransferrin significantly enhanced the anti-cancer activity of artemisinin. This study may provide a potential therapeutic choice for liver cancer.

Plasmodium falciparum Resistance to Artemisinin Derivatives and Piperaquine: A Major Challenge for Malaria Elimination in Cambodia

Science.gov (United States)

Duru, Valentine; Witkowski, Benoit; Ménard, Didier

2016-01-01

Artemisinin-based combination therapies (ACTs) are the cornerstone of current strategies for fighting malaria. Over the last decade, ACTs have played a major role in decreasing malaria burden. However, this progress is being jeopardized by the emergence of artemisinin-resistant Plasmodium falciparum parasites. Artemisinin resistance was first detected in western Cambodia in 2008 and has since been observed in neighboring countries in southeast Asia. The problem of antimalarial drug resistance has recently worsened in Cambodia, with reports of parasites resistant to piperaquine, the latest generation of partner drug used in combination with dihydroartemisinin, leading to worrying rates of clinical treatment failure. The monitoring and the comprehension of both types of resistance are crucial to prevent the spread of multidrug-resistant parasites outside southeast Asia, and particularly to Africa, where the public health consequences would be catastrophic. To this end, new tools are required for studying the biological and molecular mechanisms underlying resistance to antimalarial drugs and for monitoring the geographic distribution of the resistant parasites. In this review, we detail the major advances in our understanding of resistance to artemisinin and piperaquine and define the challenges that the malaria community will have to face in the coming years. PMID:27928074

Stable Production of the Antimalarial Drug Artemisinin in the Moss Physcomitrella patens

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Nur Kusaira Binti Khairul Ikram

2017-08-01

Full Text Available Malaria is a real and constant danger to nearly half of the world’s population of 7.4 billion people. In 2015, 212 million cases were reported along with 429,000 estimated deaths. The World Health Organization recommends artemisinin-based combinatorial therapies, and the artemisinin for this purpose is mainly isolated from the plant Artemisia annua. However, the plant supply of artemisinin is irregular, leading to fluctuation in prices. Here, we report the development of a simple, sustainable, and scalable production platform of artemisinin. The five genes involved in artemisinin biosynthesis were engineered into the moss Physcomitrella patens via direct in vivo assembly of multiple DNA fragments. In vivo biosynthesis of artemisinin was obtained without further modifications. A high initial production of 0.21 mg/g dry weight artemisinin was observed after only 3 days of cultivation. Our study shows that P. patens can be a sustainable and efficient production platform of artemisinin that without further modifications allow for industrial-scale production. A stable supply of artemisinin will lower the price of artemisinin-based treatments, hence become more affordable to the lower income communities most affected by malaria; an important step toward containment of this deadly disease threatening millions every year.

The application of biotic elicitor on Artemisia annua L. to increase artemisinin content

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Darwati, I.; Manohara, D.; Rohimatun; Nurhayati, H.

2018-01-01

Artemisinin-based Combination Therapy (ACT) has been recommended by WHO as an alternative to treat malaria overcoming drug resistance. The secondary metabolic products in plants, including artemisinin, can be increased by utilizing biotic elicitor from fungi. The research was conducted in Gunung Putri Research Installation, Cipanas, West Java from 2010 to 2011. Phytophthora sp. from eggplant and Colletotrichum sp. from Artemisia annua were applied as biotic elicitor. The types of biotic elicitor applied to the plants were 1) the medium of potato dextrose broth were inoculated with fungi and harvested after 10 days (filtrate), 2) powdery mycelium of both fungi. There were 16 treatments: control negative, control positive (uninoculated medium) 1%, 2%, 3% (v/v)], Phytophthora sp. filtrate [1, 2% and 3% (v/v)], Colletotrichum sp. filtrate [1, 2% and 3% (v/v)], Phytophthora sp. mycelium [1%, 2% and 3% (w/v)], Colletotrichum sp mycelium [1%, 2% and 3% (w/v)]. The elicitor application increased plant production by 26.21% and artemisinin yield by 72% compared to control. Furthermore, the artemisinin production of the plants treated with medium inoculated with 2% filtrate of Phytophthora sp (FP2) (25.19 kg/ha) and 1% powdery mycelium of Colletotrichum sp (MC1) (26.42 kg/ha) were higher than control (K) (11.17 kg/ha).

Clinical and molecular surveillance of artemisinin resistant falciparum malaria in Myanmar (2009-2013).

Science.gov (United States)

Nyunt, Myat Htut; Soe, Myat Thu; Myint, Hla Win; Oo, Htet Wai; Aye, Moe Moe; Han, Soe Soe; Zaw, Ni Ni; Cho, Cho; Aung, Phyo Zaw; Kyaw, Khin Thiri; Aye, Thin Thin; San, Naychi Aung; Ortega, Leonard; Thimasarn, Krongthong; Bustos, Maria Dorina G; Galit, Sherwin; Hoque, Mohammad Rafiul; Ringwald, Pascal; Han, Eun-Taek; Kyaw, Myat Phone

2017-08-14

Emergence of artemisinin-resistant malaria in Southeast Asian countries threatens the global control of malaria. Although K13 kelch propeller has been assessed for artemisinin resistance molecular marker, most of the mutations need to be validated. In this study, artemisinin resistance was assessed by clinical and molecular analysis, including k13 and recently reported markers, pfarps10, pffd and pfmdr2. A prospective cohort study in 1160 uncomplicated falciparum patients was conducted after treatment with artemisinin-based combination therapy (ACT), in 6 sentinel sites in Myanmar from 2009 to 2013. Therapeutic efficacy of ACT was assessed by longitudinal follow ups. Molecular markers analysis was done on all available day 0 samples. True recrudescence treatment failures cases and day 3 parasite positivity were detected at only the southern Myanmar sites. Day 3 positive and k13 mutants with higher prevalence of underlying genetic foci predisposing to become k13 mutant were detected only in southern Myanmar since 2009 and comparatively fewer mutations of pfarps10, pffd, and pfmdr2 were observed in western Myanmar. K13 mutations, V127M of pfarps10, D193Y of pffd, and T448I of pfmdr2 were significantly associated with day 3 positivity (OR: 6.48, 3.88, 2.88, and 2.52, respectively). Apart from k13, pfarps10, pffd and pfmdr2 are also useful for molecular surveillance of artemisinin resistance especially where k13 mutation has not been reported. Appropriate action to eliminate the resistant parasites and surveillance on artemisinin resistance should be strengthened in Myanmar. Trial registration This study was registered with ClinicalTrials.gov, identifier NCT02792816.

Artemisinin resistance without pfkelch13 mutations in Plasmodium falciparum isolates from Cambodia.

Science.gov (United States)

Mukherjee, Angana; Bopp, Selina; Magistrado, Pamela; Wong, Wesley; Daniels, Rachel; Demas, Allison; Schaffner, Stephen; Amaratunga, Chanaki; Lim, Pharath; Dhorda, Mehul; Miotto, Olivo; Woodrow, Charles; Ashley, Elizabeth A; Dondorp, Arjen M; White, Nicholas J; Wirth, Dyann; Fairhurst, Rick; Volkman, Sarah K

2017-05-12

Artemisinin resistance is associated with delayed parasite clearance half-life in vivo and correlates with ring-stage survival under dihydroartemisinin in vitro. Both phenotypes are associated with mutations in the PF3D7_1343700 pfkelch13 gene. Recent spread of artemisinin resistance and emerging piperaquine resistance in Southeast Asia show that artemisinin combination therapy, such as dihydroartemisinin-piperaquine, are losing clinical effectiveness, prompting investigation of drug resistance mechanisms and development of strategies to surmount emerging anti-malarial resistance. Sixty-eight parasites isolates with in vivo clearance data were obtained from two Tracking Resistance to Artemisinin Collaboration study sites in Cambodia, culture-adapted, and genotyped for pfkelch13 and other mutations including pfmdr1 copy number; and the RSA 0-3h survival rates and response to antimalarial drugs in vitro were measured for 36 of these isolates. Among these 36 parasites one isolate demonstrated increased ring-stage survival for a PfKelch13 mutation (D584V, RSA 0-3h  = 8%), previously associated with slow clearance but not yet tested in vitro. Several parasites exhibited increased ring-stage survival, yet lack pfkelch13 mutations, and one isolate showed evidence for piperaquine resistance. This study of 68 culture-adapted Plasmodium falciparum clinical isolates from Cambodia with known clearance values, associated the D584V PfKelch13 mutation with increased ring-stage survival and identified parasites that lack pfkelch13 mutations yet exhibit increased ring-stage survival. These data suggest mutations other than those found in pfkelch13 may be involved in conferring artemisinin resistance in P. falciparum. Piperaquine resistance was also detected among the same Cambodian samples, consistent with reports of emerging piperaquine resistance in the field. These culture-adapted parasites permit further investigation of mechanisms of both artemisinin and piperaquine

Optimization of artemisinin extraction from artemisia annua l. With supercritical carbon dioxide + ethanol using response surface methodology.

Science.gov (United States)

Ciftci, Ozan Nazim; Cahyadi, Jessica; Guigard, Selma E; Saldaña, Marleny D A

2018-05-13

Malaria is a high priority life-threatening public health concern in developing countries, and therefore there is a growing interest to obtain artemisinin for the production of artemisinin-based combination therapy products. In this study, artemisinin was extracted from the Artemisia annua L. plant using supercritical carbon dioxide (SC-CO 2 ) modified with ethanol. Response surface methodology (RSM) based on central composite rotatable design (CCRD) was employed to investigate and optimize the extraction conditions of pressure (9.9-30 MPa), temperature (33-67°C), and co-solvent (ethanol, 0-12.6 wt.%). Optimum SC-CO 2 extraction conditions were found to be 30 MPa and 33°C. Under optimized conditions, the predicted artemisinin yield was 1.09% whereas the experimental value was 0.71±0.07%. Soxhlet extraction with hexane resulted in higher artemisinin yields and there was no significant difference in the purity of the extracts obtained with SC-CO 2 and Soxhlet extractions. Results indicated that SC-CO 2 and SC-CO 2 +ethanol extraction is a promising alternative for the extraction of artemisinin to eliminate the use of organic solvents, such as hexane and produce extracts that can be used for the production of antimalarial products. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

The costs of introducing artemisinin-based combination therapy: evidence from district-wide implementation in rural Tanzania.

Science.gov (United States)

Njau, Joseph D; Goodman, Catherine A; Kachur, S Patrick; Mulligan, Jo; Munkondya, John S; McHomvu, Naiman; Abdulla, Salim; Bloland, Peter; Mills, Anne

2008-01-07

The development of antimalarial drug resistance has led to increasing calls for the introduction of artemisinin-based combination therapy (ACT). However, little evidence is available on the full costs associated with changing national malaria treatment policy. This paper presents findings on the actual drug and non-drug costs associated with deploying ACT in one district in Tanzania, and uses these data to estimate the nationwide costs of implementation in a setting where identification of malaria cases is primarily dependant on clinical diagnosis. Detailed data were collected over a three year period on the financial costs of providing ACT in Rufiji District as part of a large scale effectiveness evaluation, including costs of drugs, distribution, training, treatment guidelines and other information, education and communication (IEC) materials and publicity. The district-level costs were scaled up to estimate the costs of nationwide implementation, using four scenarios to extrapolate variable costs. The total district costs of implementing ACT over the three year period were slightly over one million USD, with drug purchases accounting for 72.8% of this total. The composite (best) estimate of nationwide costs for the first three years of ACT implementation was 48.3 million USD (1.29 USD per capita), which varied between 21 and 67.1 million USD in the sensitivity analysis (2003 USD). In all estimates drug costs constituted the majority of total costs. However, non-drug costs such as IEC materials, drug distribution, communication, and health worker training were also substantial, accounting for 31.4% of overall ACT implementation costs in the best estimate scenario. Annual implementation costs are equivalent to 9.5% of Tanzania's recurrent health sector budget, and 28.7% of annual expenditure on medical supplies, implying a 6-fold increase in the national budget for malaria treatment. The costs of implementing ACT are substantial. Although drug purchases

Feasibility and acceptability of artemisinin-based combination therapy for the home management of malaria in four African sites

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Munguti Kaendi

2008-01-01

Full Text Available Abstract Background The Home Management of Malaria (HMM strategy was developed using chloroquine, a now obsolete drug, which has been replaced by artemisinin-based combination therapy (ACT in health facility settings. Incorporation of ACT in HMM would greatly expand access to effective antimalarial therapy by the populations living in underserved areas in malaria endemic countries. The feasibility and acceptability of incorporating ACT in HMM needs to be evaluated. Methods A multi-country study was performed in four district-size sites in Ghana (two sites, Nigeria and Uganda, with populations ranging between 38,000 and 60,000. Community medicine distributors (CMDs were trained in each village to dispense pre-packaged ACT to febrile children aged 6–59 months, after exclusion of danger signs. A community mobilization campaign accompanied the programme. Artesunate-amodiaquine (AA was used in Ghana and artemether-lumefantrine (AL in Nigeria and Uganda. Harmonized qualitative and quantitative data collection methods were used to evaluate CMD performance, caregiver adherence and treatment coverage of febrile children with ACTs obtained from CMDs. Results Some 20,000 fever episodes in young children were treated with ACT by CMDs across the four study sites. Cross-sectional surveys identified 2,190 children with fever in the two preceding weeks, of whom 1,289 (59% were reported to have received ACT from a CMD. Coverage varied from 52% in Nigeria to 75% in Ho District, Ghana. Coverage rates did not appear to vary greatly with the age of the child or with the educational level of the caregiver. A very high proportion of children were reported to have received the first dose on the day of onset or the next day in all four sites (range 86–97%, average 90%. The proportion of children correctly treated in terms of dose and duration was also high (range 74–97%, average 85%. Overall, the proportion of febrile children who received prompt treatment and the

Examining equity in access to long-lasting insecticide nets and artemisinin-based combination therapy in Anambra state, Nigeria

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Mbachu Chinyere O

2012-05-01

Full Text Available Abstract Background In order to achieve universal health coverage, the government of Anambra State, southeast Nigeria has distributed free Long-lasting Insecticide treated Nets (LLINs to the general population and delivered free Artemisinin-based Combination Therapy (ACT to pregnant women and children less than 5 years. However, the levels of coverage with LLINS and ACTs is not clear, especially coverage of different socio-economic status (SES population groups. This study was carried out to determine the level of coverage and access to LLINs and ACTs amongst different SES groups. Methods A questionnaire was used to collect data from randomly selected households in 19 local government areas of the State. Selected households had a pregnant woman and/or a child less than 5 years. The lot quality assurance sampling (LQAS methodology was used in sampling. The questionnaire explored the availability and utilization of LLINs and ACTs from 2394 households. An asset-based SES index was used to examine the level of access of LLINS and ACTs to different SES quintiles. Results It was found that 80.5 % of the households had an LLIN and 64.4 % of the households stated that they actually used the nets the previous night. The findings showed that 42.3 % of pregnant women who had fever within the past month received ACTs, while 37.5 % of children ≪5 years old who had malaria in the past month had received ACTs. There was equity in ownership of nets for the range 1–5 nets per household. No significant SES difference was found in use of ACTs for treatment of malaria in children under five years old and in pregnant women. Conclusions The free distribution of LLINs and ACTs increased household coverage of both malaria control interventions and bridged the equity gap in access to them among the most vulnerable groups.

Examining equity in access to long-lasting insecticide nets and artemisinin-based combination therapy in Anambra State, Nigeria.

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Mbachu, Chinyere O; Onwujekwe, Obinna E; Uzochukwu, Benjamin S C; Uchegbu, Eloka; Oranuba, Joseph; Ilika, Amobi L

2012-05-22

In order to achieve universal health coverage, the government of Anambra State, southeast Nigeria has distributed free Long-lasting Insecticide treated Nets (LLINs) to the general population and delivered free Artemisinin-based Combination Therapy (ACT) to pregnant women and children less than 5 years. However, the levels of coverage with LLINS and ACTs is not clear, especially coverage of different socio-economic status (SES) population groups. This study was carried out to determine the level of coverage and access to LLINs and ACTs amongst different SES groups. A questionnaire was used to collect data from randomly selected households in 19 local government areas of the State. Selected households had a pregnant woman and/or a child less than 5 years. The lot quality assurance sampling (LQAS) methodology was used in sampling. The questionnaire explored the availability and utilization of LLINs and ACTs from 2394 households. An asset-based SES index was used to examine the level of access of LLINS and ACTs to different SES quintiles. It was found that 80.5% of the households had an LLIN and 64.4% of the households stated that they actually used the nets the previous night. The findings showed that 42.3% of pregnant women who had fever within the past month received ACTs, while 37.5% of children<5 years old who had malaria in the past month had received ACTs. There was equity in ownership of nets for the range 1-5 nets per household. No significant SES difference was found in use of ACTs for treatment of malaria in children under five years old and in pregnant women. The free distribution of LLINs and ACTs increased household coverage of both malaria control interventions and bridged the equity gap in access to them among the most vulnerable groups.

PENGOBATAN MALARIA DENGAN KOMBINASI ARTEMISININ

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Emilianan Tjitra

2012-09-01

Full Text Available Previous approaches in malaria treatment fail to reduce the morbidity and mortality of malaria. Widespread overuse of antimalarial treatment of clinical malaria may have contributed to increase drug resistance. Moreover, poor compliance or inadequate dosage also selects for parasite resistance. The paradigm of radical treatment using drug combinations may improve the cure rate and compliance, thereby preventing or delaying the emergence of parasites resistant to antimalarial drugs. The ideal combined antimalarial regimen in Indonesia should be safe and tolerated by all age groups, effective and rapidly acting for both P.falciparum and P.vivax malaria, short course, good compliance and acceptable, without resistance and/or cross-resistance or , not widely spread use, cost-effective and affordable. Artemisinin derivatives are the best partner drug for combination, with advantages that include: well absorbed, safe and well tolerated, rapidly converted to active metabolite, having very short half-life, broad specificity of action, and extremely potent. Current artemisinin-based combinations which are suitable for Indonesia include: amodiaquine plus artesunate given as single daily dose for 3 days (AQ3+ATS3, mefloquine plus artesunate given as single daily dose for 3 days (MQ3+ATS3, lumefantrine/benflumetol plus artemether given as twice daily dose for 3 days (COARTEMETHER, piperaquine plus dihydroartemisinin given as single daily dose for 2-3 days (PPQ2-3+DHA2-3, and piperaquine plus artemisinin given as single daily dose for 2 days (PPQ2+ATM2. Given the imbalance between rapid development of parasite resistance and slow availability of new effective antimalarial drugs, research and development of antimalarial drugs must be encouraged.

Access to artemisinin-combination therapy (ACT) and other anti-malarials: national policy and markets in Sierra Leone.

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Amuasi, John H; Diap, Graciela; Nguah, Samuel Blay; Karikari, Patrick; Boakye, Isaac; Jambai, Amara; Lahai, Wani Kumba; Louie, Karly S; Kiechel, Jean-Rene

2012-01-01

Malaria remains the leading burden of disease in post-conflict Sierra Leone. To overcome the challenge of anti-malarial drug resistance and improve effective treatment, Sierra Leone adopted artemisinin-combination therapy artesunate-amodiaquine (AS+AQ) as first-line treatment for uncomplicated P. falciparum malaria. Other national policy anti-malarials include artemether-lumefantrine (AL) as an alternative to AS+AQ, quinine and artemether for treatment of complicated malaria; and sulphadoxine-pyrimethamine (SP) for intermittent preventive treatment (IPTp). This study was conducted to evaluate access to national policy recommended anti-malarials. A cross-sectional survey of 127 medicine outlets (public, private and NGO) was conducted in urban and rural areas. The availability on the day of the survey, median prices, and affordability policy and available non-policy anti-malarials were calculated. Anti-malarials were stocked in 79% of all outlets surveyed. AS+AQ was widely available in public medicine outlets; AL was only available in the private and NGO sectors. Quinine was available in nearly two-thirds of public and NGO outlets and over one-third of private outlets. SP was widely available in all outlets. Non-policy anti-malarials were predominantly available in the private outlets. AS+AQ in the public sector was widely offered for free. Among the anti-malarials sold at a cost, the same median price of a course of AS+AQ (US$1.56), quinine tablets (US$0.63), were found in both the public and private sectors. Quinine injection had a median cost of US$0.31 in the public sector and US$0.47 in the private sector, while SP had a median cost of US$0.31 in the public sector compared to US$ 0.63 in the private sector. Non-policy anti-malarials were more affordable than first-line AS+AQ in all sectors. A course of AS+AQ was affordable at nearly two days' worth of wages in both the public and private sectors.

Pitfalls in new artemisinin-containing antimalarial drug development.

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Jambou, Ronan; Le Bras, Jacques; Randrianarivelojosia, Milijaona

2011-02-01

Artemisinin combination therapy (ACT) paves the way for new opportunities to eliminate malaria in the tropics. However, the huge increase of ACT consumption raises major concerns about their availability over the next few years. At the same time a decrease in their efficacy has already been reported. Alongside the deployment of multifocal control programs, the process ranging from artemisia crop production to accreditation of new ACT combinations urgently needs to be strengthened to supply sufficient quantities of high-quality drugs. New suppliers will have the opportunity to enter this market to develop new formulations, and bioequivalence studies are required to validate these new formulations. It is thus crucial for national malaria control teams to be able to better scrutinize the dossier of these new formulations. Copyright © 2010 Elsevier Ltd. All rights reserved.

Competing intermolecular interactions of artemisinin-type agents and aspirin with membrane phospholipids: Combined model mass spectrometry and quantum-chemical study

International Nuclear Information System (INIS)

Pashynska, Vlada; Stepanian, Stepan; Gömöry, Agnes; Vekey, Karoly; Adamowicz, Ludwik

2015-01-01

Highlights: • Competitive binding of artemisinin agents and aspirin with phospholipids is shown. • Complexation between the antimalarial drugs and aspirin molecules is also found. • Energetically favorable structures of the model complexes are identified by DFT. • Membranotropic activity of the studied drugs can be modified under joint usage. - Abstract: Study of intermolecular interactions of antimalarial artemisinin-type drugs and aspirin with membrane phospholipids is important in term of elucidation of the drugs activity modification under their joint usage. Combined experimental and computational study of the interaction of dihydroartemisinin, α-artemether, and artesunate with aspirin (ASP) and dipalmitoylphosphatidylcholine (DPPC) is performed by electrospray ionization (ESI) mass spectrometry and by DFT B3LYP/aug-cc-pVDZ methods. The results of the ESI investigation of systems containing artemisinin-type agent, ASP and DPPC, reveal a competition between the antimalarial agents and ASP for binding with DPPC molecules. The complexation between the antimalarial drugs and ASP is also found. Observed phenomena suggest that membranotropic activity of artemisin-type agents and aspirin is modified under their combined usage. To elucidate structure-energy characteristics of the non-covalent complexes studied the model DFT calculations are performed for dihydroartemisinin · ASP complex and complexes of the each drug with phosphatidylcholine head of DPPC in neutral and cationized forms

Competing intermolecular interactions of artemisinin-type agents and aspirin with membrane phospholipids: Combined model mass spectrometry and quantum-chemical study

Energy Technology Data Exchange (ETDEWEB)

Pashynska, Vlada, E-mail: vlada@vl.kharkov.ua [B.Verkin Institute for Low Temperature Physics and Engineering of the National Academy of Sciences of Ukraine, Lenin Ave., 47, 61103 Kharkov (Ukraine); Stepanian, Stepan [B.Verkin Institute for Low Temperature Physics and Engineering of the National Academy of Sciences of Ukraine, Lenin Ave., 47, 61103 Kharkov (Ukraine); Gömöry, Agnes; Vekey, Karoly [Institute of Organic Chemistry of Research Centre for Natural Sciences of the Hungarian Academy of Sciences, Magyar tudosok korutja, 2, Budapest H-1117 (Hungary); Adamowicz, Ludwik [University of Arizona, Department of Chemistry and Biochemistry, Tucson, AZ 85721 (United States)

2015-07-09

Highlights: • Competitive binding of artemisinin agents and aspirin with phospholipids is shown. • Complexation between the antimalarial drugs and aspirin molecules is also found. • Energetically favorable structures of the model complexes are identified by DFT. • Membranotropic activity of the studied drugs can be modified under joint usage. - Abstract: Study of intermolecular interactions of antimalarial artemisinin-type drugs and aspirin with membrane phospholipids is important in term of elucidation of the drugs activity modification under their joint usage. Combined experimental and computational study of the interaction of dihydroartemisinin, α-artemether, and artesunate with aspirin (ASP) and dipalmitoylphosphatidylcholine (DPPC) is performed by electrospray ionization (ESI) mass spectrometry and by DFT B3LYP/aug-cc-pVDZ methods. The results of the ESI investigation of systems containing artemisinin-type agent, ASP and DPPC, reveal a competition between the antimalarial agents and ASP for binding with DPPC molecules. The complexation between the antimalarial drugs and ASP is also found. Observed phenomena suggest that membranotropic activity of artemisin-type agents and aspirin is modified under their combined usage. To elucidate structure-energy characteristics of the non-covalent complexes studied the model DFT calculations are performed for dihydroartemisinin · ASP complex and complexes of the each drug with phosphatidylcholine head of DPPC in neutral and cationized forms.

Status of potential PfATP6 molecular markers for artemisinin resistance in Suriname

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Adhin Malti R

2012-09-01

Full Text Available Abstract Background Polymorphisms within the PfATP6 gene have been indicated as potential molecular markers for artemisinin efficacy. Since 2004, the use of artemisinin combination therapy (ACT was introduced as first-line treatment of the uncomplicated malaria cases in Suriname. The aim of this research was to determine changes in Suriname in the status of the polymorphic markers in the PfATP6 gene before and after the adoption of the ACT-regimen, particularly of the S769N mutation, which was reported to be associated with in vitro Artemether resistance in the neighboring country French Guiana. Methods The PfATP6 gene from Plasmodium falciparum parasites in Suriname was investigated in 28 samples using PCR amplification and restriction enzyme analysis, to assess and determine the prevalence of potentially interesting single nucleotide polymorphisms. The polymorphisms [L263E; A623E; S769N], which may be associated with the artemisinin resistant phenotype were characterized in parasites from three endemic regions before and after the adoption of the ACT-regimen. In addition, the status of these molecular markers was compared in paired P. falciparum isolates from patients with recurring malaria after controlled ACT. Results All the investigated samples exhibit the wild-type genotype at all three positions; L263, A623, S769. Conclusion All investigated isolates before and after the adoption of the ACT-regimen and independent of endemic region harbored the wild-type genotype for the three investigated polymorphisms. The study revealed that decreased artemisinin susceptibility could occur independent from PfATP6 mutations, challenging the assumption that artemisinin resistance is associated with these mutations in the PfATP6 gene.

Subsidising artemisinin-based combination therapy in the private retail sector.

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Opiyo, Newton; Yamey, Gavin; Garner, Paul

2016-03-09

Malaria causes ill health and death in Africa. Treating illness promptly with artemisinin-based combination therapy (ACT) is likely to cure people and avoid the disease progressing to more severe forms and death. In many countries, ACT use remains low. Part of the problem is that most people seek treatment from the retail sector where ACTs are expensive; this expense is a barrier to their use.The Global Fund and other international organisations are subsidising the cost of ACTs for private retail providers to improve access to ACTs. The subsidy was initially organised through a stand-alone initiative, called the Affordable Medicines Facility-malaria (AMFm), but has since been integrated into the Global Fund core grant management and financial processes. To assess the effect of programmes that include ACT price subsidies for private retailers on ACT use, availability, price and market share. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 1, The Cochrane Library, including the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register); MEDLINE (OvidSP), EMBASE (OvidSP), CINAHL (EbscoHost), EconLit (ProQuest), Global Health (OvidSP), Regional Indexes (Global Health Library, WHO), LILACS (Global Health Library, WHO), Science Citation Index and Social Sciences Citation Index (ISI Web of Science) and Health Management (ProQuest). All databases were searched February 2015, except for Health Management which was searched November 2013, without any date, language or publication status restrictions. We also searched the International Clinical Trials Registry Platform (ICTRP; WHO), ClinicalTrials.gov (NIH) and various grey literature sources. We also conducted a cited reference search for all included studies in ISI Web of Knowledge, checked references of identified articles and contacted authors to identify additional studies. Randomised trials, non-randomised trials, controlled before-after studies and

The costs of introducing artemisinin-based combination therapy: evidence from district-wide implementation in rural Tanzania

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Abdulla Salim

2008-01-01

Full Text Available Abstract Background The development of antimalarial drug resistance has led to increasing calls for the introduction of artemisinin-based combination therapy (ACT. However, little evidence is available on the full costs associated with changing national malaria treatment policy. This paper presents findings on the actual drug and non-drug costs associated with deploying ACT in one district in Tanzania, and uses these data to estimate the nationwide costs of implementation in a setting where identification of malaria cases is primarily dependant on clinical diagnosis. Methods Detailed data were collected over a three year period on the financial costs of providing ACT in Rufiji District as part of a large scale effectiveness evaluation, including costs of drugs, distribution, training, treatment guidelines and other information, education and communication (IEC materials and publicity. The district-level costs were scaled up to estimate the costs of nationwide implementation, using four scenarios to extrapolate variable costs. Results The total district costs of implementing ACT over the three year period were slightly over one million USD, with drug purchases accounting for 72.8% of this total. The composite (best estimate of nationwide costs for the first three years of ACT implementation was 48.3 million USD (1.29 USD per capita, which varied between 21 and 67.1 million USD in the sensitivity analysis (2003 USD. In all estimates drug costs constituted the majority of total costs. However, non-drug costs such as IEC materials, drug distribution, communication, and health worker training were also substantial, accounting for 31.4% of overall ACT implementation costs in the best estimate scenario. Annual implementation costs are equivalent to 9.5% of Tanzania's recurrent health sector budget, and 28.7% of annual expenditure on medical supplies, implying a 6-fold increase in the national budget for malaria treatment. Conclusion The costs of

Probabilistic record linkage for monitoring the safety of artemisinin-based combination therapy in the first trimester of pregnancy in Senegal

NARCIS (Netherlands)

Dellicour, Stephanie; Brasseur, Philippe; Thorn, Per; Gaye, Oumar; Olliaro, Piero; Badiane, Malik; Stergachis, Andy; ter Kuile, Feiko O.

2013-01-01

There are insufficient data on the safety in early pregnancy of the artemisinins, a new class of antimalarials. Assessment of drug teratogenicity requires large sample sizes for an adequate risk-benefit assessment. There is currently limited pharmacovigilance infrastructure in malaria-endemic

Phenotypic and genotypic characterization of Thai isolates of Plasmodium falciparum after an artemisinin resistance containment project.

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Thita, Thunyapit; Jadsri, Pimrat; Thamkhantho, Jarupatr; Ruang-Areerate, Toon; Suwandittakul, Nantana; Sitthichot, Naruemon; Mahotorn, Kittiya; Tan-Ariya, Peerapan; Mungthin, Mathirut

2018-05-15

In Thailand, artemisinin-based combination therapy (ACT) has been used to treat uncomplicated falciparum malaria since 1995. Unfortunately, artemisinin resistance has been reported from Thailand and other Southeast Asian countries since 2003. Malarone ® , a combination of atovaquone-proguanil (ATQ-PG), has been used to cease artemisinin pressure in some areas along Thai-Cambodia border, as part of an artemisinin resistance containment project since 2009. This study aimed to determine genotypes and phenotypes of Plasmodium falciparum isolates collected from the Thai-Cambodia border after the artemisinin resistance containment project compared with those collected before. One hundred and nine of P. falciparum isolates collected from Thai-Cambodia border from Chanthaburi and Trat provinces during 1988-2016 were used in this study. Of these, 58 isolates were collected after the containment. These parasite isolates were characterized for in vitro antimalarial sensitivities including chloroquine (CQ), quinine (QN), mefloquine (MQ), piperaquine (PPQ), artesunate (AS), dihydroartemisinin (DHA), ATQ and PG and genetic markers for drug resistance including the Kelch13 (k13), Plasmodium falciparum chloroquine resistance transporter (pfcrt), P. falciparum multidrug resistance 1 (pfmdr1) and cytochrome b (cytb) genes. Mean CQ, QN, MQ, PPQ and AS IC 50 s of the parasite isolates collected from 2009 to 2016 exhibited significantly higher than those of parasites collected before 2009. Approximately 57% exhibited in vitro MQ resistance. Approximately 94% of the isolates collected from 2009 to 2016 contained the pfmdr1 184F allele. Mutations of the k13 gene were detected in approximately 90% of the parasites collected from 2009 to 2016 which were significantly higher than the parasite isolates collected before. No ATQ-resistant genotype and phenotype of P. falciparum were found among the isolates collected after the containment project. Although the containment project had been

Quality of Artemisinin-Containing Antimalarials in Tanzania's Private Sector--Results from a Nationally Representative Outlet Survey.

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Act Consortium Drug Quality Project Team And The Impact Study Team

2015-06-01

Ensuring that artemisinin-containing antimalarials (ACAs) are of good quality is a key component of effective malaria treatment. There are concerns that a high proportion of ACAs are falsified or substandard, though estimates are rarely based on representative data. During a nationally representative survey in Tanzania, ACAs were purchased from private retail drug outlets, and the active pharmaceutical ingredient (API) was measured. All 1,737 ACAs contained the labeled artemisinin derivative, with 4.1% being outside the 85-115% artemisinin API range defined as acceptable quality. World Health Organization (WHO) prequalified drugs had 0.1 times the odds of being poor quality compared with non-prequalified ACAs for the artemisinin component. When partner components of combination therapies were also considered, 12.1% were outside the acceptable API range, and WHO prequalified ACAs had 0.04 times the odds of being poor quality. Although the prevalence of poor quality ACAs was lower than reported elsewhere, the minority of samples found to be substandard is a cause for concern. Improvements in quality could be achieved by increasing the predominance of WHO prequalified products in the market. Continued monitoring of quality standards is essential. © The American Society of Tropical Medicine and Hygiene.

Effect of the Affordable Medicines Facility--malaria (AMFm) on the availability, price, and market share of quality-assured artemisinin-based combination therapies in seven countries: a before-and-after analysis of outlet survey data.

Science.gov (United States)

Tougher, Sarah; Ye, Yazoume; Amuasi, John H; Kourgueni, Idrissa A; Thomson, Rebecca; Goodman, Catherine; Mann, Andrea G; Ren, Ruilin; Willey, Barbara A; Adegoke, Catherine A; Amin, Abdinasir; Ansong, Daniel; Bruxvoort, Katia; Diallo, Diadier A; Diap, Graciela; Festo, Charles; Johanes, Boniface; Juma, Elizabeth; Kalolella, Admirabilis; Malam, Oumarou; Mberu, Blessing; Ndiaye, Salif; Nguah, Samuel B; Seydou, Moctar; Taylor, Mark; Rueda, Sergio Torres; Wamukoya, Marilyn; Arnold, Fred; Hanson, Kara

2012-12-01

Malaria is one of the greatest causes of mortality worldwide. Use of the most effective treatments for malaria remains inadequate for those in need, and there is concern over the emergence of resistance to these treatments. In 2010, the Global Fund launched the Affordable Medicines Facility--malaria (AMFm), a series of national-scale pilot programmes designed to increase the access and use of quality-assured artemisinin based combination therapies (QAACTs) and reduce that of artemisinin monotherapies for treatment of malaria. AMFm involves manufacturer price negotiations, subsidies on the manufacturer price of each treatment purchased, and supporting interventions such as communications campaigns. We present findings on the effect of AMFm on QAACT price, availability, and market share, 6-15 months after the delivery of subsidised ACTs in Ghana, Kenya, Madagascar, Niger, Nigeria, Uganda, and Tanzania (including Zanzibar). We did nationally representative baseline and endpoint surveys of public and private sector outlets that stock antimalarial treatments. QAACTs were identified on the basis of the Global Fund's quality assurance policy. Changes in availability, price, and market share were assessed against specified success benchmarks for 1 year of AMFm implementation. Key informant interviews and document reviews recorded contextual factors and the implementation process. In all pilots except Niger and Madagascar, there were large increases in QAACT availability (25·8-51·9 percentage points), and market share (15·9-40·3 percentage points), driven mainly by changes in the private for-profit sector. Large falls in median price for QAACTs per adult equivalent dose were seen in the private for-profit sector in six pilots, ranging from US$1·28 to $4·82. The market share of oral artemisinin monotherapies decreased in Nigeria and Zanzibar, the two pilots where it was more than 5% at baseline. Subsidies combined with supporting interventions can be effective in

Measuring the association between artemisinin-based case management and malaria incidence in southern Vietnam, 1991-2010.

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Peak, Corey M; Thuan, Phung Duc; Britton, Amadea; Nguyen, Tran Dang; Wolbers, Marcel; Thanh, Ngo Viet; Buckee, Caroline O; Boni, Maciej F

2015-04-01

In addition to being effective, fast-acting, and well tolerated, artemisinin-based combination therapies (ACTs) are able to kill certain transmission stages of the malaria parasite. However, the population-level impacts of ACTs on reducing malaria transmission have been difficult to assess. In this study on the history of malaria control in Vietnam, we assemble annual reporting on malaria case counts, coverage with insecticide-treated nets (ITN) and indoor residual spraying (IRS), and drug purchases by provincial malaria control programs from 1991 to 2010 in Vietnam's 20 southern provinces. We observe a significant negative association between artemisinin use and malaria incidence, with a 10% absolute increase in the purchase proportion of artemisinin-containing regimens being associated with a 29.1% (95% confidence interval: 14.8-41.0%) reduction in slide-confirmed malaria incidence, after accounting for changes in urbanization, ITN/IRS coverage, and two indicators of health system capacity. One budget-related indicator of health system capacity was found to have a smaller association with malaria incidence, and no other significant factors were found. Our findings suggest that including an artemisinin component in malaria drug regimens was strongly associated with reduced malaria incidence in southern Vietnam, whereas changes in urbanization and coverage with ITN or IRS were not. © The American Society of Tropical Medicine and Hygiene.

Increasing Access to Subsidized Artemisinin-based Combination Therapy through Accredited Drug Dispensing Outlets in Tanzania

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Gabra Michael

2011-06-01

Full Text Available Abstract Background In Tanzania, many people seek malaria treatment from retail drug sellers. The National Malaria Control Program identified the accredited drug dispensing outlet (ADDO program as a private sector mechanism to supplement the distribution of subsidized artemisinin-based combination therapies (ACTs from public facilities and increase access to the first-line antimalarial in rural and underserved areas. The ADDO program strengthens private sector pharmaceutical services by improving regulatory and supervisory support, dispenser training, and record keeping practices. Methods The government's pilot program made subsidized ACTs available through ADDOs in 10 districts in the Morogoro and Ruvuma regions, covering about 2.9 million people. The program established a supply of subsidized ACTs, created a price system with a cost recovery plan, developed a plan to distribute the subsidized products to the ADDOs, trained dispensers, and strengthened the adverse drug reactions reporting system. As part of the evaluation, 448 ADDO dispensers brought their records to central locations for analysis, representing nearly 70% of ADDOs operating in the two regions. ADDO drug register data were available from July 2007-June 2008 for Morogoro and from July 2007-September 2008 for Ruvuma. This intervention was implemented from 2007-2008. Results During the pilot, over 300,000 people received treatment for malaria at the 448 ADDOs. The percentage of ADDOs that dispensed at least one course of ACT rose from 26.2% during July-September 2007 to 72.6% during April-June 2008. The number of malaria patients treated with ACTs gradually increased after the start of the pilot, while the use of non-ACT antimalarials declined; ACTs went from 3% of all antimalarials sold in July 2007 to 26% in June 2008. District-specific data showed substantial variation among the districts in ACT uptake through ADDOs, ranging from ACTs representing 10% of all antimalarial sales

Induction of high tolerance to artemisinin by sub-lethal administration: A new in vitro model of P. falciparum.

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Serena De Lucia

Full Text Available Artemisinin resistance is a major threat to malaria control efforts. Resistance is characterized by an increase in the Plasmodium falciparum parasite clearance half-life following treatment with artemisinin-based combination therapies (ACTs and an increase in the percentage of surviving parasites. The remarkably short blood half-life of artemisinin derivatives may contribute to drug-resistance, possibly through factors including sub-lethal plasma concentrations and inadequate exposure. Here we selected for a new strain of artemisinin resistant parasites, termed the artemisinin resistant strain 1 (ARS1, by treating P. falciparum Palo Alto (PA cultures with sub-lethal concentrations of dihydroartemisinin (DHA. The resistance phenotype was maintained for over 1 year through monthly maintenance treatments with low doses of 2.5 nM DHA. There was a moderate increase in the DHA IC50 in ARS1 when compared with parental strain PA after 72 h of drug exposure (from 0.68 nM to 2 nM DHA. In addition, ARS1 survived treatment physiologically relevant DHA concentrations (700 nM observed in patients. Furthermore, we confirmed a lack of cross-resistance against a panel of antimalarials commonly used as partner drugs in ACTs. Finally, ARS1 did not contain Pfk13 propeller domain mutations associated with ART resistance in the Greater Mekong Region. With a stable growth rate, ARS1 represents a valuable tool for the development of new antimalarial compounds and studies to further elucidate the mechanisms of ART resistance.

Efficacy of monotherapies and artesunate-based combination therapies in children with uncomplicated malaria in Somalia.

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Warsame, Marian; Atta, Hoda; Klena, John D; Waqar, Butt Ahmed; Elmi, Hussein Haji; Jibril, Ali Mohamed; Hassan, Hassan Mohamed; Hassan, Abdullahi Mohamed

2009-02-01

In order to guide the antimalarial treatment policy of Somalia, we conducted therapeutic efficacy studies of routinely used antimalarial monotherapies as well as artemisinin-based combination therapies (ACTs) for uncomplicated malaria in three sentinel sites during 2003-2006. Therapeutic efficacy of chloroquine (CQ), amodiaquine (AQ) and sulfadoxine/pyrimetahmine (SP) monotherapies, and artesunate plus SP (AS+SP) or AQ (AS+AQ) were evaluated in children 6 months to 10 years old with uncomplicated malaria. For the assessment of the monotherapies, 2003 WHO protocol with 14-day follow-up was used while the 2005 WHO protocol with 28-day follow-up was used for testing the ACTs. Of the monotherapies, CQ performed very poorly with treatment failures varying from 76.5% to 88% between the sites. AQ treatment failure was low except for Janale site with treatment failure of 23.4% compared to 2.8% and 8% in Jamame and Jowhar, respectively. For SP, treatment failures from 7.8% to 12.2% were observed. A 28-day test of artemisinin-based combinations, AS+SP and AS+AQ, proved to be highly efficacious with cure rates of 98-100% supporting the choice of AS+SP combination as first line treatment for uncomplicated malaria for Somalia.

Anticancer Effect of AntiMalarial Artemisinin Compounds

African Journals Online (AJOL)

Artemisinin is a naturally occurring antimalarial showing anticancer properties. ..... Artemisinins usually promote apoptosis rather than necrosis in most cases ... artemisinin-mediated inhibition of vascular endothelial growth factor C (VEGF-C).

Cytotoxic effect and radiation enhancement of artemisinin in uterine cervical carcinoma cell line HeLa

International Nuclear Information System (INIS)

Gong Xiaomei; Zhou Daoan; Cao Jianping; Fan Saijun; Zhu Wei

2010-01-01

Objective: To investigate cytotoxic and radiosensitizing effect of Artemisinin on cervical carcinoma cell line HeLa. Methods: In order to measure the optimized effective time, cytotoxic effect of Artemisinin on HeLa cell line was investigated with MTT assay. The radiosensitization effect of different doses and different treatment duration of Artemisinin on HeLa cell line were evaluated by MTT test, the SER is 1.17 and radiosensitizing effect was measured with multi-target single hit model through SER of HeLa cell. Cell cycles in different groups were calculated by flow cytometry. Results: The 50% inhibition concentration of Artemisinin interacted with HeLa cells for 24 h is 600.19 nmol/ml, and for 48 h is 160.71 nmol/ml. The HeLa cells'surival ratio is 93.51%, 91.87%, and 87.28% after adding Atemisinin of 110.69 nmol/ml and 1 Gy radiation exposure. There are three groups: the chemotherapy only group, the radiotherapy only group and the combination group. The result of the cell cycles showed that cells in G 2 /M period decreased in the combination group. Conclusion: Artemisinin has radiosensitization effect on cervical carcinoma HeLa cells, whichshows dose and time dependent. Artemisinin can inhibit the G 2 /M block by ionizing radiation. (authors)

Artemisinin derivatives for treating severe malaria.

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McIntosh, H M; Olliaro, P

2000-01-01

Artemisinin derivatives may have advantages over quinoline drugs for treating severe malaria since they are fast acting and effective against quinine resistant malaria parasites. The objective of this review was to assess the effects of artemisinin drugs for severe and complicated falciparum malaria in adults and children. We searched the Cochrane Infectious Diseases Group trials register, Cochrane Controlled Trials Register, Medline, Embase, Science Citation Index, Lilacs, African Index Medicus, conference abstracts and reference lists of articles. We contacted organisations, researchers in the field and drug companies. Randomised and pseudo-randomised trials comparing artemisinin drugs (rectal, intramuscular or intravenous) with standard treatment, or comparisons between artemisinin derivatives in adults or children with severe or complicated falciparum malaria. Eligibility, trial quality assessment and data extraction were done independently by two reviewers. Study authors were contacted for additional information. Twenty three trials are included, allocation concealment was adequate in nine. Sixteen trials compared artemisinin drugs with quinine in 2653 patients. Artemisinin drugs were associated with better survival (mortality odds ratio 0.61, 95% confidence interval 0.46 to 0.82, random effects model). In trials where concealment of allocation was adequate (2261 patients), this was barely statistically significant (odds ratio 0.72, 95% CI 0.54 to 0.96, random effects model). In 1939 patients with cerebral malaria, mortality was also lower with artemisinin drugs overall (odds ratio 0.63, 95% CI 0.44 to 0.88, random effects model). The difference was not significant however when only trials reporting adequate concealment of allocation were analysed (odds ratio 0.78, 95% CI 0.55 to 1.10, random effects model) based on 1607 patients. No difference in neurological sequelae was shown. Compared with quinine, artemisinin drugs showed faster parasite clearance from

Understanding the impact of subsidizing artemisinin-based combination therapies (ACTs in the retail sector--results from focus group discussions in rural Kenya.

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Sarah V Kedenge

Full Text Available There is considerable interest in the potential of private sector subsidies to increase availability and affordability of artemisinin-based combination therapies (ACTs for malaria treatment. A cluster randomized trial of such subsidies was conducted in 3 districts in Kenya, comprising provision of subsidized packs of paediatric ACT to retail outlets, training of retail staff, and community awareness activities. The results demonstrated a substantial increase in ACT availability and coverage, though patient counselling and adherence were suboptimal. We conducted a qualitative study in order to understand why these successes and limitations occurred.Eighteen focus group discussions were conducted, 9 with retailers and 9 with caregivers, to document experiences with the intervention. Respondents were positive about intervention components, praising the focused retailer training, affordable pricing, strong promotional activities, dispensing job aids, and consumer friendly packaging, which are likely to have contributed to the positive access and coverage outcomes observed. However, many retailers still did not stock ACT, due to insufficient supplies, lack of capital and staff turnover. Advice to caregivers was poor due to insufficient time, and poor recall of instructions. Adherence by caregivers to dosing guidelines was sub-optimal, because of a wish to save tablets for other episodes, doses being required at night, stopping treatment when the child felt better, and the number and bitter taste of the tablets. Caregivers used a number of strategies to obtain paediatric ACT for older age groups.This study has highlighted that important components of a successful ACT subsidy intervention are regular retailer training, affordable pricing, a reliable supply chain and community mobilization emphasizing patient adherence and when to seek further care.

Understanding the impact of subsidizing artemisinin-based combination therapies (ACTs) in the retail sector--results from focus group discussions in rural Kenya.

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Kedenge, Sarah V; Kangwana, Beth P; Waweru, Evelyn W; Nyandigisi, Andrew J; Pandit, Jayesh; Brooker, Simon J; Snow, Robert W; Goodman, Catherine A

2013-01-01

There is considerable interest in the potential of private sector subsidies to increase availability and affordability of artemisinin-based combination therapies (ACTs) for malaria treatment. A cluster randomized trial of such subsidies was conducted in 3 districts in Kenya, comprising provision of subsidized packs of paediatric ACT to retail outlets, training of retail staff, and community awareness activities. The results demonstrated a substantial increase in ACT availability and coverage, though patient counselling and adherence were suboptimal. We conducted a qualitative study in order to understand why these successes and limitations occurred. Eighteen focus group discussions were conducted, 9 with retailers and 9 with caregivers, to document experiences with the intervention. Respondents were positive about intervention components, praising the focused retailer training, affordable pricing, strong promotional activities, dispensing job aids, and consumer friendly packaging, which are likely to have contributed to the positive access and coverage outcomes observed. However, many retailers still did not stock ACT, due to insufficient supplies, lack of capital and staff turnover. Advice to caregivers was poor due to insufficient time, and poor recall of instructions. Adherence by caregivers to dosing guidelines was sub-optimal, because of a wish to save tablets for other episodes, doses being required at night, stopping treatment when the child felt better, and the number and bitter taste of the tablets. Caregivers used a number of strategies to obtain paediatric ACT for older age groups. This study has highlighted that important components of a successful ACT subsidy intervention are regular retailer training, affordable pricing, a reliable supply chain and community mobilization emphasizing patient adherence and when to seek further care.

Artemisinin: The journey from natural product to Nobel Prize ...

African Journals Online (AJOL)

The 2014 Nobel Prize for Physiology and Medicine was announced on 5th October. One-half ... The novel therapy that was given this huge recognition was artemisinin, a drug (isolated from the plant Artemisia annua) that has saved millions of lives and rekindled the dream of a world where malaria has been eradicated.

Isolation of dihydroatemisinic acid from the artemisia annua l. by-product by combining Ultrasound-assisted extraction with response surface methodology

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Malaria is one of the world’s most important parasitic diseases, affecting 300-500 million people worldwide and killing more than one million per year. Artemisinin is currently the only raw material for the production of artemisinin combination therapies (ACT), the only medicine that cures drug-resi...

Antimalarial Activity of C-10 Substituted Triazolyl Artemisinin.

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Park, Gab-Man; Park, Hyun; Oh, Sangtae; Lee, Seokjoon

2017-12-01

We synthesized C-10 substituted triazolyl artemisinins by the Huisgen cycloaddition reaction between dihydroartemisinins (2) and variously substituted 1, 2, 3-triazoles (8a-8h). The antimalarial activities of 32 novel artemisinin derivatives were screened against a chloroquine-resistant parasite. Among them, triazolyl artemisinins with electron-withdrawing groups showed stronger antimalarial activities than those shown by the derivatives having electron-donating groups. In particularly, m-chlorotriazolyl artemisinin (9d-12d) showed antimalarial activity equivalent to that of artemisinin and could be a strong drug candidate.

Severe malaria not responsive to artemisinin derivatives in man returning from Angola to Vietnam.

Science.gov (United States)

Van Hong, Nguyen; Amambua-Ngwa, Alfred; Tuan, Nguyen Quang; Cuong, Do Duy; Giang, Nguyen Thi Huong; Van Dung, Nguyen; Tinh, Ta Thi; Van Tien, Nguyen; Phuc, Bui Quang; Duong, Tran Thanh; Rosanas-Urgell, Anna; D'Alessandro, Umberto; Van Geertruyden, Jean-Pierre; Erhart, Annette

2014-07-01

Resistance to artemisinin derivatives, the most potent antimalarial drugs currently used, has emerged in Southeast Asia and threatens to spread to Africa. We report a case of malaria in a man who returned to Vietnam after 3 years in Angola that did not respond to intravenous artesunate and clindamycin or an oral artemisinin-based combination.

From bark to weed: The history of artemisinin

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Faurant C.

2011-08-01

Full Text Available In the 1970’s, in China, some brilliant and courageous scientists carried out a research programme, which lead to the discovery of artemisinin derivatives and new quinoleines that are used today, in combination, as first line treatment of malaria.

Expanding the Therapeutic Spectrum of Artemisinin: Activity Against Infectious Diseases Beyond Malaria and Novel Pharmaceutical Developments

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Thomas Efferth

2016-08-01

Full Text Available The interest of Western medicine in Traditional Chinese Medicine (TCM as a source of drug leads/new drugs to treat diseases without available efficient therapies has been dramatically augmented in the last decades by the extensive work and the outstanding findings achieved within this kind of medicine. The practice of TCM over thousands of years has equipped scientists with substantial experience with hundreds of plants that led to the discovery of artemisinin (qinghaosu, which is extracted from the medicinal plant Artemisia annua L. (qinghao. The unexpected success of artemisinin in combating malaria has drawn strong attention from the scientific community towards TCM. Artemisinin was discovered by Youyou Tu in 1972. Since then, several novel pharmacological activities based on the well-known properties of the sesquiterpene lactone structure with the oxepane ring and an endoperoxide bridge have been unravelled. Beyond malaria, artemisinin and its derivatives (artemisinins exert profound activities towards other protozoans (Leishmania, Trypanosoma, amoebas, Neospora caninum, and Eimeria tenella, trematodes (Schistosoma, liver flukes, and viruses (human cytomegalovirus, hepatitis B and C viruses. Less clear is the effect against bacteria and fungi. Based on the promising results of artemisinin and the first generation derivatives (artesunate, artemether, arteether, novel drug development strategies have been pursued. These included the synthesis of acetal- and non-acetal-type artemisinin dimeric molecules as well as developing nanotechnological approaches, e.g. artemisinin-based liposomes, niosomes, micelles, solid lipid nanocarriers, nanostructured lipid carriers, nanoparticles, fullerenes and nanotubes. The current review presents an overview on different aspects of artemisinins, including sources, chemistry, biological/pharmacological properties, types of infectious pathogens that are susceptible to artemisinins in vitro and in vivo, in

Artemisia scoparia – A new source of artemisinin

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Aditi Singh

2010-03-01

Full Text Available Artemisinin is considered as the most active and potent antimalarial drug. Till date Artemisia annua Linn. plant is the only source for its production The present investigation was carried out with an objective to search a new plant for artemisinin. An attempt was made on a perennial faintly odoratus herb, Artemisia scoparia Waldst et Kit. to find out an alternative of A. annua for the production of artemisinin. The yield of artemisinin was higher in aerial plant parts (0.015% in comparison to callus culture (0.001%. The present study concluded that Artemisia scoparia contains an antimalarial drug artemisinin.

Artemisia scoparia – A new source of artemisinin

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Aditi Singh

2010-06-01

Full Text Available Artemisinin is considered as the most active and potent antimalarial drug. Till date Artemisia annua Linn. plant is the only source for its production The present investigation was carried out with an objective to search a new plant for artemisinin. An attempt was made on a perennial faintly odoratus herb, Artemisia scoparia Waldst et Kit. to find out an alternative of A. annua for the production of artemisinin. The yield of artemisinin was higher in aerial plant parts (0.015% in comparison to callus culture (0.001%. The present study concluded that Artemisia scoparia contains an antimalarial drug artemisinin.

Chemical proteomics approach reveals the direct targets and the heme-dependent activation mechanism of artemisinin in Plasmodium falciparum using an activity-based artemisinin probe

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Jigang Wang

2016-04-01

Full Text Available Artemisinin and its analogues are currently the most effective anti-malarial drugs. The activation of artemisinin requires the cleavage of the endoperoxide bridge in the presence of iron sources. Once activated, artemisinins attack macromolecules through alkylation and propagate a series of damages, leading to parasite death. Even though several parasite proteins have been reported as artemisinin targets, the exact mechanism of action (MOA of artemisinin is still controversial and its high potency and specificity against the malaria parasite could not be fully accounted for. Recently, we have developed an unbiased chemical proteomics approach to directly probe the MOA of artemisinin in P. falciparum. We synthesized an activity-based artemisinin probe with an alkyne tag, which can be coupled with biotin through click chemistry. This enabled selective purification and identification of 124 protein targets of artemisinin. Many of these targets are critical for the parasite survival. In vitro assays confirmed the specific artemisinin binding and inhibition of selected targets. We thus postulated that artemisinin kills the parasite through disrupting its biochemical landscape. In addition, we showed that artemisinin activation requires heme, rather than free ferrous iron, by monitoring the extent of protein binding using a fluorescent dye coupled with the alkyne-tagged artemisinin. The extremely high level of heme released from the hemoglobin digestion by the parasite makes artemisinin exceptionally potent against late-stage parasites (trophozoite and schizont stages compared to parasites at early ring stage, which have low level of heme, possibly derived from endogenous synthesis. Such a unique activation mechanism also confers artemisinin with extremely high specificity against the parasites, while the healthy red blood cells are unaffected. Our results provide a sound explanation of the MOA of artemisinin and its specificity against malaria

Willingness-to-pay for a rapid malaria diagnostic test and artemisinin-based combination therapy from private drug shops in Mukono district, Uganda

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Hansen, Kristian Schultz; Pedrazzoli, Debora; Mbonye, Anthony; Clarke, Sian; Cundill, Bonnie; Magnussen, Pascal; Yeung, Shunmay

2013-01-01

In Uganda, as in many parts of Africa, the majority of the population seek treatment for malaria in drug shops as their first point of care; however, parasitological diagnosis is not usually offered in these outlets. Rapid diagnostic tests (RDTs) for malaria have attracted interest in recent years as a tool to improve malaria diagnosis, since they have proved accurate and easy to perform with minimal training. Although RDTs could feasibly be performed by drug shop vendors, it is not known how much customers would be willing to pay for an RDT if offered in these settings. We conducted a contingent valuation survey among drug shop customers in Mukono District, Uganda. Exit interviews were undertaken with customers aged 15 years and above after leaving a drug shop having purchased an antimalarial and/or paracetamol. The bidding game technique was used to elicit the willingness-to-pay (WTP) for an RDT and a course of artemisinin-based combination therapy (ACT) with and without RDT confirmation. Factors associated with WTP were investigated using linear regression. The geometric mean WTP for an RDT was US$0.53, US$1.82 for a course of ACT and US$2.05 for a course of ACT after a positive RDT. Factors strongly associated with a higher WTP for these commodities included having a higher socio-economic status, no fever/malaria in the household in the past 2 weeks and if a malaria diagnosis had been obtained from a qualified health worker prior to visiting the drug shop. The findings further suggest that the WTP for an RDT and a course of ACT among drug shop customers is considerably lower than prevailing and estimated end-user prices for these commodities. Increasing the uptake of ACTs in drug shops and restricting the sale of ACTs to parasitologically confirmed malaria will therefore require additional measures. PMID:22589226

Using supply side evidence to inform oral artemisinin monotherapy replacement in Myanmar: a case study.

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Khin, Hnin Su Su; Aung, Tin; Aung, Moe; Thi, Aung; Boxshall, Matt; White, Chris

2016-08-18

In 2012, alarmingly high rates of oral artemisinin monotherapy availability and use were detected along Eastern Myanmar, threatening efforts to halt the spread of artemisinin resistance in the Greater Mekong Subregion (GMS), and globally. The aim of this paper is to exemplify how the use of supply side evidence generated through the ACTwatch project shaped the artemisinin monotherapy replacement malaria (AMTR) project's design and interventions to rapidly displace oral artemisinin monotherapy with subsidized, quality-assured ACT in the private sector. The AMTR project was implemented as part of the Myanmar artemisinin resistance containment (MARC) framework along Eastern Myanmar. Guided by outlet survey and supply chain evidence, the project implemented a high-level subsidy, including negotiations with a main anti-malarial distributor, with the aim of squeezing oral artemisinin monotherapy out of the market through price competition and increased availability of quality-assured artemisinin-based combinations. This was complemented with a plethora of demand-creation activities targeting anti-malarial providers and consumers. Priority outlet types responsible for the distribution of oral artemisinin monotherapy were identified by the outlet survey, and this evidence was used to target the AMTR project's supporting interventions. The widespread availability and use of oral artemisinin monotherapy in Myanmar has been a serious threat to malaria control and elimination in the country and across the region. Practical anti-malarial market evidence was rapidly generated and used to inform private sector approaches to address these threats. The program design approach outlined in this paper is illustrative of the type of evidence generation and use that will be required to ensure effective containment of artemisinin drug resistance and progress toward regional and global malaria elimination goals.

Estimating antimalarial drugs consumption in Africa before the switch to artemisinin-based combination therapies (ACTs).

Science.gov (United States)

Kindermans, Jean-Marie; Vandenbergh, Daniel; Vreeke, Ed; Olliaro, Piero; D'Altilia, Jean-Pierre

2007-07-10

Having reliable forecasts is critical now for producers, malaria-endemic countries and agencies in order to adapt production and procurement of the artemisinin-based combination treatments (ACTs), the new first-line treatments of malaria. There is no ideal method to quantify drug requirements for malaria. Morbidity data give uncertain estimations. This study uses drug consumption to provide elements to help estimate quantities and financial requirements of ACTs. The consumption of chloroquine, sulphadoxine/pyrimethamine and quinine both through the private and public sector was assessed in five sub-Saharan Africa countries with different epidemiological patterns (Senegal, Rwanda, Tanzania, Malawi, Zimbabwe). From these data the number of adult treatments per capita was calculated and the volumes and financial implications derived for the whole of Africa. Identifying and obtaining data from the private sector was difficult. The quality of information on drug supply and distribution in countries must be improved. The number of adult treatments per capita and per year in the five countries ranged from 0.18 to 0.50. Current adult treatment prices for ACTs range US$ 1-1.8. Taking the upper range for both volumes and costs, the highest number of adult treatments consumed for Africa was estimated at 314.5 million, corresponding to an overall maximum annual need for financing ACT procurement of US$ 566.1 million. In reality, both the number of cases treated and the cost of treatment are likely to be lower (projections for the lowest consumption estimate with the least expensive ACT would require US $ 113 million per annum). There were substantial variations in the market share between public and private sources among these countries (the public sector share ranging from 98% in Rwanda to 33% in Tanzania). Additional studies are required to build a more robust methodology, and to assess current consumptions more accurately in order to better quantify volumes and finances for

Estimating antimalarial drugs consumption in Africa before the switch to artemisinin-based combination therapies (ACTs

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Vreeke Ed

2007-07-01

Full Text Available Abstract Background Having reliable forecasts is critical now for producers, malaria-endemic countries and agencies in order to adapt production and procurement of the artemisinin-based combination treatments (ACTs, the new first-line treatments of malaria. There is no ideal method to quantify drug requirements for malaria. Morbidity data give uncertain estimations. This study uses drug consumption to provide elements to help estimate quantities and financial requirements of ACTs. Methods The consumption of chloroquine, sulphadoxine/pyrimethamine and quinine both through the private and public sector was assessed in five sub-Saharan Africa countries with different epidemiological patterns (Senegal, Rwanda, Tanzania, Malawi, Zimbabwe. From these data the number of adult treatments per capita was calculated and the volumes and financial implications derived for the whole of Africa. Results Identifying and obtaining data from the private sector was difficult. The quality of information on drug supply and distribution in countries must be improved. The number of adult treatments per capita and per year in the five countries ranged from 0.18 to 0.50. Current adult treatment prices for ACTs range US$ 1–1.8. Taking the upper range for both volumes and costs, the highest number of adult treatments consumed for Africa was estimated at 314.5 million, corresponding to an overall maximum annual need for financing ACT procurement of US$ 566.1 million. In reality, both the number of cases treated and the cost of treatment are likely to be lower (projections for the lowest consumption estimate with the least expensive ACT would require US $ 113 million per annum. There were substantial variations in the market share between public and private sources among these countries (the public sector share ranging from 98% in Rwanda to 33% in Tanzania. Conclusion Additional studies are required to build a more robust methodology, and to assess current consumptions

Potential ecological roles of artemisinin produced by Artemisia annua L.

Science.gov (United States)

Knudsmark Jessing, Karina; Duke, Stephen O; Cedergreeen, Nina

2014-02-01

Artemisia annua L. (annual wormwood, Asteraceae) and its secondary metabolite artemisinin, a unique sesquiterpene lactone with an endoperoxide bridge, has gained much attention due to its antimalarial properties. Artemisinin has a complex structure that requires a significant amount of energy for the plant to synthesize. So, what are the benefits to A. annua of producing this unique compound, and what is the ecological role of artemisinin? This review addresses these questions, discussing evidence of the potential utility of artemisinin in protecting the plant from insects and other herbivores, as well as pathogens and competing plant species. Abiotic factors affecting the artemisinin production, as well as mechanisms of artemisinin release to the surroundings also are discussed, and new data are provided on the toxicity of artemisinin towards soil and aquatic organisms. The antifungal and antibacterial effects reported are not very pronounced. Several studies have reported that extracts of A. annua have insecticidal effects, though few studies have proven that artemisinin could be the single compound responsible for the observed effects. However, the pathogen(s) or insect(s) that may have provided the selection pressure for the evolution of artemisinin synthesis may not have been represented in the research thus far conducted. The relatively high level of phytotoxicity of artemisinin in soil indicates that plant/plant allelopathy could be a beneficial function of artemisinin to the producing plant. The release routes of artemisinin (movement from roots and wash off from leaf surfaces) from A. annua to the soil support the rationale for allelopathy.

A pharmacy too far? Equity and spatial distribution of outcomes in the delivery of subsidized artemisinin-based combination therapies through private drug shops.

Science.gov (United States)

Cohen, Justin M; Sabot, Oliver; Sabot, Kate; Gordon, Megumi; Gross, Isaac; Bishop, David; Odhiambo, Moses; Ipuge, Yahya; Ward, Lorrayne; Mwita, Alex; Goodman, Catherine

2010-07-02

Millions of individuals with malaria-like fevers purchase drugs from private retailers, but artemisinin-based combination therapies (ACTs), the only effective treatment in regions with high levels of resistance to older drugs, are rarely obtained through these outlets due to their relatively high cost. To encourage scale up of ACTs, the Affordable Medicines Facility--malaria is being launched to subsidize their price. The Government of Tanzania and the Clinton Foundation piloted this subsidized distribution model in two Tanzanian districts to examine concerns about whether the intervention will successfully reach poor, rural communities. Stocking of ACTs and other antimalarial drugs in all retail shops was observed at baseline and in four subsequent surveys over 15 months. Exit interviews were conducted with antimalarial drug customers during each survey period. All shops and facilities were georeferenced, and variables related to population density and proximity to distribution hubs, roads, and other facilities were calculated. To understand the equity of impact, shops stocking ACTs and consumers buying them were compared to those that did not, according to geographic and socioeconomic variables. Patterning in ACT stocking and sales was evaluated against that of other common antimalarials to identify factors that may have impacted access. Qualitative data were used to assess motivations underlying stocking, distribution, and buying disparities. Results indicated that although total ACT purchases rose from negligible levels to nearly half of total antimalarial sales over the course of the pilot, considerable geographic variation in stocking and sales persisted and was related to a variety of socio-spatial factors; ACTs were stocked more often in shops located closer to district towns (ppotential for increased ACT usage but suggest that additional efforts to increase access in remote areas will be needed for the scale-up to have equitable impact. Current Controlled

Comparison of artemisinin suppositories, intramuscular artesunate and intravenous quinine for the treatment of severe childhood malaria.

Science.gov (United States)

Cao, X T; Bethell, D B; Pham, T P; Ta, T T; Tran, T N; Nguyen, T T; Pham, T T; Nguyen, T T; Day, N P; White, N J

1997-01-01

Severe malaria remains a major cause of mortality and morbidity for children living in many tropical regions. With the emergence of strains of Plasmodium falciparum resistant to both chloroquine and quinine, alternative antimalarial agents are required. The artemisinin group of compounds are rapidly effective in severe disease when given by intramuscular or intravenous injection. However, these routes of administration are not always available in rural areas. In an open, randomized comparison 109 Vietnamese children, aged between 3 months and 14 years, with severe P.falciparum malaria, were allocated at random to receive artemisinin suppositories followed by mefloquine (n = 37), intramuscular artesunate followed by mefloquine (n = 37), or intravenous quinine followed by pyrimethamine/sulfadoxine (n = 35). There were 9 deaths: 2 artemisinin, 4 artesunate and 5 quinine-treated children. There was no difference in fever clearance time, coma recovery, or length of hospital stay among the 3 groups. However, parasite clearance times were significantly faster in artemisinin and artesunate-treated patients than in those who received quinine (P children receiving these drugs had lower peripheral reticulocyte counts by day 5 of treatment than those in the quinine group (P = 0.011). No other adverse effect or toxicity was found. There was no treatment failure in these 2 groups, but 4 patients in the quinine group failed to clear their parasites within 7 d of starting treatment and required alternative antimalarial therapy. Artemisinin suppositories are easy to administer, cheap, and very effective for treating children with severe malaria. In rural areas where medical facilities are lacking these drugs will allow antimalarial therapy to be instituted earlier in the course of the disease and may therefore save lives.

Chemistry of artemisinin: an EPR study and nucleobases interaction

International Nuclear Information System (INIS)

Mustafa, Damra Elhaj

2000-10-01

In the present, the radical transformations of artemisinin, a potent antimalarial drug have been examined using EPR and EPR spin trapping techniques. The effect of light on artemisinin has been investigated at 77 K as well as with the use of phenyl butyl nitrone (PBN) spin trapping agent. While no EPR signal was observed at 77 K, intense light irradiation of artemisinin/PBN gave EPR signal characteristic of radical transformation of the PBN. The reactions of artemisinin with iron (II), manganese (II), hemin and ferrocyanide ion have been investigated by spin trapping techniques. Artemisinin/iron (II) formed spin adducts with nitrosobenzene, nitroso-t-butane and PBN. The hypertine splittings of the spin adducts were a N =1.08 mT/a N =1.25 mT/a N =0.09 mT and a N =1.56 mT/a N =0.29 mT respectively. PBN trapping of artemether/iron (II) gave similar result to artemisinin/iron (II). These results are indicative of secondary carbon-centered radical formation. While artemisinin/hemin/PBN gave very weak EPR signal, ferrocyanide under the same condition gave no signal. Incubation of artemisinin with RNA at different reaction conditions, including irradiation with light, heat and mild acidic media, revealed no RNA damage when examined by agarose electrophoresis. However, artemisinin/iron (II) caused RNA damage in pH-dependant manner. In contrast, hemin did not show the same effect when it was used instead of iron (II). (Author)

Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial Agent to a Potential Anticancer Drug

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Maria P. Crespo-Ortiz

2012-01-01

Full Text Available Improvement of quality of life and survival of cancer patients will be greatly enhanced by the development of highly effective drugs to selectively kill malignant cells. Artemisinin and its analogs are naturally occurring antimalarials which have shown potent anticancer activity. In primary cancer cultures and cell lines, their antitumor actions were by inhibiting cancer proliferation, metastasis, and angiogenesis. In xenograft models, exposure to artemisinins substantially reduces tumor volume and progression. However, the rationale for the use of artemisinins in anticancer therapy must be addressed by a greater understanding of the underlying mechanisms involved in their cytotoxic effects. The primary targets for artemisinin and the chemical base for its preferential effects on heterologous tumor cells need yet to be elucidated. The aim of this paper is to provide an overview of the recent advances and new development of this class of drugs as potential anticancer agents.

Anti-Inflammatory and Immunoregulatory Functions of Artemisinin and Its Derivatives

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Chenchen Shi

2015-01-01

Full Text Available Artemisinin and its derivatives are widely used in the world as the first-line antimalarial drug. Recently, growing evidences reveal that artemisinin and its derivatives also possess potent anti-inflammatory and immunoregulatory properties. Meanwhile, researchers around the world are still exploring the unknown bioactivities of artemisinin derivatives. In this review, we provide a comprehensive discussion on recent advances of artemisinin derivatives affecting inflammation and autoimmunity, the underlying molecular mechanisms, and also drug development of artemisinins beyond antimalarial functions.

Mn(ii) mediated degradation of artemisinin based on Fe3O4@MnSiO3-FA nanospheres for cancer therapy in vivo

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Chen, Jian; Zhang, Weijie; Zhang, Min; Guo, Zhen; Wang, Haibao; He, Mengni; Xu, Pengping; Zhou, Jiajia; Liu, Zhenbang; Chen, Qianwang

2015-07-01

Artemisinin (ART) is a natural drug with potent anticancer activities related with Fe2+ mediated cleavage of the endoperoxide bridge in ART. Herein, we reported that Mn2+ could substitute for Fe2+ to react with ART and generate toxic products, inducing a much higher anticancer efficiency. On this basis, we prepared pH-responsive Fe3O4@MnSiO3-FA nanospheres which can efficiently deliver hydrophobic ART into tumors in mice models. Mn2+ was released in acidic tumor environments and intracellular lysosomes, interacting with ART to kill cancer cells. The ART-loaded nanocarriers could suppress tumor growth more efficiently than free ART, which could be further illustrated by magnetic resonance imaging (MRI). Histological analysis revealed that the drug delivery system had no obvious effect on the major organs of mice. ART has been reported to have lower toxicity than chemotherapeutics. The ART-loaded nanocarriers are promising to be used in improving the survival of chemotherapy patients, providing a novel method for clinical tumor therapy.Artemisinin (ART) is a natural drug with potent anticancer activities related with Fe2+ mediated cleavage of the endoperoxide bridge in ART. Herein, we reported that Mn2+ could substitute for Fe2+ to react with ART and generate toxic products, inducing a much higher anticancer efficiency. On this basis, we prepared pH-responsive Fe3O4@MnSiO3-FA nanospheres which can efficiently deliver hydrophobic ART into tumors in mice models. Mn2+ was released in acidic tumor environments and intracellular lysosomes, interacting with ART to kill cancer cells. The ART-loaded nanocarriers could suppress tumor growth more efficiently than free ART, which could be further illustrated by magnetic resonance imaging (MRI). Histological analysis revealed that the drug delivery system had no obvious effect on the major organs of mice. ART has been reported to have lower toxicity than chemotherapeutics. The ART-loaded nanocarriers are promising to be used in

Hemin potentiates the anti-hepatitis C virus activity of the antimalarial drug artemisinin

International Nuclear Information System (INIS)

Paeshuyse, Jan; Coelmont, Lotte; Vliegen, Inge; Hemel, Johan van; Vandenkerckhove, Jan; Peys, Eric; Sas, Benedikt; Clercq, Erik De; Neyts, Johan

2006-01-01

We report that the antimalarial drug artemisinin inhibits hepatitis C virus (HCV) replicon replication in a dose-dependent manner in two replicon constructs at concentrations that have no effect on the proliferation of the exponentially growing host cells. The 50% effective concentration (EC 5 ) for inhibition of HCV subgenomic replicon replication in Huh 5-2 cells (luciferase assay) by artemisinin was 78 ± 21 μM. Hemin, an iron donor, was recently reported to inhibit HCV replicon replication [mediated by inhibition of the viral polymerase (C. Fillebeen, A.M. Rivas-Estilla, M. Bisaillon, P. Ponka, M. Muckenthaler, M.W. Hentze, A.E. Koromilas, K. Pantopoulos, Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus, J. Biol. Chem. 280 (2005) 9049-9057.)] at a concentration that had no adverse effect on the host cells. When combined, artemisinin and hemin resulted, over a broad concentration range, in a pronounced synergistic antiviral activity. Also at a concentration (2 μM) that alone had no effect on HCV replication, hemin still potentiated the anti-HCV activity of artemisinin

Hemin potentiates the anti-hepatitis C virus activity of the antimalarial drug artemisinin

Energy Technology Data Exchange (ETDEWEB)

Paeshuyse, Jan [Rega Institute for Medical Research, Minderbroedersstraat 10, KULeuven, B-3000 Leuven (Belgium); Coelmont, Lotte [Rega Institute for Medical Research, Minderbroedersstraat 10, KULeuven, B-3000 Leuven (Belgium); Vliegen, Inge [Rega Institute for Medical Research, Minderbroedersstraat 10, KULeuven, B-3000 Leuven (Belgium); Hemel, Johan van [Kemin Pharma, Atealaan 4H, B-2200 Herentals (Belgium); Vandenkerckhove, Jan [Kemin Pharma, Atealaan 4H, B-2200 Herentals (Belgium); Peys, Eric [Kemin Pharma, Atealaan 4H, B-2200 Herentals (Belgium); Sas, Benedikt [Kemin Pharma, Atealaan 4H, B-2200 Herentals (Belgium); Clercq, Erik De [Rega Institute for Medical Research, Minderbroedersstraat 10, KULeuven, B-3000 Leuven (Belgium); Neyts, Johan [Rega Institute for Medical Research, Minderbroedersstraat 10, KULeuven, B-3000 Leuven (Belgium)

2006-09-15

We report that the antimalarial drug artemisinin inhibits hepatitis C virus (HCV) replicon replication in a dose-dependent manner in two replicon constructs at concentrations that have no effect on the proliferation of the exponentially growing host cells. The 50% effective concentration (EC{sub 5}) for inhibition of HCV subgenomic replicon replication in Huh 5-2 cells (luciferase assay) by artemisinin was 78 {+-} 21 {mu}M. Hemin, an iron donor, was recently reported to inhibit HCV replicon replication [mediated by inhibition of the viral polymerase (C. Fillebeen, A.M. Rivas-Estilla, M. Bisaillon, P. Ponka, M. Muckenthaler, M.W. Hentze, A.E. Koromilas, K. Pantopoulos, Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus, J. Biol. Chem. 280 (2005) 9049-9057.)] at a concentration that had no adverse effect on the host cells. When combined, artemisinin and hemin resulted, over a broad concentration range, in a pronounced synergistic antiviral activity. Also at a concentration (2 {mu}M) that alone had no effect on HCV replication, hemin still potentiated the anti-HCV activity of artemisinin.

Chemistry of artemisinin: an EPR study and nucleobases interaction

Energy Technology Data Exchange (ETDEWEB)

Mustafa, Damra Elhaj [Department of Chemistry, Faculty of Education, University of Khartoum, Khartoum (Sudan)

2000-10-01

In the present, the radical transformations of artemisinin, a potent antimalarial drug have been examined using EPR and EPR spin trapping techniques. The effect of light on artemisinin has been investigated at 77 K as well as with the use of phenyl butyl nitrone (PBN) spin trapping agent. While no EPR signal was observed at 77 K, intense light irradiation of artemisinin/PBN gave EPR signal characteristic of radical transformation of the PBN. The reactions of artemisinin with iron (II), manganese (II), hemin and ferrocyanide ion have been investigated by spin trapping techniques. Artemisinin/iron (II) formed spin adducts with nitrosobenzene, nitroso-t-butane and PBN. The hypertine splittings of the spin adducts were a{sub N}=1.08 mT/a{sub N}=1.25 mT/a{sub N}=0.09 mT and a{sub N}=1.56 mT/a{sub N}=0.29 mT respectively. PBN trapping of artemether/iron (II) gave similar result to artemisinin/iron (II). These results are indicative of secondary carbon-centered radical formation. While artemisinin/hemin/PBN gave very weak EPR signal, ferrocyanide under the same condition gave no signal. Incubation of artemisinin with RNA at different reaction conditions, including irradiation with light, heat and mild acidic media, revealed no RNA damage when examined by agarose electrophoresis. However, artemisinin/iron (II) caused RNA damage in pH-dependant manner. In contrast, hemin did not show the same effect when it was used instead of iron (II). (Author)

Expression of Beta-glucosidase increases trichome density and artemisinin content in transgenic Artemisia annua plants

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Singh, Nameirakpam Dolendro; Kumar, Shashi; Daniell, Henry

2015-01-01

Artemisinin is highly effective against multidrug-resistant strains of Plasmodium falciparum, the etiological agent of the most severe form of malaria. However, a low level of accumulation of artemisinin in Artemisia annua is a major limitation for its production and delivery to malaria endemic areas of the world. While several strategies to enhance artemisinin have been extensively explored, enhancing storage capacity in trichome has not yet been considered. Therefore, trichome density was increased with the expression of β glucosidase (bgl1) gene in A. annua through Agrobacterium-mediated transformation. Transgene (bgl1) integration and transcript was confirmed by molecular analysis. Trichome density increased up to 20% in leaves and 66% in flowers of BGL1 transgenic plants than Artemisia control plants. High-performance liquid chromatography (HPLC, MS-TOF) data showed that artemisinin content increased up to 1.4% in leaf and 2.56% in flowers (g-1DW), similar to the highest yields achieved so far through metabolic engineering. Artemisinin was enhanced up to 5-fold in BGL1 transgenic flowers. The present study opens the possibility of increasing artemisinin content by manipulating trichomes density, which is a major reservoir of artemisinin. Combining biosynthetic pathway engineering with enhancing trichome density may further increase artemisinin yield in A. annua. Because oral feeding of Artemisia plant cells reduced parasitemia more efficiently than the purified drug, reduced drug resistance and cost of prohibitively expensive purification process, enhanced expression should play a key role in making this valuable drug affordable to treat malaria in a large global population that disproportionally impacts low-socioeconomic areas and underprivileged children. PMID:26360801

Incidence of malaria and efficacy of combination antimalarial therapies over 4 years in an urban cohort of Ugandan children.

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Tamara D Clark

2010-07-01

Full Text Available Combination therapies are now recommended to treat uncomplicated malaria. We used a longitudinal design to assess the incidence of malaria and compare the efficacies of 3 combination regimens in Kampala, Uganda.Children aged 1-10 years were enrolled from randomly selected households in 2004-05 and 2007, and were followed at least monthly through 2008. Insecticide-treated bednets (ITNs were provided in 2006. Children were randomized upon their first episode, and then treated for all episodes of uncomplicated malaria with amodiaquine/sulfadoxine-pyrimethamine (AQ/SP, artesunate/amodiaquine (AS/AQ, or artemether/lumefantrine (AL. Risks of parasitological failure were determined for each episode of uncomplicated malaria and clinical parameters were followed. A total of 690 children experienced 1464 episodes of malaria. 96% of these episodes were uncomplicated malaria and treated with study drugs; 94% were due to Plasmodium falciparum. The rank order of treatment efficacy was AL > AS/AQ > AQ/SP. Failure rates increased over time for AQ/SP, but not the artemisinin-based regimens. Over the 4-year course of the study the prevalence of asymptomatic parasitemia decreased from 11.8% to 1.4%, the incidence of malaria decreased from 1.55 to 0.32 per person year, and the prevalence of anemia (hemoglobin <10 gm/dL decreased from 5.9% to 1.0%. No episodes of severe malaria (based on WHO criteria and no deaths were seen.With ready access to combination therapies and distribution of ITNs, responses were excellent for artemisinin-containing regimens, severe malaria was not seen, and the incidence of malaria and prevalence of parasitemia and anemia decreased steadily over time.isrctn.org ISRCTN37517549.

Investigation of drug polymorphism: Case of artemisinin

International Nuclear Information System (INIS)

Horosanskaia, E.; Seidel-Morgenstern, A.; Lorenz, H.

2014-01-01

Highlights: • The Artemisinin dimorphic system was found to be enantiotropic. • The Orthorhombic modification is the form stable at low-temperatures and the triclinic modification the form stable at high-temperatures. • The polymorphic phase transition occurs at ∼130 °C. - Abstract: The polymorphism of the anti-malarial compound artemisinin was examined. The phase behavior of solid artemisinin has experimentally been investigated using differential scanning calorimetry and temperature-resolved X-Ray powder diffraction. In addition, complementary solution studies and suspension experiments were performed. The results clearly confirm the existence of two modifications of artemisinin, which are related enantiotropically. The orthorhombic modification is the thermodynamically stable form at low temperatures, while the triclinic form is the stable one at higher temperatures with a transition temperature of ∼130 °C. Problems associated with analysis of the polymorphic phase behavior are comprehensively addressed

Dissolution of artemisinin/polymer composite nanoparticles fabricated by evaporative precipitation of nanosuspension.

Science.gov (United States)

Kakran, Mitali; Sahoo, Nanda Gopal; Li, Lin; Judeh, Zaher

2010-04-01

An evaporative precipitation of nanosuspension (EPN) method was used to fabricate composite particles of a poorly water-soluble antimalarial drug, artemisinin, with a hydrophilic polymer, polyethylene glycol (PEG), with the aim of enhancing the dissolution rate of artemisinin. We investigated the effect of polymer concentration on the physical, morphological and dissolution properties of the EPN-prepared artemisinin/PEG composites. The original artemisinin powder, EPN-prepared artemisinin nanoparticles and artemisinin/PEG composites were characterised by scanning electron microscopy, Fourier-transform infrared spectroscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD), dissolution testing and HPLC. The percentage dissolution efficiency, relative dissolution, time to 75% dissolution and mean dissolution time were calculated. The experimental drug dissolution data were fitted to various mathematical models (Weibull, first-order, Korsemeyer-Peppas, Hixson-Crowell cube root and Higuchi models) in order to analyse the release mechanism. The DSC and XRD studies suggest that the crystallinity of the EPN-prepared artemisinin decreased with increasing polymer concentration. The phase-solubility studies revealed an A(L)-type curve, indicating a linear increase in drug solubility with PEG concentration. The dissolution rate of the EPN-prepared artemisinin and artemisinin/PEG composites increased markedly compared with the original artemisinin powder. EPN can be used to prepare artemisinin nanoparticles and artemisinin/PEG composite particles that have a significantly enhanced dissolution rate. The mechanism of drug release involved diffusion and erosion.

Expression of β-glucosidase increases trichome density and artemisinin content in transgenic Artemisia annua plants.

Science.gov (United States)

Singh, Nameirakpam Dolendro; Kumar, Shashi; Daniell, Henry

2016-03-01

Artemisinin is highly effective against multidrug-resistant strains of Plasmodium falciparum, the aetiological agent of the most severe form of malaria. However, a low level of accumulation of artemisinin in Artemisia annua is a major limitation for its production and delivery to malaria endemic areas of the world. While several strategies to enhance artemisinin have been extensively explored, enhancing storage capacity in trichome has not yet been considered. Therefore, trichome density was increased with the expression of β-glucosidase (bgl1) gene in A. annua through Agrobacterium-mediated transformation. Transgene (bgl1) integration and transcript were confirmed by molecular analysis. Trichome density increased up to 20% in leaves and 66% in flowers of BGL1 transgenic plants than Artemisia control plants. High-performance liquid chromatography, time of flight mass spectrometer data showed that artemisinin content increased up to 1.4% in leaf and 2.56% in flowers (per g DW), similar to the highest yields achieved so far through metabolic engineering. Artemisinin was enhanced up to five-fold in BGL1 transgenic flowers. This study opens the possibility of increasing artemisinin content by manipulating trichomes' density, which is a major reservoir of artemisinin. Combining biosynthetic pathway engineering with enhancing trichome density may further increase artemisinin yield in A. annua. Because oral feeding of Artemisia plant cells reduced parasitemia more efficiently than the purified drug, reduced drug resistance and cost of prohibitively expensive purification process, enhanced expression should play a key role in making this valuable drug affordable to treat malaria in a large global population that disproportionally impacts low-socioeconomic areas and underprivileged children. © 2015 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

The Safety of Artemisinin Derivatives for the Treatment of Malaria in the 2nd or 3rd Trimester of Pregnancy: A Systematic Review and Meta-Analysis.

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Stephanie D Kovacs

Full Text Available Given the high morbidity for mother and fetus associated with malaria in pregnancy, safe and efficacious drugs are needed for treatment. Artemisinin derivatives are the most effective antimalarials, but are associated with teratogenic and embryotoxic effects in animal models when used in early pregnancy. However, several organ systems are still under development later in pregnancy. We conducted a systematic review and meta-analysis of the occurrence of adverse pregnancy outcomes among women treated with artemisinins monotherapy or as artemisinin-based combination therapy during the 2nd or 3rd trimesters relative to pregnant women who received non-artemisinin antimalarials or none at all. Pooled odds ratio (POR were calculated using Mantel-Haenszel fixed effects model with a 0.5 continuity correction for zero events. Eligible studies were identified through Medline, Embase, and the Malaria in Pregnancy Consortium Library. Twenty studies (11 cohort studies and 9 randomized controlled trials contributed to the analysis, with 3,707 women receiving an artemisinin, 1,951 a non-artemisinin antimalarial, and 13,714 no antimalarial. The PORs (95% confidence interval (CI for stillbirth, fetal loss, and congenital anomalies when comparing artemisinin versus quinine were 0.49 (95% CI 0.24-0.97, I2 = 0%, 3 studies; 0.58 (95% CI 0.31-1.16, I2 = 0%, 6 studies; and 1.00 (95% CI 0.27-3.75, I2 = 0%, 3 studies, respectively. The PORs comparing artemisinin users to pregnant women who received no antimalarial were 1.13 (95% CI 0.77-1.66, I2 = 86.7%, 3 studies; 1.10 (95% CI 0.79-1.54, I2 = 0%, 4 studies; and 0.79 (95% CI 0.37-1.67, I2 = 0%, 3 studies for miscarriage, stillbirth and congenital anomalies respectively. Treatment with artemisinin in 2nd and 3rd trimester was not associated with increased risks of congenital malformations or miscarriage and may be was associated with a reduced risk of stillbirths compared to quinine. This study updates the reviews

Trypsin inhibitory activity of artemisinin and its biotransformed product

International Nuclear Information System (INIS)

Shahwar, D.; Raza, M.A.

2013-01-01

Summary: Artemisinin (1 ), a sesquiterpene lactone is an important constituent of anti-malarial drugs. In the present study, it was extracted from aerial parts of Artemisia roxburghiana Besser. Biotransformation of artemisinin ( 1 ) was carried out in the culture of Aspergillus niger GC-4 which yielded 5-hydroxy artemisinin (2 ) The structures of 1-2 were confirmed through spectral studies. Both compounds were screened against trypsin using colorimetric method. The biotransformed product 2 showed significant protease inhibitory activity with 53.5 +- 1.6% inhibition and IC/sub 50/ = 0.29 +- 0.02 mM as compared to artemisinin (20.4 +- 0.3% inhibition). (author)

Considerations on the mechanism of action of artemisinin antimalarials: part 1--the 'carbon radical' and 'heme' hypotheses.

Science.gov (United States)

Haynes, Richard K; Cheu, Kwan-Wing; N'Da, David; Coghi, Paolo; Monti, Diego

2013-08-01

The isolation of artemisinin from the traditional medicinal herb qīng hāo (Artemisia annua), its characterization as a peroxide and preparation of the derivatives dihydroartemisinin, artemether and artesunate in the 1970s and 1980s by Chinese scientists under the umbrella of Project 523 collectively represents one of the great events in medicine in the latter third of the 20(th) Century. Artemisinins have become the most important component of chemotherapy of malaria: although used initially in monotherapy, they are now used in combination therapies or ACTs with longer half-life quinolines or arylmethanols. Nevertheless, the recent emergence of artemisinin-tolerant strains of the malaria parasite as reflected in increased clearance times of parasitaemia in patients treated with ACTs represents the greatest threat to control of malaria since resistance to chloroquine was first reported over 55 years ago. Importantly, the event brings into sharp focus the realization that relatively little is precisely understood, as opposed to widely assumed, for the mechanism of drug action of artemisinins and their synthetic peroxide analogues. Thus, we review here their antimalarial activities, the use of artemisinins in combination therapies, drug-drug interactions with the quinolines and arylmethanols, and metabolism of the artemisinins and synthetic peroxides. The mechanism of action of quinolines and arylmethanols, in particular their ability to induce redistribution of heme into the parasite cytosol, is also highlighted. This collective information is then used as a counterpoint to screen the validity of two of the prevailing hypotheses of drug action of artemisinins and synthetic peroxides, namely i. 'the C-radical hypothesis' wherein the peroxide undergoes 'bioactivation' by ferrous iron to generate C-radicals that are held to be the cytotoxic agents and ii. the 'heme hypothesis' wherein ferrous heme may generate either the same type of 'cytotoxic' C-radical, or the

Saleability of anti-malarials in private drug shops in Muheza, Tanzania: a baseline study in an era of assumed artemisinin combination therapy (ACT

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Ringsted Frank M

2011-08-01

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

A pharmacy too far? Equity and spatial distribution of outcomes in the delivery of subsidized artemisinin-based combination therapies through private drug shops

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Ward Lorrayne

2010-07-01

Full Text Available Abstract Background Millions of individuals with malaria-like fevers purchase drugs from private retailers, but artemisinin-based combination therapies (ACTs, the only effective treatment in regions with high levels of resistance to older drugs, are rarely obtained through these outlets due to their relatively high cost. To encourage scale up of ACTs, the Affordable Medicines Facility – malaria is being launched to subsidize their price. The Government of Tanzania and the Clinton Foundation piloted this subsidized distribution model in two Tanzanian districts to examine concerns about whether the intervention will successfully reach poor, rural communities. Methods Stocking of ACTs and other antimalarial drugs in all retail shops was observed at baseline and in four subsequent surveys over 15 months. Exit interviews were conducted with antimalarial drug customers during each survey period. All shops and facilities were georeferenced, and variables related to population density and proximity to distribution hubs, roads, and other facilities were calculated. To understand the equity of impact, shops stocking ACTs and consumers buying them were compared to those that did not, according to geographic and socioeconomic variables. Patterning in ACT stocking and sales was evaluated against that of other common antimalarials to identify factors that may have impacted access. Qualitative data were used to assess motivations underlying stocking, distribution, and buying disparities. Results Results indicated that although total ACT purchases rose from negligible levels to nearly half of total antimalarial sales over the course of the pilot, considerable geographic variation in stocking and sales persisted and was related to a variety of socio-spatial factors; ACTs were stocked more often in shops located closer to district towns (p Conclusions As this subsidy model is scaled up across multiple countries, these results confirm the potential for increased

First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies.

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Stephanie Dellicour

2017-05-01

.04 (95% CI 0.54-2.01, I2 = 0%, p = 0.910; aHR = 0.73 (95% CI 0.26-2.06, p = 0.551; and aHR = 0.98 (95% CI 0.52-2.04, p = 0.603. The prevalence of major congenital anomalies was similar for first-trimester artemisinin (1.5% [95% CI 0.6%-3.5%] and quinine exposures (1.2% [95% CI 0.6%-2.4%]. Key limitations of the study include the inability to control for confounding by indication in the African studies, the paucity of data on potential confounders, the limited statistical power to detect differences in congenital anomalies, and the lack of assessment of cardiovascular defects in newborns.Compared to quinine, artemisinin treatment in the first trimester was not associated with an increased risk of miscarriage or stillbirth. While the data are limited, they indicate no difference in the prevalence of major congenital anomalies between treatment groups. The benefits of 3-d artemisinin combination therapy regimens to treat malaria in early pregnancy are likely to outweigh the adverse outcomes of partially treated malaria, which can occur with oral quinine because of the known poor adherence to 7-d regimens.PROSPERO CRD42015032371.

Incidence of Malaria and Efficacy of Combination Antimalarial Therapies over 4 Years in an Urban Cohort of Ugandan Children

Science.gov (United States)

Clark, Tamara D.; Njama-Meya, Denise; Nzarubara, Bridget; Maiteki-Sebuguzi, Catherine; Greenhouse, Bryan; Staedke, Sarah G.; Kamya, Moses R.; Dorsey, Grant; Rosenthal, Philip J.

2010-01-01

Background Combination therapies are now recommended to treat uncomplicated malaria. We used a longitudinal design to assess the incidence of malaria and compare the efficacies of 3 combination regimens in Kampala, Uganda. Methodology/Principal Findings Children aged 1–10 years were enrolled from randomly selected households in 2004–05 and 2007, and were followed at least monthly through 2008. Insecticide-treated bednets (ITNs) were provided in 2006. Children were randomized upon their first episode, and then treated for all episodes of uncomplicated malaria with amodiaquine/sulfadoxine-pyrimethamine (AQ/SP), artesunate/amodiaquine (AS/AQ), or artemether/lumefantrine (AL). Risks of parasitological failure were determined for each episode of uncomplicated malaria and clinical parameters were followed. A total of 690 children experienced 1464 episodes of malaria. 96% of these episodes were uncomplicated malaria and treated with study drugs; 94% were due to Plasmodium falciparum. The rank order of treatment efficacy was AL > AS/AQ > AQ/SP. Failure rates increased over time for AQ/SP, but not the artemisinin-based regimens. Over the 4-year course of the study the prevalence of asymptomatic parasitemia decreased from 11.8% to 1.4%, the incidence of malaria decreased from 1.55 to 0.32 per person year, and the prevalence of anemia (hemoglobin <10 gm/dL) decreased from 5.9% to 1.0%. No episodes of severe malaria (based on WHO criteria) and no deaths were seen. Conclusions/Significance With ready access to combination therapies and distribution of ITNs, responses were excellent for artemisinin-containing regimens, severe malaria was not seen, and the incidence of malaria and prevalence of parasitemia and anemia decreased steadily over time. Trial Registration isrctn.org ISRCTN37517549 PMID:20689585

Genetic architecture of artemisinin-resistant Plasmodium falciparum

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Miotto, Olivo; Amato, Roberto; Ashley, Elizabeth A; MacInnis, Bronwyn; Almagro-Garcia, Jacob; Amaratunga, Chanaki; Lim, Pharath; Mead, Daniel; Oyola, Samuel O; Dhorda, Mehul; Imwong, Mallika; Woodrow, Charles; Manske, Magnus; Stalker, Jim; Drury, Eleanor; Campino, Susana; Amenga-Etego, Lucas; Thanh, Thuy-Nhien Nguyen; Tran, Hien Tinh; Ringwald, Pascal; Bethell, Delia; Nosten, Francois; Phyo, Aung Pyae; Pukrittayakamee, Sasithon; Chotivanich, Kesinee; Chuor, Char Meng; Nguon, Chea; Suon, Seila; Sreng, Sokunthea; Newton, Paul N; Mayxay, Mayfong; Khanthavong, Maniphone; Hongvanthong, Bouasy; Htut, Ye; Han, Kay Thwe; Kyaw, Myat Phone; Faiz, Md Abul; Fanello, Caterina I; Onyamboko, Marie; Mokuolu, Olugbenga A; Jacob, Christopher G; Takala-Harrison, Shannon; Plowe, Christopher V; Day, Nicholas P; Dondorp, Arjen M; Spencer, Chris C A; McVean, Gilean; Fairhurst, Rick M; White, Nicholas J; Kwiatkowski, Dominic P

2015-01-01

We report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin, the frontline antimalarial drug. Across 15 locations in Southeast Asia, we identified at least 20 mutations in kelch13 (PF3D7_1343700) affecting the encoded propeller and BTB/POZ domains, which were associated with a slow parasite clearance rate after treatment with artemisinin derivatives. Nonsynonymous polymorphisms in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2) and crt (chloroquine resistance transporter) also showed strong associations with artemisinin resistance. Analysis of the fine structure of the parasite population showed that the fd, arps10, mdr2 and crt polymorphisms are markers of a genetic background on which kelch13 mutations are particularly likely to arise and that they correlate with the contemporary geographical boundaries and population frequencies of artemisinin resistance. These findings indicate that the risk of new resistance-causing mutations emerging is determined by specific predisposing genetic factors in the underlying parasite population. PMID:25599401

Who continues to stock oral artemisinin monotherapy? Results of a provider survey in Myanmar.

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Thein, Si Thu; Sudhinaraset, May; Khin, Hnin Su Su; McFarland, Willi; Aung, Tin

2016-06-22

Artemisinin-based combination therapy (ACT) is a key strategy for global malaria elimination efforts. However, the development of artemisinin-resistant malaria parasites threatens progress and continued usage of oral artemisinin monotherapies (AMT) predisposes the selection of drug resistant strains. This is particularly a problem along the Myanmar/Thailand border. The artemisinin monotherapy replacement programme (AMTR) was established in 2012 to remove oral AMT from stocks in Myanmar, specifically by replacing oral AMT with quality-assured ACT and conducting behavioural change communication activities to the outlets dispensing anti-malarial medications. This study attempts to quantify the characteristics of outlet providers who continue to stock oral AMT despite these concerted efforts. A cross-sectional survey of all types of private sector outlets that were stocking anti-malarial drugs in 13 townships of Eastern Myanmar was implemented from July to August 2014. A total of 573 outlets were included. Bivariate and multivariable logistic regressions were conducted to assess outlet and provider-level characteristics associated with stocking oral AMT. In total, 2939 outlets in Eastern Myanmar were screened for presence of any anti-malarial drugs in August 2014. The study found that 573 (19.5 %) had some kind of oral anti-malarial drug in stock at the time of survey and among them, 96 (16.8 %) stocked oral AMT. In bivariate analyses, compared to health care facilities, itinerant drug vendors, retailers and health workers were less likely to stock oral AMT (33.3 vs 12.9, 10.0, 8.1 %, OR = 0.30, 0.22, 0.18, respectively). Providers who cut blister pack or sell partial courses (40.6 vs 11.7 %, OR 5.18, CI 3.18-8.44) and those who based their stock decision on consumer demand (32.8 vs 12.1 %, OR 3.54, CI 2.21-5.63) were more likely to stock oAMT. Multivariate logistic regressions produced similar significant associations. Private healthcare facilities and drug

Artemisinin resistance marker of Plasmodium falciparum in Osogbo ...

African Journals Online (AJOL)

Artemisinin derivatives constitute a key component of the present-day treatment for Plasmodium falciparum malaria. Resistance with artemisinins is generally associated with S769N point mutation in the sarco-endoplasmic reticulumdependant ATPase6 (SERCA ATPase6) gene of Plasmodium falciparum, few studies have ...

Prevalence of Malaria Parasitemia and Purchase of Artemisinin-Based Combination Therapies (ACTs) among Drug Shop Clients in Two Regions in Tanzania with ACT Subsidies

Science.gov (United States)

Briggs, Melissa A.; Kalolella, Admirabilis; Bruxvoort, Katia; Wiegand, Ryan; Lopez, Gerard; Festo, Charles; Lyaruu, Pierre; Kenani, Mitya; Abdulla, Salim; Goodman, Catherine; Kachur, S. Patrick

2014-01-01

Background Throughout Africa, many people seek care for malaria in private-sector drug shops where diagnostic testing is often unavailable. Recently, subsidized artemisinin-based combination therapies (ACTs), a first-line medication for uncomplicated malaria, were made available in these drug shops in Tanzania. This study assessed the prevalence of malaria among and purchase of ACTs by drug shop clients in the setting of a national ACT subsidy program and sub-national drug shop accreditation program. Method and Findings A cross-sectional survey of drug shop clients was performed in two regions in Tanzania, one with a government drug shop accreditation program and one without, from March-May, 2012. Drug shops were randomly sampled from non-urban districts. Shop attendants were interviewed about their education, training, and accreditation status. Clients were interviewed about their symptoms and medication purchases, then underwent a limited physical examination and laboratory testing for malaria. Malaria prevalence and predictors of ACT purchase were assessed using univariate analysis and multiple logistic regression. Amongst 777 clients from 73 drug shops, the prevalence of laboratory-confirmed malaria was 12% (95% CI: 6–18%). Less than a third of clients with malaria had purchased ACTs, and less than a quarter of clients who purchased ACTs tested positive for malaria. Clients were more likely to have purchased ACTs if the participant was 5 years, experience (aOR: 2.8; 95% CI: 1.2–6.3). Having malaria was only a predictor of ACT purchase in the region with a drug shop accreditation program (aOR: 3.4; 95% CI: 1.5–7.4). Conclusion Malaria is common amongst persons presenting to drug shops with a complaint of fever. The low proportion of persons with malaria purchasing ACTs, and the high proportion of ACTs going to persons without malaria demonstrates a need to better target who receives ACTs in these drug shops. PMID:24732258

Multiple Phenotypic and Genotypic Artemisinin Sensitivity Evaluation of Malian Plasmodium falciparum Isolates.

Science.gov (United States)

Niaré, Karamoko; Paloque, Lucie; Ménard, Sandie; Tor, Pety; Ramadani, Arba P; Augereau, Jean-Michel; Dara, Antoine; Berry, Antoine; Benoit-Vical, Françoise; Doumbo, Ogobara K

2018-04-01

We assessed the ex vivo/in vitro sensitivity of 54 Malian Plasmodium falciparum isolates to artemisinin for the monitoring of drug resistance in this area. The artemisinin sensitivity of parasites was evaluated using 1) the ex vivo and in vitro parasite recrudescence detection after treatment of the ring stage with 1-200 nM artemisinin for 48 hours and 2) the in vitro parasite recrudescence kinetics assay over 7 days after 6-hour treatment of the ring stage with 700 nM dihydroartemisinin (DHA). In addition, as recommended by the World Health Organization for artemisinin resistance characterization, the ring-stage survival assay (RSA 0-3 h ) was performed and the parasite isolates were sequenced at the kelch 13 propeller locus. No clinical and molecular evidence of artemisinin resistance was observed. However, these isolates present different phenotypic profiles in response to artemisinin treatments. Despite all RSA 0-3 h values less than 1.5%, six out of 46 (13.0%) isolates tested ex vivo and four out of six (66.7%) isolates tested in vitro were able to multiply after 48-hour treatments with 100 nM artemisinin. Moreover, five out of eight isolates tested showed faster parasite recovery after DHA treatment in kinetic assays. The presence of such phenotypes needs to be taken into account in the assessment of the efficacy of artemisinins in Mali. The assays presented here appear as valuable tools for the monitoring of artemisinin sensitivity in the field and thus could help to evaluate the risk of emergence of artemisinin resistance in Africa.

Oral artemisinin monotherapy removal from the private sector in Eastern Myanmar between 2012 and 2014.

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Khin, Hnin Su Su; Aung, Tin; Thi, Aung; White, Chris

2016-05-23

In 2012 the Artemisinin Monotherapy Therapy Replacement (AMTR) project was implemented in Eastern Myanmar to increase access to subsidized, quality-assured artemisinin combination therapy (ACT) and to remove oral artemisinin monotherapy (AMT) from the private sector. The aim of this paper is to examine changes over time in the private sector anti-malarial landscape and to illustrate the value of complementary interventions in the context of a national ACT subsidy. Three rounds of cross-sectional malaria medicine outlet surveys were conducted, in 2012, 2013 and 2014. Project intervention areas were selected from the Myanmar Artemisinin Resistance Containment (MARC) area. Provider detailing was implemented in these selected areas. Comparison areas were selected outside of this catchment area, from townships in close proximity to the MARC framework. Within each domain, multi-staged sampling was used to select areas for the survey. Outlets with the potential to sell or distribute anti-malarials in the private sector were screened for eligibility. The total number of outlets approached for an interview was as follows in the intervention and comparison areas, respectively: 2012, N = 2046 and 1612; 2013, N = 1636 and 1884; 2014, N = 2939 and 2941. The percentage of pharmacies, general retailers and mobile providers (classed as 'priority outlets') with oral AMT in stock on the day of the survey decreased over time in the intervention areas (2012 = 68 %; 2013 = 48 %; 2014 = 10 %). Conversely, quality-assured ACT availability increased among these outlets (2012 = 4 %; 2013 = 62 %; 2014 = 79 %). Relative oral AMT market share among priority outlets also decreased over time (2012 = 44 %; 2013 = 18 %; 2014 = 14 %), while market share of quality-assured ACT increased (2012 = 3 %; 2013 = 59 %; 2014 = 51 %). Among priority outlets in the comparison area, similar trends were observed, though changes over time were less substantial

Applying green chemistry to the photochemical route to artemisinin

Science.gov (United States)

Amara, Zacharias; Bellamy, Jessica F. B.; Horvath, Raphael; Miller, Samuel J.; Beeby, Andrew; Burgard, Andreas; Rossen, Kai; Poliakoff, Martyn; George, Michael W.

2015-06-01

Artemisinin is an important antimalarial drug, but, at present, the environmental and economic costs of its semi-synthetic production are relatively high. Most of these costs lie in the final chemical steps, which follow a complex acid- and photo-catalysed route with oxygenation by both singlet and triplet oxygen. We demonstrate that applying the principles of green chemistry can lead to innovative strategies that avoid many of the problems in current photochemical processes. The first strategy combines the use of liquid CO2 as solvent and a dual-function solid acid/photocatalyst. The second strategy is an ambient-temperature reaction in aqueous mixtures of organic solvents, where the only inputs are dihydroartemisinic acid, O2 and light, and the output is pure, crystalline artemisinin. Everything else—solvents, photocatalyst and aqueous acid—can be recycled. Some aspects developed here through green chemistry are likely to have wider application in photochemistry and other reactions.

Applying green chemistry to the photochemical route to artemisinin.

Science.gov (United States)

Amara, Zacharias; Bellamy, Jessica F B; Horvath, Raphael; Miller, Samuel J; Beeby, Andrew; Burgard, Andreas; Rossen, Kai; Poliakoff, Martyn; George, Michael W

2015-06-01

Artemisinin is an important antimalarial drug, but, at present, the environmental and economic costs of its semi-synthetic production are relatively high. Most of these costs lie in the final chemical steps, which follow a complex acid- and photo-catalysed route with oxygenation by both singlet and triplet oxygen. We demonstrate that applying the principles of green chemistry can lead to innovative strategies that avoid many of the problems in current photochemical processes. The first strategy combines the use of liquid CO2 as solvent and a dual-function solid acid/photocatalyst. The second strategy is an ambient-temperature reaction in aqueous mixtures of organic solvents, where the only inputs are dihydroartemisinic acid, O2 and light, and the output is pure, crystalline artemisinin. Everything else-solvents, photocatalyst and aqueous acid-can be recycled. Some aspects developed here through green chemistry are likely to have wider application in photochemistry and other reactions.

Evidence for the contribution of the hemozoin synthesis pathway of the murine Plasmodium yoelii to the resistance to artemisinin-related drugs.

Science.gov (United States)

Witkowski, Benoit; Lelièvre, Joel; Nicolau-Travers, Marie-Laure; Iriart, Xavier; Njomnang Soh, Patrice; Bousejra-Elgarah, Fatima; Meunier, Bernard; Berry, Antoine; Benoit-Vical, Françoise

2012-01-01

Plasmodium falciparum malaria is a major global health problem, causing approximately 780,000 deaths each year. In response to the spreading of P. falciparum drug resistance, WHO recommended in 2001 to use artemisinin derivatives in combination with a partner drug (called ACT) as first-line treatment for uncomplicated falciparum malaria, and most malaria-endemic countries have since changed their treatment policies accordingly. Currently, ACT are often the last treatments that can effectively and rapidly cure P. falciparum infections permitting to significantly decrease the mortality and the morbidity due to malaria. However, alarming signs of emerging resistance to artemisinin derivatives along the Thai-Cambodian border are of major concern. Through long-term in vivo pressures, we have been able to select a murine malaria model resistant to artemisinins. We demonstrated that the resistance of Plasmodium to artemisinin-based compounds depends on alterations of heme metabolism and on a loss of hemozoin formation linked to the down-expression of the recently identified Heme Detoxification Protein (HDP). These artemisinins resistant strains could be able to detoxify the free heme by an alternative catabolism pathway involving glutathione (GSH)-mediation. Finally, we confirmed that artemisinins act also like quinolines against Plasmodium via hemozoin production inhibition. The work proposed here described the mechanism of action of this class of molecules and the resistance to artemisinins of this model. These results should help both to reinforce the artemisinins activity and avoid emergence and spread of endoperoxides resistance by focusing in adequate drug partners design. Such considerations appear crucial in the current context of early artemisinin resistance in Asia.

Visual characterization and quantitative measurement of artemisinin-induced DNA breakage

Energy Technology Data Exchange (ETDEWEB)

Cai Huaihong [Bionanotechnology Lab, and Department of Chemistry, Jinan University, Guangzhou 510632 (China); Yang Peihui [Bionanotechnology Lab, and Department of Chemistry, Jinan University, Guangzhou 510632 (China)], E-mail: typh@jnu.edu.cn; Chen Jianan [Bionanotechnology Lab, and Department of Chemistry, Jinan University, Guangzhou 510632 (China); Liang Zhihong [Experiment and Technology Center, Jinan University, Guangzhou 510632 (China); Chen Qiongyu [Institute of Genetic Engineering, Jinan University, Guangzhou 510632 (China); Cai Jiye [Bionanotechnology Lab, and Department of Chemistry, Jinan University, Guangzhou 510632 (China)], E-mail: tjycai@jnu.edu.cn

2009-05-01

DNA conformational change and breakage induced by artemisinin, a traditional Chinese herbal medicine, have been visually characterized and quantitatively measured by the multiple tools of electrochemistry, UV-vis absorption spectroscopy, atomic force microscopy (AFM), and DNA electrophoresis. Electrochemical and spectroscopic results confirm that artemisinin can intercalate into DNA double helix, which causes DNA conformational changes. AFM imaging vividly demonstrates uneven DNA strand breaking induced by QHS interaction. To assess these DNA breakages, quantitative analysis of the extent of DNA breakage has been performed by analyzing AFM images. Basing on the statistical analysis, the occurrence of DNA breaks is found to depend on the concentration of artemisinin. DNA electrophoresis further validates that the intact DNA molecules are unwound due to the breakages occur at the single strands. A reliable scheme is proposed to explain the process of artemisinin-induced DNA cleavage. These results can provide further information for better understanding the anticancer activity of artemisinin.

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

Science.gov (United States)

Mohapatra, Pradyumna Kishore; Sarma, Devojit Kumar; Prakash, Anil; Bora, Khukumoni; Ahmed, Md. Atique; Sarma, Bibhas; Goswami, Basanta Kumar; Bhattacharyya, Dibya Ranjan; Mahanta, Jagadish

2014-01-01

relation to the efficacy of the currently used artemisinin combination therapy are discussed. PMID:25184337

Stable production of the antimalarial drug artemisinin in the moss Physcomitrella patens

DEFF Research Database (Denmark)

Binti Khairul Ikram, Nur Kusaira; Kashkooli, Arman Beyraghdar; Peramuna, Anantha Vithakshana

2017-01-01

study shows that P. patens can be a sustainable and efficient production platform of artemisinin that without further modifications allow for industrial scale production. A stable supply of artemisinin will lower the price of artemisinin-based treatments, hence become more affordable to the lower income...

Loss of artemisinin produced by Artemisia annua L. to the soil environment

Science.gov (United States)

Artemisia annua L. synthesizes and accumulates the secondary metabolite artemisinin, a compound with antimalarial properties. As cultivation of the plant is still the only cost effective source of artemisinin, the production takes place in monocultures of A. annua. Artemisinin is known to have inse...

Biological Actions of Artemisinin: Insights from Medicinal Chemistry Studies

Directory of Open Access Journals (Sweden)

Jian Li

2010-03-01

Full Text Available Artemisinins have become essential antimalarial drugs for increasingly widespread drug-resistant malaria strains. Although tremendous efforts have been devoted to decipher how this class of molecules works, their exact antimalarial mechanism is still an enigma. Several hypotheses have been proposed to explain their actions, including alkylation of heme by carbon-centered free radicals, interference with proteins such as the sarcoplasmic/endoplasmic calcium ATPase (SERCA, as well as damaging of normal mitochondrial functions. Besides artemisinins, other endoperoxides with various backbones have also been synthesized, some of which showed comparable or even higher antimalarial effects. It is noteworthy that among these artemisinin derivatives, some enantiomers displayed similar in vitro malaria killing efficacy. In this article, the proposed mechanisms of action of artemisinins are reviewed in light of medicinal chemistry findings characterized by efficacy-structure studies, with the hope of gaining more insight into how these potent drugs work.

Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia

Science.gov (United States)

Miotto, Olivo; Almagro-Garcia, Jacob; Manske, Magnus; MacInnis, Bronwyn; Campino, Susana; Rockett, Kirk A; Amaratunga, Chanaki; Lim, Pharath; Suon, Seila; Sreng, Sokunthea; Anderson, Jennifer M; Duong, Socheat; Nguon, Chea; Chuor, Char Meng; Saunders, David; Se, Youry; Lon, Chantap; Fukuda, Mark M; Amenga-Etego, Lucas; Hodgson, Abraham VO; Asoala, Victor; Imwong, Mallika; Takala-Harrison, Shannon; Nosten, Francois; Su, Xin-zhuan; Ringwald, Pascal; Ariey, Frédéric; Dolecek, Christiane; Hien, Tran Tinh; Boni, Maciej F; Thai, Cao Quang; Amambua-Ngwa, Alfred; Conway, David J; Djimdé, Abdoulaye A; Doumbo, Ogobara K; Zongo, Issaka; Ouedraogo, Jean-Bosco; Alcock, Daniel; Drury, Eleanor; Auburn, Sarah; Koch, Oliver; Sanders, Mandy; Hubbart, Christina; Maslen, Gareth; Ruano-Rubio, Valentin; Jyothi, Dushyanth; Miles, Alistair; O’Brien, John; Gamble, Chris; Oyola, Samuel O; Rayner, Julian C; Newbold, Chris I; Berriman, Matthew; Spencer, Chris CA; McVean, Gilean; Day, Nicholas P; White, Nicholas J; Bethell, Delia; Dondorp, Arjen M; Plowe, Christopher V; Fairhurst, Rick M; Kwiatkowski, Dominic P

2013-01-01

We describe an analysis of genome variation in 825 Plasmodium falciparum samples from Asia and Africa that reveals an unusual pattern of parasite population structure at the epicentre of artemisinin resistance in western Cambodia. Within this relatively small geographical area we have discovered several distinct but apparently sympatric parasite subpopulations with extremely high levels of genetic differentiation. Of particular interest are three subpopulations, all associated with clinical resistance to artemisinin, which have skewed allele frequency spectra and remarkably high levels of haplotype homozygosity, indicative of founder effects and recent population expansion. We provide a catalogue of SNPs that show high levels of differentiation in the artemisinin-resistant subpopulations, including codon variants in various transporter proteins and DNA mismatch repair proteins. These data provide a population genetic framework for investigating the biological origins of artemisinin resistance and for defining molecular markers to assist its elimination. PMID:23624527

The challenges of changing national malaria drug policy to artemisinin-based combinations in Kenya

Directory of Open Access Journals (Sweden)

Otieno Dorothy N

2007-05-01

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

Comparison of 9-hydroxy-artemisinin with artemisinin: interaction with bovine hemoglobin

Energy Technology Data Exchange (ETDEWEB)

Xiao, Mengsi; Yuan, Xiuxue; Xie, Wenli; Ge, Xuefeng [Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of Biomedical Materials, College of Chemistry and Materials Science, Analysis and Testing Center, Key Laboratory of applied photochemistry, Nanjing Normal University, Nanjing 210023 (China); Zhou, Yanhuai [Department of Physical Science and Technology, Nanjing Normal University, Nanjing 210023 (China); Zhou, Lin, E-mail: zhoulin@njnu.edu.cn [Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of Biomedical Materials, College of Chemistry and Materials Science, Analysis and Testing Center, Key Laboratory of applied photochemistry, Nanjing Normal University, Nanjing 210023 (China); Zhou, Jiahong, E-mail: zhoujiahong@njnu.edu.cn [Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of Biomedical Materials, College of Chemistry and Materials Science, Analysis and Testing Center, Key Laboratory of applied photochemistry, Nanjing Normal University, Nanjing 210023 (China); Shen, Jian [Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of Biomedical Materials, College of Chemistry and Materials Science, Analysis and Testing Center, Key Laboratory of applied photochemistry, Nanjing Normal University, Nanjing 210023 (China)

2015-04-15

In this article, the UV–vis absorption, steady state/time resolved fluorescence spectroscopy and synchronous fluorescence, circular dichrosim (CD) spectroscopy are used to investigate the interaction of artemisinin (QHS) and 9-hydroxy-artemisinin (9-OH QHS) with BHb, respectively. The UV–vis studies present that QHS and 9-OH QHS can disturb the structure of bovine hemoglobin (BHb). Fluorescence data presents that the binding constant of QHS and 9-OH QHS with BHb complex at 298 K is 4.32×10{sup 5} and 5.98×10{sup 5} M{sup −1}. CD spectra indicate QHS and 9-OH QHS can change the conformation of BHb. The comparison results suggest that the binding of BHb with 9-OH QHS is more stable and stronger than QHS, which means the structure modification of 9-OH QHS is meaningful. - Highlights: • QHS and 9-OH QHS both induce the heme group of BHb • QHS and 9-OH QHS both can change the polarity of BHb • The interaction between BHb and 9-OH QHS is stronger than QHS.

Artemisinins from folklore to modern medicine--transforming an herbal extract to life-saving drugs.

Science.gov (United States)

Weina, P J

2008-06-01

The history of the artemisinins from Ge Hong in China during the 4th century, to the re-discovery of the qing hao derivatives in the 1970s, to the explosion of artemisinin derivatives and combinations throughout the world today is a fascinating story. The central and underappreciated role of the United States Army's 'drug company' known as the Division of Experimental Therapeutics at the Walter Reed Army Institute of Research is a story worth relating. From being the first group outside China to extract the active component of qing hao, to leading the work on neurotoxicity of the class in animals, to bringing a Good Manufacturing Practices intravenous formulation to the worldwide market is traced.

Mobility dynamics of migrant workers and their socio-behavioral parameters related to malaria in Tier II, Artemisinin Resistance Containment Zone, Myanmar.

Science.gov (United States)

Hlaing, Thaung; Wai, Khin Thet; Oo, Tin; Sint, Nyan; Min, Tun; Myar, Shwe; Lon, Khin Nan; Naing, Myo Myint; Tun, Tet Toe; Maung, Nay Lin Yin; Galappaththy, Gawrie N L; Thimarsan, Krongthong; Wai, Tin Tin; Thaung, Lwin Ni Ni

2015-09-14

Areas with dynamic population movements are likely to be associated with higher levels of drug-resistant malaria. Myanmar Artemisinin Resistance Containment (MARC) Project has been launching since 2012. One of its components includes enhancing strategic approaches for mobile/migrant populations. We aimed to ascertain the estimated population of mobile migrant workers and their families in terms of stability in work setting in townships classified as tier II (areas with significant inflows of people from areas with credible evidence of artemisinin resistance) for Artemisinin resistance; to identify knowledge, attitudes and practices related to prevention and control of malaria and to recommend cost-effective strategies in planning for prevention and control of malaria. A prospective cross-sectional study conducted between June to December 2013 that covered 1,899 migrant groups from 16 tier II townships of Bago Region, and Kayin and Kayah States. Trained data collectors used a pre-tested and subsequently modified questionnaire and interviewed 2,381 respondents. Data of migrant groups were analyzed and compared by category depending upon the stability of their work setting. The estimated population of the 1,899 migrant groups categorized into three on the nature of their work setting was 56,030. Bago region was the commonest reported source of origin of migrant groups as well as their transit. Malaria volunteers were mostly within the reach of category 1 migrant groups (43/66, 65.2 %). Less stable migrant groups in category 3 had limited access to malaria information (14.7 %) and malaria care providers (22.1 %), low level of awareness and use of long-lasting insecticide-treated nets (46.6 and 38.8 %). Also, they had poor knowledge on malaria prevention on confirming suspected malaria and on using artemisinin combined therapy (ACT). Within two weeks prior to the survey, only 16.5 % of respondents in all categories combined reported acute undifferentiated fever

Stereoselective chlorothiolation of artemisinin-derived C-10 oxa terminal alkynes.

Science.gov (United States)

Surineni, Naresh; Buragohain, Pori; Barua, Nabin C

2015-11-01

A mild and efficient strategy is explored on the highly sensitive artemisinin-derived C-10 oxa terminal alkynes. Several novel artemisinin-derived (E)-2-chloroalkenyl sulfides (20) have been synthesized by using this protocol to study their anticancer activities.

Artemisinin, a miracle of traditional Chinese medicine.

Science.gov (United States)

Kong, Ling Yi; Tan, Ren Xiang

2015-12-19

The 2015 Nobel Prize in Physiology or Medicine, shared by Professor Youyou Tu, focused worldwide attention on artemisinin, a natural product antimalarial drug inspired by traditional Chinese medicine (TCM). This is the first Nobel Prize in natural sciences presented to a Chinese scientist for her impactful research work in China in collaboration with other Chinese scientists. We are delighted to provide the background and implications of the discovery of artemisinin, along with our personal viewpoints toward the affordability of modern medicines from natural products.

Stress Response and Artemisinin Resistance in Malaria Parasite

Science.gov (United States)

2017-07-01

AWARD NUMBER: W81XWH-16-1-0241 TITLE: Stress Response and Artemisinin Resistance in Malaria Parasite PRINCIPAL INVESTIGATOR: Juan C. Pizarro...SUBTITLE Stress Response and Artemisinin Resistance in Malaria Parasite 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-16-1-0241 5c. PROGRAM ELEMENT...13. SUPPLEMENTARY NOTES 14. ABSTRACT In malaria , drug resistance is a major treat to disease control efforts. Unfortunately, there is a significant

CYTOTOXICITY OF ARTEMISININ-RELATED ENDOPEROXIDES TO EHRLICH ASCITES TUMOR-CELLS

NARCIS (Netherlands)

WOERDENBAG, HJ; MOSKAL, TA; PRAS, N; MALINGRE, TM; ELFERALY, FS; KAMPINGA, HH; KONINGS, AWT

A series of artemisinin-related endoperoxides was tested for cytotoxicity to Ehrlich ascites tumor (EAT) cells using the microculture tetrazolium (MTT) assay. Artemisinin [1] had an IC50 value of 29.8 muM. Derivatives of dihydroartemisinin [2], being developed as antimalarial drugs (artemether [3],

Multiwalled carbon nanotubes effect on the bioavailability of artemisinin and its cytotoxity to cancerous cells

Science.gov (United States)

Rezaei, Behzad; Majidi, Najmeh; Noori, Shokoofe; Hassan, Zuhair M.

2011-12-01

Artemisinin regarded as one of the most promising anticancer drugs can bind to DNA with a binding constant of 1.04 × 104 M-1. The electrochemical experiments indicated that for longer incubation time periods, the reduction peak current of artemisinin on carbon nanotube modified electrode increases. Therefore, the uptake of drug molecules from a solution into CNTs will be achieved automatically by adsorption of 88.7% of artemisinin onto carbon nanotubes surface without alteration in drug properties. Hence, capability of carbon nanotubes to have synergistic effect on the bioavailability of artemisinin was investigated. Experimental tests on K562 cancer cell lines growth by MTT assay proved that multi-walled carbon nanotubes can enhance the cytotoxity of artemisinin to the targeted cancer cells with unprecedented accuracy and efficiency. The IC50 values were 65 and 35 μM for artemisinin and artemisinin loaded on multi-walled carbon nanotubes, respectively; demonstrating that artemisinin loaded on multi-walled carbon nanotubes is more effective in inhibition of cancer cell lines growth.

Multiwalled carbon nanotubes effect on the bioavailability of artemisinin and its cytotoxity to cancerous cells

International Nuclear Information System (INIS)

Rezaei, Behzad; Majidi, Najmeh; Noori, Shokoofe; Hassan, Zuhair M.

2011-01-01

Artemisinin regarded as one of the most promising anticancer drugs can bind to DNA with a binding constant of 1.04 × 10 4 M −1 . The electrochemical experiments indicated that for longer incubation time periods, the reduction peak current of artemisinin on carbon nanotube modified electrode increases. Therefore, the uptake of drug molecules from a solution into CNTs will be achieved automatically by adsorption of 88.7% of artemisinin onto carbon nanotubes surface without alteration in drug properties. Hence, capability of carbon nanotubes to have synergistic effect on the bioavailability of artemisinin was investigated. Experimental tests on K562 cancer cell lines growth by MTT assay proved that multi-walled carbon nanotubes can enhance the cytotoxity of artemisinin to the targeted cancer cells with unprecedented accuracy and efficiency. The IC 50 values were 65 and 35 μM for artemisinin and artemisinin loaded on multi-walled carbon nanotubes, respectively; demonstrating that artemisinin loaded on multi-walled carbon nanotubes is more effective in inhibition of cancer cell lines growth.

An artemisinin-mediated ROS evolving and dual protease light-up nanocapsule for real-time imaging of lysosomal tumor cell death.

Science.gov (United States)

Huang, Liwei; Luo, Yingping; Sun, Xian; Ju, Huangxian; Tian, Jiangwei; Yu, Bo-Yang

2017-06-15

Lysosomes are critical organelles for cellular homeostasis and can be used as potential targets to kill tumor cells from inside. Many photo-therapeutic methods have been developed to overproduce reactive oxygen species (ROS) to trigger lysosomal membrane permeabilization (LMP)-associated cell death pathway. However, these technologies rely on extra irradiation to activate the photosensitizers, which limits the applications in treating deep seated tumors and widespread metastatic lesions. This work reports a multifunctional nanocapsule to achieve targeted lysosomal tumor cell death without irradiation and real-time monitoring of drug effect through encapsulating artemisinin and dual protease light-up nanoprobe in a folate-functionalized liposome. The nanocapsule can be specifically uptaken by tumor cells via folate receptor-mediated endocytosis to enter lysosomes, in which artemisinin reacts with ferrous to generate ROS for LMP-associated cell death. By virtue of confocal fluorescence imaging, the artemisinin location in lysosome, ROS-triggered LMP and ultimate cell apoptosis can be visualized with the cathepsin B and caspase-3 activatable nanoprobe. Notably, the artemisinin-mediated ROS evolving for tumor therapy and real-time therapeutic monitoring were successfully implemented by living imaging in tumor-bearing mice, which broaden the nanocapsule for in vivo theranostics and may offer new opportunities for precise medicine. Copyright © 2016 Elsevier B.V. All rights reserved.

The pharmacokinetics of artemisinin suppositories in Vietnamese patients with malaria

NARCIS (Netherlands)

Koopmans, R.; Duc, D. D.; Kager, P. A.; Khanh, N. X.; Dien, T. K.; de Vries, P. J.; van Boxtel, C. J.

1998-01-01

Eight male Vietnamese malaria patients received 600 mg of artemisinin in a single dose of 3 suppositories containing 200 mg each; 24 h later they received a single oral dose of mefloquine, 15 mg/kg. Plasma artemisinin concentrations were measured until 24 h after dosing, and parasites were counted

Quality of Artemisinin-Based Combination Formulations for Malaria Treatment: Prevalence and Risk Factors for Poor Quality Medicines in Public Facilities and Private Sector Drug Outlets in Enugu, Nigeria

Science.gov (United States)

Kaur, Harparkash; Allan, Elizabeth Louise; Mamadu, Ibrahim; Hall, Zoe; Ibe, Ogochukwu; El Sherbiny, Mohamed; van Wyk, Albert; Yeung, Shunmay; Swamidoss, Isabel; Green, Michael D.; Dwivedi, Prabha; Culzoni, Maria Julia; Clarke, Siân; Schellenberg, David; Fernández, Facundo M.; Onwujekwe, Obinna

2015-01-01

Background Artemisinin-based combination therapies are recommended by the World Health Organisation (WHO) as first-line treatment for Plasmodium falciparum malaria, yet medication must be of good quality for efficacious treatment. A recent meta-analysis reported 35% (796/2,296) of antimalarial drug samples from 21 Sub-Saharan African countries, purchased from outlets predominantly using convenience sampling, failed chemical content analysis. We used three sampling strategies to purchase artemisinin-containing antimalarials (ACAs) in Enugu metropolis, Nigeria, and compared the resulting quality estimates. Methods ACAs were purchased using three sampling approaches - convenience, mystery clients and overt, within a defined area and sampling frame in Enugu metropolis. The active pharmaceutical ingredients were assessed using high-performance liquid chromatography and confirmed by mass spectrometry at three independent laboratories. Results were expressed as percentage of APIs stated on the packaging and used to categorise each sample as acceptable quality, substandard, degraded, or falsified. Results Content analysis of 3024 samples purchased from 421 outlets using convenience (n=200), mystery (n=1,919) and overt (n=905) approaches, showed overall 90.8% ACAs to be of acceptable quality, 6.8% substandard, 1.3% degraded and 1.2% falsified. Convenience sampling yielded a significantly higher prevalence of poor quality ACAs, but was not evident by the mystery and overt sampling strategies both of which yielded results that were comparable between each other. Artesunate (n=135; 4 falsified) and dihydroartemisinin (n=14) monotherapy tablets, not recommended by WHO, were also identified. Conclusion Randomised sampling identified fewer falsified ACAs than previously reported by convenience approaches. Our findings emphasise the need for specific consideration to be given to sampling frame and sampling approach if representative information on drug quality is to be obtained

[Extraction of artemisinin and synthesis of its derivates artesunate and artemether].

Science.gov (United States)

Chekem, L; Wierucki, S

2006-12-01

Artemisinin is extracted from Artemisia annua, a shrub also known as sweet wormwood that was used in traditional medicine in Asia for more than 1500 years. Recent studies in numerous malarious zones have demonstrated the effectiveness of artemisinin and have reported no evidence of the resistance now associated with almost all other antimalarials on the market. Despite its remarkable activity, artermisinin is not accessible to many patients due to high cost. This situation confronts all players in the fight against malaria with the urgent need to develop a simple process to produce massive supplies of artemisinin and its derivative at an affordable price. The purpose of the study described here was to develop a simple, cost-effective method that could be used by all professionals to extract artemisinin and transform it into artesunate or artemether. Artemisinin was extracted with dichloromethane and purified on the basis of variations in polarity and in the hydrophile/lipophile balance of solvents. Transformation into artesunate was a two-step process involving reduction to dihydroartemisinin using diisobutylaluminium hydride (DIBAL) followed by esterification using succinic anhydride. Artemether was obtained from dihydroartemisinin using boron trifluoride. Extraction using dichloromethane presents several advantages. Since dichloromethane is not explosive it can be safely transported and used for extraction on farms where Artemisia annua is grown. Evaporation and recovery of dichloromethane is relatively easy so that it can be re-used. These advantages result in a significant decrease in purchasing and shipping costs. Extraction on the farm eliminates the expense and facilities that would otherwise be required to transport and store leaves at the laboratory (250 kg of leaves yield 4 to 5 kg of raw artemisinin extract that yields approximately 1 kg of pure artemisinin). The low-cost process described here is feasible for any pharmaceutical laboratory including

The radio-sensitizing effects and mechanisms of artemisinin and its derivates

Energy Technology Data Exchange (ETDEWEB)

Jing, Zeng; Jianping, Cao; Saijun, Fan [School of Radiation Medicine and Public Health, Suzhou Univ., Suzhou (China)

2008-10-15

It has been proved that the antimalarial agent, Artemisinin and its derivates (such as artemether, arteether, artesunate, dihydroartemisinine, etc) boast powerful antitumor effects. Recently, researches have found that Artemisinin and its derivates can also enhance the radio-sensitivity of tumors through regulating cell cycle, creating cytotoxic effects induced by ROS, suppressing GSH activity and inhibiting the reparation of DNA damage etc. Moreover, they can reduce cell survival in a dose-dependent manner. This paper is paying more attention on the radio-sensitizing effects, characteristics and mechanisms of artemisinin and its derivates. (authors)

The radio-sensitizing effects and mechanisms of artemisinin and its derivates

International Nuclear Information System (INIS)

Zeng Jing; Cao Jianping; Fan Saijun

2008-01-01

It has been proved that the antimalarial agent, Artemisinin and its derivates (such as artemether, arteether, artesunate, dihydroartemisinine, etc) boast powerful antitumor effects. Recently, researches have found that Artemisinin and its derivates can also enhance the radio-sensitivity of tumors through regulating cell cycle, creating cytotoxic effects induced by ROS, suppressing GSH activity and inhibiting the reparation of DNA damage etc. Moreover, they can reduce cell survival in a dose-dependent manner. This paper is paying more attention on the radio-sensitizing effects, characteristics and mechanisms of artemisinin and its derivates. (authors)

RNAi down-regulation of cinnamate-4-hydroxylase increases artemisinin biosynthesis in Artemisia annua.

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Kumar, Ritesh; Vashisth, Divya; Misra, Amita; Akhtar, Md Qussen; Jalil, Syed Uzma; Shanker, Karuna; Gupta, Madan Mohan; Rout, Prashant Kumar; Gupta, Anil Kumar; Shasany, Ajit Kumar

2016-05-25

Cinnamate-4-hydroxylase (C4H) converts trans-cinnamic acid (CA) to p-coumaric acid (COA) in the phenylpropanoid/lignin biosynthesis pathway. Earlier we reported increased expression of AaCYP71AV1 (an important gene of artemisinin biosynthesis pathway) caused by CA treatment in Artemisia annua. Hence, AaC4H gene was identified, cloned, characterized and silenced in A. annua with the assumption that the elevated internal CA due to knock down may increase the artemisinin yield. Accumulation of trans-cinnamic acid in the plant due to AaC4H knockdown was accompanied with the reduction of p-coumaric acid, total phenolics, anthocyanin, cinnamate-4-hydroxylase (C4H) and phenylalanine ammonia lyase (PAL) activities but increase in salicylic acid (SA) and artemisinin. Interestingly, feeding trans-cinnamic acid to the RNAi line increased the level of artemisinin along with benzoic (BA) and SA with no effect on the downstream metabolites p-coumaric acid, coniferylaldehyde and sinapaldehyde, whereas p-coumaric acid feeding increased the content of downstream coniferylaldehyde and sinapaldehyde with no effect on BA, SA, trans-cinnamic acid or artemisinin. SA is reported earlier to be inducing the artemisinin yield. This report demonstrates the link between the phenylpropanoid/lignin pathway with artemisinin pathway through SA, triggered by accumulation of trans-cinnamic acid because of the blockage at C4H.

Nanoliposomal artemisinin for the treatment of murine visceral leishmaniasis

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Want MY

2017-03-01

Full Text Available Muzamil Y Want,1 Mohammad Islammudin,1 Garima Chouhan,1 Hani A Ozbak,2 Hassan A Hemeg,2 Asoke P Chattopadhyay,3 Farhat Afrin2 1Parasite Immunology Laboratory, Department of Biotechnology, Jamia Hamdard, Hamdard University, New Delhi, India; 2Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Taibah University, Medina, Saudi Arabia; 3Department of Chemistry, University of Kalyani, Kalyani, India Abstract: Visceral leishmaniasis (VL is a fatal, vector-borne disease caused by the intracellular protozoa of the genus Leishmania. Most of the therapeutics for VL are toxic, expensive, or ineffective. Sesquiterpenes are a new class of drugs with proven antimicrobial and antiviral activities. Artemisinin is a sesquiterpene lactone with potent antileishmanial activity, but with limited access to infected cells, being a highly lipophilic molecule. Association of artemisinin with liposome is a desirable strategy to circumvent the problem of poor accessibility, thereby improving its efficacy, as demonstrated in a murine model of experimental VL. Nanoliposomal artemisinin (NLA was prepared by thin-film hydration method and optimized using Box–Behnken design with a mean particle diameter of 83±16 nm, polydispersity index of 0.2±0.03, zeta potential of -27.4±5.7 mV, and drug loading of 33.2%±2.1%. Morphological study of these nanoliposomes by microscopy showed a smooth and spherical surface. The mechanism of release of artemisinin from the liposomes followed the Higuchi model in vitro. NLA was free from concomitant signs of toxicity, both ex vivo in murine macrophages and in vivo in healthy BALB/c mice. NLA significantly denigrated the intracellular infection of Leishmania donovani amastigotes and the number of infected macrophages ex vivo with an IC50 of 6.0±1.4 µg/mL and 5.1±0.9 µg/mL, respectively. Following treatment in a murine model of VL, NLA demonstrated superior efficacy compared to artemisinin with a

The use of paediatric artemisinin combinations in sub-Saharan Africa: a snapshot questionnaire survey of health care personnel

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Agnandji Selidji T

2011-12-01

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

Artemisinin, related sesquiterpenes, and essential oil in artemisia-annua during a vegetation period in vietnam

NARCIS (Netherlands)

Woerdenbag, HJ; Pras, N; CHAN, NG; BANG, BT; Bos, R; van Uden, W; Y, PV; BOI, NV; Batterman, S; LUGT, CB

The active principle of Artemisia annua L., artemisinin, is currently being developed to a registered antimalarial drug. For production purposes, plants with a high artemisinin content are required. We followed the development of the artemisinin content and of the biosynthetically related

Production of artemisinin and its derivatives in hairy roots of Artemisia dubia induced by rolA gene transformation

International Nuclear Information System (INIS)

Amanullah, M.; Mirza, B.; Zia, M.

2016-01-01

Artemisinin and its derivatives are phytochemical constituents of genus Artemisia. Demand of these plant secondary metabolitesis increasing due to their immense therapeutic significance. Besides their established antimalarial role, recent studies have also disclosed their anticancer potentials. It has made imperative to develop new and efficient sources of these compounds. Inherent synthetic challenges give biological sources preference over chemical synthesis of artemisinin and its derivatives. Therefore, genetic improvement of plants and, rather less preferentially, microbes is focus of current research to gain increase productivity of these valuable drugs. This study has analyzed A. dubiaas potential source of artemisinin and its derivatives. Transformation of Artemisia dubia was carried out using A. tumefaciens strain LBA 4404 containing rolA gene constructed on pRB 29. Healthy and acclimatizable transgenic plants were produced using optimized concentrations of BAP and NAA. Previously acclimatized rol ABC transgenic plants were also In vitro regenerated for comparative analysis of artemisinin and its derivatives. PCR amplification of rolA gene was done to confirm the integration of T-DNA in transgenic plants.TLC analysis was performed to evaluate comparative production of artemisinin and derivatives in rolA and rol ABC transgenic A. dubia. It revealed that rolA transgenic plants contain comparable amounts of these metabolites. Both type of transgenic plants manifested the enhancement of other uncharacterized compounds as well. Besides systematic optimization of In vitro regenerative protocol for Artemisia dubia, relative regeneration ability of rol transgenic and controlplants was also assessed at four regenerative stages. It was observed that unlike control, rol transgenic plants showed best root induction only on combination of auxins and cytokines. It was concluded that rol genes transformation of plants is an efficient tool to enhance their secondary

Genetic Transformation of Artemisia carvifolia Buch with rol Genes Enhances Artemisinin Accumulation.

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Erum Dilshad

Full Text Available The potent antimalarial drug artemisinin has a high cost, since its only viable source to date is Artemisia annua (0.01-0.8% DW. There is therefore an urgent need to design new strategies to increase its production or to find alternative sources. In the current study, Artemisia carvifolia Buch was selected with the aim of detecting artemisinin and then enhancing the production of the target compound and its derivatives. These metabolites were determined by LC-MS in the shoots of A. carvifolia wild type plants at the following concentrations: artemisinin (8μg/g, artesunate (2.24μg/g, dihydroartemisinin (13.6μg/g and artemether (12.8μg/g. Genetic transformation of A. carvifolia was carried out with Agrobacterium tumefaciens GV3101 harboring the rol B and rol C genes. Artemisinin content increased 3-7-fold in transgenics bearing the rol B gene, and 2.3-6-fold in those with the rol C gene. A similar pattern was observed for artemisinin analogues. The dynamics of artemisinin content in transgenics and wild type A.carvifolia was also correlated with the expression of genes involved in its biosynthesis. Real time qPCR analysis revealed the differential expression of genes involved in artemisinin biosynthesis, i.e. those encoding amorpha-4, 11 diene synthase (ADS, cytochrome P450 (CYP71AV1, and aldehyde dehydrogenase 1 (ALDH1, with a relatively higher transcript level found in transgenics than in the wild type plant. Also, the gene related to trichome development and sesquiterpenoid biosynthesis (TFAR1 showed an altered expression in the transgenics compared to wild type A.carvifolia, which was in accordance with the trichome density of the respective plants. The trichome index was significantly higher in the rol B and rol C gene-expressing transgenics with an increased production of artemisinin, thereby demonstrating that the rol genes are effective inducers of plant secondary metabolism.

Pharmacovigilance of artemether-lumefantrine in pregnant women followed until delivery in Rwanda

NARCIS (Netherlands)

Rulisa, Stephen; Kaligirwa, Nadine; Agaba, Steven; Karema, Corine; Mens, Petra F.; de Vries, Peter J.

2012-01-01

Background: The World Health Organization presently recommends Artemisinin-based combination therapy (ACT) as first-line therapy for uncomplicated P. falciparum malaria. Many malaria-endemic countries, including Rwanda, have adopted these treatment guidelines. The Artemisinin derivative Artemether,

Investigation on the relationship between solubility of artemisinin and polyvinylpyrroli done addition by using DAOSD approach

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Zhang, Jin; Guo, Ran; He, Anqi; Weng, Shifu; Gao, Xiuxiang; Xu, Yizhuang; Noda, Isao; Wu, Jinguang

2017-07-01

In this work, we investigated the influence of polyvinylpyrrolidone (PVP) on the solubility of artemisinin in aqueous solution by using quantitative 1H NMR. Experimental results demonstrate that about 4 times of incremental increase occurs on the solubility of artemisinin upon introducing PVP. In addition, dipole-dipole interaction between the ester group of artemisinin and the amide group of N-methylpyrrolidone (NMP), a model compound of PVP, is characterized by two-dimensional (2D) correlation FTIR spectroscopy with the DAOSD (Double Asynchronous Orthogonal Sample Design) approach developed in our previous work. The observation of cross peaks in a pair of 2D asynchronous spectra suggests that dipole-dipole interaction indeed occurs between the ester group of artemisinin and amide group of NMP. Moreover, the pattern of cross peaks indicates that the carbonyl band of artemisinin undergoes blue-shift while the bandwidth and absorptivity increases via interaction with NMP, and the amide band of NMP undergoes blue-shift while the absorptivity increases via interaction with artemisinin. Dipole-dipole interaction, as one of the strongest intermolecular interaction between artemisinin and excipient, may play an important role in the enhancement of the solubility of artemisinin in aqueous solution.

Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance.

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Con Dogovski

2015-04-01

Full Text Available Successful control of falciparum malaria depends greatly on treatment with artemisinin combination therapies. Thus, reports that resistance to artemisinins (ARTs has emerged, and that the prevalence of this resistance is increasing, are alarming. ART resistance has recently been linked to mutations in the K13 propeller protein. We undertook a detailed kinetic analysis of the drug responses of K13 wild-type and mutant isolates of Plasmodium falciparum sourced from a region in Cambodia (Pailin. We demonstrate that ART treatment induces growth retardation and an accumulation of ubiquitinated proteins, indicative of a cellular stress response that engages the ubiquitin/proteasome system. We show that resistant parasites exhibit lower levels of ubiquitinated proteins and delayed onset of cell death, indicating an enhanced cell stress response. We found that the stress response can be targeted by inhibiting the proteasome. Accordingly, clinically used proteasome inhibitors strongly synergize ART activity against both sensitive and resistant parasites, including isogenic lines expressing mutant or wild-type K13. Synergy is also observed against Plasmodium berghei in vivo. We developed a detailed model of parasite responses that enables us to infer, for the first time, in vivo parasite clearance profiles from in vitro assessments of ART sensitivity. We provide evidence that the clinical marker of resistance (delayed parasite clearance is an indirect measure of drug efficacy because of the persistence of unviable parasites with unchanged morphology in the circulation, and we suggest alternative approaches for the direct measurement of viability. Our model predicts that extending current three-day ART treatment courses to four days, or splitting the doses, will efficiently clear resistant parasite infections. This work provides a rationale for improving the detection of ART resistance in the field and for treatment strategies that can be employed in areas

Design of Drug Delivery Systems Containing Artemisinin and Its Derivatives

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Blessing Atim Aderibigbe

2017-02-01

Full Text Available Artemisinin and its derivatives have been reported to be experimentally effective for the treatment of highly aggressive cancers without developing drug resistance, they are useful for the treatment of malaria, other protozoal infections and they exhibit antiviral activity. However, they are limited pharmacologically by their poor bioavailability, short half-life in vivo, poor water solubility and long term usage results in toxicity. They are also expensive for the treatment of malaria when compared to other antimalarials. In order to enhance their therapeutic efficacy, they are incorporated onto different drug delivery systems, thus yielding improved biological outcomes. This review article is focused on the currently synthesized derivatives of artemisinin and different delivery systems used for the incorporation of artemisinin and its derivatives.

PERBANDINGAN EFEKTIFITAS DOSIS SEKALI MINUM ARTEMISININ-NAFTOKUIN DENGAN DIHIDROARTEMISININ-PIPERAKUIN PADA PENGOBATAN PASIEN DEWASA MALARIA FALSIPARUM TANPA KOMPLIKASI

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Hadjar Siswantoro

2015-01-01

Full Text Available AbstrakKombinasi pengobatan berbasis artemisinin yang praktis dan sederhana dengan kepatuhan minum obat yang baik telah ditunjukkan dalam artikel utama: “Efficacy and Safety of Artemisinin-naphthoquine versus  dihydroartemisinin-piperaquine  in  adult  patients  with  uncomplicated  malaria:  a  multi-centre study in Indonesia” pada pasien dewasa dengan malaria apapun. Untuk melengkapi data terdahulu, disajikan  data  keamanan  dan  efikasi  obat  sekali  minum  artemisinin-naftokuin  (ANT  dibandingkan dihidroartemisinin-piperakuin  (DHP  pada  pengobatan  pasien  dewasa  dengan  malaria  falsiparum. Tujuan penelitian ini adalah untuk membandingkan efikasi dan keamanan antara ANT dengan DHP pada pasien dewasa dengan malaria falsiparum. Studi dilakukan dengan uji klinik fase III, acak, terbuka menggunakan amplop terbuka, menggunakan protokol who untuk menilai efikasi obat antimalaria yang dipantau selama 42 hari. Hasil penelitian menunjukkan efikasi ANT dan DHP pada hari ke-42 berturutturut adalah 100% (74/74 dan 97,1% (66/68 dengan 2,9% (2/68 mengalami kegagalan pengobatan kasep.  Kejadian  sampingan  adalah  2,5%  batuk  setelah  pengobatan  ANT,  dan  1,4%  batuk  setelah pengobatan  DHP.  Kesimpulan  yang  diambil ANT  dosis  tunggal  aman  dan  efektif  seperti  DHP  dosis tunggal harian selama 3 hari untuk pengobatan malaria falsiparum dewasa tanpa komplikasi.Kata  kunci:  malaria,  dihidroartemisinin-piperakuin,  artemisinin-naftokuin,  Plasmodium  falciparum, Indonesia.AbstractA practical and simple Artemisinin based combination  therapy (ACT with good compliance  in adult patients for all malaria species has been shown in the first article: “Efficacy and Safety of Artemisininnaphthoquine  versus  dihydroartemisinin-piperaquine  in  adult  patients  with  uncomplicated  malaria:  a multi-centre study in Indonesia”. It is worth to add data safety and efficacy of

Ensuring sustained ACT production and reliable artemisinin supply

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Olliaro Piero

2007-09-01

Full Text Available Abstract Introduction This paper reviews recent trends in the production, supply and price of the active ingredients as well as finished ACT products. Production and cost data provided in this paper are based on an ongoing project (Artepal. Stability data are derived from a development project on rectal artesunate. Discussion The artemisinin raw material and its derivatives appear to be very stable compared to the finished products. Supply of artemisinin changed in May 2004 when the Global Fund shifted financial support to qualified countries from chloroquine or sulphadoxine-pyrimethamine to an ACT for treatment of malaria. First, there was a sudden shortage of the starting material, and short term scarcity led to a steep rise in API price: it increased dramatically in 2004, from $350 per kg to more than $1000. Second, there was a parallel increase in the number of companies extracting artemisinin from 10 to 80 between 2003 and 2005 in China, and from 3 to 20 in Vietnam. Commercial cultivation began also in East Africa and Madagascar. A steady and predictable demand for the crop can eliminate such wide fluctuations and indirectly contribute to price stability of the herb, the API and ACT. With appropriate mechanisms to reduce those fluctuations, the cost of artemisinin might decrease sustainably to US$ 250–300 per kg. Conclusion Today the global health community is facing the risk of another cyclical swing with lower demand feeding into reduced planting of A. annua and, thereafter, a new shortage of the raw material and higher API prices. International donors, the largest purchasers for ACTs could better coordinate their activities, in order to guarantee purchase of ACTs and consequently of API with manufacturers. In parallel, the base of quality producers of APIs and finished ACT products needs to be broadened. While the ACT programme is still in its early stages, the consequences of another wave of artemisinin and ACT shortages would

Ensuring sustained ACT production and reliable artemisinin supply.

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Kindermans, Jean-Marie; Pilloy, Jacques; Olliaro, Piero; Gomes, Melba

2007-09-15

This paper reviews recent trends in the production, supply and price of the active ingredients as well as finished ACT products. Production and cost data provided in this paper are based on an ongoing project (Artepal). Stability data are derived from a development project on rectal artesunate. The artemisinin raw material and its derivatives appear to be very stable compared to the finished products. Supply of artemisinin changed in May 2004 when the Global Fund shifted financial support to qualified countries from chloroquine or sulphadoxine-pyrimethamine to an ACT for treatment of malaria. First, there was a sudden shortage of the starting material, and short term scarcity led to a steep rise in API price: it increased dramatically in 2004, from $350 per kg to more than $1000. Second, there was a parallel increase in the number of companies extracting artemisinin from 10 to 80 between 2003 and 2005 in China, and from 3 to 20 in Vietnam. Commercial cultivation began also in East Africa and Madagascar.A steady and predictable demand for the crop can eliminate such wide fluctuations and indirectly contribute to price stability of the herb, the API and ACT. With appropriate mechanisms to reduce those fluctuations, the cost of artemisinin might decrease sustainably to US$ 250-300 per kg. Today the global health community is facing the risk of another cyclical swing with lower demand feeding into reduced planting of A. annua and, thereafter, a new shortage of the raw material and higher API prices. International donors, the largest purchasers for ACTs could better coordinate their activities, in order to guarantee purchase of ACTs and consequently of API with manufacturers. In parallel, the base of quality producers of APIs and finished ACT products needs to be broadened.While the ACT programme is still in its early stages, the consequences of another wave of artemisinin and ACT shortages would permanently discredit it and impede any progress in rolling malaria back.

Biotransformation of artemisinin using cell suspension cultures of Catharanthus roseus (L.) G.Don and Lavandula officinalis L.

Science.gov (United States)

Patel, Suman; Gaur, Rashmi; Verma, Priyanka; Bhakuni, Rajendra S; Mathur, Archana

2010-08-01

Artemisinin, an antimalarial compound, at 5 mg/40 ml, was transformed by cell suspension cultures of Catharanthus roseus (L.) G.Don and Lavandula officinalis L. into deoxyartemisinin with yields >78% (3.93 mg deoxyartemisinin from 5 mg artemisinin). Maximum conversion (78.6 and 78%) occurred after 6 and 7 days of adding artemisinin to 20 and 9 days old cultures of C. roseus and L. officinalis, respectively. The procedure was scaled up by and 500 mg artemisinin was transformed into 390 mg deoxyartemisinin. Addition of artemisinin at the beginning of the culture cycle resulted in >50% reduction in dry biomass production with no bioconversion. Conversion of artemisinin occurred intracellularly followed by leaching of the product into the medium.

PUVA combination therapy.

Science.gov (United States)

Morison, W L

1985-08-01

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.

Feasibility, safety and effectiveness of combining home based malaria management and seasonal malaria chemoprevention in children less than 10 years in Senegal

DEFF Research Database (Denmark)

Tine, Roger C K; Ndour, Cheikh T; Faye, Babacar

2014-01-01

Home-based management of malaria (HMM) may improve access to diagnostic testing and treatment with artemisinin combination therapy (ACT). In the Sahel region, seasonal malaria chemoprevention (SMC) is now recommended for the prevention of malaria in children. It is likely that combinations...... of antimalarial interventions can reduce the malaria burden. This study assessed the feasibility, effectiveness and safety of combining SMC and HMM delivered by community health workers (CHWs)....

Temperature-dependent toxicity of artemisinin toward the macrophyte Lemna minor and the algae Pseudokirchneriella subcapitata

DEFF Research Database (Denmark)

Jessing, Karina Knudsmark; Andresen, Marianne; Cedergreen, Nina

2014-01-01

- and groundwater. To make better risk assessments of A. annua which is cultivated under varying climatic conditions, the temperature-dependent toxicity of artemisinin toward the green algae Pseudokirchneriella subcapitata and the macrophyte Lemna minor was evaluated at temperatures ranging from 10 to 30°C....... To include a possible effect of temperature on the degradation rate of artemisinin, artemisinin concentrations were measured during the experiment and toxicity was related to the time-weighted averages of exposure concentrations. The toxicity of artemisinin toward the macrophyte L. minor and the algae P....... subcapitata increased with increasing growth rates, and we conclude that bioavailability plays a minor role in the observed relation between temperature and toxicity of artemisinin. The obtained results are important for possible future risk assessment of A. annua cultivation....

Cold stress improves the production of artemisinin depending on the increase in endogenous jasmonate.

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Liu, Wanhong; Wang, Huanyan; Chen, Yupei; Zhu, Shunqin; Chen, Min; Lan, Xiaozhong; Chen, Guoping; Liao, Zhihua

2017-05-01

Previous publications reported that the artemisinin level was increased in Artemisia annua following a night-frost period. However, the molecular mechanism was not clear. In this study, we found that exogenous jasmonate (JA) effectively enhanced the freezing tolerance of A. annua. The JA biosynthetic genes (LOX1, LOX2, allene oxide cyclase [AOC], and jasmonate resistant 1 [JAR1]) were induced by cold stress, leading to an increase in endogenous JA in cold-treated A. annua. Increased endogenous JA enhanced the expression of three JA-responsive transcription factors, ethylene response factor 1, ethylene response factor 2, and octadecanoid-responsive AP2/ERF, all of which were reported to transcriptionally activate the expression of artemisinin biosynthetic genes, such as amorpha-4,11-diene synthase (ADS), CYP71AV1, DBR2, and aldehyde dehydrogenase 1 (ALDH1). Furthermore, the expression levels of the four artemisinin biosynthetic genes were also significantly increased under cold stress. Consequently, the levels of artemisinin and related secondary metabolites, such as dihydroartemisinic acid, artemisinin B, and artemisinic acid, were increased in A. annua under cold stress. Our study points to a molecular mechanism in which the production of artemisinin is regulated by cold stress in A. annua. © 2016 International Union of Biochemistry and Molecular Biology, Inc.

Assessing the potential impact of artemisinin and partner drug resistance in sub-Saharan Africa.

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Slater, Hannah C; Griffin, Jamie T; Ghani, Azra C; Okell, Lucy C

2016-01-06

Artemisinin and partner drug resistant malaria parasites have emerged in Southeast Asia. If resistance were to emerge in Africa it could have a devastating impact on malaria-related morbidity and mortality. This study estimates the potential impact of artemisinin and partner drug resistance on disease burden in Africa if it were to emerge. Using data from Asia and Africa, five possible artemisinin and partner drug resistance scenarios are characterized. An individual-based malaria transmission model is used to estimate the impact of each resistance scenario on clinical incidence and parasite prevalence across Africa. Artemisinin resistance is characterized by slow parasite clearance and partner drug resistance is associated with late clinical failure or late parasitological failure. Scenarios with high levels of recrudescent infections resulted in far greater increases in clinical incidence compared to scenarios with high levels of slow parasite clearance. Across Africa, it is estimated that artemisinin and partner drug resistance at levels similar to those observed in Oddar Meanchey province in Cambodia could result in an additional 78 million cases over a 5 year period, a 7% increase in cases compared to a scenario with no resistance. A scenario with high levels of slow clearance but no recrudescence resulted in an additional 10 million additional cases over the same period. Artemisinin resistance is potentially a more pressing concern than partner drug resistance due to the lack of viable alternatives. However, it is predicted that a failing partner drug will result in greater increases in malaria cases and morbidity than would be observed from artemisinin resistance only.

Isoprenoid drugs, biofuels, and chemicals--artemisinin, farnesene, and beyond.

Science.gov (United States)

George, Kevin W; Alonso-Gutierrez, Jorge; Keasling, Jay D; Lee, Taek Soon

2015-01-01

Isoprenoids have been identified and used as natural pharmaceuticals, fragrances, solvents, and, more recently, advanced biofuels. Although isoprenoids are most commonly found in plants, researchers have successfully engineered both the eukaryotic and prokaryotic isoprenoid biosynthetic pathways to produce these valuable chemicals in microorganisms at high yields. The microbial synthesis of the precursor to artemisinin--an important antimalarial drug produced from the sweet wormwood Artemisia annua--serves as perhaps the most successful example of this approach. Through advances in synthetic biology and metabolic engineering, microbial-derived semisynthetic artemisinin may soon replace plant-derived artemisinin as the primary source of this valuable pharmaceutical. The richness and diversity of isoprenoid structures also make them ideal candidates for advanced biofuels that may act as "drop-in" replacements for gasoline, diesel, and jet fuel. Indeed, the sesquiterpenes farnesene and bisabolene, monoterpenes pinene and limonene, and hemiterpenes isopentenol and isopentanol have been evaluated as fuels or fuel precursors. As in the artemisinin project, these isoprenoids have been produced microbially through synthetic biology and metabolic engineering efforts. Here, we provide a brief review of the numerous isoprenoid compounds that have found use as pharmaceuticals, flavors, commodity chemicals, and, most importantly, advanced biofuels. In each case, we highlight the metabolic engineering strategies that were used to produce these compounds successfully in microbial hosts. In addition, we present a current outlook on microbial isoprenoid production, with an eye towards the many challenges that must be addressed to achieve higher yields and industrial-scale production.

Artemisinin inhibits chloroplast electron transport activity: mode of action.

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Adyasha Bharati

Full Text Available Artemisinin, a secondary metabolite produced in Artemisia plant species, besides having antimalarial properties is also phytotoxic. Although, the phytotoxic activity of the compound has been long recognized, no information is available on the mechanism of action of the compound on photosynthetic activity of the plant. In this report, we have evaluated the effect of artemisinin on photoelectron transport activity of chloroplast thylakoid membrane. The inhibitory effect of the compound, under in vitro condition, was pronounced in loosely and fully coupled thylakoids; being strong in the former. The extent of inhibition was drastically reduced in the presence of uncouplers like ammonium chloride or gramicidin; a characteristic feature described for energy transfer inhibitors. The compound, on the other hand, when applied to plants (in vivo, behaved as a potent inhibitor of photosynthetic electron transport. The major site of its action was identified to be the Q(B; the secondary quinone moiety of photosystemII complex. Analysis of photoreduction kinetics of para-benzoquinone and duroquinone suggest that the inhibition leads to formation of low pool of plastoquinol, which becomes limiting for electron flow through photosystemI. Further it was ascertained that the in vivo inhibitory effect appeared as a consequence of the formation of an unidentified artemisinin-metabolite rather than by the interaction of the compound per se. The putative metabolite of artemisinin is highly reactive in instituting the inhibition of photosynthetic electron flow eventually reducing the plant growth.

Mechanism of artemisinin phytotoxicity action: induction of reactive oxygen species and cell death in lettuce seedlings.

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Yan, Zhi-Qiang; Wang, Dan-Dan; Ding, Lan; Cui, Hai-Yan; Jin, Hui; Yang, Xiao-Yan; Yang, Jian-She; Qin, Bo

2015-03-01

Artemisinin has been recognized as an allelochemical that inhibits growth of several plant species. However, its mode of action is not well clarified. In this study, the mechanism of artemisinin phytotoxicity on lettuce seedlings was investigated. Root and shoot elongation of lettuce seedlings were inhibited by artemisinin in a concentration-dependent manner. The compound effectively arrested cell division and caused loss of cell viability in root tips of lettuce. Overproduction of reactive oxygen species (ROS) was induced by artemisinin. Lipid peroxidation, proline overproduction and reduction of chlorophyll content in lettuce seedlings were found after treatments. These results suggested that artemisinin could induce ROS overproduction, which caused membrane lipids peroxidation and cell death, and impacted mitosis and physiological processes, resulting in growth inhibition of receptor plants. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Profil Fenotipik Plasmodium falciparum Galur Papua 2300 Akibat Paparan Antimalaria Artemisinin in Vitro

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Lilik Maslachah

2015-03-01

Full Text Available The presence of the P. falciparum resistance and decreased of efficacy against artemisinin and its derivatives result in increasingly complex malaria issues. Malaria has become one of the currently unresolved world’s health problems due to the lack of new artemisinin replacement drugs. This study aimed to provide evidence that the repeated exposure of in vitro artemisinin may cause a change in P. falciparum Papua 2300 strain phenotypic. This study was conducted during the period of February to November 2013 in Biomedics Brawijaya University and the Faculty of Veterinary Medicine, Airlangga University. A post-test control only experimental design was used. In vitro cultures of P. falciparum Papua 2300 strain were treated by repeated artemisin in IC50 concentration and were observed for their viability and IC50 using probit analysis. The control group did not show any changes after IC50value and PO1 treatment. An increase in IC50 value was occurred after PO2. Repeated exposures of artemisinin in PO2, PO3 and PO4 had shorter viability periods than PO1. The viability of was stable after PO3 in this group. In conclusion, repeated exposures of artemisinin influence changes in IC50 value and viability period of P. falciparum Papua 2300 strain.

Interaction analysis of hemin with antimalaria artemisinin groups ...

African Journals Online (AJOL)

Arun Kumar Agnihotri

spectrophotometric method are consistent with molecular mechanical calculations ... of a significant interaction between hemin with antimalarial artemisinin ... Bioinformatics Protein Data Bank through ... Compute-Simulation dock program.

The pharmacokinetics of artemisinin after administration of two different suppositories to healthy Vietnamese subjects

NARCIS (Netherlands)

Koopmans, R.; Ha, L. D.; Duc, D. D.; Dien, T. K.; Kager, P. A.; Khanh, N. X.; van Boxtel, C. J.; de Vries, P. J.

1999-01-01

Eight healthy Vietnamese male subjects received 400 mg artemisinin formulated into fatty suppositories (FS), and six different subjects received 500 mg of artemisinin formulated in polyethylene glycol suppositories (PEGS). Plasma concentrations were measured by high-performance liquid chromatography

Effect of food intake on pharmacokinetics of oral artemisinin in healthy Vietnamese subjects

NARCIS (Netherlands)

Dien, T. K.; de Vries, P. J.; Khanh, N. X.; Koopmans, R.; Binh, L. N.; Duc, D. D.; Kager, P. A.; van Boxtel, C. J.

1997-01-01

The influence of food intake on the pharmacokinetics of artemisinin was studied with six healthy Vietnamese male subjects. In a crossover study, artemisinin capsules (500 mg) were administered with and without food after an overnight fast. Plasma samples were obtained up to 24 h after intake of each

Artemisinin and sesquiterpene precursors in dead and green leaves of Artemisia annua L. crops

NARCIS (Netherlands)

Lommen, W.J.M.; Elzinga, S.; Verstappen, F.W.A.; Bouwmeester, H.J.

2007-01-01

This paper analyses the accumulation and concentrations of the antimalarial artemisinin in green and dead leaves of Artemisia annua crops in two field experiments. Concentration differences were analysed as being determined by (a) the total production of artemisinin plus its upstream precursors

Pharmacovigilance of artemether-lumefantrine in pregnant women followed until delivery in Rwanda

OpenAIRE

Rulisa Stephen; Kaligirwa Nadine; Agaba Steven; Karema Corine; Mens Petra F; de Vries Peter J

2012-01-01

Abstract Background The World Health Organization presently recommends Artemisinin-based combination therapy (ACT) as first-line therapy for uncomplicated P. falciparum malaria. Many malaria-endemic countries, including Rwanda, have adopted these treatment guidelines. The Artemisinin derivative Artemether, in combination with lumefantrine, is currently used in Rwanda for malaria during the second and third trimesters of pregnancy. Safety data on the use of ACT in pregnancy are still limited t...

Artemisinin derivatives versus quinine in treating severe malaria in children: a systematic review

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de Frey Albie

2008-10-01

Full Text Available Abstract Background The efficacy of intravenous quinine, which is the mainstay for treating severe malaria in children, is decreasing in South East Asia and Africa. Artemisinin derivatives are a potential alternative to quinine. However, their efficacy compared to quinine in treating severe malaria in children is not clearly understood. The objective of this review was to assess the efficacy of parenteral artemisinin derivatives versus parenteral quinine in treating severe malaria in children. Methods All randomized controlled studies comparing parenteral artemisinin derivatives with parenteral quinine in treating severe malaria in children were included in the review. Data bases searched were: The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2007, MEDLINE (1966 to February 2008, EMBASE (1980 to February 2008, and LILACS (1982 to February 2008. Dichotomous variables were compared using risk ratios (RR and the continuous data using weighted mean difference (WMD. Results Twelve trials were included (1,524 subjects. There was no difference in mortality between artemisinin derivatives and quinine (RR = 0.90, 95% CI 0.73 to 1.12. The artemisinin derivatives resolved coma faster than quinine (WMD = -4.61, 95% CI: -7.21 to -2.00, fixed effect model, but when trials with adequate concealment only were considered this differences disappeared. There was no statistically significant difference between the two groups in parasite clearance time, fever clearance time, incidence of neurological sequelae and 28th day cure rate. One trial reported significantly more local reactions at the injection site with intramuscular quinine compared to artemether. None of the trials was adequately powered to demonstrate equivalence. Conclusion There was no evidence that treatment of children with severe malaria with parenteral artemisinin derivatives was associated with lower mortality or long-term morbidity compared to parenteral quinine

Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker.

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Tun, Kyaw M; Imwong, Mallika; Lwin, Khin M; Win, Aye A; Hlaing, Tin M; Hlaing, Thaung; Lin, Khin; Kyaw, Myat P; Plewes, Katherine; Faiz, M Abul; Dhorda, Mehul; Cheah, Phaik Yeong; Pukrittayakamee, Sasithon; Ashley, Elizabeth A; Anderson, Tim J C; Nair, Shalini; McDew-White, Marina; Flegg, Jennifer A; Grist, Eric P M; Guerin, Philippe; Maude, Richard J; Smithuis, Frank; Dondorp, Arjen M; Day, Nicholas P J; Nosten, François; White, Nicholas J; Woodrow, Charles J

2015-04-01

Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations. We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar. Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations. Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation. Copyright © 2015

Examining appropriate diagnosis and treatment of malaria: availability and use of rapid diagnostic tests and artemisinin-based combination therapy in public and private health facilities in south east Nigeria

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Uzochukwu Benjamin SC

2010-08-01

Full Text Available Abstract Background Rapid diagnostic tests (RDTs and Artemisinin-based combination therapy (ACT have been widely advocated by government and the international community as cost-effective tools for diagnosis and treatment of malaria. ACTs are now the first line treatment drug for malaria in Nigeria and RDTs have been introduced by the government to bridge the existing gaps in proper diagnosis. However, it is not known how readily available these RDTs and ACTs are in public and private health facilities and whether health workers are actually using them. Hence, this study investigated the levels of availability and use of RDTs and ACTs in these facilities. Methods The study was undertaken in Enugu state, southeast Nigeria in March 2009. Data was collected from heads of 74 public and private health facilities on the availability and use of RDTs and ACTs. Also, the availability of RDTs and the types of ACTs that were available in the facilities were documented. Results Only 31.1% of the health facilities used RDTs to diagnose malaria. The majority used the syndromic approach. However, 61.1% of healthcare providers were aware of RDTs. RDTs were available in 53.3% of the facilities. Public health facilities and health facilities in the urban areas were using RDTs more and these were mainly bought from pharmacy shops and supplied by NGOs. The main reasons given for non use are unreliability of RDTs, supply issues, costs, preference for other methods of diagnosis and providers' ignorance. ACTs were the drug of choice for most public health facilities and the drugs were readily available in these facilities. Conclusion Although many providers were knowledgeable about RDTs, not many facilities used it. ACTS were readily available and used in public but not private health facilities. However, the reported use of ACTs with limited proper diagnosis implies that there could be high incidence of inappropriate case management of malaria which can also increase

Compartmentalized Metabolic Engineering for Artemisinin Biosynthesis and Effective Malaria Treatment by Oral Delivery of Plant Cells.

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Malhotra, Karan; Subramaniyan, Mayavan; Rawat, Khushboo; Kalamuddin, Md; Qureshi, M Irfan; Malhotra, Pawan; Mohmmed, Asif; Cornish, Katrina; Daniell, Henry; Kumar, Shashi

2016-11-07

Artemisinin is highly effective against drug-resistant malarial parasites, which affects nearly half of the global population and kills >500 000 people each year. The primary cost of artemisinin is the very expensive process used to extract and purify the drug from Artemisia annua. Elimination of this apparently unnecessary step will make this potent antimalarial drug affordable to the global population living in endemic regions. Here we reported the oral delivery of a non-protein drug artemisinin biosynthesized (∼0.8 mg/g dry weight) at clinically meaningful levels in tobacco by engineering two metabolic pathways targeted to three different cellular compartments (chloroplast, nucleus, and mitochondria). The doubly transgenic lines showed a three-fold enhancement of isopentenyl pyrophosphate, and targeting AACPR, DBR2, and CYP71AV1 to chloroplasts resulted in higher expression and an efficient photo-oxidation of dihydroartemisinic acid to artemisinin. Partially purified extracts from the leaves of transgenic tobacco plants inhibited in vitro growth progression of Plasmodium falciparum-infected red blood cells. Oral feeding of whole intact plant cells bioencapsulating the artemisinin reduced the parasitemia levels in challenged mice in comparison with commercial drug. Such novel synergistic approaches should facilitate low-cost production and delivery of artemisinin and other drugs through metabolic engineering of edible plants. Copyright © 2016 The Author. Published by Elsevier Inc. All rights reserved.

Growth and artemisinin content of artemisia Annua L. As a result of gamma irradiation on shoot culture

International Nuclear Information System (INIS)

Tri Muji Ermayanti; Erwin Al Hafiizh; Andri Fadillah Martin; Arthur A Lelono; Wiguna Rahman

2016-01-01

Artemisinin is the main compound produced by Artemisia annua is used as antimalarial drug. Many research have been conducted in order to increase artemisinin content in A. annua so that it can be produced economically. In several plants, mutation can be induced by Gamma irradiation to increase their secondary metabolite production. The aim of this research was to investigate the growth and artemisinin content of A. annua after Gamma irradiation. Irradiation was conducted using in vitro shoot tips with 5-50 Gy. Survival rate, growth of shoot culture, ploidy level confirmation, acclimatization, growth of plants in the field and artemisinin content were recorded. The results showed that LD_5_0 of A. annua was 37 Gy, therefore, shoots only grew in the control environment in the laboratory, their growth in the field was inhibited. Irradiation with 50 Gy, shoots only grew for 8 weeks, and died afterwards. Irradiation dose affected on growth of plants in the field as well as their artemisinin content. (author)

Routine delivery of artemisinin-based combination treatment at fixed health facilities reduces malaria prevalence in Tanzania: an observational study

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Khatib Rashid A

2012-04-01

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

Calculation of Quantitative Structure-Activity Relationship Descriptors of Artemisinin Derivatives

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Jambalsuren Bayarmaa

2008-06-01

Full Text Available Quantitative structure-activity relationships are based on the construction of predictive models using a set of known molecules and associated activity value. This accurate methodology, developed with adequate mathematical and computational tools, leads to a faster, cheaper and more comprehensive design of new products, reducing the experimental synthesis and testing on animals. Preparation of the QSAR models of artemisinin derivatives was carried out by the genetic function algorithm (GFA method for 91 molecules. The results show some relationships to the observed antimalarial activities of the artemisinin derivatives. The most statistically signi fi cant regression equation obtained from the fi nal GFA relates to two molecular descriptors.

A Study on Course of Infection and Haematological Changes in falciparum-Infected in Comparison with Artemisinin(s-Treated Mice

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Kalyan Kumar Kuthala

2013-01-01

Full Text Available To find out the efficacy and effect of artemisinin derivatives on haematological indices, C57BL/6J mice were challenged with Plasmodium falciparum and treated with therapeutic doses of AS, AE, and AL. Course of infection was studied in the infected and treated groups up to day 42. Peak level of parasitaemia (38% was observed on day 11 in infected group. Haematological indices indicated significant (P0.05 in all drug-treated groups. Percent of peak parasitaemia was much reduced in AL- (3.2% on day 3 treated group in comparison with AE- (2.4% on day 4 and AS- (4% on day 2 treated groups. Parasites were completely cleared on day 6 in AS group, day 5 in AE group, and day 4 in AL group. Hence, our results strongly support that combination therapy has high efficacy rates than monotherapy. No adverse effects were observed on haematological parameters when animals were treated with therapeutic dosages.

Chemotherapy and molecular target therapy combined with radiation therapy

International Nuclear Information System (INIS)

Akimoto, Tetsuo

2012-01-01

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)

Effectiveness of artemisinin-based combination therapy used in the context of home management of malaria: A report from three study sites in sub-Saharan Africa

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Mugittu Kefas

2008-09-01

Full Text Available Abstract Background The use of artemisinin-based combination therapy (ACT at the community level has been advocated as a means to increase access to effective antimalarial medicines by high risk groups living in underserved areas, mainly in sub-Saharan Africa. This strategy has been shown to be feasible and acceptable to the community. However, the parasitological effectiveness of ACT when dispensed by community medicine distributors (CMDs within the context of home management of malaria (HMM and used unsupervised by caregivers at home has not been evaluated. Methods In a sub-set of villages participating in a large-scale study on feasibility and acceptability of ACT use in areas of high malaria transmission in Ghana, Nigeria and Uganda, thick blood smears and blood spotted filter paper were prepared from finger prick blood samples collected from febrile children between six and 59 months of age reporting to trained CMDs for microscopy and PCR analysis. Presumptive antimalarial treatment with ACT (artesunate-amodiaquine in Ghana, artemether-lumefantrine in Nigeria and Uganda was then initiated. Repeat finger prick blood samples were obtained 28 days later for children who were parasitaemic at baseline. For children who were parasitaemic at follow-up, PCR analyses were undertaken to distinguish recrudescence from re-infection. The extent to which ACTs had been correctly administered was assessed through separate household interviews with caregivers having had a child with fever in the previous two weeks. Results Over a period of 12 months, a total of 1,740 children presenting with fever were enrolled across the study sites. Patent parasitaemia at baseline was present in 1,189 children (68.3% and varied from 60.1% in Uganda to 71.1% in Ghana. A total of 606 children (51% of infected children reported for a repeat test 28 days after treatment. The crude parasitological failure rate varied from 3.7% in Uganda (C.I. 1.2%–6.2% to 41.8% in Nigeria (C

Characterization of xanthophyll pigments, photosynthetic performance, photon energy dissipation, reactive oxygen species generation and carbon isotope discrimination during artemisinin-induced stress in Arabidopsis thaliana.

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M Iftikhar Hussain

Full Text Available Artemisinin, a potent antimalarial drug, is phytotoxic to many crops and weeds. The effects of artemisinin on stress markers, including fluorescence parameters, photosystem II photochemistry, photon energy dissipation, lipid peroxidation, reactive oxygen species generation and carbon isotope discrimination in Arabidopsis thaliana were studied. Arabidopsis ecotype Columbia (Col-0 seedlings were grown in perlite and watered with 50% Hoagland nutrient solution. Adult plants of Arabidopsis were treated with artemisinin at 0, 40, 80, 160 μM for one week. Artemisinin, in the range 40-160 μM, decreased the fresh biomass, chl a, b and leaf mineral contents. Photosynthetic efficiency, yield and electron transport rate in Arabidopsis were also reduced following exposure to 80 and 160 μM artemisinin. The ΦNPQ and NPQ were less than control. Artemisinin treatment caused an increase in root oxidizability and lipid peroxidation (MDA contents of Arabidopsis. Calcium and nitrogen contents decreased after 80 and 160 μM artemisinin treatment compared to control. δ13C values were less negative following treatment with artemisinin as compared to the control. Artemisinin also decreased leaf protein contents in Arabidopsis. Taken together, these data suggest that artemisinin inhibits many physiological and biochemical processes in Arabidopsis.

Anticancer Effect of AntiMalarial Artemisinin Compounds | Das ...

African Journals Online (AJOL)

A PubMed search of about 127 papers on anti‑cancer effects of antimalarials has revealed that this class of drug, including other antimalarials, have several biological characteristics that include anticancer properties. ... Keywords: Anticancer agents, Antimalarials, Antitumor activity, Artemisinins, Novel chemotherapy ...

Relative stability of radicals derived from artemisinin: A semiempirical and DFT study

Science.gov (United States)

Arantes, C.; de Araujo, M. T.; Taranto, A. G.; de M. Carneiro, J. W.

The semiempirical AM1 and PM3 methods, as well as the density functional (DFT/B3LYP) approach using the 6-31g(d) basis set, were employed to calculate the relative stability of intermediate radicals derived from artemisinin, a sesquiterpene lactone having an endoperoxide bridge that is essential for its antimalarial activity. The compounds studied have their nonperoxidic oxygen atom of the trioxane ring and/or the carbonyl group replaced by a CH2 unit. Relative stabilities were calculated by means of isodesmic equations using artemisinin as reference. It was found that replacement of oxygen atoms decreases the relative stability of the anionic radical intermediates. In contrast, for compounds with inverted stereochemistry the intermediate radicals were found to be more stable than those with the artemisinin-like stereochemistry. These relative stabilities may modulate the antimalarial potency. Radicals centered on carbon are always more stable than the corresponding radicals centered on oxygen.

A Review of Biotechnological Artemisinin Production in Plants

DEFF Research Database (Denmark)

Ikram, Nur K. B. K.; Simonsen, Henrik Toft

2017-01-01

Malaria is still an eminent threat to major parts of the world population mainly in sub-Saharan Africa. Researchers around the world continuously seek novel solutions to either eliminate or treat the disease. Artemisinin, isolated from the Chinese medicinal herb Artemisia annua, is the active...

Potentiation of Artemisinin Activity against Chloroquine-Resistant Plasmodium falciparum Strains by Using Heme Models

Science.gov (United States)

Benoit-Vical, Françoise; Robert, Anne; Meunier, Bernard

1999-01-01

The influence of different metalloporphyrin derivatives on the antimalarial activity of artemisinin was studied with two chloroquine-resistant strains of Plasmodium falciparum (FcB1-Colombia and FcM29-Cameroon) cultured in human erythrocytes. This potentiation study indicates that the manganese complex of meso-tetrakis(4-sulfonatophenyl)porphyrin has a significant synergistic effect on the activity of artemisinin against both Plasmodium strains. PMID:10508044

Quantitative structure-activity relationships of the antimalarial agent artemisinin and some of its derivatives - a DFT approach.

Science.gov (United States)

Rajkhowa, Sanchaita; Hussain, Iftikar; Hazarika, Kalyan K; Sarmah, Pubalee; Deka, Ramesh Chandra

2013-09-01

Artemisinin form the most important class of antimalarial agents currently available, and is a unique sesquiterpene peroxide occurring as a constituent of Artemisia annua. Artemisinin is effectively used in the treatment of drug-resistant Plasmodium falciparum and because of its rapid clearance of cerebral malaria, many clinically useful semisynthetic drugs for severe and complicated malaria have been developed. However, one of the major disadvantages of using artemisinins is their poor solubility either in oil or water and therefore, in order to overcome this difficulty many derivatives of artemisinin were prepared. A comparative study on the chemical reactivity of artemisinin and some of its derivatives is performed using density functional theory (DFT) calculations. DFT based global and local reactivity descriptors, such as hardness, chemical potential, electrophilicity index, Fukui function, and local philicity calculated at the optimized geometries are used to investigate the usefulness of these descriptors for understanding the reactive nature and reactive sites of the molecules. Multiple regression analysis is applied to build up a quantitative structure-activity relationship (QSAR) model based on the DFT based descriptors against the chloroquine-resistant, mefloquine-sensitive Plasmodium falciparum W-2 clone.

Curcumin-arteether combination therapy of Plasmodium berghei-infected mice prevents recrudescence through immunomodulation.

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Palakkod G Vathsala

Full Text Available Earlier studies in this laboratory have shown the potential of artemisinin-curcumin combination therapy in experimental malaria. In a parasite recrudescence model in mice infected with Plasmodium berghei (ANKA, a single dose of alpha,beta-arteether (ART with three oral doses of curcumin prevented recrudescence, providing almost 95% protection. The parasites were completely cleared in blood with ART-alone (AE or ART+curcumin (AC treatments in the short-term, although the clearance was faster in the latter case involving increased ROS generation. But, parasites in liver and spleen were not cleared in AE or AC treatments, perhaps, serving as a reservoir for recrudescence. Parasitemia in blood reached up to 60% in AE-treated mice during the recrudescence phase, leading to death of animals. A transient increase of up to 2-3% parasitemia was observed in AC-treatment, leading to protection and reversal of splenomegaly. A striking increase in spleen mRNA levels for TLR2, IL-10 and IgG-subclass antibodies but a decrease in those for INFγ and IL-12 was observed in AC-treatment. There was a striking increase in IL-10 and IgG subclass antibody levels but a decrease in INFγ levels in sera leading to protection against recrudescence. AC-treatment failed to protect against recrudescence in TLR2(-/- and IL-10(-/- animals. IL-10 injection to AE-treated wild type mice and AC-treated TLR2(-/- mice was able to prolong survival. Blood from the recrudescence phase in AE-treatment, but not from AC-treatment, was able to reinfect and kill naïve animals. Sera from the recrudescence phase of AC-treated animals reacted with several parasite proteins compared to that from AE-treated animals. It is proposed that activation of TLR2-mediated innate immune response leading to enhanced IL-10 production and generation of anti-parasite antibodies contribute to protective immunity in AC-treated mice. These results indicate a potential for curcumin-based combination therapy to

RNAi down-regulation of cinnamate-4-hydroxylase increases artemisinin biosynthesis in Artemisia annua

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Kumar, Ritesh; Vashisth, Divya; Misra, Amita; Akhtar, Md Qussen; Jalil, Syed Uzma; Shanker, Karuna; Gupta, Madan Mohan; Rout, Prashant Kumar; Gupta, Anil Kumar; Shasany, Ajit Kumar

2016-01-01

Cinnamate-4-hydroxylase (C4H) converts trans-cinnamic acid (CA) to p-coumaric acid (COA) in the phenylpropanoid/lignin biosynthesis pathway. Earlier we reported increased expression of AaCYP71AV1 (an important gene of artemisinin biosynthesis pathway) caused by CA treatment in Artemisia annua. Hence, AaC4H gene was identified, cloned, characterized and silenced in A. annua with the assumption that the elevated internal CA due to knock down may increase the artemisinin yield. Accumulation of t...

Simulated Digestion of Dried Leaves of Artemisia annua Consumed as a Treatment (pACT) for Malaria

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Weathers, Pamela J.; Jordan, Nikole; Lasin, Praphapan; Towler, Melissa J.

2014-01-01

Ethnopharmacological Relevance Artemisinin (AN) is produced by Artemisia annua, a medicinal herb long used as a tea infusion in traditional Chinese medicine to treat fever; it is also the key ingredient in current artemisinin-based combination therapies (ACTs) effective in treating malaria. Recently we showed that dried leaves from the whole plant A. annua that produces artemisinin and contains artemisinin-synergistic flavonoids seems to be more effective and less costly than ACT oral malaria therapy; however little is known about how digestion affects release of artemisinin and flavonoids from dried leaves. Material and Methods In the current study we used a simulated digestion system to determine how artemisinin and flavonoids are released prior to absorption into the bloodstream. Various delivery methods and staple foods were combined with dried leaves for digestion in order to investigate their impact on the bioavailability of artemisinin and flavonoids. Digestate was recovered at the end of the oral, gastric, and intestinal stages, separated into solid and liquid fractions, and extracted for measurement of artemisinin and total flavonoids. Results Compared to unencapsulated digested dried leaves, addition of sucrose, various cooking oils, and rice did not reduce the amount of artemisinin released in the intestinal liquid fraction, but the amount of released flavonoids nearly doubled. When dried leaves were encapsulated into either hydroxymethylcellulose or gelatin capsules, there was >50% decrease in released artemisinin but no change in released flavonoids. In the presence of millet or corn meal, the amount of released artemisinin declined, but there was no change in released flavonoids. Use of a mutant A. annua lacking artemisinin showed that the plant matrix is critical in determining how artemisinin is affected during the digestion process. Conclusions This study provides evidence showing how both artemisinin and flavonoids are affected by digestion and

Oxidative stress in malaria and artemisinin combination therapy

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Kavishe, Reginald A.; Koenderink, Jan B.; Alifrangis, Michael

2017-01-01

in their mechanisms of action. This review gives a brief account of the oxidative stress and redox systems in malaria and discusses the context of antimalarial effectiveness of different ACTs compared with monotherapies of the partner drugs. A final account on the Pros and Cons of ACT as a strategy is discussed....

Effects of artemisinin in broiler chickens challenged with Eimeria acervulina, E. maxima and E. tenella in battery trials.

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Pop, Loredana; Györke, Adriana; Tǎbǎran, Alexandru Flaviu; Dumitrache, Mirabela Oana; Kalmár, Zsuzsa; Magdaş, Cristian; Mircean, Viorica; Zagon, Diana; Balea, Anamaria; Cozma, Vasile

2015-12-15

Four experiments were conceived in order to test the efficacy of artemisinin, a sesquiterpene lactone derived from Artemisia annua, in single experimental infection of broiler chickens with Eimeria acervulina (1 × 10(5) oocysts), Eimeria maxima (5 × 10(4) oocysts) or Eimeria tenella (1 × 10(4) oocysts), and mixed infection with all 3 species (3.2 × 10(4) Eimeria spp. oocysts). For each experiment, three different dosages of artemisinin (5, 50 and 500 ppm) were compared with a negative control (uninfected, unmedicated), a positive control (infected, unmedicated) and a classical anticoccidial (monensin). The weight gain (WG), feed conversion ratio (FCR), oocysts shedded per gram of feces (OPG), lesion score, oocysts sporulation rates and mortality rate were recorded in all groups. The dosage of 5 ppm of artemisinin improved the WG and FCR for the chickens infected with E. acervulina. The OPG was significantly decreased in all the groups medicated with artemisinin and challenged with a mixed infection (p ≤ 0.01). The lesion score of the chickens challenged with Eimeria was reduced by different concentrations of artemisinin, depending on the species involved, but this compound did not have a positive effect on the lesions caused by E. acervulina. Histopathological analysis revealed superficial erosions of the intestinal mucosa, mixt. mononuclear and heterophilic inflammatory infiltrate in the lamina propria and intralesional presence of various developmental stages of parasite in groups infected with Eimeria spp.The sporulation rate of E. acervulina and E. maxima oocysts was significantly affected by 500 ppm of artemisinin, whilst the dosage of 5 ppm affected the sporulation of E. tenella oocysts. These data suggest that artemisinin is not effective against single eimerian infections but could be used as an alternative in mixed coccidiosis, especially if its effect on the oocysts sporulation would be fully investigated. Copyright © 2015 Elsevier B.V. All rights

Hairy roots induction and artemisinin analysis in Artemisia dubia ...

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STORAGESEVER

2008-09-17

Sep 17, 2008 ... When transformed roots were cultured in liquid medium, highest root fresh weight as well as .... To make the final volume 4 ml,. 400 µL of ..... and bubble column reactors in the in vitro production of artemisinin. Plant Cell Rep.

Strategies for combinational cancer therapies

International Nuclear Information System (INIS)

Khleif, Samir

2014-01-01

The countless pre-clinical studies and many clinical trials that have applied tumor antigen-based therapies for the cancer treatment, and although the necessary tumor-specific immune response may be elicited in tumor-bearing hosts, this was not sufficient for the positive therapeutic outcome since there are multiple mechanisms that tumors develop to escape immune surveillance. The tumor-mediated inhibitory mechanisms involve co-inhibitory receptor-ligand interactions, such as PD-1/ PD-L1, secretion of inhibitory molecules, such as TGFb, and recruitment of suppressive cells, such as regulatory T cells (Treg), myeloid derived suppressor cells (MDSC), etc. Therefore, we hypothesized that successful cancer immunotherapy requires not only induction and enhancement of effector immune response but also simultaneous targeting of suppressor arm of immune system, thus in addition to enhancing antigen-specific immunity using vaccines or radiation therapy, one should also target tumor-mediated immune suppression to improve the overall efficacy of therapy. We developed multiple strategies to target various tumor-mediated immune inhibitory mechanisms that can enhance anti-tumor immunity and restructure tumor microenvironment to allow effector cells generated due to vaccination or radiation therapy to function potently. We evaluated the immune and therapeutic efficacy of multiple combinational therapies, including blocking and agonist antibodies to co-inhibitory/co-stimulatory molecules, such as PD-1, PD-L1, OX40, CTLA-4, GITR, inhibitors and neutralizing antibodies to inhibitory cytokines/molecules, such as IL-10, TGFb, IDO, and small molecules for selective inhibition of Tregs. In addition to evaluation of anti-tumor efficacy we are also investigated cellular and molecular mechanisms of action for these agents when combined with vaccine or radiation therapy and exploring the interactions between compounds within combinational therapies in animal tumor models. We are

Acquired resistance of malarial parasites against artemisinin-based drugs: social and economic impacts

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Johanna M Porter-Kelley

2010-08-01

Full Text Available Johanna M Porter-Kelley1, Joann Cofie2, Sophonie Jean2, Mark E Brooks1, Mia Lassiter1, DC Ghislaine Mayer21Life Sciences Department, ­Winston-Salem State University, Winston Salem, NC, USA; 2Department of Biology, Virginia Commonwealth University, Richmond, VA, USAAbstract: Malaria, a disease of poverty and high morbidity and mortality in the tropical world, has led to a worldwide search for control measures. To that end, good antimalarial chemotherapies have been difficult to find in the global market and those that seem to be most effective are rapidly becoming ineffective due to the emergence and spread of drug resistance. Artemisinin, a very effective yet expensive antimalarial, has quickly become the recommended drug of choice when all other possibilities fail. However, for all its promise as the next great antimalarial, the outlook is bleak. Resistance is developing to artemisinin while another effective antimalarial is not in sight. Malaria endemic areas which are mostly in developing countries must deal with the multifaceted process of changing and implementing new national malaria treatment guidelines. This requires complex interactions between several sectors of the affected society which in some cases take place within the context of political instability. Moreover, the cost associated with preventing and containing the spread of antimalarial resistance is detrimental to economic progress. This review addresses the impact of artemisinin resistance on the socioeconomic structure of malaria endemic countries.Keywords: artemisinin-based drugs, social, economic, malarial parasite resistance

Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasites

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Hunt, Paul

2010-09-16

Background: Classical and quantitative linkage analyses of genetic crosses have traditionally been used to map genes of interest, such as those conferring chloroquine or quinine resistance in malaria parasites. Next-generation sequencing technologies now present the possibility of determining genome-wide genetic variation at single base-pair resolution. Here, we combine in vivo experimental evolution, a rapid genetic strategy and whole genome re-sequencing to identify the precise genetic basis of artemisinin resistance in a lineage of the rodent malaria parasite, Plasmodium chabaudi. Such genetic markers will further the investigation of resistance and its control in natural infections of the human malaria, P. falciparum.Results: A lineage of isogenic in vivo drug-selected mutant P. chabaudi parasites was investigated. By measuring the artemisinin responses of these clones, the appearance of an in vivo artemisinin resistance phenotype within the lineage was defined. The underlying genetic locus was mapped to a region of chromosome 2 by Linkage Group Selection in two different genetic crosses. Whole-genome deep coverage short-read re-sequencing (IlluminaSolexa) defined the point mutations, insertions, deletions and copy-number variations arising in the lineage. Eight point mutations arise within the mutant lineage, only one of which appears on chromosome 2. This missense mutation arises contemporaneously with artemisinin resistance and maps to a gene encoding a de-ubiquitinating enzyme.Conclusions: This integrated approach facilitates the rapid identification of mutations conferring selectable phenotypes, without prior knowledge of biological and molecular mechanisms. For malaria, this model can identify candidate genes before resistant parasites are commonly observed in natural human malaria populations. 2010 Hunt et al; licensee BioMed Central Ltd.

Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription

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Newton Paul N

2011-08-01

Full Text Available Abstract Background Artemisinin resistance in Plasmodium falciparum malaria has emerged in Western Cambodia. This is a major threat to global plans to control and eliminate malaria as the artemisinins are a key component of antimalarial treatment throughout the world. To identify key features associated with the delayed parasite clearance phenotype, we employed DNA microarrays to profile the physiological gene expression pattern of the resistant isolates. Results In the ring and trophozoite stages, we observed reduced expression of many basic metabolic and cellular pathways which suggests a slower growth and maturation of these parasites during the first half of the asexual intraerythrocytic developmental cycle (IDC. In the schizont stage, there is an increased expression of essentially all functionalities associated with protein metabolism which indicates the prolonged and thus increased capacity of protein synthesis during the second half of the resistant parasite IDC. This modulation of the P. falciparum intraerythrocytic transcriptome may result from differential expression of regulatory proteins such as transcription factors or chromatin remodeling associated proteins. In addition, there is a unique and uniform copy number variation pattern in the Cambodian parasites which may represent an underlying genetic background that contributes to the resistance phenotype. Conclusions The decreased metabolic activities in the ring stages are consistent with previous suggestions of higher resilience of the early developmental stages to artemisinin. Moreover, the increased capacity of protein synthesis and protein turnover in the schizont stage may contribute to artemisinin resistance by counteracting the protein damage caused by the oxidative stress and/or protein alkylation effect of this drug. This study reports the first global transcriptional survey of artemisinin resistant parasites and provides insight to the complexities of the molecular basis

Artemisinin disrupts androgen responsiveness of human prostate cancer cells by stimulating the 26S proteasome-mediated degradation of the androgen receptor protein.

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Steely, Andrea M; Willoughby, Jamin A; Sundar, Shyam N; Aivaliotis, Vasiliki I; Firestone, Gary L

2017-10-01

Androgen receptor (AR) expression and activity is highly linked to the development and progression of prostate cancer and is a target of therapeutic strategies for this disease. We investigated whether the antimalarial drug artemisinin, which is a sesquiterpene lactone isolated from the sweet wormwood plant Artemisia annua, could alter AR expression and responsiveness in cultured human prostate cancer cell lines. Artemisinin treatment induced the 26S proteasome-mediated degradation of the receptor protein, without altering AR transcript levels, in androgen-responsive LNCaP prostate cancer cells or PC-3 prostate cancer cells expressing exogenous wild-type AR. Furthermore, artemisinin stimulated AR ubiquitination and AR receptor interactions with the E3 ubiquitin ligase MDM2 in LNCaP cells. The artemisinin-induced loss of AR protein prevented androgen-responsive cell proliferation and ablated total AR transcriptional activity. The serine/threonine protein kinase AKT-1 was shown to be highly associated with artemisinin-induced proteasome-mediated degradation of AR protein. Artemisinin treatment activated AKT-1 enzymatic activity, enhanced receptor association with AKT-1, and induced AR serine phosphorylation. Treatment of LNCaP cells with the PI3-kinase inhibitor LY294002, which inhibits the PI3-kinase-dependent activation of AKT-1, prevented the artemisinin-induced AR degradation. Furthermore, in transfected receptor-negative PC-3 cells, artemisinin failed to stimulate the degradation of an altered receptor protein (S215A/S792A) with mutations in its two consensus AKT-1 serine phosphorylation sites. Taken together, our results indicate that artemisinin induces the degradation of AR protein and disrupts androgen responsiveness of human prostate cancer cells, suggesting that this natural compound represents a new potential therapeutic molecule that selectively targets AR levels.

School-based diagnosis and treatment of malaria by teachers using rapid diagnostic tests and artemisinin-based combination therapy: experiences and perceptions of users and implementers of the Learner Treatment Kit, southern Malawi.

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Mphwatiwa, Treza; Witek-McManus, Stefan; Mtali, Austin; Okello, George; Nguluwe, Paul; Chatsika, Hard; Roschnik, Natalie; Halliday, Katherine E; Brooker, Simon J; Mathanga, Don P

2017-08-07

Training teachers to diagnose uncomplicated malaria using malaria rapid diagnostic tests and treat with artemisinin-based combination therapy has the potential to improve the access of primary school children (6-14 years) to prompt and efficient treatment for malaria, but little is known about the acceptability of such an intervention. This qualitative study explored experiences and perceptions of users and implementers of a programme of school-based malaria case management via a first-aid kit-the Learner Treatment Kit (LTK)-implemented as part of a cluster-randomized controlled trial in Zomba district, Malawi. From 29 primary schools where teachers were trained to test and treat school children for malaria using the LTK, six schools were purposively selected on the basis of relative intervention usage (low, medium or high); school size and geographical location. In total eight focus group discussions were held with school children, parents and guardians, and teachers; and 20 in-depth interviews were conducted with key stakeholders at the school, district and national levels. Interviews were recorded, transcribed, and analysed using a thematic analysis approach. The LTK was widely perceived by respondents to be a worthwhile intervention, with the opinion that trained teachers were trusted providers of malaria testing and treatment to school children. Benefits of the programme included a perception of improved access to malaria treatment for school children; decreased school absenteeism; and that the programme supported broader national health and education policies. Potential barriers to successful implementation expressed included increased teacher workloads, a feeling of inadequate supervision from health workers, lack of incentives and concerns for the sustainability of the programme regarding the supply of drugs and commodities. Training teachers to test for and treat uncomplicated malaria in schools was well received by both users and implementers alike, and

Optimal sampling designs for estimation of Plasmodium falciparum clearance rates in patients treated with artemisinin derivatives

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2013-01-01

Background The emergence of Plasmodium falciparum resistance to artemisinins in Southeast Asia threatens the control of malaria worldwide. The pharmacodynamic hallmark of artemisinin derivatives is rapid parasite clearance (a short parasite half-life), therefore, the in vivo phenotype of slow clearance defines the reduced susceptibility to the drug. Measurement of parasite counts every six hours during the first three days after treatment have been recommended to measure the parasite clearance half-life, but it remains unclear whether simpler sampling intervals and frequencies might also be sufficient to reliably estimate this parameter. Methods A total of 2,746 parasite density-time profiles were selected from 13 clinical trials in Thailand, Cambodia, Mali, Vietnam, and Kenya. In these studies, parasite densities were measured every six hours until negative after treatment with an artemisinin derivative (alone or in combination with a partner drug). The WWARN Parasite Clearance Estimator (PCE) tool was used to estimate “reference” half-lives from these six-hourly measurements. The effect of four alternative sampling schedules on half-life estimation was investigated, and compared to the reference half-life (time zero, 6, 12, 24 (A1); zero, 6, 18, 24 (A2); zero, 12, 18, 24 (A3) or zero, 12, 24 (A4) hours and then every 12 hours). Statistical bootstrap methods were used to estimate the sampling distribution of half-lives for parasite populations with different geometric mean half-lives. A simulation study was performed to investigate a suite of 16 potential alternative schedules and half-life estimates generated by each of the schedules were compared to the “true” half-life. The candidate schedules in the simulation study included (among others) six-hourly sampling, schedule A1, schedule A4, and a convenience sampling schedule at six, seven, 24, 25, 48 and 49 hours. Results The median (range) parasite half-life for all clinical studies combined was 3.1 (0

Mutations in Plasmodium falciparum K13 propeller gene from Bangladesh (2009–2013)

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Mohon, Abu Naser; Alam, Mohammad Shafiul; Bayih, Abebe Genetu; Folefoc, Asongna; Shahinas, Dea; Haque, Rashidul; Pillai, Dylan R

2014-01-01

Background Bangladesh is a malaria hypo-endemic country sharing borders with India and Myanmar. Artemisinin combination therapy (ACT) remains successful in Bangladesh. An increase of artemisinin-resistant malaria parasites on the Thai-Cambodia and Thai-Myanmar borders is worrisome. K13 propeller gene (PF3D7_1343700 or PF13_0238) mutations have been linked to both in vitro artemisinin resistance and in vivo slow parasite clearance rates. This group undertook to evaluate if mutations seen in Ca...

Knowledge, access and utilization of bed-nets among stable and seasonal migrants in an artemisinin resistance containment area of Myanmar.

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Phyo Than, Wint; Oo, Tin; Wai, Khin Thet; Thi, Aung; Owiti, Philip; Kumar, Binay; Deepak Shewade, Hemant; Zachariah, Rony

2017-09-14

Myanmar lies in the Greater Mekong sub-region of South-East Asia faced with the challenge of emerging resistance to artemisinin combination therapies (ACT). Migrant populations are more likely than others to spread ACT resistance. A vital intervention to reduce malaria transmission, resistance spread and eliminate malaria is the use of bed nets. Among seasonal and stable migrants in an artemisinin resistance containment region of Myanmar, we compared a) their household characteristics, b) contact with health workers and information material, and c) household knowledge, access and utilization of bed nets. Secondary data from community-based surveys on 2484 migrant workers (2013 and 2014, Bago Region) were analyzed of which 37% were seasonal migrants. Bed net access and utilization were assessed using a) availability of at least one bed net per household, and b) one bed net per two persons, and c) proportion of household members who slept under abed net during the previous night (Indicator targets = 100%). Over 70% of all migrants were from unstable work settings with short transitory stays. Average household size was five (range 1-25) and almost half of all households had children under-five years. Roughly 10 % of migrants were night-time workers. Less than 40% of households had contact with health workers and less than 30% had exposure to information education and communication (IEC) materials, the latter being significantly lower among seasonal migrants. About 70% of households were aware of the importance of insecticide-treated bed-nets/long-lasting insecticidal nets (ITNs/LLINs), but knowledge on insecticide impregnation and retreatment of ITNs was poor (Myanmar. Possible ways forward include frequent distribution campaigns to compensate for short transitory stays, matching household distributions to household size, enhanced information campaigns and introducing legislation to make mosquito repellents available for night-time workers at plantations and farms

In vitro sensitivity pattern of chloroquine and artemisinin in Plasmodium falciparum

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Supriya Sharma

2016-01-01

Full Text Available Artemisinin (ART and its derivatives form the mainstay of antimalarial therapy. Emergence of resistance to them poses a potential threat to future malaria control and elimination on a global level. It is important to know the mechanism of action of drug and development of drug resistance. We put forwards probable correlation between the mode of action of chloroquine (CQ and ART. Modified trophozoite maturation inhibition assay, WHO Mark III assay and molecular marker study for CQ resistance at K76T codon in Plasmodium falciparum CQ-resistant transporter gene were carried out on cultured P. falciparum. On comparing trophozoite and schizont growth for both CQ-sensitive (MRC-2 and CQ-resistant (RKL-9 culture isolates, it was observed that the clearance of trophozoites and schizonts was similar with both drugs. The experiment supports that CQ interferes with heme detoxification pathway in food vacuoles of parasite, and this may be correlated as one of the plausible mechanisms of ART.

Malaria profiles and challenges in artemisinin resistance containment in Myanmar.

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Nwe, Thet Wai; Oo, Tin; Wai, Khin Thet; Zhou, Shuisen; van Griensven, Johan; Chinnakali, Palanivel; Shah, Safieh; Thi, Aung

2017-04-25

This study examined evolving malaria profiles from January, 2010 to December, 2014 to evaluate achievements and challenges of implementing measures to prevent and control spread of artemisinin resistance in Myanmar. Using National Malaria Control Programme (NMCP) data, a cross-sectional descriptive study of 52 townships in artemisinin-resistant containment areas in Myanmar was conducted. Annual program data were analysed, and trends over time are graphically presented. In the 52 study townships populated by 8.7 million inhabitants, malaria incidence showed a decreasing trend from 10.54 per 1 000 population in 2010 to 2.53 in 2014, and malaria mortalities also decreased from 1.83 per 100 000 population in 2010 to 0.17 in 2014. The proportion of confirmed to total tested malaria cases also decreased from 6 to 1%, while identification of cases improved. All cases from all parasites species, including Plasmodium falciparum, decreased. Coverage of LLIN (long-lasting insecticidal net)/ITN (insecticide-treated mosquito nets) and indoor residual spraying (IRS) was high in targeted areas with at-risk persons, even though the total population was not covered. In addition to passive case detection (PCD), active case detection (ACD) was conducted in hard-to-reach areas and worksites where mobile migrant populations were present. ACD improved in most areas from 2012 to 2014, but continues to need to be strengthened. The findings provide useful data on the malaria situation in artemisinin-resistant initiative areas, which may be useful for the NMCP to meet its elimination goal. These profiles could contribute to better planning, implementation, and evaluation of intervention activities.

Two distinct and competitive pathways confer the cellcidal actions of artemisinins

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Chen Sun

2015-01-01

Full Text Available The biological actions of artemisinin (ART, an antimalarial drug derived from Artemisia annua, remain poorly understood and controversial. Besides potent antimalarial activity, some of artemisinin derivatives (together with artemisinin, hereafter referred to as ARTs, in particular dihydroartemisinin (DHA, are also associated with anticancer and other antiparasitic activities. In this study, we used baker’s yeast Saccharomyces cerevisiae as cellular and genetic model to investigate the molecular and cellular properties of ARTs. Two clearly separable pathways exist. While all ARTs exhibit potent anti-mitochondrial actions as shown before, DHA exerts an additional strong heme-dependent, likely mitochondria-independent inhibitory action. More importantly, heme antagonizes the mitochondria-dependent cellcidal action. Indeed, when heme synthesis was inhibited, the mitochondria-dependent cellcidal action of ARTs could be dramatically strengthened, and significant yeast growth inhibition at as low as 100 nM ART, an increase of about 25 folds in sensitivity, was observed. We conclude that ARTs are endowed with two major and distinct types of properties: a potent and specific mitochondria-dependent reaction and a more general and less specific heme-mediated reaction. The competitive nature of these two actions could be explained by their shared source of the consumable ARTs, so that inhibition of the heme-mediated degradation pathway would enable more ARTs to be available for the mitochondrial action. These properties of ARTs can be used to interpret the divergent antimalarial and anticancer actions of ARTs.

Effect of concomitant artesunate administration and cytochrome P4502C8 polymorphisms on the pharmacokinetics of amodiaquine in Ghanaian children with uncomplicated malaria

DEFF Research Database (Denmark)

Adjei, George O; Kristensen, Kim; Goka, Bamenla Q

2008-01-01

Artesunate (AS) is used in combination with amodiaquine (AQ) as first-line treatment for uncomplicated malaria in many countries. We investigated the effect of concomitant AS administration on the pharmacokinetics of AQ and compared concentrations of desethylamodiaquine (DEAQ), the main metabolite...... implications for weight-based dosing of higher-body-weight children with AQ. The pharmacokinetics of artemisinin combination therapies should be studied in malaria patients, because the rapid parasite clearance caused by the artemisinin may affect the kinetics of the partner drug and the combination....

Village malaria worker performance key to the elimination of artemisinin-resistant malaria: a Western Cambodia health system assessment.

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Canavati, Sara E; Lawpoolsri, Saranath; Quintero, Cesia E; Nguon, Chea; Ly, Po; Pukrittayakamee, Sasithon; Sintasath, David; Singhasivanon, Pratap; Peeters Grietens, Koen; Whittaker, Maxine Anne

2016-05-20

Village malaria workers (VMWs) and mobile malaria workers (MMWs) are a critical component of Cambodia's national strategy to eliminate Plasmodium falciparum malaria by 2025. Since 2004, VMWs have been providing malaria diagnosis through the use of rapid diagnostic tests and free-of-charge artemisinin-based combination therapy in villages more than 5 km away from the closest health facility. They have also played a key role in the delivery of behaviour change communication interventions to this target population. This study aimed to assess the job performance of VMWs/MMWs, and identify challenges they face, which may impede elimination efforts. A mixed-methods assessment was conducted in five provinces of western Cambodia. One hundred and eighty five VMW/MMW participants were surveyed using a structured questionnaire. Qualitative data was gathered through a total of 60 focus group discussions and 65 in-depth interviews. Data triangulation of the qualitative and quantitative data was used during analysis. Overall, VMWs/MMWs met or exceeded the expected performance levels (80 %). Nevertheless, some performance gaps were identified. Misconceptions regarding malaria transmission and prevention were found among workers. The recommended approach for malaria treatment, directly-observed treatment (DOT), had low implementation rates. Stock-outs, difficulties in reaching out to migrant and mobile populations, insufficient means of transportation and dwindling worker satisfaction also affected job performance. VMW/MMW job performance must be increased from 80 to 100 % in order to achieve elimination. In order to do this, it is recommended for the national malaria programme to eliminate worker malaria knowledge gaps. Barriers to DOT implementation and health system failures also need to be addressed. The VMW programme should be expanded on several fronts in order to tackle remaining performance gaps. Findings from this evaluation are useful to inform the planning of future

Artificial intelligence in drug combination therapy.

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Tsigelny, Igor F

2018-02-09

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: journals.permissions@oup.com.

Analytical purification of a 60-kDa target protein of artemisinin detected in Trypanosoma brucei brucei

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Benetode Konziase

2015-12-01

Full Text Available Here we describe the isolation and purity determination of Trypanosoma brucei (T. b. brucei candidate target proteins of artemisinin. The candidate target proteins were detected and purified from their biological source (T. b. brucei lysate using the diazirine-free biotinylated probe 5 for an affinity binding to a streptavidin-tagged resin and, subsequently, the labeled target proteins were purified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE. We herein showed the electrophoresis gel and the immunoblotting film containing the 60-kDa trypanosomal candidate target protein of artemisinin as a single band, which was visualized on-gel by the reverse-staining method and on a Western blotting film by enhanced chemiluminescence. The data provided in this article are related to the original research article “Biotinylated probes of artemisinin with labeling affinity toward Trypanosoma brucei brucei target proteins”, by Konziase (Anal. Biochem., vol. 482, 2015, pp. 25–31. http://dx.doi.org/10.1016/j.ab.2015.04.020.

QUANTITATIVE ELECTRONIC STRUCTURE - ACTIVITY RELATIONSHIP OF ANTIMALARIAL COMPOUND OF ARTEMISININ DERIVATIVES USING PRINCIPAL COMPONENT REGRESSION APPROACH

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Paul Robert Martin Werfette

2010-06-01

Full Text Available Analysis of quantitative structure - activity relationship (QSAR for a series of antimalarial compound artemisinin derivatives has been done using principal component regression. The descriptors for QSAR study were representation of electronic structure i.e. atomic net charges of the artemisinin skeleton calculated by AM1 semi-empirical method. The antimalarial activity of the compound was expressed in log 1/IC50 which is an experimental data. The main purpose of the principal component analysis approach is to transform a large data set of atomic net charges to simplify into a data set which known as latent variables. The best QSAR equation to analyze of log 1/IC50 can be obtained from the regression method as a linear function of several latent variables i.e. x1, x2, x3, x4 and x5. The best QSAR model is expressed in the following equation,  (;;   Keywords: QSAR, antimalarial, artemisinin, principal component regression

Advances in combination therapy of lung cancer

DEFF Research Database (Denmark)

Wu, Lan; Leng, Donglei; Cun, Dongmei

2017-01-01

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....

Transient Serotonin Toxicity Evoked by Combination of Electroconvulsive Therapy and Fluoxetine

DEFF Research Database (Denmark)

Klysner, René; Bjerg Bendsen, Birgitte; Hansen, Maja Soon

2014-01-01

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....

Evaluation of the Quality of Artemisinin-Based Antimalarial Medicines Distributed in Ghana and Togo

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Dorcas Osei-Safo

2014-01-01

Full Text Available This study, conducted as part of our overall goal of regular pharmacovigilance of antimalarial medicines, reports on the quality of 132 artemisinin-based antimalarial medicines distributed in Ghana and Togo. Three methods were employed in the quality evaluation—basic (colorimetric tests for establishing the identity of the requisite active pharmaceutical ingredients (APIs, semi-quantitative TLC assay for the identification and estimation of API content, and HPLC assay for a more accurate quantification of API content. From the basic tests, only one sample totally lacked API. The HPLC assay, however, showed that 83.7% of the ACTs and 57.9% of the artemisinin-based monotherapies failed to comply with international pharmacopoeia requirements due to insufficient API content. In most of the ACTs, the artemisinin component was usually the insufficient API. Generally, there was a good correlation between the HPLC and SQ-TLC assays. The overall failure rates for both locally manufactured (77.3% and imported medicines (77.5% were comparable. Similarly the unregistered medicines recorded a slightly higher overall failure rate (84.7% than registered medicines (70.8%. Only two instances of possible cross-border exchange of medicines were observed and there was little difference between the medicine quality of collections from border towns and those from inland parts of both countries.

Asthma Severity in patients initiating controller monotherapy versus combination therapy.

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Diette, Gregory B; Fuhlbrigge, Anne L; Allen-Ramey, Felicia; Hopper, April; Sajjan, Shiva G; Markson, Leona E

2011-04-01

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.

Effectiveness of medication / auricular therapy / phyto-therapy combination in the treatment of hypertensive patients

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José Ramón Martínez Pérez

2015-10-01

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.

The MSPDBL2 codon 591 polymorphism is associated with lumefantrine in vitro drug responses in Plasmodium falciparum isolates from Kilifi, Kenya.

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Ochola-Oyier, Lynette Isabella; Okombo, John; Mwai, Leah; Kiara, Steven M; Pole, Lewa; Tetteh, Kevin K A; Nzila, Alexis; Marsh, Kevin

2015-03-01

The mechanisms of drug resistance development in the Plasmodium falciparum parasite to lumefantrine (LUM), commonly used in combination with artemisinin, are still unclear. We assessed the polymorphisms of Pfmspdbl2 for associations with LUM activity in a Kenyan population. MSPDBL2 codon 591S was associated with reduced susceptibility to LUM (P = 0.04). The high frequency of Pfmspdbl2 codon 591S in Kenya may be driven by the widespread use of lumefantrine in artemisinin combination therapy (Coartem). Copyright © 2015, Ochola-Oyier et al.

The Presence of Amorpha-4, 11-Diene Synthase, a Key Enzyme in Artemisinin Production in Ten Artemisia Species

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GA. Garoosi

2011-12-01

Full Text Available Background and the purpose of the study: Artemisinin is one of the most effective medicine against malaria, which is produced naturally by Artemisia annua in low yield. It is produced in a metabolic pathway, in which several genes and gene products are involved. One of the key genes in this pathway is am1, which encodes amorpha-4, 11-diene synthase (ADS, a key enzyme in artemisinin biosynthesis pathway. The aim of this study was to determine the presence of this gene in ten Artemisia species in order to increase the yield of production of Artemisinin. Methods : The experiments were carried out using PCR. Specific primers were designed based on the published am1 gene sequence obtained from A. annua (NCBI, accession number AF327527. Results: The amplification of this gene by the specific primers was considered as a positive sign for the potentiality of artemisinin production. Since the entire am1 gene was not amplified in any of the 10 species used, four parts of the gene, essential in ADS enzyme function, corresponding to a pair site of Arg10-Pro12 in the first 100 amino acids, b aspartate rich motif (DDXXD, c active site final lid and d active site including farnesyl diphosphate (FDP ionization sites and catalytic site in the ADS enzyme, were investigated. Major conclusion: The sequence corresponding to ADS active site was amplified only in A. annua, A. aucheri and A. chamaemelifolia. The negative results obtained with other species could be due to some sequence alteration, such as point mutations or INDELs. We propose A. aucheri and A. chamaemelifolia as two potential candidate species for further characterization, breeding and transferring am1 gene for artemisinin overproduction.

Chitosan oligosaccharide and salicylic acid up-regulate gene expression differently in relation to the biosynthesis of artemisinin in Artemisia annua L

DEFF Research Database (Denmark)

Yin, Heng; Kjær, Anders; Fretté, Xavier

2012-01-01

oligosaccharide (COS) and salicylic acid (SA) on both artemisinin production and gene expression related to the biosynthetic pathway of artemisinin. COS up-regulated the transcriptional levels of the genes ADS and TTG1 2.5 fold and 1.8 fold after 48 h individually, whereas SA only up-regulated ADS 2.0 fold after...

Nanomedicine of synergistic drug combinations for cancer therapy - Strategies and perspectives.

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Zhang, Rui Xue; Wong, Ho Lun; Xue, Hui Yi; Eoh, June Young; Wu, Xiao Yu

2016-10-28

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.

Availability and quality of anti-malarials among private sector outlets in Myanmar in 2012: results from a large, community-based, cross-sectional survey before a large-scale intervention.

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Khin, Hnin Su Su; Chen, Ingrid; White, Chris; Sudhinaraset, May; McFarland, Willi; Littrell, Megan; Montagu, Dominic; Aung, Tin

2015-07-14

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.

Determinants of price setting decisions on anti-malarial drugs at retail shops in Cambodia

OpenAIRE

Patouillard, Edith; Hanson, Kara; Kleinschmidt, Immo; Palafox, Benjamin; Tougher, Sarah; Pok, Sochea; O?Connell, Kate; Goodman, Catherine

2015-01-01

Background In many low-income countries, the private commercial sector plays an important role in the provision of malaria treatment. However, the quality of care it provides is often poor, with artemisinin combination therapy (ACT) generally being too costly for consumers. Decreasing ACT prices is critical for improving private sector treatment outcomes and reducing the spread of artemisinin resistance. Yet limited evidence exists on the factors influencing retailers? pricing decisions. This...

Nanomedicine-based combination anticancer therapy between nucleic acids and small-molecular drugs.

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Huang, Wei; Chen, Liqing; Kang, Lin; Jin, Mingji; Sun, Ping; Xin, Xin; Gao, Zhonggao; Bae, You Han

2017-06-01

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.

Combination antiretroviral therapy and cancer risk

DEFF Research Database (Denmark)

Borges, Álvaro H

2017-01-01

PURPOSE OF REVIEW: To review the newest research about the effects of combination antiretroviral therapy (cART) on cancer risk. RECENT FINDINGS: HIV+ persons are at increased risk of cancer. As this risk is higher for malignancies driven by viral and bacterial coinfections, classifying malignanci......ART initiation in reducing cancer risk, understand the relationship between long-term cART exposure and cancer incidence and assess whether adjuvant anti-inflammatory therapies can reduce cancer risk during treated HIV infection.......PURPOSE OF REVIEW: To review the newest research about the effects of combination antiretroviral therapy (cART) on cancer risk. RECENT FINDINGS: HIV+ persons are at increased risk of cancer. As this risk is higher for malignancies driven by viral and bacterial coinfections, classifying malignancies...... into infection-related and infection-unrelated has been an emerging trend. Cohorts have detected major reductions in the incidence of Kaposi sarcoma and non-Hodgkin lymphoma (NHL) following cART initiation among immunosuppressed HIV+ persons. However, recent randomized data indicate that cART reduces risk...

Risks and safety of combination therapy for hypothyroidism.

Science.gov (United States)

Jonklaas, Jacqueline

2016-08-01

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.

Improving pharmacokinetic-pharmacodynamic modeling to investigate anti-infective chemotherapy with application to the current generation of antimalarial drugs.

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Katherine Kay

Full Text Available Mechanism-based pharmacokinetic-pharmacodynamic (PK/PD modelling is the standard computational technique for simulating drug treatment of infectious diseases with the potential to enhance our understanding of drug treatment outcomes, drug deployment strategies, and dosing regimens. Standard methodologies assume only a single drug is used, it acts only in its unconverted form, and that oral drugs are instantaneously absorbed across the gut wall to their site of action. For drugs with short half-lives, this absorption period accounts for a significant period of their time in the body. Treatment of infectious diseases often uses combination therapies, so we refined and substantially extended the PK/PD methodologies to incorporate (i time lags and drug concentration profiles resulting from absorption across the gut wall and, if required, conversion to another active form; (ii multiple drugs within a treatment combination; (iii differing modes of action of drugs in the combination: additive, synergistic, antagonistic; (iv drugs converted to an active metabolite with a similar mode of action. This methodology was applied to a case study of two first-line malaria treatments based on artemisinin combination therapies (ACTs, artemether-lumefantrine and artesunate-mefloquine where the likelihood of increased artemisinin tolerance/resistance has led to speculation on their continued long-term effectiveness. We note previous estimates of artemisinin kill rate were underestimated by a factor of seven, both the unconverted and converted form of the artemisinins kill parasites and the extended PK/PD methodology produced results consistent with field observations. The simulations predict that a potentially rapid decline in ACT effectiveness is likely to occur as artemisinin resistance spreads, emphasising the importance of containing the spread of artemisinin resistance before it results in widespread drug failure. We found that PK/PD data is generally very

Is there really no benefit to combination therapy with colistin?

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Pogue, Jason M; Kaye, Keith S

2013-09-01

Despite many theoretical and in vitro advantages, clinical data comparing combination therapy with colistin + rifampicin to colistin alone for infection due to extremely-drug resistant (XDR) Acinetobacter baumanni are scarce and limited by small numbers and/or low quality evidence. This article represents the first large, randomized, controlled, prospective study comparing colistin monotherapy and combination therapy. The reviewed article found no difference in all cause or infection related mortality, though there was an improved rate of microbiological clearance in the combination therapy arm. This study adds important new data to the literature and sets the stage for future studies that can be designed to overcome the limitations of this study, which are discussed in detail below. Based on this study, we cannot say definitively that combination therapy is not warranted for treatment of invasive infection due to A. baumannii, but the results do suggest that rifampicin is not an ideal agent to be combined with colistin.

Intravenous artesunate plus Artemisnin based Combination Therapy (ACT) or intravenous quinine plus ACT for treatment of severe malaria in Ugandan children: a randomized controlled clinical trial.

Science.gov (United States)

Byakika-Kibwika, Pauline; Achan, Jane; Lamorde, Mohammed; Karera-Gonahasa, Carine; Kiragga, Agnes N; Mayanja-Kizza, Harriet; Kiwanuka, Noah; Nsobya, Sam; Talisuna, Ambrose O; Merry, Concepta

2017-12-28

Severe malaria is a medical emergency associated with high mortality. Adequate treatment requires initial parenteral therapy for fast parasite clearance followed by longer acting oral antimalarial drugs for cure and prevention of recrudescence. In a randomized controlled clinical trial, we evaluated the 42-day parasitological outcomes of severe malaria treatment with intravenous artesunate (AS) or intravenous quinine (QNN) followed by oral artemisinin based combination therapy (ACT) in children living in a high malaria transmission setting in Eastern Uganda. We enrolled 300 participants and all were included in the intention to treat analysis. Baseline characteristics were similar across treatment arms. The median and interquartile range for number of days from baseline to parasite clearance was significantly lower among participants who received intravenous AS (2 (1-2) vs 3 (2-3), P malaria symptoms. In this high transmission setting, we observed adequate initial treatment outcomes followed by very high rates of malaria re-infection post severe malaria treatment. The impact of recurrent antimalarial treatment on the long term efficacy of antimalarial regimens needs to be investigated and surveillance mechanisms for resistance markers established since recurrent malaria infections are likely to be exposed to sub-therapeutic drug concentrations. More strategies for prevention of recurrent malaria infections in the most at risk populations are needed. The study was registered with the Pan African Clinical Trial Registry ( PACTR201110000321348 ).

Combined statin-fibrate therapy-induced rhabdomyolysis: Case report

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Jozić Tanja L.

2014-01-01

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.

Combining Oncolytic Virotherapy with p53 Tumor Suppressor Gene Therapy

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Christian Bressy

2017-06-01

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.

Effectiveness of Manual Therapy Combined With Physical Therapy in Treatment of Patellofemoral Pain Syndrome: Systematic Review.

Science.gov (United States)

Espí-López, Gemma Victoria; Arnal-Gómez, Anna; Balasch-Bernat, Mercè; Inglés, Marta

2017-06-01

The purpose of this study was to conduct a review of randomized controlled trials (RCTs) to determine the treatment effectiveness of the combination of manual therapy (MT) with other physical therapy techniques. Systematic searches of scientific literature were undertaken on PubMed and the Cochrane Library (2004-2014). The following terms were used: "patellofemoral pain syndrome," "physical therapy," "manual therapy," and "manipulation." RCTs that studied adults diagnosed with patellofemoral pain syndrome (PFPS) treated by MT and physical therapy approaches were included. The quality of the studies was assessed by the Jadad Scale. Five RCTs with an acceptable methodological quality (Jadad ≥ 3) were selected. The studies indicated that MT combined with physical therapy has some effect on reducing pain and improving function in PFPS, especially when applied on the full kinetic chain and when strengthening hip and knee muscles. The different combinations of MT and physical therapy programs analyzed in this review suggest that giving more emphasis to proximal stabilization and full kinetic chain treatments in PFPS will help better alleviation of symptoms.

PRODUCTION OF THE NEW ANTIMALARIAL DRUG ARTEMISININ IN SHOOT CULTURES OF ARTEMISIA-ANNUA L

NARCIS (Netherlands)

WOERDENBAG, HJ; LUERS, JFJ; VANUDEN, W; PRAS, N; MALINGRE, TM; ALFERMANN, AW

From aseptically grown Artemisia annua plantlets, shoot cultures were initiated. Using different concentrations of auxine, cytokinine and sucrose, a suitable culture medium was developed, with respect to the growth of the shoots and their artemisinin accumulation. Nitrate concentration and

Inhibition of SIRT1 combined with gemcitabine therapy for pancreatic carcinoma

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Gong DJ

2013-07-01

Full Text Available Dao-Jun Gong,1 Jia-Min Zhang,1 Min Yu,1 Bo Zhuang,1 Qing-Qu Guo21Department of Hepatobiliary-Pancreatic Surgery, Jinhua Hospital of Zhejiang University, Jinhua, People's Republic of China; 2Department of Surgery, Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, People's Republic of ChinaBackground: Pancreatic carcinoma possesses one of the highest lethality rates, highest drug-resistance, and highest incidence rates. The objective of this research was to enhance the efficacy and drug-resistance for pancreatic carcinoma by using inhibition of SIRT1 combined with gemcitabine therapy methods.Methods: Three pancreatic carcinoma cells (PANC-1 cells, BxPC-3 cells, and SW1990 cells received treatment with physiological saline, inhibition of SIRT1, gemcitabine, and combination therapy with inhibition of SIRT1 and gemcitabine in vitro; then BxPC-3 pancreatic cancer xenogeneic mice also received treatment with physiological saline, inhibition of SIRT1, gemcitabine, and combination therapy with inhibition of SIRT1 and gemcitabine in vivo.Results: The cleaved poly ADP ribose polymerase (PARP-1 effect of drug in pancreatic carcinoma cells was significantly different (P < 0.05 and the efficacy in descending order was the combination therapy with inhibition of SIRT1 and gemcitabine, inhibition of SIRT1, and gemcitabine. The BxPC-3 pancreatic cancer xenogeneic mice model received treatment with physiological saline, inhibition of SIRT1, gemcitabine, and combination therapy with inhibition of SIRT1 and gemcitabine in vivo and the results showed that the tumor volumes decreased and the survival rate within 45 days increased according to the order of the given drugs and the difference was significant (P < 0.05.Conclusion: Combination therapy with inhibition of SIRT1 and gemcitabine could improve efficacy and survival time in a BxPC-3 pancreatic cancer xenogeneic mice model, compared with single inhibition of SIRT1, or single

Combined therapy of radiation and hyperthermia on a metastatic tumor of angiosarcoma

International Nuclear Information System (INIS)

Yasuda, Hiroshi; Kitayama, Yoshiaki

1987-01-01

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)

Combination stem cell therapy for heart failure

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Ichim Thomas E

2010-04-01

Full Text Available Abstract Patients with congestive heart failure (CHF that are not eligible for transplantation have limited therapeutic options. Stem cell therapy such as autologous bone marrow, mobilized peripheral blood, or purified cells thereof has been used clinically since 2001. To date over 1000 patients have received cellular therapy as part of randomized trials, with the general consensus being that a moderate but statistically significant benefit occurs. Therefore, one of the important next steps in the field is optimization. In this paper we discuss three ways to approach this issue: a increasing stem cell migration to the heart; b augmenting stem cell activity; and c combining existing stem cell therapies to recapitulate a "therapeutic niche". We conclude by describing a case report of a heart failure patient treated with a combination stem cell protocol in an attempt to augment beneficial aspects of cord blood CD34 cells and mesenchymal-like stem cells.

Combination therapy in patients with benign prostatic hyperplasia

Directory of Open Access Journals (Sweden)

Bojan Tršinar

2006-11-01

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.

Combination therapy of gastric carcinoma with radiation and chemotherapy

Energy Technology Data Exchange (ETDEWEB)

Asakawa, Hiroshi; Otawa, Hirokazu; Yamada, Shogo; Matsumoto, Ko [Miyagi Prefectural Adult Disease Center, Natori (Japan)

1982-08-01

The concurrent combination therapy of radiation and chemotherapy was performed in a total of 134 cases of stomach cancer. Radiation response of tumor was remarkable in 35 (37%) of 95 cases, irradiated more than 5,000 rad. Yearly survival rates in 81 cases, in which the scheduled curative treatment was completed, were 63% in one, 31% in two, 21% in three, 17% in four and 13% in five years. These rates were intimately correlated to tumor size and cancer type. However, this combination therapy accompanied some fatal complications in a few percent. From the results, it was concluded that this combination therapy should be valuable to prolong the life of patients with gastric cancer, and that the curable indications for this treatment should be T1-T3: M0 cases with radio-responsive tumor.

Enhancing Photodynamyc Therapy Efficacy by Combination Therapy: Dated, Current and Oncoming Strategies

International Nuclear Information System (INIS)

Postiglione, Ilaria; Chiaviello, Angela; Palumbo, Giuseppe

2011-01-01

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

A QSAR, Pharmacokinetic and Toxicological Study of New Artemisinin Compounds with Anticancer Activity

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Josinete B. Vieira

2014-07-01

Full Text Available The Density Functional Theory (DFT method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with different degrees of cytotoxicity against the human hepatocellular carcinoma HepG2 line. Principal component analysis (PCA and hierarchical cluster analysis (HCA were employed to select the most important descriptors related to anticancer activity. The significant molecular descriptors related to the compounds with anticancer activity were the ALOGPS_log, Mor29m, IC5 and GAP energy. The Pearson correlation between activity and most important descriptors were used for the regression partial least squares (PLS and principal component regression (PCR models built. The regression PLS and PCR were very close, with variation between PLS and PCR of R2 = ±0.0106, R2ajust = ±0.0125, s = ±0.0234, F(4,11 = ±12.7802, Q2 = ±0.0088, SEV = ±0.0132, PRESS = ±0.4808 and SPRESS = ±0.0057. These models were used to predict the anticancer activity of eight new artemisinin compounds (test set with unknown activity, and for these new compounds were predicted pharmacokinetic properties: human intestinal absorption (HIA, cellular permeability (PCaCO2, cell permeability Maden Darby Canine Kidney (PMDCK, skin permeability (PSkin, plasma protein binding (PPB and penetration of the blood-brain barrier (CBrain/Blood, and toxicological: mutagenicity and carcinogenicity. The test set showed for two new artemisinin compounds satisfactory results for anticancer activity and pharmacokinetic and toxicological properties. Consequently, further studies need be done to evaluate the different proposals as well as their actions, toxicity, and potential use for treatment of cancers.

Therapeutic Cancer Vaccines in Combination with Conventional Therapy

DEFF Research Database (Denmark)

Andersen, Mads Hald; Junker, N.; Ellebaek, E.

2010-01-01

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...

Therapeutic cancer vaccines in combination with conventional therapy

DEFF Research Database (Denmark)

Andersen, Mads Hald; Junker, Niels; Ellebaek, Eva

2010-01-01

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...

[Combination drug therapy in patients with BPH].

Science.gov (United States)

Kuzmenko, A V; Kuzmenko, V V; Gyaurgiev, T A

2018-03-01

Introuction. One of the risk factors for LUTS is an infravesical obstruction, which is most often caused by benign prostatic hyperplasia (BPH). BPH symptoms are formed due to three components: static (mechanical), dynamic, and impaired functional capacity of the bladder. Medical treatment with 1-blockers decreases the outflow obstruction. 5-alpha reductase inhibitors are used to inhibit the static component of BPH. To investigate the effectiveness of various modifications of medical therapy of BPH using -blockers and 5-reductase inhibitors and combinations thereof. The study comprised 90 BPH patients who were divided into three groups, with each group containing 30 people. Patients of group I, II and III received monotherapy with -blockers, a combination of 5-reductase and -blockers, and fixed-dose combination drug Duodart, respectively. Evaluation of the treatment effectiveness included filling out voiding diaries, completing the I-PSS and QL questionnaires, uroflowmetry, transrectal ultrasonography of the prostate and estimation of the incidence of adverse effects. Also, compliance with the treatment was evaluated, and the number of patients who had episodes of acute urinary retention and required surgical treatment during the 12 month treatment course was registered. Compared to monotherapy, combination therapy with -blockers and 5-reductase inhibitors more effectively reduces the LUTS, increases Qmax and prevents the disease progression, which manifests in a lower incidence of AUR and fewer surgical interventions in groups II and III. However, the combination therapy can be associated with some side effects. Patients who received fixed-dose combination drug Duodart had a greater compliance rate than patients on the combination of drugs, which, in our opinion, is associated with fewer cases of AUR and surgical interventions. The use of Duodart in patients with BPH effectively alleviates LUTS and reduces the risk of the disease progression, which manifests itself

Transient Serotonin Toxicity Evoked by Combination of Electroconvulsive Therapy and Fluoxetine

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René Klysner

2014-01-01

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.

Little effect of praziquantel or artemisinin on clonorchiasis in Northern Vietnam. A pilot study

NARCIS (Netherlands)

Tinga, N.; de, N.; Vien, H. V.; Chau, L.; Toan, N. D.; Kager, P. A.; Vries, P. J.

1999-01-01

The first choice for treatment of Clonorchis sinensis infections is praziquantel. Experimental data suggest that artemisinin derivatives are active against C. sinensis. The efficacy of both drugs against clonorchiasis was evaluated in a pilot study in clonorchiasis patients in an endemic area in the

Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes

DEFF Research Database (Denmark)

Venkatesan, Meera; Gadalla, Nahla B; Stepniewska, Kasia

2014-01-01

Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated...... with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized...

The use of combined radiation therapy and hormonal therapy in the management of lymph node-positive prostate cancer

Energy Technology Data Exchange (ETDEWEB)

Whittington, Richard; Malkowicz, S Bruce; Machtay, Mitchell; Van Arsdalen, Keith; Barnes, Margaret M; Broderick, Gregory A; Wein, Alan J

1997-10-01

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

The use of combined radiation therapy and hormonal therapy in the management of lymph node-positive prostate cancer

International Nuclear Information System (INIS)

Whittington, Richard; Malkowicz, S. Bruce; Machtay, Mitchell; Van Arsdalen, Keith; Barnes, Margaret M.; Broderick, Gregory A.; Wein, Alan J.

1997-01-01

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

A SAR and QSAR study of new artemisinin compounds with antimalarial activity.

Science.gov (United States)

Santos, Cleydson Breno R; Vieira, Josinete B; Lobato, Cleison C; Hage-Melim, Lorane I S; Souto, Raimundo N P; Lima, Clarissa S; Costa, Elizabeth V M; Brasil, Davi S B; Macêdo, Williams Jorge C; Carvalho, José Carlos T

2013-12-30

The Hartree-Fock method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with antimalarial activity. Maps of molecular electrostatic potential (MEPs) and molecular docking were used to investigate the interaction between ligands and the receptor (heme). Principal component analysis and hierarchical cluster analysis were employed to select the most important descriptors related to activity. The correlation between biological activity and molecular properties was obtained using the partial least squares and principal component regression methods. The regression PLS and PCR models built in this study were also used to predict the antimalarial activity of 30 new artemisinin compounds with unknown activity. The models obtained showed not only statistical significance but also predictive ability. The significant molecular descriptors related to the compounds with antimalarial activity were the hydration energy (HE), the charge on the O11 oxygen atom (QO11), the torsion angle O1-O2-Fe-N2 (D2) and the maximum rate of R/Sanderson Electronegativity (RTe+). These variables led to a physical and structural explanation of the molecular properties that should be selected for when designing new ligands to be used as antimalarial agents.

The role of combination medical therapy in the treatment of acromegaly.

Science.gov (United States)

Lim, Dawn Shao Ting; Fleseriu, Maria

2017-02-01

Uncontrolled acromegaly results in approximately 2-fold excess mortality. Pituitary surgery is first-line therapy, and medical treatment is indicated for persistent disease. While cabergoline and pegvisomant are used in select patients, somatostatin receptor ligands (SRLs) remain the cornerstone of medical treatment. Management of patients poorly responsive to SRLs is therefore, challenging. The purpose of this review is to highlight the options for combination medical therapy in the treatment of acromegaly, with an emphasis on efficacy and safety. All original articles/abstracts detailing combination medical therapy in acromegaly were identified from a PubMed search. Studies reviewed included retrospective and open-label prospective studies. While the combination of SRL and cabergoline was generally well tolerated, a lower baseline insulin-like growth factor-1 (IGF-1) level was the best predictor of efficacy; this combination may be most effective in patients with mildly elevated IGF-1. SRL-pegvisomant combination normalized IGF-1 in the majority of patients; continued efficacy despite individual drug dosing reduction was also reported. The risk of significant liver enzyme elevation was, however, higher than that reported with SRL monotherapy; close monitoring is recommended. Data on pegvisomant-cabergoline combination is limited, but this may be an option in the setting of SRL intolerance. Reports on temozolomide used in combination with other medical therapies in patients with aggressive GH-secreting tumors are also summarized. While more prospective, randomized controlled trials on long-term efficacy and safety are needed, combination medical therapy remains a treatment strategy that should be considered for acromegaly patients poorly responsive to SRLs.

Current concepts in combination therapy for the treatment of hypertension: combined calcium channel blockers and RAAS inhibitors

Directory of Open Access Journals (Sweden)

Alberto F Rubio-Guerra

2009-11-01

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

Response to combination antiretroviral therapy: variation by age

DEFF Research Database (Denmark)

Lundgren, Jens

2008-01-01

-naive individuals starting combination antiretroviral therapy from 1998 to 2006. OUTCOME MEASURES: Time from combination antiretroviral therapy initiation to HIV RNA less than 50 copies/ml (virological response), CD4 increase of more than 100 cells/microl (immunological response) and new AIDS/death were analysed...... 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...... and reduced in those 60 years or older. Those aged 55-59 and 60 years or older had poorer clinical outcomes after adjusting for the latest CD4 cell count. CONCLUSION: Better virological responses but poorer immunological responses in older individuals, together with low precombination antiretroviral therapy...

Combinations of Radiation Therapy and Immunotherapy for Melanoma: A Review of Clinical Outcomes

International Nuclear Information System (INIS)

Barker, Christopher A.; Postow, Michael A.

2014-01-01

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

Combinations of Radiation Therapy and Immunotherapy for Melanoma: A Review of Clinical Outcomes

Energy Technology Data Exchange (ETDEWEB)

Barker, Christopher A., E-mail: barkerc@mskcc.org [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)

2014-04-01

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.

Synergistic combination therapy of antitumor agents, membrane modification agents and irradiation

International Nuclear Information System (INIS)

Watarai, Jiro; Itagaki, Takatomo; Akutsu, Thoru; Yamaguchi, Kouichi; Kato, Isao

1983-01-01

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)

Radiotherapy in combination with vascular-targeted therapies

International Nuclear Information System (INIS)

Ciric, Eva; Sersa, Gregor

2010-01-01

Given the critical role of tumor vasculature in tumor development, considerable efforts have been spent on developing therapeutic strategies targeting the tumor vascular network. A variety of agents have been developed, with two general approaches being pursued. Antiangiogenic agents (AAs) aim to interfere with the process of angiogenesis, preventing new tumor blood vessel formation. Vascular-disrupting agents (VDAs) target existing tumor vessels causing tumor ischemia and necrosis. Despite their great therapeutic potential, it has become clear that their greatest clinical utility may lie in combination with conventional anticancer therapies. Radiotherapy is a widely used treatment modality for cancer with its distinct therapeutic challenges. Thus, combining the two approaches seems reasonable. Strong biological rationale exist for combining vascular-targeted therapies with radiation. AAs and VDAs were shown to alter the tumor microenvironment in such a way as to enhance responses to radiation. The results of preclinical and early clinical studies have confirmed the therapeutic potential of this new treatment strategy in the clinical setting. However, concerns about increased normal tissue toxicity, have been raised

Pancreatitis associated with potassium bromide/phenobarbital combination therapy in epileptic dogs.

OpenAIRE

Gaskill, C L; Cribb, A E

2000-01-01

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.

Is there a decline in cognitive functions after combined electroconvulsive therapy and antipsychotic therapy in treatment-refractory schizophrenia?

Science.gov (United States)

Pawełczyk, Agnieszka; Kołodziej-Kowalska, Emilia; Pawełczyk, Tomasz; Rabe-Jabłońska, Jolanta

2015-03-01

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.

Combined Antirelapse Therapy in Patients with Schizoaffective Disorder: A Prospective Cohort Study

Directory of Open Access Journals (Sweden)

Zhanna R. Gardanova

2016-06-01

Full Text Available Background: In most studies, patients with schizoaffective disorder (SAD are often combined into one group along with schizophrenia patients or less commonly with those suffering from affective disorders, which makes it difficult to obtain data about the peculiarities of SAD treatment. Articles dedicated to SAD treatment in the interictal period are rare. Methods and Results: The prospective cohort study was conducted from 2011 to 2015. The study involved 86 patients diagnosed with SAD according to ICD-10. Patients received neuroleptics (NLs as antirelapse therapy for 2 years (NL therapy; then mood stabilizers (MSs were added to the antirelapse treatment (NL+MS therapy. The results of this combined therapy with MSs were evaluated after 2 years of treatment. Our results suggest that the use of combination therapy that includes antipsychotics and MSs leads to maintenance of a higher quality remission. Remission becomes more prolonged and affective swings less pronounced, resulting in improved quality of life in SAD patients. Improving the quality of remission can be attributed to the following characteristics of the combined therapy: a the use of lower doses of neuroleptics; b a reduction in the frequency and severity of mood swings; and c an increase in patient compliance. Conclusion: The use of combined pharmacotherapy including antipsychotics and MSs produces a longer, high-quality remission. The inclusion of MSs in the scheme of treatment increases the patient adherence to a medication regimen. The use of MSs in combination therapy reduces affective fluctuations, thereby increasing the probability of maintaining remission with complete symptom relief.

Treating Hypothyroidism with Thyroxine/Triiodothyronine Combination Therapy in Denmark

DEFF Research Database (Denmark)

Michaelsson, Luba Freja; Medici, Bjarke Borregaard; la Cour, Jeppe Lerche

2015-01-01

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...

Antimalarial drug prescribing practice in private and public health facilities in South-east Nigeria: a descriptive study

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Okebe Joseph

2007-05-01

Full Text Available Abstract Background Nigeria's national standard has recently moved to artemisinin combination treatments for malaria. As clinicians in the private sector are responsible for attending a large proportion of the population ill with malaria, this study compared prescribing in the private and public sector in one State in Nigeria prior to promoting ACTs. Objective To assess prescribing for uncomplicated malaria in government and private health facilities in Cross River State. Method Audit of 665 patient records at six private and seven government health facilities in 2003. Results Clinicians in the private sector were less likely to record history or physical examination than those in public facilities, but otherwise practice and prescribing were similar. Overall, 45% of patients had a diagnostic blood slides; 77% were prescribed monotherapy, either chloroquine (30.2%, sulphadoxine-pyrimethamine (22.7% or artemisinin derivatives alone (15.8%. Some 20.8% were prescribed combination therapy; the commonest was chloroquine with sulphadoxine-pyrimethamine. A few patients (3.5% were prescribed sulphadoxine-pyrimethamine-mefloquine in the private sector, and only 3.0% patients were prescribed artemisinin combination treatments. Conclusion Malaria treatments were varied, but there were not large differences between the public and private sector. Very few are following current WHO guidelines. Monotherapy with artemisinin derivatives is relatively common.

A theoretical and experimental study on the molecular and electronic structures of artemisinin and related drug molecules

International Nuclear Information System (INIS)

Galasso, V.; Kovac, B.; Modelli, A.

2007-01-01

The equilibrium structures of artemisinin and a selection of its derivatives (potent antimalarial drugs) have been studied with the density functional theory ansatz B3LYP. Of the five rings of the artemisinin framework, it is only the pyranose ring B that exhibits a marked conformational flexibility, especially on addition of a pendant side chain at C-10. For the derivatives, the β isomer with the axial substituent group is found to be energetically more stable than the α isomer with the equatorial group. The assignment of the vibrational fundamentals has been supported by calculations on related model molecules and a normal coordinate analysis. This allows for a reliable characterization of the normal modes, mainly involving the peroxide linkage, in the claimed fingerprint region of 1,2,4-trioxanes. The electronic structures have also been studied by measuring and calculating significant features of the NMR, photoelectron and electron transmission spectra. In particular, a representative set of NMR chemical shifts and nuclear spin-spin coupling constants, obtained with DFT formalisms, compares favourably with experiment and fits expectation in terms of stereoelectronic effects of the vicinal oxygen lone pairs. Based on ab initio outer valence Green's function calculations, a consistent interpretation of the uppermost bands in the photoelectron spectra of artemisinin and derivatives has been advanced. The top ionization energies reflect a complex interaction of the various oxygen lone pair orbitals. Electron transmission spectroscopy is applied for the first time to compounds containing the peroxide bond and elucidates the empty level electronic structure of artemisinin and derivatives in the 0-6 eV energy range, with the support of MO calculations and comparison with the spectra of reference molecules. Electron attachment to the lowest-lying empty σ* MO, mainly localized on the O-O bridge, occurs at an energy (1.7 eV) exceptionally low for compounds not

Triple combination antibiotic therapy for carbapenemase-producing Klebsiella pneumoniae: a systematic review.

Science.gov (United States)

Jacobs, David M; Safir, M Courtney; Huang, Dennis; Minhaj, Faisal; Parker, Adam; Rao, Gauri G

2017-11-25

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.

Women's Access and Provider Practices for the Case Management of Malaria during Pregnancy: A Systematic Review and Meta-Analysis

NARCIS (Netherlands)

Hill, Jenny; D'Mello-Guyett, Lauren; Hoyt, Jenna; van Eijk, Anna M.; ter Kuile, Feiko O.; Webster, Jayne

2014-01-01

Background: WHO recommends prompt diagnosis and quinine plus clindamycin for treatment of uncomplicated malaria in the first trimester and artemisinin-based combination therapies in subsequent trimesters. We undertook a systematic review of women's access to and healthcare provider adherence to WHO

Factors impeding the acceptability and use of malaria preventive measures: implications for malaria elimination in eastern Rwanda

NARCIS (Netherlands)

Ingabire, Chantal Marie; Rulisa, Alexis; van Kempen, Luuk; Muvunyi, Claude; Koenraadt, Constantianus J. M.; van Vugt, Michele; Mutesa, Leon; van den Borne, Bart; Alaii, Jane

2015-01-01

Long-lasting insecticidal nets (LLIN), indoor residual spraying (IRS) and malaria case treatment with artemisinin-based combination therapy (ACT) have been proven to significantly reduce malaria, but may not necessarily lead to malaria elimination. This study explored factors hindering the

Survival of lung cancer patients after combined therapy with hyperglycemia

International Nuclear Information System (INIS)

Zharkov, V.V.; Demidchik, Yu.E.; Khodina, T.V.

1991-01-01

The results of a randomized study of combined therapy of lung cancer patients including large field radiotherapy (total irradiation of 20 Gy, daily fractionation of 4 Gy) and induced hyperglycemia (22-23 mmol/1) are presented. The use of new variants of combined therapy was shown to increase significantly the survival of patients, however therapeutic efficacy was different depending on the time of hyperglycemia: wheter it was used before radiotherapy sessions of after their discontinuation

A SAR and QSAR Study of New Artemisinin Compounds with Antimalarial Activity

Directory of Open Access Journals (Sweden)

Cleydson Breno R. Santos

2013-12-01

Full Text Available The Hartree-Fock method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with antimalarial activity. Maps of molecular electrostatic potential (MEPs and molecular docking were used to investigate the interaction between ligands and the receptor (heme. Principal component analysis and hierarchical cluster analysis were employed to select the most important descriptors related to activity. The correlation between biological activity and molecular properties was obtained using the partial least squares and principal component regression methods. The regression PLS and PCR models built in this study were also used to predict the antimalarial activity of 30 new artemisinin compounds with unknown activity. The models obtained showed not only statistical significance but also predictive ability. The significant molecular descriptors related to the compounds with antimalarial activity were the hydration energy (HE, the charge on the O11 oxygen atom (QO11, the torsion angle O1-O2-Fe-N2 (D2 and the maximum rate of R/Sanderson Electronegativity (RTe+. These variables led to a physical and structural explanation of the molecular properties that should be selected for when designing new ligands to be used as antimalarial agents.

Gastrointestinal Toxicities With Combined Antiangiogenic and Stereotactic Body Radiation Therapy

Energy Technology Data Exchange (ETDEWEB)

Pollom, Erqi L.; Deng, Lei [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Pai, Reetesh K. [Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (United States); Brown, J. Martin; Giaccia, Amato; Loo, Billy W.; Shultz, David B.; Le, Quynh Thu; Koong, Albert C. [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Chang, Daniel T., E-mail: dtchang@stanford.edu [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States)

2015-07-01

Combining the latest targeted biologic agents with the most advanced radiation technologies has been an exciting development in the treatment of cancer patients. Stereotactic body radiation therapy (SBRT) is an ablative radiation approach that has become established for the treatment of a variety of malignancies, and it has been increasingly used in combination with biologic agents, including those targeting angiogenesis-specific pathways. Multiple reports have emerged describing unanticipated toxicities arising from the combination of SBRT and angiogenesis-targeting agents, particularly of late luminal gastrointestinal toxicities. In this review, we summarize the literature describing these toxicities, explore the biological mechanism of action of toxicity with the combined use of antiangiogenic therapies, and discuss areas of future research, so that this combination of treatment modalities can continue to be used in broader clinical contexts.

The molecular cloning of dihydroartemisinic aldehyde reductase and its implication in artemisinin biosynthesis in Artemisia annua

NARCIS (Netherlands)

Ryden, A.M.; Ruyter-Spira, C.P.; Quax, W.J.; Hiroyuki, O.; Toshiya, M.; Kayser, O.; Bouwmeester, H.J.

2010-01-01

A key point in the biosynthesis of the antimalarial drug artemisinin is the formation of dihydroartemisinic aldehyde which represents the key difference between chemotype specific pathways. This key intermediate is the substrate for several competing enzymes, some of which increase the metabolic

Combinational chelation therapy abrogates lead-induced neurodegeneration in rats

International Nuclear Information System (INIS)

Pachauri, Vidhu; Saxena, Geetu; Mehta, Ashish; Mishra, Deepshikha; Flora, Swaran J.S.

2009-01-01

Lead, a ubiquitous and potent neurotoxicant causes oxidative stress which leads to numerous neurobehavioral and physiological alterations. The ability of lead to bind sulfhydryl groups or compete with calcium could be one of the reasons for its debilitating effects. In the present study, we addressed: i) if chelation therapy could circumvent the altered oxidative stress and prevent neuronal apoptosis in chronic lead-intoxicated rats, ii) whether chelation therapy could reverse biochemical and behavioral changes, and iii) if mono or combinational therapy with captopril (an antioxidant) and thiol chelating agents (DMSA/MiADMSA) is more effective than individual thiol chelator in lead-exposed rats. Results indicated that lead caused a significant increase in reactive oxygen species, nitric oxide, and intracellular free calcium levels along with altered behavioral abnormalities in locomotor activity, exploratory behavior, learning, and memory that were supported by changes in neurotransmitter levels. A fall in membrane potential, release of cytochrome c, and DNA damage indicated mitochondrial-dependent apoptosis. Most of these alterations showed significant recovery following combined therapy with captopril with MiADMSA and to a smaller extend with captopril + DMSA over monotherapy with these chelators. It could be concluded from our present results that co-administration of a potent antioxidant (like captopril) might be a better treatment protocol than monotherapy to counter lead-induced oxidative stress. The major highlight of the work is an interesting experimental evidence of the efficacy of combinational therapy using an antioxidant with a thiol chelator in reversing neurological dystrophy caused due to chronic lead exposure in rats.

A Systematic Review of Clinical Practice Guidelines' Recommendations on Levothyroxine Therapy Alone versus Combination Therapy (LT4 plus LT3) for Hypothyroidism.

Science.gov (United States)

Kraut, Eyal; Farahani, Pendar

2015-12-04

Patients with hypothyroidism are increasingly enquiring about the benefit of using combination therapy of levothyroxine (LT4) and liothyronine (LT3) as a potential treatment for hypothyroidism. Combination therapy, however, remains controversial. The purpose of this study was to systematically review available hypothyroidism treatment recommendations from clinical practice guidelines from around the world to identify the consensus regarding combination therapy. Clinical practice guidelines were obtained from searches of PubMed, EMBASE, and MEDLINE, using several combinations of MeSH terms. The search was limited to clinical guidelines in English-language publications, published between January 1, 1990 and May 1, 2015. A quantitative approach was utilized for data synthesis. Thirteen guidelines were identified, including three regarding pregnancy, two regarding pediatric populations and eight regarding adult populations. There were six guidelines from North America, four guidelines from Europe and three guidelines from South America. Twelve of the guidelines were published after 2010. Nine guidelines addressed combination therapy of LT4 plus LT3, and all nine concluded that LT4 therapy alone is the standard of care, with insufficient evidence to recommend widespread combination therapy. Only the 2012 ETA Guidelines and the 2015 BTA Guidelines concluded that combination therapy could be used, although only in certain circumstances and as an experimental treatment. This systematic review illustrates that clinical practice guidelines worldwide do not recommend and do not support routine use of combination LT4 and LT3 therapy to treat hypothyroidism.

Oral combination therapy: repaglinide plus metformin for treatment of type 2 diabetes.

Science.gov (United States)

Raskin, P

2008-12-01

Type 2 diabetes is characterized by decreases in insulin secretion and insulin sensitivity. Several classes of oral antidiabetic medications are currently approved for the treatment of type 2 diabetes. A stepwise treatment approach from monotherapy to combination therapy is traditionally used; however, the frequency of treatment failure with monotherapy has resulted in a move towards earlier treatment with combination therapies that target the two principal defects in glycaemic control. One such combination regimen is repaglinide (a prandial glucose regulator that increases insulin release) plus metformin (an insulin sensitizer that inhibits hepatic glucose output, increases peripheral glucose uptake and utilization and minimizes weight gain). Findings from several clinical trials have shown that combination therapy with repaglinide plus metformin is well tolerated and results in greater reductions of haemoglobin A(1c) and fasting plasma glucose values compared with either monotherapy. Repaglinide may also provide a more suitable alternative to combination therapy with sulphonylureas and metformin because of its reduced propensity for hypoglycaemia. The combination regimen of repaglinide plus metformin should therefore be considered as a valuable option in the management of patients with type 2 diabetes when monotherapy is no longer adequate.

pH-responsive artemisinin derivatives and lipid nanoparticle formulations inhibit growth of breast cancer cells in vitro and induce down-regulation of HER family members.

Directory of Open Access Journals (Sweden)

Yitong J Zhang

Full Text Available Artemisinin (ART dimers show potent anti-proliferative activities against breast cancer cells. To facilitate their clinical development, novel pH-responsive artemisinin dimers were synthesized for liposomal nanoparticle formulations. A new ART dimer was designed to become increasingly water-soluble as pH declines. The new artemisinin dimer piperazine derivatives (ADPs remained tightly associated with liposomal nanoparticles (NPs at neutral pH but were efficiently released at acidic pH's that are known to exist within solid tumors and organelles such as endosomes and lysosomes. ADPs incorporated into nanoparticles down regulated the anti-apoptotic protein, survivin, and cyclin D1 when incubated at low concentrations with breast cancer cell lines. We demonstrate for the first time, for any ART derivative, that ADP NPs can down regulate the oncogenic protein HER2, and its counterpart, HER3 in a HER2+ cell line. We also show that the wild type epidermal growth factor receptor (EGFR or HER1 declines in a triple negative breast cancer (TNBC cell line in response to ADP NPs. The declines in these proteins are achieved at concentrations of NP109 at or below 1 µM. Furthermore, the new artemisinin derivatives showed improved cell-proliferation inhibition effects compared to known dimer derivatives.

Pfmdr1 copy number and arteminisin derivatives combination therapy failure in falciparum malaria in Cambodia

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Wongsrichanalai Chansuda

2009-01-01

Full Text Available Abstract Background The combination of artesunate and mefloquine was introduced as the national first-line treatment for Plasmodium falciparum malaria in Cambodia in 2000. However, recent clinical trials performed at the Thai-Cambodian border have pointed to the declining efficacy of both artesunate-mefloquine and artemether-lumefantrine. Since pfmdr1 modulates susceptibility to mefloquine and artemisinin derivatives, the aim of this study was to assess the link between pfmdr1 copy number, in vitro susceptibility to individual drugs and treatment failure to combination therapy. Methods Blood samples were collected from P. falciparum-infected patients enrolled in two in vivo efficacy studies in north-western Cambodia: 135 patients were treated with artemether-lumefantrine (AL group in Sampovloun in 2002 and 2003, and 140 patients with artesunate-mefloquine (AM group in Sampovloun and Veal Veng in 2003 and 2004. At enrollment, the in vitro IC50 was tested and the strains were genotyped for pfmdr1 copy number by real-time PCR. Results The pfmdr1 copy number was analysed for 115 isolates in the AM group, and for 109 isolates in the AL group. Parasites with increased pfmdr1 copy number had significantly reduced in vitro susceptibility to mefloquine, lumefantrine and artesunate. There was no association between pfmdr1 polymorphisms and in vitro susceptibilities. In the patients treated with AM, the mean pfmdr1copy number was lower in subjects with adequate clinical and parasitological response compared to those who experienced late treatment failure (n = 112, p p = 0.364. The presence of three or more copies of pfmdr1 were associated with recrudescence in artesunate-mefloquine treated patients (hazard ratio (HR = 7.80 [95%CI: 2.09–29.10], N = 115, p = 0.002 but not with recrudescence in artemether-lumefantrine treated patients (HR = 1.03 [95%CI: 0.24–4.44], N = 109, p = 0.969. Conclusion This study shows that pfmdr1 copy number is a molecular

Efficacy of intense pulse light therapy and tripple combination cream versus intense pulse light therapy and tripple combination cream alone in epidermal melasma treatment

International Nuclear Information System (INIS)

Shakeeb, N.; Noor, S.M.; Paracha, M.M.; Ullah, G.

2018-01-01

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)

Experimental study of chemical embolus therapy combined with radiotherapy for VX2 bone tumors

International Nuclear Information System (INIS)

Yamaguchi, Hiroshi; Mochizuki, Kazuo; Ishii, Yoshiaki

2000-01-01

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)

Atorvastatin/trimetazidine combination therapy in patients with ...

African Journals Online (AJOL)

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 impact of fixed-dose combination versus free-equivalent combination therapies on adherence for hypertension: a meta-analysis.

Science.gov (United States)

Du, Li-Ping; Cheng, Zhong-Wei; Zhang, Yu-Xuan; Li, Ying; Mei, Dan

2018-04-27

Nonadherence to antihypertensive medication is considered as a reason of inadequate control of blood pressure. This meta-analysis aimed to systemically evaluate the impact of fixed-dose combination (FDC) therapy on hypertensive medication adherence compared with free-equivalent combination therapies. Articles were retrieved from MEDLINE and Embase databases using a combination of terms "fixed-dose combinations" and "adherence or compliance or persistence" and "hypertension or antihypertensive" from January 2000 to June 2017 without any language restriction. A meta-analysis was performed to parallel compare the impact of FDC vs free-equivalent combination on medicine adherence or persistence. Studies were independently reviewed by two investigators. Data from eligible studies were extracted and a meta-analysis was performed using R version 3.1.0 software. A total of nine studies scored as six of nine to eight of nine for Newcastle-Ottawa rating with 62 481 patients with hypertension were finally included for analysis. Results showed that the mean difference of medication adherence for FDC vs free-equivalent combination therapies was 14.92% (95% confidence interval, 7.38%-22.46%). Patients in FDC group were more likely to persist with their antihypertensive treatment, with a risk ratio of 1.84 (95% confidence interval, 1.00-3.39). This meta-analysis confirmed that FDC therapy, compared with free-equivalent combinations, was associated with better medication adherence or persistence for patients with hypertension. It can be reasonable for physicians, pharmacists, and policy makers to facilitate the use of FDCs for patients who need to take two or more antihypertensive drugs. ©2018 Wiley Periodicals, Inc.

The effect of dose on the antimalarial efficacy of artemether-lumefantrine

DEFF Research Database (Denmark)

Anstey, N. M.; Price, R. N.; Davis, T. M E

2015-01-01

Background: Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malaria-endemic sett...

76 ORIGINAL ARTICLE

African Journals Online (AJOL)

boaz

AFRICAN JOURNAL OF CLINICAL AND EXPERIMENTAL MICROBIOLOGY MAY 2016 ... in South-West Nigeria and perception of artemisinin-based combination therapy (ACT). Design and methods-About 180 pre-tested questionnaires were ... Discussion-The high rate of CQ prescription in this study showed that many of ...

Parents' perceptions, attitudes and acceptability of Treatment of ...

African Journals Online (AJOL)

Background: There is little information on sociocultural and contextual factors that may influence attitudes of patients to new treatments, such as artemisinin combination therapies (ACT). Methods: Semi-structured questionnaires and focus group discussions were used to assess views of parents of children with ...

[Clinical study of cervical spondylotic radiculopathy treated with massage therapy combined with Magnetic sticking therapy at the auricular points and the cost comparison].

Science.gov (United States)

Wang, Saina; Sheng, Feng; Pan, Yunhua; Xu, Feng; Wang, Zhichao; Cheng, Lei

2015-08-01

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 Pmassage therapy, the massage therapy combined with magnetic sticking therapy at auricular points achieves the better effect and lower cost in health economics.

Modular synthesis and in vitro and in vivo antimalarial assessment of C-10 pyrrole mannich base derivatives of artemisinin.

Science.gov (United States)

Pacorel, Bénédicte; Leung, Suet C; Stachulski, Andrew V; Davies, Jill; Vivas, Livia; Lander, Hollie; Ward, Stephen A; Kaiser, Marcel; Brun, Reto; O'Neill, Paul M

2010-01-28

In two steps from dihydroartemisinin, a small array of 16 semisynthetic C-10 pyrrole Mannich artemisinin derivatives (7a-p) have been prepared in moderate to excellent yield. In vitro analysis against both chloroquine sensitive and resistant strains has demonstrated that these analogues have nanomolar antimalarial activity, with several compounds being more than 3 times more potent than the natural product artemisinin. In addition to a potent antimalarial profile, these molecules also have very high in vitro therapeutic indices. Analysis of the optimal Mannich side chain substitution for in vitro and in vivo activity reveals that the morpholine and N-methylpiperazine Mannich side chains provide analogues with the best activity profiles, both in vitro and in vivo in the Peter's 4 day test.

[Combination therapy of chronic bacterial prostatitis].

Science.gov (United States)

Khryanin, A A; Reshetnikov, O V

2016-08-01

The article discusses the possible etiological factors in the development of chronic bacterial prostatitis. The authors presented a comparative long-term analysis of morbidity from non-viral sexually transmitted infections (STIs) in Russia. Against the background of general decline in STIs incidence, a significant percentage of them is made up by urogenital trichomoniasis. The findings substantiated the advantages of combination therapy (ornidazole and ofloxacin) for bacterial urinary tract infections.

Combination Therapy Strategies Against Multiple-Resistant Streptococcus Suis

Directory of Open Access Journals (Sweden)

Yang Yu

2018-05-01

Full Text Available Streptococcus suis is a major swine pathogen, an emerging zoonotic agent responsible for meningitis, endocarditis and septicaemia followed by deafness in humans. The development of antimicrobial resistance in S. suis increases the risk for therapeutic failure in both animals and humans. In this study, we report the synergism of combination therapy against multi-resistant S. suis isolates from swine. Twelve antibiotic profiles were determined against 11 S. suis strains. To investigate their synergistic/antagonistic activity, checkerboard assay was performed for all the possible combinations. In-vitro killing curves and in-vivo treatment trials were used to confirm the synergistic activity of special combinations against S. suis dominant clones. In this study, 11 S. suis isolates were highly resistant to erythromycin, clindamycin, trimethoprim/sulfamethoxazole, and tetracycline with ratios of 80–100%, and the resistance percentages to enrofloxacin, florfenicol, and spectinomycin were ~50%. The checkerboard data identified two combination regimens, ampicillin plus apramycin and tiamulin plus spectinomycin which gave the greatest level of synergism against the S. suis strains. In-vitro kill-curves showed a bacterial reduction of over 3-logCFU with the use of combination treatments, whilst the application of mono-therapies achieve less than a 2-logCFU cell killing. In-vivo models confirm that administration of these two combinations significantly reduced the number of bacterial cells after 24 h of treatment. In conclusions, the combinations of ampicillin plus apramycin and tiamulin plus spectinomycin showed the greatest synergism and may be potential strategies for treatment of multi-resistant S. suis in animal.

Combined tumor therapy

International Nuclear Information System (INIS)

Wrba, H.

1990-01-01

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

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.

Science.gov (United States)

Triscari, Maria Teresa; Faraci, Palmira; Catalisano, Dario; D'Angelo, Valerio; Urso, Viviana

2015-01-01

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.

Atypical and Typical Winter Depressive Symptoms and Responsiveness to Light Therapy, Cognitive-Behavioral Therapy, or Combination Treatment

National Research Council Canada - National Science Library

Johnson, Leigh G; Rohan, Kelly J

2005-01-01

...), 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...

Fixed-dose combination therapy for the prevention of cardiovascular disease

Science.gov (United States)

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

2014-01-01

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

Research advances in traditional Chinese medicine combined with interventional therapy for hepatocellular carcinoma

Directory of Open Access Journals (Sweden)

LIU Yang

2015-01-01

Full Text Available Interventional therapy has become the first choice of non-surgical treatment for hepatocellular carcinoma (HCC due to its advantages such as little trauma and marked local effect. However, the clinical efficiency is less than expected. One of the possibilities is the resistance of cancer cells to anti-cancer drugs. Increasing attention has been paid to the combination of traditional Chinese medicine (TCM and interventional therapy in HCC treatment. This paper reviews the progress in TCM combined with interventional therapy for HCC at animal experiment and clinical study levels in recent ten years. It is pointed out that the combination therapy with TCM and intervention for HCC has a unique advantage.

Orthodontics-surgical combination therapy for Class III skeletal malocclusion

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M S Ravi

2012-01-01

Full Text Available The correction of skeletal Class III malocclusion with severe mandibular prognathism in an adult individual requires surgical and Othodontic combination therapy. The inter disciplinary approach is the treatment of choice in most of the skeletal malocclusions. A case report of an adult individual with Class III malocclusion, having mandibular excess in sagittal and vertical plane and treated with orthodontics,, bilateral sagittal split osteotomy and Le - Forte I osteotomy for the correction of skeletal, dental and soft tissue discrepancies is herewith presented. The surgical-orthodontic combination therapy has resulted in near-normal skeletal, dental and soft tissue relationship, with marked improvement in the facial esthetics in turn, has helped the patient to improve the self-confidence level.

Plasmodium falciparum malaria

African Journals Online (AJOL)

Durrheim, Karen Barnes. Objectives. To assess the therapeutic efficacy of sulfadoxine- pyrimethamine (SP) after 5 years of use as first-line treatment of uncomplicated Plasmodium falciparum malaria, and thus guide the selection of artemisinin-based combination therapy in Mpumalanga, South Africa. Design. An open-label ...

ECONOMIC EVALUATION OF COMBINED THERAPY OF ARTERIAL HYPERTENSION BY MARKOV’S MODELING

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N. S. Maksimchuk-Kolobova

2015-09-01

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

Evaluation of the Efficacy of Combined Therapy of Methotrexate and Etanercept versus Methotrexate as a Mono-Therapy.

Science.gov (United States)

Rexhepi, Sylejman; Rexhepi, Mjellma; Rexhepi, Blerta; Sahatçiu-Meka, Vjollca; Mahmutaj, Vigan

2018-05-20

This study aims to evaluate the efficacy of Methotrexate (MTX) alone and combined therapy with Etanercept (ETN) and Methotrexate in patients with active rheumatoid arthritis (RA). In the randomised control study, conducted in the period from March 2014 until March 2016, we evaluated the efficacy of the treatment of patients with RA with MTX as monotherapy and combination treatment with MTX and ETN. In the Clinic of Rheumatology in Prishtina, 90 adult patients with RA were treated in combination with ETN (doses of 50 mg subcutaneously/weekly), with oral MTX (doses up to 20 mg weekly), and MTX alone (doses up to 20 mg weekly) during this period of two years. Clinical response was assessed using European League against Rheumatism (EULAR)/American College of Rheumatology (ACR) Criteria and the Disease Activity Score (DAS28). Radiographic changes were measured in the beginning and at the end of the study using Larsen's method. Of the cohort groups of 90 patients, mean age of 55.63, 15 patients, (16.6 %) were treated with combined therapy (ETN plus MTX) and 75 patients (83.3%) with monotherapy (MTX). After two years of treatment the group with combined therapy resulted with improvement of acute phase reactants as erythrocyte sedimentation rate (ESR) for the first hour (41.1 vs. 10.3 mm/hour) and C - reactive protein (CRP) (40.8 vs. 6 mg/liter), and compared to the group treated with monotherapy, there were no significant changes (ESR: 45.7 vs 34.3 mm/hour; CRP: 48 vs 24 mg/liter). Before the treatment, the severity of the disease was high, wherein the group with combined therapy DAS28 was 5.32, compared to the monotherapy group whom DAS28 was 5.90. After 2 years of treatment, we had significant changes in the results of DAS28, wherein the group treated with ETN plus MTX DAS28 was 2.12 ± 0.15, while in the group of patients treated with MTX DAS28 were 3.75 ± 0.39 (t = 13.03; df = 58; p < 0.0001). The group with combined therapy showed no evidence of radiographic

Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance.

Science.gov (United States)

Khdair, Ayman; Chen, Di; Patil, Yogesh; Ma, Linan; Dou, Q Ping; Shekhar, Malathy P V; Panyam, Jayanth

2010-01-25

Tumor drug resistance significantly limits the success of chemotherapy in the clinic. Tumor cells utilize multiple mechanisms to prevent the accumulation of anticancer drugs at their intracellular site of action. In this study, we investigated the anticancer efficacy of doxorubicin in combination with photodynamic therapy using methylene blue in a drug-resistant mouse tumor model. Surfactant-polymer hybrid nanoparticles formulated using an anionic surfactant, Aerosol-OT (AOT), and a naturally occurring polysaccharide polymer, sodium alginate, were used for synchronized delivery of the two drugs. Balb/c mice bearing syngeneic JC tumors (mammary adenocarcinoma) were used as a drug-resistant tumor model. Nanoparticle-mediated combination therapy significantly inhibited tumor growth and improved animal survival. Nanoparticle-mediated combination treatment resulted in enhanced tumor accumulation of both doxorubicin and methylene blue, significant inhibition of tumor cell proliferation, and increased induction of apoptosis. These data suggest that nanoparticle-mediated combination chemotherapy and photodynamic therapy using doxorubicin and methylene blue has significant therapeutic potential against drug-resistant tumors. Copyright 2009 Elsevier B.V. All rights reserved.

Methyl jasmonate counteracts boron toxicity by preventing oxidative stress and regulating antioxidant enzyme activities and artemisinin biosynthesis in Artemisia annua L.

Science.gov (United States)

Aftab, Tariq; Khan, M Masroor A; Idrees, Mohd; Naeem, M; Moinuddin; Hashmi, Nadeem

2011-07-01

Boron is an essential plant micronutrient, but it is phytotoxic if present in excessive amounts in soil for certain plants such as Artemisia annua L. that contains artemisinin (an important antimalarial drug) in its areal parts. Artemisinin is a sesquiterpene lactone with an endoperoxide bridge. It is quite expensive compound because the only commercial source available is A. annua and the compound present in the plant is in very low concentration. Since A. annua is a major source of the antimalarial drug and B stress is a deadly threat to its cultivation, the present research was conducted to determine whether the exogenous application of methyl jasmonate (MeJA) could combat the ill effects of excessive B present in the soil. According to the results obtained, the B toxicity induced oxidative stress and reduced the stem height as well as fresh and dry masses of the plant remarkably. The excessive amounts of soil B also lowered the net photosynthetic rate, stomatal conductance, internal CO(2) concentration and total chlorophyll content in the leaves. In contrast, the foliar application of MeJA enhanced the growth and photosynthetic efficiency both in the stressed and non-stressed plants. The excessive B levels also increased the activities of antioxidant enzymes, such as catalase, peroxidase and superoxide dismutase. Endogenous H(2)O(2) and O(2)(-) levels were also high in the stressed plants. However, the MeJA application to the stressed plants reduced the amount of lipid peroxidation and stimulated the synthesis of antioxidant enzymes, enhancing the content and yield of artemisinin as well. Thus, it was concluded that MeJA might be utilized in mitigating the B toxicity and improving the content and yield of artemisinin in A. annua plant.

Combination therapy in a patient with chronic neuronopathic Gaucher disease: a case report.

Science.gov (United States)

Ceravolo, Ferdinando; Grisolia, Michele; Sestito, Simona; Falvo, Francesca; Moricca, Maria Teresa; Concolino, Daniela

2017-01-20

The variants of neuronopathic Gaucher disease may be viewed as a clinical phenotypic continuum divided into acute and chronic forms. The chronic neuronopathic form of Gaucher disease is characterized by a later onset of neurological symptoms and protracted neurological and visceral involvement. The first-choice treatment for nonneuronopathic Gaucher disease is enzyme replacement therapy with recombinant analogues of the deficient human enzyme glucocerebrosidase. Enzyme replacement therapy has been shown to improve hematological and bone manifestations associated with Gaucher disease, but, as with most proteins, recombinant enzymes cannot cross the blood-brain barrier, which prevents effects on neurological manifestations. Substrate reduction therapy with miglustat (N-butyldeoxynojirimycin) inhibits glucosylceramide synthase, which catalyzes the first step in glycosphingolipid synthesis. Because miglustat can cross the blood-brain barrier, it has been suggested that, combined with enzyme replacement therapy, it might be effective in treating neurological symptoms in patients with neuronopathic Gaucher disease. We report observed effects of combined enzyme replacement therapy and substrate reduction therapy in a 7-year-old Caucasian boy with neuronopathic Gaucher disease who was homozygous for L444P mutations. He had received enzyme replacement therapy from the age of 18 months, and concomitant miglustat treatment was commenced, with dosing according to body surface area uptitrated over 1 month with dietary modifications when he reached the age of 30 months. He experienced mild diarrhea after commencing miglustat therapy, which decreased in frequency/severity over time. His splenomegaly was reduced, and his hematological values and plasma angiotensin-converting enzyme activity normalized. Plasma chitotriosidase also showed substantial and sustained decreases. After 5 years of combination therapy, the patient showed no signs of neurological impairment. This case

Ribavirin-induced anemia in hepatitis C virus patients undergoing combination therapy.

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Sheeja M Krishnan

2011-02-01

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

Biological basis of combination therapy with radiation and bleomycin

International Nuclear Information System (INIS)

Fukuda, Hiroshi; Matsuzawa, Taiju; Yokoyama, Kumiko; Okuyama, Shinichi; Yamaura, Hiroshi

1976-01-01

The biological basis for combination therapy with radiation and bleomycin (BLM) was studied on C 2 W cells growing in vitro. When BLM was added to the medium before or after irradiation, a potentiating effect was observed. The potentiation remained for 4-6 hours after irradiation. To make clear the mechanism, both type of repair from radiation damage (Elkind type and PLD) by BLM were examined. BLM didn't inhibit the Elkind type recovery but it did inhibit the repair of potentially lethal damage (PLD repair). Plateau phase C 2 W cells were irradiated, incubated at 37 0 C for a various number of hours, then trypsinized for colony formation. PLD repair was inhibited when BLM was added immediately after irradiation. Based on such experimental results, we treated lung cancer with combination of radiation and BLM. BLM was injected intravenously within 30 minutes after irradiation. Although it seems too early to discuss the result of the combination therapy, it is very promising. (J.P.N.)

Biological basis of combination therapy with radiation and bleomycin

Energy Technology Data Exchange (ETDEWEB)

Fukuda, H; Matsuzawa, T; Yokoyama, K; Okuyama, S; Yamaura, H [Tohoku Univ., Sendai (Japan). Research Inst. for Tuberculosis, Leprosy and Cancer

1976-01-01

The biological basis for combination therapy with radiation and bleomycin (BLM) was studied on C/sub 2/W cells growing in vitro. When BLM was added to the medium before or after irradiation, a potentiating effect was observed. The potentiation remained for 4-6 hours after irradiation. To make clear the mechanism, both type of repair from radiation damage (Elkind type and PLD) by BLM were examined. BLM didn't inhibit the Elkind type recovery but it did inhibit the repair of potentially lethal damage (PLD repair). Plateau phase C/sub 2/W cells were irradiated, incubated at 37/sup 0/C for a various number of hours, then trypsinized for colony formation. PLD repair was inhibited when BLM was added immediately after irradiation. Based on such experimental results, we treated lung cancer with combination of radiation and BLM. BLM was injected intravenously within 30 minutes after irradiation. Although it seems too early to discuss the result of the combination therapy, it is very promising.

Combined Therapy at Persistent Herpes Virus Infection in Sickly Children

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F. S. Kharlamova

2012-01-01

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. 

Ethical hot spots of combined individual and group therapy: applying four ethical systems.

Science.gov (United States)

Brabender, Virginia M; Fallon, April

2009-01-01

Abstract Combined therapy presents ethical quandaries that occur in individual psychotherapy and group psychotherapy, and dilemmas specifically associated with their integration. This paper examines two types of ethical frameworks (a classical principle-based framework and a set of context-based frameworks) for addressing the ethical hot spots of combined therapy: self-referral, transfer of information, and termination. The principle-based approach enables the practitioner to see what core values may be served or violated by different courses of action in combined therapy dilemmas. Yet, the therapist is more likely to do justice to the complexity and richness of the combined therapy situation by supplementing a principle analysis with three additional ethical frameworks. These approaches are: virtue ethics, feminist ethics, and casuistry. An analysis of three vignettes illustrates how these contrasting ethical models not only expand the range of features to which the therapist attends but also the array of solutions the therapist generates.

Early experience of proton beam therapy combined with chemotherapy for locally advanced oropharyngeal cancer

International Nuclear Information System (INIS)

Ishikawa, Youjirou; Nakamura, Tatsuya; Takada, Akinori; Takayama, Kanako; Makita, Chiyoko; Suzuki, Motohisa; Azami, Yusuke; Kikuchi, Yasuhiro; Fuwa, Nobukazu

2013-01-01

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)

Molecular screening of S769N mutation for PFAT PASE in subjects ...

African Journals Online (AJOL)

Background: The emergence and spread of drug-resistant Plasmodium falciparum is a major problem of public health concern. Due to the high incidence of parasite resistance to antimalarial drugs, artemisinin-based combination therapies (ACTs) have now replaced those failing drugs in order to combat the growing drug ...

Options for empagliflozin in combination therapy in type 2 diabetes mellitus

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Hershon KS

2016-05-01

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

Cost-effectiveness Analysis of Antipsychotic Combination Therapy in Schizophrenia Inpatients

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Rizky Abdulah

2017-03-01

Full Text Available Schizophrenia is one of mental disorders with high cost and lifetime morbidity risk. Hence, it is necessary to analyze the cost-effectiveness of various combinations of antipsychotics. The aim of this study was to analyze the most cost-effective group of antipsychotic combinations in schizophrenia inpatients in West Java Psychiatric Hospital during 2012–2013. Data were collected retrospectively from medical record of patients who used antipsychotics clozapine-haloperidol or clozapine-risperidone therapy. Direct medical costs were obtained from antipsychotics costs, costs of medical treatment, medical expenses, hospitalization costs, and administrative costs. The results showed that the average cost-effectiveness ratio of antipsychotic clozapine-haloperidol was Rp126.898/day and Rp132.781/day for the combination of clozapine-haloperidol and clozapine-risperidone, respectively. Considering length of stay as the therapy effectiveness, it can be concluded that the combination of clozapine-haloperidol is more cost-effective than clozapine-risperidone.

Application of a cDNA microarray for profiling the gene expression of Echinococcus granulosus protoscoleces treated with albendazole and artemisinin.

Science.gov (United States)

Lü, Guodong; Zhang, Wenbao; Wang, Jianhua; Xiao, Yunfeng; Zhao, Jun; Zhao, Jianqin; Sun, Yimin; Zhang, Chuanshan; Wang, Junhua; Lin, Renyong; Liu, Hui; Zhang, Fuchun; Wen, Hao

2014-12-01

Cystic echinoccocosis (CE) is a neglected zoonosis that is caused by the dog-tapeworm Echinococcus granulosus. The disease is endemic worldwide. There is an urgent need for searching effective drug for the treatment of the disease. In this study, we sequenced a cDNA library constructed using RNA isolated from oncospheres, protoscoleces, cyst membrane and adult worms of E. granulosus. A total of 9065 non-redundant or unique sequences were obtained and spotted on chips as uniEST probes to profile the gene expression in protoscoleces of E. granulosus treated with the anthelmintic drugs albendazole and artemisinin, respectively. The results showed that 7 genes were up-regulated and 38 genes were down-regulated in the protoscoleces treated with albendazole. Gene analysis showed that these genes are responsible for energy metabolism, cell cycle and assembly of cell structure. We also identified 100 genes up-regulated and 6 genes down-regulated in the protoscoleces treated with artemisinin. These genes play roles in the transduction of environmental signals, and metabolism. Albendazole appeared its drug efficacy in damaging cell structure, while artemisinin was observed to increase the formation of the heterochromatin in protoscolex cells. Our results highlight the utility of using cDNA microarray methods to detect gene expression profiles of E. granulosus and, in particular, to understand the pharmacologic mechanism of anti-echinococcosis drugs. Copyright © 2014 Elsevier B.V. All rights reserved.

Laboratory evaluation of Artemisia annua L. extract and artemisinin activity against Epilachna paenulata and Spodoptera eridania.

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Maggi, María E; Mangeaud, Arnaldo; Carpinella, María C; Ferrayoli, Carlos G; Valladares, Graciela R; Palacios, Sara M

2005-07-01

Ethanolic extract of aerial parts of Artemisia annua L. and artemisinin were evaluated as anti-insect products. In a feeding deterrence assay on Epilachna paenulata Germ (Coleoptera: Coccinellidae) larvae, complete feeding rejection was observed at an extract concentration of 1.5 mg/cm2 on pumpkin leaf tissue. The same concentration produced a feeding inhibition of 87% in Spodoptera eridania (Cramer) (Lepidoptera: Noctuidae). In a no-choice assay, both species ate less and gained less weight when fed on leaves treated with the extract. Complete mortality in E. paenulata and 50% mortality in S. eridania were observed with extract at 1.5 mg/cm2. Artemisinin exhibited a moderate antifeedant effect on E. paenulata and S. eridania at 0.03-0.375 mg/cm2. However, a strong effect on survival and body weight was observed when E. paenulata larvae were forced to feed on leaves treated at 0.03 and 0.075 mg/cm2. Artemisia annua ethanolic extract of aerial parts at 1.5 mg/cm2 showed no phytotoxic effect on pumpkin seedlings.

Combined use of Dexa-Scheroson and Primobolan-Depot in radiation therapy

Energy Technology Data Exchange (ETDEWEB)

Nagai, J [Shizuoka Rosai Hospital (Japan)

1976-05-01

Dexa-Scheroson and Primobolan-Depot were used together with radiation therapy (Linac therapy) required in 13 cases. The following results were obtained. The decrease in white cell counts, which often occurs in radiation therapy, was inhibited by the drugs. There was no case in which radiation therapy should necessarily withdraw because the number of leuckocytes was decreased to less than 3,000. The patients whose liver function was poor should be treated with both drugs at the beginning of radiation therapy. It was found that the combined use of the drugs is effective in the prevention and the treatment of cerebral edema in radiation therapy of intracranial lesion.

EFFECTS OF COMBINATION THERAPY ON PLATELET COUNT IN PATIENTS OF MYOCARDIAL INFARCTION

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Sadaf Ahmed

2014-12-01

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.

Overexpression of allene oxide cyclase improves the biosynthesis of artemisinin in Artemisia annua L.

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Xu Lu

Full Text Available Jasmonates (JAs are important signaling molecules in plants and play crucial roles in stress responses, secondary metabolites' regulation, plant growth and development. In this study, the promoter of AaAOC, which was the key gene of jasmonate biosynthetic pathway, had been cloned. GUS staining showed that AaAOC was expressed ubiquitiously in A. annua. AaAOC gene was overexpressed under control of 35S promoter. RT-Q-PCR showed that the expression levels of AaAOC were increased from 1.6- to 5.2-fold in AaAOC-overexpression transgenic A. annua. The results of GC-MS showed that the content of endogenous jasmonic acid (JA was 2- to 4.7-fold of the control level in AaAOC-overexpression plants. HPLC showed that the contents of artemisinin, dihydroartemisinic acid and artemisinic acid were increased significantly in AaAOC-overexpression plants. RT-Q-PCR showed that the expression levels of FPS (farnesyl diphosphate synthase, CYP71AV1 (cytochrome P450 dependent hydroxylase and DBR2 (double bond reductase 2 were increased significantly in AaAOC-overexpression plants. All data demonstrated that increased endogenous JA could significantly promote the biosynthesis of artemisinin in AaAOC-overexpression transgenic A. annua.

Combined Therapies of Modified Taiyi Miraculous Moxa Roll and Cupping for Patients with Lumbar Intervertebral Disc Herniation.

Science.gov (United States)

Cai, Chunyue; Gong, Yuefeng; Dong, Dayong; Xue, Jinbiao; Zheng, Xiaoting; Zhong, Zhangfeng; Shao, Jialong; Mi, Daguo

2018-01-01

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 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 applications.

the role of community participation in intermittent preventive

African Journals Online (AJOL)

2014-06-01

Jun 1, 2014 ... paid to community participation in malaria control in the past and this ... current Artemisinin Combination Therapy (ACT)for malaria treatment is ..... Malaria Journal. 2009; 8:292. . 2. Ghana Health Service: Final draft antimalarial drug policy for Ghana, Accra. 2004. 3. Keta District Report. Keta, 2001. 4. Pitt C ...

Efficacies of artesunate plus either sulfadoxine-pyrimethamine or amodiaquine, for the treatment of uncomplicated, Plasmodium falciparum malaria in eastern Sudan

DEFF Research Database (Denmark)

Ibrahium, A M; Kheir, M M; Osman, M E

2007-01-01

Artemisinin-based combination therapy (ACT) is increasingly being adopted as the first-line treatment for malaria in sub-Saharan Africa. In September-November 2005, in New Halfa, eastern Sudan, the efficacy of artesunate-sulfadoxine-pyrimethamine (AS-SP) for the treatment of uncomplicated...... of uncomplicated, P. falciparum malaria in eastern Sudan....

Effect of Smilax China Capsules and azithromycin combined therapy on chronic annexitis

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Rong-Jun Cong

2016-11-01

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.

The Fate of the Red Cells: Insights from Two Models of Severe Malarial Anemia

Science.gov (United States)

2011-03-07

Diagnosis of malaria is generally performed with a blood smear or by rapid diagnostic tests. The WHO recommends artemisinin-based combination therapy (ACT...phosphatides, lecithin and sphingomyelin. J.Immunol. 1974;112:2135- 2147. 77. Ebenbichler CF, Thielens NM, Vornhagen R et al. Human immunodeficiency...of host responses to blood- stage malaria by interleukin-12: from therapy to adjuvant activity. Microbes.Infect. 2001;3:49-59. 148. Feng C

Combined anti-tumor necrosis factor-α therapy and DMARD therapy in rheumatoid arthritis patients reduces inflammatory gene expression in whole blood compared to DMARD therapy alone

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Carl K Edwards

2012-12-01

Full Text Available Periodic assessment of gene expression for diagnosis and monitoring in rheumatoid arthritis (RA may provide a readily available and useful method to detect subclinical disease progression and follow responses to therapy with disease modifying anti-rheumatic agents (DMARDs or anti-TNF-α therapy. We used quantitative real-time PCR to compare peripheral blood gene expression profiles in active ("unstable" RA patients on DMARDs, stable RA patients on DMARDs, and stable RA patients treated with a combination of a DMARD and an anti-TNF-α agent (infliximab or etanercept to healthy human controls. The expression of 48 inflammatory genes were compared between healthy controls (N=122, unstable DMARD patients (N=18, stable DMARD patients (N=26, and stable patients on combination therapy (N=20. Expression of 13 genes was very low or undetectable in all study groups. Compared to healthy controls, patients with unstable RA on DMARDs exhibited increased expression of 25 genes, stable DMARD patients exhibited increased expression of 14 genes and decreased expression of five genes, and combined therapy patients exhibited increased expression of six genes and decreased expression of 10 genes. These findings demonstrate that active RA is associated with increased expression of circulating inflammatory markers whereas increases in inflammatory gene expression are diminished in patients with stable disease on either DMARD or anti-TNF-α therapy. Furthermore, combination DMARD and anti-TNF-α therapy is associated with greater reductions in circulating inflammatory gene expression compared to DMARD therapy alone. These results suggest that assessment of peripheral blood gene expression may prove useful to monitor disease progression and response to therapy.

Modeling antibiotic treatment in hospitals: A systematic approach shows benefits of combination therapy over cycling, mixing, and mono-drug therapies.

Science.gov (United States)

Tepekule, Burcu; Uecker, Hildegard; Derungs, Isabel; Frenoy, Antoine; Bonhoeffer, Sebastian

2017-09-01

Multiple treatment strategies are available for empiric antibiotic therapy in hospitals, but neither clinical studies nor theoretical investigations have yielded a clear picture when which strategy is optimal and why. Extending earlier work of others and us, we present a mathematical model capturing treatment strategies using two drugs, i.e the multi-drug therapies referred to as cycling, mixing, and combination therapy, as well as monotherapy with either drug. We randomly sample a large parameter space to determine the conditions determining success or failure of these strategies. We find that combination therapy tends to outperform the other treatment strategies. By using linear discriminant analysis and particle swarm optimization, we find that the most important parameters determining success or failure of combination therapy relative to the other treatment strategies are the de novo rate of emergence of double resistance in patients infected with sensitive bacteria and the fitness costs associated with double resistance. The rate at which double resistance is imported into the hospital via patients admitted from the outside community has little influence, as all treatment strategies are affected equally. The parameter sets for which combination therapy fails tend to fall into areas with low biological plausibility as they are characterised by very high rates of de novo emergence of resistance to both drugs compared to a single drug, and the cost of double resistance is considerably smaller than the sum of the costs of single resistance.

[Combined l-thyroxine and l-triiodothyronine replacement therapy in congenital hypothyroidism].

Science.gov (United States)

Péter, Ferenc; Muzsnai, Agota

2013-05-12

L-thyroxine replacement therapy is the treatment of choice for hypothyroidism. Recently, several studies suggested to complete it with l-triiodothyronine in acquired hypothyroidism. To study the role of combined l-thyroxine and l-triiodothyronine therapy in special cases with congenital hypothyroidism. Data of 16 patients (age: 11.9 ± 6.3 years; mean ± SD) are presented who had high serum free thyroxine values or even above the upper limit of reference range (21.16 ± 2.5 pmol/l) together with nonsuppressed TSH levels (15.7 ± 5.7 mIU/l), and therefore received l-triiodothyronine in completion (0.18 ± 0.09 μg/kg) once a day. The combined replacement therapy resulted in a rapid improvement of the hormone parameters (TSH: 4.2 ± 3.15 mIU/l; free thyroxine: 16.55 ± 2.4 and free triiodothyronine: 7.4 ± 1.8 pmol/l). The efficiency of this combined therapy proved to be more evident (TSH: 4.33 ± 3.2 mIU/l; free thyroxine: 16.85 ± 3.1 and free triiodothyronine: 6.4 ± 0.85 pmol/l) in 10 patients treated for a longer period of time (duration of treatment: 2.9 ± 2.0 years). The dose of thyroxine substitution decreased from 2.6 ± 0.9 to 2.18 ± 0.6 μg/kg/day), the ratio of these hormones was between 5:1 and 19:1 and the quotient of free fractions was normalized (3.8 ± 0.4→2.6 ± 0.3) during the replacement therapy. According to the observation of the authors a serious disturbance of feed-back mechanism may develop in some (>5%) children with congenital hypothyroidism (increased TSH release despite elevated free thyroxine level) after normal function of the feed-back system for years. Hormone parameters of these patients improve, then become normal on combined therapy supporting the rationale for this treatment method.

Combined Therapies of Modified Taiyi Miraculous Moxa Roll and Cupping for Patients with Lumbar Intervertebral Disc Herniation

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Chunyue Cai

2018-01-01

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

Anti-tumor effects of Egr-IFN gamma gene therapy combined with {sup 125}I-UdR radionuclide therapy

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Jingguo, Zhao [No.403 Hospital of PLA, Dalian (China); Yanjun, Ni; Xiangfu, Song; Yanyi, Li; Wei, Yang; Ting, Sun; Qingjie, Ma; Fengtong, Gao

2008-12-15

Objective: To explore the anti-tumor effects of Egr-IFNgamma gene therapy combined with {sup 125}I-UdR radionuclide therapy in mice bearing H22 hepatocarcinoma and its mechanism. Methods: The recombinant plasmid pcDNAEgr-IFNgamma mixed with liposome was injected into tumor. 48 h later, 370 kBq {sup 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 IFNgamma 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-IFNgamma + {sup 125}I-UdR group were obviously lower than those of control group, {sup 125}I-UdR group and pcDNAEgr-1 + {sup 125}I-UdR group 6-15 d after gene-radionuclide therapy. IFNgamma protein was found in cytoplasm of H22 cells in pcDNAEgr-IFNgamma + {sup 125}I-UdR group after 3 d gene-radionuclide therapy. Cytotoxic activity of splenic CTL in pcDNAEgr-IFNgamma + {sup 125}I-UdR group was significantly higher than that in the other groups (P<0.01). Conclusions: The anti-tumor effects in vivo of pcDNAEgr-IFNgamma gene therapy combined with {sup 125}I-UdR radionuclide therapy are better than those of {sup 125}I-UdR therapy. (authors)

Effects of Hormone Deprivation, 2-Methoxyestradiol Combination Therapy on Hormone-Dependent Prostate Cancer In Vivo

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Fuminori Sato

2005-09-01

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.

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

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Triscari MT

2015-10-01

Full Text Available Maria Teresa Triscari,1 Palmira Faraci,2 Dario Catalisano,3 Valerio D’Angelo,1 Viviana Urso1 1Laboratory for Psychosomatic Disorders, Local Health Trust, Palermo, Italy; 2Faculty of Human and Social Sciences, University of Enna “Kore”, Enna, Italy; 3Italian Flight Safety Committee, Aeroporto di Fiumicino, Fiumicino (RM, Italy Abstract: 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. Keywords: flight anxiety, fear of flying, aerophobia, cognitive behavioral therapy, EMDR, VRET 

Combined miglustat and enzyme replacement therapy in two patients with type 1 Gaucher disease: two case reports.

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Amato, Dominick; Patterson, Mary Anne

2018-01-27

Intravenous enzyme replacement therapy is a first-line therapy for Gaucher disease type 1, and substrate reduction therapy represents an oral treatment alternative. Both enzyme replacement therapy and substrate reduction therapy are generally used as monotherapies in Gaucher disease. However, one randomized study and several case reports have described combination therapy over short time periods. We report two female Gaucher disease type 1 patients of mainly Anglo-Saxon descent, where combined enzyme replacement therapy and miglustat substrate reduction therapy were administered to overcome refractory clinical symptoms. The first patient was diagnosed at age 17 and developed Gaucher disease-related bone manifestations that worsened despite starting imiglucerase enzyme replacement therapy. After switching to miglustat substrate reduction therapy, her bone symptoms improved, but she developed tremors and eventually switched back to enzyme replacement therapy. Miglustat was later recommenced in combination with ongoing enzyme replacement therapy due to continued bone pain, and her bone symptoms improved along with maintained visceral manifestations. Enzyme replacement therapy was subsequently tapered off and the patient has since been successfully maintained on miglustat. The second patient was diagnosed aged 3, and commenced imiglucerase enzyme replacement therapy aged 15. After 9 years on enzyme replacement therapy she switched to miglustat substrate reduction therapy and her core symptoms were maintained/stable for 3 years. Imiglucerase enzyme replacement therapy was later added as a boost to therapy and her symptoms were subsequently maintained over a 2.3-year period. However, miglustat was discontinued due to her relocation, necessitating an increase in enzyme replacement therapy dose. Overall, both patients benefited from combination therapy. While the majority of Gaucher disease type 1 patients will not need treatment with both substrate reduction therapy

Haemolysis associated with the treatment of malaria with artemisinin derivatives: a systematic review of current evidence

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Khalid Rehman

2014-12-01

Conclusions: Haemolysis is commonly associated with the class of artemisinin drugs when used for the treatment of severe malaria. Potential causes of this safety issue are discussed. Although no deaths attributed to haemolysis have been reported so far, this safety issue may lead to life-threatening anaemia and is particularly worrying for regions where safe blood products are not readily available.

Combined analgesics in (headache pain therapy: shotgun approach or precise multi-target therapeutics?

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Fiebich Bernd L

2011-03-01

Full Text Available Abstract Background Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix" are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics. Discussion In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect. As an example the fixesd-dose combination of acetylsalicylic acid (ASA, paracetamol (acetaminophen and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy. Summary Multitarget therapeutics like combined analgesics broaden

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

Science.gov (United States)

2011-01-01

Background Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics. Discussion In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect. As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy. Summary Multitarget therapeutics like combined analgesics broaden the array of therapeutic

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

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Straube, Andreas; Aicher, Bernhard; Fiebich, Bernd L; Haag, Gunther

2011-03-31

Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics. In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect.As an example the fixed-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy. Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness

Combination Therapy for Airflow Limitation In COPD

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Jafar Aslani

2012-08-01

Full Text Available Background and the purpose of the study Existing evidence confirms that no pharmacologic agent ameliorates the decline in the lung function or changes the prognosis of chronic obstructive pulmonary disease (COPD. We tried a critical combination therapy for management of COPD. Methods Current or past smoker (passive or active COPD patients with moderate to severe COPD who did not respond to primitive therapy (i.e., oral prednisolone (50 mg in the morning for 5 days; with Beclomethasone Fort (3 puff q12h, totally 1500 micrograms/day, Salmeterol (2 puffs q12h, 50 micrograms/puff and ipratropium bromide (4 puffs q8h for two months, enrolled to study. Furthermore they were received N-Acetylcysteine (1200 mg/daily, Azithromycin (tablet 250 mg/every other day and Theophylline (100 mg BD.Results The study group consisted of 44 men and 4 women, with a mean age and standard deviation of 63.6+/-12.7 years (range 22-86 years. Thirteen of 48 patients (27.0% was responder based on 15% increasing in FEV 1 (27.7+/-7.9 after 6.7+/-6.1 months (57.9+/-12.9 year old. There were statistically significant differences in age and smoking between responders and nonresponders (P value was 0.05 and 0.04 respectively. There was no difference in emphysema and air trapping between two groups (p=0.13. Conclusion Interestingly considerable proportion of patients with COPD can be reversible using combination drug therapy and patients will greatly benefit from different and synergic action of the drugs. The treatment was more effective in younger patients who smoke less.

Effect of Polycosanol, a grape seed extract and its combined therapy on oxidation markers in rats

International Nuclear Information System (INIS)

Oyarzabal Yera, Ambar; Molina Cuevas, Vivian; Jimenez Despaigne, Sonia

2010-01-01

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

Theranostic GO-based nanohybrid for tumor induced imaging and potential combinational tumor therapy.

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Qin, Si-Yong; Feng, Jun; Rong, Lei; Jia, Hui-Zhen; Chen, Si; Liu, Xiang-Ji; Luo, Guo-Feng; Zhuo, Ren-Xi; Zhang, Xian-Zheng

2014-02-12

Graphene oxide (GO)-based theranostic nanohybrid is designed for tumor induced imaging and potential combinational tumor therapy. The anti-tumor drug, Doxorubicin (DOX) is chemically conjugated to the poly(ethylenimine)-co-poly(ethylene glycol) (PEI-PEG) grafted GO via a MMP2-cleavable PLGLAG peptide linkage. The therapeutic efficacy of DOX is chemically locked and its intrinsic fluorescence is quenched by GO under normal physiological condition. Once stimulated by the MMP2 enzyme over-expressed in tumor tissues, the resulting peptide cleavage permits the unloading of DOX for tumor therapy and concurrent fluorescence recovery of DOX for in situ tumor cell imaging. Attractively, this PEI-bearing nanohybrid can mediate efficient DNA transfection and shows great potential for combinational drug/gene therapy. This tumor induced imaging and potential combinational therapy will open a window for tumor treatment by offering a unique theranostic approach through merging the diagnostic capability and pathology-responsive therapeutic function. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Trigeminal neuralgia: successful antiepileptic drug combination therapy in three refractory cases

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Prisco L

2011-08-01

Full Text Available Lara Prisco1, Mario Ganau2, Federica Bigotto1, Francesca Zornada11Department of Anaesthesiology, Intensive Care and Emergency Medicine, University Hospital of Cattinara, 2Graduate School of Nanotechnology, University of Trieste, ItalyAbstract: Antiepileptic drug combination therapy remains an empirical second-line treatment approach in trigeminal neuralgia, after treatment with one antiepileptic drug or other nonantiepileptic drugs have failed. The results in three patients followed in our clinic are not sufficient to draw definitive conclusions, but suggest the possibility of developing this type of therapeutic approach further.Keywords: trigeminal neuralgia, antiepileptic drugs, combination therapy

Feasibility Study Combining Art Therapy or Cognitive Remediation Therapy with Family-based Treatment for Adolescent Anorexia Nervosa.

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Lock, James; Fitzpatrick, Kathleen Kara; Agras, William S; Weinbach, Noam; Jo, Booil

2018-01-01

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.

Discordant perspectives of rheumatologists and patients on COBRA combination therapy in rheumatoid arthritis.

NARCIS (Netherlands)

Tuyl, L.H.D. van; Plass, A.M.C.; Lems, W.F.; Voskuyl, A.E.; Kerstens, P.J.S.M.; Dijkmans, B.A.C.; Boers, M.

2008-01-01

Objective. The COBRA therapy (combination therapy in early rheumatoid arthritis) has proven to be an effective treatment for early RA, but is rarely prescribed. A survey showed reluctance of Dutch reumatologists to apply COBRA therapy in early RA. The present qualitative study was carried out to

Cancer treatment: the combination of vaccination with other therapies

DEFF Research Database (Denmark)

Andersen, M.H.; Sorensen, R.B.; Schrama, D.

2008-01-01

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...... and endothelial cells. The efficacy of therapeutic vaccination against cancer will over the next few years be studied in settings taking advantage of strategies in which vaccination is combined with other treatment modalities. These combinations should be based on current knowledge not only regarding the biology...... of the cancer cell per se, but also considering how treatment may influence the malignant cell population as well as the immune system Udgivelsesdato: 2008/11...

Cancer Nanomedicine: From Targeted Delivery to Combination Therapy

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Xu, Xiaoyang; Ho, William; Zhang, Xueqing; Bertrand, Nicolas; Farokhzad, Omid

2015-01-01

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

Efficacy of artemether-lumefantrine and dihydroartemisinin-piperaquine for treatment of uncomplicated malaria in children in Zaire and Uíge Provinces, angola.

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Plucinski, Mateusz M; Talundzic, Eldin; Morton, Lindsay; Dimbu, Pedro Rafael; Macaia, Aleixo Panzo; Fortes, Filomeno; Goldman, Ira; Lucchi, Naomi; Stennies, Gail; MacArthur, John R; Udhayakumar, Venkatachalam

2015-01-01

The development of resistance to antimalarials is a major challenge for global malaria control. Artemisinin-based combination therapies, the newest class of antimalarials, are used worldwide but there have been reports of artemisinin resistance in Southeast Asia. In February through May 2013, we conducted open-label, nonrandomized therapeutic efficacy studies of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) in Zaire and Uíge Provinces in northern Angola. The parasitological and clinical responses to treatment in children with uncomplicated Plasmodium falciparum monoinfection were measured over 28 days, and the main outcome was a PCR-corrected adequate clinical and parasitological response (ACPR) proportion on day 28. Parasites from treatment failures were analyzed for the presence of putative molecular markers of resistance to lumefantrine and artemisinins, including the recently identified mutations in the K13 propeller gene. In the 320 children finishing the study, 25 treatment failures were observed: 24 in the AL arms and 1 in the DP arm. The PCR-corrected ACPR proportions on day 28 for AL were 88% (95% confidence interval [CI], 78 to 95%) in Zaire and 97% (91 to 100%) in Uíge. For DP, the proportions were 100% (95 to 100%) in Zaire, and 100% (96 to 100%) in Uíge. None of the treatment failures had molecular evidence of artemisinin resistance. In contrast, 91% of AL late-treatment failures had markers associated with lumefantrine resistance on the day of failure. The absence of molecular markers for artemisinin resistance and the observed efficacies of both drug combinations suggest no evidence of artemisinin resistance in northern Angola. There is evidence of increased lumefantrine resistance in Zaire, which should continue to be monitored. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Cancer nanomedicine: gold nanoparticle mediated combined cancer therapy

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Yang, C.; Bromma, Kyle; Chithrani, B. D.

2018-02-01

Recent developments in nanotechnology has provided new tools for cancer therapy and diagnosis. Among other nanomaterial systems, gold nanoparticles are being used as radiation dose enhancers and anticancer drug carriers in cancer therapy. Fate of gold nanoparticles within biological tissues can be probed using techniques such as TEM (transmission electron microscopy) and SEM (Scanning Electron Microscopy) due to their high electron density. We have shown for the first time that cancer drug loaded gold nanoparticles can reach the nucleus (or the brain) of cancer cells enhancing the therapeutic effect dramatically. Nucleus of the cancer cells are the most desirable target in cancer therapy. In chemotherapy, smart delivery of highly toxic anticancer drugs through packaging using nanoparticles will reduce the side effects and improve the quality and care of cancer patients. In radiation therapy, use of gold nanoparticles as radiation dose enhancer is very promising due to enhanced localized dose within the cancer tissue. Recent advancement in nanomaterial characterization techniques will facilitate mapping of nanomaterial distribution within biological specimens to correlate the radiobiological effects due to treatment. Hence, gold nanoparticle mediated combined chemoradiation would provide promising tools to achieve personalized and tailored cancer treatments in the near future.

Clinical impact of a combined therapy of peritoneal dialysis and hemodialysis.

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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

2010-09-01

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.

Targeting the NF-κB Pathway as a Combination Therapy for Advanced Thyroid Cancer.

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Nikita Pozdeyev

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

Research progress in combination therapy with pegylated interferon and nucleos(tide analogues in treatment of chronic hepatitis B

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YU Yiqi

2015-09-01

Full Text Available Current antiviral treatment strategy for chronic hepatitis B (CHB includes pegylated interferon (PEG-IFN and nucleos(tide analogues (NAs. Whether combination therapy with PEG-IFN and NAs improve therapeutic efficacy has become the key question regarding the antiviral therapy for CHB. This article reviews the recent progress in combination therapy for the management of CHB. The results indicate that the efficacy of simultaneous combination of PEG-IFN and NAs is not superior to that of PEG-IFN monotherapy in terms of HBeAg seroconversion and response after drug withdrawal. Sequential combination or switching therapy in PEG-IFN- or NAs-treated patients, as well as combination with immune cell therapy, is a promising treatment strategy.

Antimicrobial photodynamic therapy combined with conventional endodontic treatment to eliminate root canal biofilm infection.

Science.gov (United States)

Garcez, Aguinaldo S; Ribeiro, Martha S; Tegos, George P; Núñez, Silvia C; Jorge, Antonio O C; Hamblin, Michael R

2007-01-01

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. 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-micro fiber, and this was compared and combined with standard endodontic treatment using mechanical debridement and antiseptic irrigation. 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 (Ptreatment. Bioluminescence imaging is an efficient way to monitor endodontic therapy. Antimicrobial PDT may have a role to play in optimized endodontic therapy. (c) 2006 Wiley-Liss, Inc.

Combination use of lentinan with x-ray therapy in mouse experimental tumor system, (3). Combination effect on the metastatic tumors

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Shiio, Tsuyoshi; Ohishi, Kazuo; Niitsu, Iwayasu; Hayashibara, Hiromi; Tsuchiya, Yoshiharu; Yoshihama, Takashi; Moriyuki, Hirobumi

1988-03-01

Combination effect of lentinan with X-ray irradiation on the metastatic mouse tumors, L1210, KLN205 and Lewis lung carcinoma were studied. Combination use of lentinan with X-ray therapy prolonged the life of BDF/sub 1/ mice bearing L1210 leukemia in the suitable combination conditions. Combination effects of lentinan with X-ray therapy were also observed on the suppression of the growth of KLN205 squamus cell carcinoma and on the suppression of the metastasis of Lewis lung carcinoma. Especially, in the case that lentinan was administered before or after X-ray local irradiation in the pulmorary metastasis system of Lewis lung carcinoma, a marked suppressin of pulmonary metastasis was observed and 2 to 4 mice among 8 tested mice were tumor free.

Adenovirus-mediated IL-12 gene therapy in combination with radiotherapy for murine liver cancer

International Nuclear Information System (INIS)

Wei Daoyan; Dai Bingbing; Wang Zhonghe; Chen Shishu

2001-01-01

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

Combination photodynamic therapy of human breast cancer using salicylic acid and methylene blue

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Hosseinzadeh, Reza; Khorsandi, Khatereh; Jahanshiri, Maryam

2017-09-01

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.

Combined aquaretic and diuretic therapy in acute heart failure

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Goyfman M

2017-06-01

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

Building a roadmap for developing combination therapies for Alzheimer's disease.

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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

2015-03-01

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.

Well-established and more recent aspects of combined therapy of gynaecological tumours

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Ladner, H.A.

1981-01-01

The question of superiority concerning operative or radiation therapy should not make us forget that the combined therapy of gynaecologic carcinomas was proven to be good. The differing therapy results are due to the problems of classifying the phases, the ages of the patients, the histology, and, not less important, the radiation sensibility of gynaecologic tumours. The psychological and psychosomatic aspects of treating gynaecologic tumours are discussed. (APR) [de

Smart activatable and traceable dual-prodrug for image-guided combination photodynamic and chemo-therapy.

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Hu, Fang; Yuan, Youyong; Mao, Duo; Wu, Wenbo; Liu, Bin

2017-11-01

Activatable photosensitizers (PSs) and chemo-prodrugs are highly desirable for anti-cancer therapy to reduce systemic toxicity. However, it is difficult to integrate both together into a molecular probe for combination therapy due to the complexity of introducing PS, singlet oxygen quencher, chemo-drug, chemo-drug inhibitor and active linker at the same time. To realize activatable PS and chemo-prodrug combination therapy, we develop a smart therapeutic platform in which the chemo-prodrug serves as the singlet oxygen quencher for the PS. Specifically, the photosensitizing activity and fluorescence of the PS (TPEPY-SH) are blocked by the chemo-prodrug (Mitomycin C, MMC) in the probe. Meanwhile, the cytotoxicity of MMC is also inhibited by the electron-withdrawing acyl at the nitrogen position next to the linker. Upon glutathione activation, TPEPY-S-MMC can simultaneously release active PS and MMC for combination therapy. The restored fluorescence of TPEPY-SH is also used to report the activation for both PS and MMC as well as to guide the photodynamic therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dynamics of tumor growth and combination of anti-angiogenic and cytotoxic therapies

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Kohandel, M.; Kardar, M.; Milosevic, M.; Sivaloganathan, S.

2007-07-01

Tumors cannot grow beyond a certain size (about 1-2 mm in diameter) through simple diffusion of oxygen and other essential nutrients into the tumor. Angiogenesis, the formation of blood vessels from pre-existing vessels, is a crucial and observed step, through which a tumor obtains its own blood supply. Thus, strategies that interfere with the development of this tumor vasculature, known as anti-angiogenic therapy, represent a novel approach to controlling tumor growth. Several pre-clinical studies have suggested that currently available angiogenesis inhibitors are unlikely to yield significant sustained improvements in tumor control on their own, but rather will need to be used in combination with conventional treatments to achieve maximal benefit. Optimal sequencing of anti-angiogenic treatment and radiotherapy or chemotherapy is essential to the success of these combined treatment strategies. Hence, a major challenge to mathematical modeling and computer simulations is to find appropriate dosages, schedules and sequencing of combination therapies to control or eliminate tumor growth. Here, we present a mathematical model that incorporates tumor cells and the vascular network, as well as their interplay. We can then include the effects of two different treatments, conventional cytotoxic therapy and anti-angiogenic therapy. The results are compared with available experimental and clinical data.

Combined therapy with peritoneal dialysis and hemodialysis: a multicenter retrospective observational cohort study in Japan.

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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

2014-01-01

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.

Second-line combination therapies in nonsmall cell lung cancer without known driver mutations

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Maria-Virginia Bluthgen

2015-12-01

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.

Trial of radiation therapy combined with hyperthermia

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Takegawa, Y; Fujiwara, K; Oe, J; Nagase, M; Akiyama, H [Tokushima Univ. (Japan). School of Medicine

1978-08-01

Nine patients were treated by the combination therapy of external irradiation and hyperthermia, 5 patients with metastatic lesions; two breast cancer, one lung cancer, one malignant melanoma, one vulva cancer, 1 patient with recurrent lesion of skin cancer and 3 patients with bladder cancer. All patients were treated by heating locally (42/sup 0/C, 30 min) followed by external irradiation with 4,000 - 5,000 rad over 4 to 5 weeks. No local recurrence was found in 4 of 9 patients.

Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance in vitro.

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Khdair, Ayman; Handa, Hitesh; Mao, Guangzhao; Panyam, Jayanth

2009-02-01

Drug resistance limits the success of many anticancer drugs. Reduced accumulation of the drug at its intracellular site of action because of overexpression of efflux transporters such as P-glycoprotein (P-gp) is a major mechanism of drug resistance. In this study, we investigated whether photodynamic therapy (PDT) using methylene blue, also a P-gp inhibitor, can be used to enhance doxorubicin-induced cytotoxicity in drug-resistant tumor cells. Aerosol OT (AOT)-alginate nanoparticles were used as a carrier for the simultaneous cellular delivery of doxorubicin and methylene blue. Methylene blue was photoactivated using light of 665 nm wavelength. Induction of apoptosis and necrosis following treatment with combination chemotherapy and PDT was investigated in drug-resistant NCI/ADR-RES cells using flow cytometry and fluorescence microscopy. Effect of encapsulation in nanoparticles on the intracellular accumulation of doxorubicin and methylene blue was investigated qualitatively using fluorescence microscopy and was quantitated using HPLC. Encapsulation in AOT-alginate nanoparticles significantly enhanced the cytotoxicity of combination therapy in resistant tumor cells. Nanoparticle-mediated combination therapy resulted in a significant induction of both apoptosis and necrosis. Improvement in cytotoxicity could be correlated with enhanced intracellular and nuclear delivery of the two drugs. Further, nanoparticle-mediated combination therapy resulted in significantly elevated reactive oxygen species (ROS) production compared to single drug treatment. In conclusion, nanoparticle-mediated combination chemotherapy and PDT using doxorubicin and methylene blue was able to overcome resistance mechanisms and resulted in improved cytotoxicity in drug-resistant tumor cells.

Combined cisplatin and radiation therapy for advanced bladder cancer

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Tajima, Masaharu; Sawamura, Yoshikatsu; Kase, Takahisa

1991-01-01

The combined effects of cisplatin and irradiation were investigated in 44 patients with bladder cancer accompanied by the infiltration of T 2 ∼T 4 cells, in a study commencing in September 1985. The antitumor effect and adverse reactions to the therapy were recorded. The majority of these patients had not undergone total bladder excision, for a variety of reasons. Thirty-two patients were male and 12 were female; the average age was 66.7 years, with ranging from 33∼83 years of age. Irradiation was performed using table cobalt 60 or a linear accelerator at a dose of 2 Gy per day, 5 days a week. The total radiation dose ranged from 40 to 70 Gy. Cisplatin was administered systemically at a dose of 20∼30 mg/day for 5 consecutive days during the first and fourth weeks of irradiation. At the time of final assessment of the antitumor effect, 24 out of 40 eligible patients (60%) had achieved complete remission (CR). The duration of CR averaged 18.8 months, with a range of 1∼50 months. The actual survival rates were as follows: 81% at 1 year, 69% at 2 years, and 52% at 3 and 4 years. Regarding adverse reactions, anorexia occurred in 28 patients (70%), nausea and vomiting in 21 (53%), diarrhea in 8 (20%), leukopenia in 16 (40%), mild thrombocytopenia in 5 (13%), and dermatitis in 8 (20%). All of these adverse reactions were mild and were alleviated after completion of the combined therapy. The present investigation demonstrated that combined therapy with cisplatin and irradiation is effective for the regional treatment of invasive bladder cancer. (author)

Combined immunotherapy and antiangiogenic therapy of cancer with microencapsulated cells.

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Cirone, Pasquale; Bourgeois, Jacqueline M; Shen, Feng; Chang, Patricia L

2004-10-01

An alternative form of gene therapy involves immunoisolation of a nonautologous cell line engineered to secrete a therapeutic product. Encapsulation of these cells in a biocompatible polymer serves to protect these allogeneic cells from host-versus-graft rejection while recombinant products and nutrients are able to pass by diffusion. This strategy was applied to the treatment of cancer with some success by delivering either interleukin 2 or angiostatin. However, as cancer is a complex, multifactorial disease, a multipronged approach is now being developed to attack tumorigenesis via multiple pathways in order to improve treatment efficacy. A combination of immunotherapy with angiostatic therapy was investigated by treating B16-F0/neu melanoma-bearing mice with intraperitoneally implanted, microencapsulated mouse myoblasts (C2C12) genetically modified to deliver angiostatin and an interleukin 2 fusion protein (sFvIL-2). The combination treatment resulted in improved survival, delayed tumor growth, and increased histological indices of antitumor activity (apoptosis and necrosis). In addition to improved efficacy, the combination treatment also ameliorated some of the undesirable side effects from the individual treatments that have led to the previous failure of the single treatments, for example, inflammatory response to IL-2 or vascular mimicry due to angiostatin. In conclusion, the combination of immuno- and antiangiogenic therapies delivered by immunoisolated cells was superior to individual treatments for antitumorigenesis activity, not only because of their known mechanisms of action but also because of unexpected protection against the adverse side effects of the single treatments. Thus, the concept of a "cocktail" strategy, with microencapsulation delivering multiple antitumor recombinant molecules to improve efficacy, is validated.

The combined application of biological therapy and methotrexate in case of escape phenomenon progressing

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Ponich E.S.

2015-09-01

Full Text Available Aim: the study of the efficacy of methotrexate in patients with the "escape effect" during the ustekinumab therapy. Materials and Methods. The results of methotrexate at a dose of 15-20mg/week in treatment of 4 patients receiving biologic and developed "escape effect". Ustekinumab is used as a hypodermic injection at a dose of 45 mg for a body weight of a patient no more than 100 kg, and 90 mg of body weight over 100 kg, at the zero week, the 4th week and then every 12 weeks. Patients control meets the standard management of patients in biological therapy. Results. The study shows that in the case of the resistance progressing when applying preparations of biological therapy, methotrexate is useful at a dose of 15-20mg/week for up to 6 months. The combined use of biologic therapy and methotrexate in the treatment of patients with psoriasis vulgaris, "escape effect" contributes to the marked regression of clinical symptoms and allows to control the process long enough, which is confirmed by the dynamics of the index PASI, BRS and DLQI. The combined method is highly safe, as evidenced by the lack of inhibition of hematopoiesis, the normal level of hepatic transaminases and serum creatinine, which greatly improves patient compliance in this type of therapy. Conclusion. The article presents the data of the combined application of biological medication therapy (ustekinumab and methotrexate for the treatment of patients with the common form of psoriasis vulgaris. In the case of the development of resistance of biological therapy recommended the appointment of methotrexate. The combined use of methotrexate and biologic therapy in the treatment of patients with psoriasis vulgaris contributes to marked regression of clinical symptoms and allows to control the process for a long time.

K13 mutations and pfmdr1 copy number variation in Plasmodium falciparum malaria in Myanmar.

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Win, Aye A; Imwong, Mallika; Kyaw, Myat P; Woodrow, Charles J; Chotivanich, Kesinee; Hanboonkunupakarn, Borimas; Pukrittayakamee, Sasithon

2016-02-24

Artemisinin-based combination therapy has been first-line treatment for falciparum malaria in Myanmar since 2005. The wide extent of artemisinin resistance in the Greater Mekong sub-region and the presence of mefloquine resistance at the Myanmar-Thailand border raise concerns over resistance patterns in Myanmar. The availability of molecular markers for resistance to both drugs enables assessment even in remote malaria-endemic areas. A total of 250 dried blood spot samples collected from patients with Plasmodium falciparum malarial infection in five malaria-endemic areas across Myanmar were analysed for kelch 13 sequence (k13) and pfmdr1 copy number variation. K13 mutations in the region corresponding to amino acids 210-726 (including the propeller region of the protein) were detected by nested PCR amplification and sequencing, and pfmdr1 copy number variation by real-time PCR. In two sites, a sub-set of patients were prospectively followed up for assessment of day-3 parasite clearance rates after a standard course of artemether-lumefantrine. K13 mutations and pfmdr1 amplification were successfully analysed in 206 and 218 samples, respectively. Sixty-nine isolates (33.5 %) had mutations within the k13 propeller region with 53 of these (76.8 %) having mutations already known to be associated with artemisinin resistance. F446I (32 isolates) and P574L (15 isolates) were the most common examples. K13 mutation was less common in sites in western border regions (29 of 155 isolates) compared to samples from the east and north (40 of 51 isolates; p Myanmar. There is a low prevalence of parasites with multiple pfmdr1 copies across the country. The efficacy of artemisinin-based combination therapy containing mefloquine and lumefantrine is, therefore, expected to be high, although regular monitoring of efficacy will be important.

Assessment of immunomodulating action of combined therapy with UHF-hyperthermia in children with osteogenic sarcoma

International Nuclear Information System (INIS)

Neprina, G.S.; Panteleeva, E.S.; Vatin, O.E.; Bizer, V.A.; Bojko, I.N.

1989-01-01

The paper is concerned with immunological evaluation of different stages of combined therapy with local UHF-hyperthermia in children with osteogenic sarcoma. Combined therapy (polychemo- and raditherapy) was shown to cause a decrease in the number of immunocompetent cells, to enhance dysbalance of immunoregulatory T-lymphocytes, to weaken T-lymphocyte function on PHA; immunosuppressive action of combined therapy did not depend on a tumor site. The incorporation of UHF-hyperthermia in the therapeutic scheme weakened the manifestations of secondary immunodeficiency, got back to normal structure of T-lymphocyte population. A favorable immunomodulating effect of hyperthermia was more frequently observed in patients with crural bone tumors. The effect of hyperthermia was revealed after direct influence of thermotherapy but it was absent in continuation of combined treatment

Combined EGFR and VEGFR versus single EGFR signaling pathways inhibition therapy for NSCLC: a systematic review and meta-analysis.

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Xinji Zhang

Full Text Available BACKGROUND: Lung cancer is a heterogeneous disease with multiple signaling pathways influencing tumor cell survival and proliferation, and it is likely that blocking only one of these pathways allows others to act as salvage or escape mechanisms for cancer cells. Whether combined inhibition therapy has greater anti-tumor activity than single inhibition therapy is a matter of debate. Hence, a meta-analysis comparing therapy inhibiting both VEGFR and EGFR signaling pathways with that inhibiting EGFR signaling pathway alone was performed. METHODOLOGY AND PRINCIPAL FINDINGS: We searched PubMed, EMBASE database and the proceedings of major conferences for relevant clinical trials. Outcomes analyzed were objective tumor response rate (ORR, progression-free survival (PFS, overall survival (OS and toxicity. Besides, subgroup analyses were performed to investigate whether the combined inhibition therapy is best performed using combination of selective agents or a single agent with multiple targets. Six trials recruiting 3,302 patients were included in the analysis. Combined inhibition therapy was associated with a 3% improvement in OS as compared with single-targeted therapy, but this difference was not statistically significant (HR, 0.97; 95% CI, 0.89-1.05; P=0.472. Patients receiving combined inhibition therapy had significant longer PFS than the group with single-targeted therapy (HR, 0.80; 95% CI, 0.67-0.95; P=0.011. There was no difference in the ORR between the groups (OR, 1.44; 95% CI, 0.95-2.18; P=0.085. Subgroup analysis revealed that combined inhibition therapy using combination regimens was associated with statistically significant improvement in both ORR and PFS. Toxicity was greater in combined inhibition therapy. CONCLUSIONS: There is no evidence to support the use of combined inhibition therapy in unselected patients with advanced NSCLC. However, given the significant advantage in ORR and PFS, combined inhibition therapy using combination

Photodynamic therapy combined with antivascular endothelial growth factor treatment for recalcitrant chronic central serous chorioretinopathy

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Asahi MG

2017-11-01

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

A Systematic Review of the Combined Use of Electroconvulsive Therapy and Psychotherapy for Depression

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McClintock, Shawn M.; Brandon, Anna R.; Husain, Mustafa M.; Jarrett, Robin B.

2011-01-01

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

Cyclophosphamide/x-ray: combined mode preparation for transplantation therapy

International Nuclear Information System (INIS)

Meredith, R.; Okunewick, J.; Shadduck, R.; Raikow, R.; Brozovich, B.; Seeman, P.

1979-01-01

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

Preliminary clinical evaluation of continuous infusion of 5-FU and low-dose cisplatin (LFP) therapy alone and combined with radiation therapy for treatment of advanced or recurrent esophageal cancer

International Nuclear Information System (INIS)

Itoh, Satoshi; Morita, Sojiro; Ohnishi, Takenao; Tsuji, Akihito; Takamatsu, Masahiro; Horimi, Tadashi

2002-01-01

We evaluated the clinical effect of 5-FU and low-dose Cisplatin (LFP) therapy alone and LFP therapy combined with radiation therapy in patients with advanced or recurrent esophageal cancer. From March 1995 to September 2000, 11 patients with inoperable esophageal cancer, 8 patients with adjuvant chemotherapy post operation, and 14 patients with recurrent esophageal cancer were treated with LFP therapy. 5-FU (160 mg/m 2 /day) was continuously infused over 24 hours, and CDDP (3-7 mg/m 2 /day) was infused for 30 minutes. The administration schedule consisted of 5-FU for 7 consecutive days and CDDP for 5 days followed by a 2-day rest, each for four weeks. We combined radiation therapy for the patients with all lesions that could be included in the radiation field. Of 30 patients with measurable lesions the response rates of LFP therapy alone and LFP therapy combined with radiation therapy were 33% and 60%, respectively. Toxicity over grade 3 appeared in 3 of 15 patients with LFP therapy combined with radiation therapy. There was no significant difference between LFP therapy alone and LFP therapy combined with radiation therapy with regard to survival rate of inoperable and recurrent esophageal cancer. In conclusion, LFP therapy alone may be effective for esophageal cancer. (author)

Nobel prize for the artemisinin and ivermectin discoveries: a great boost towards elimination of the global infectious diseases of poverty.

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Tambo, Ernest; Khater, Emad I M; Chen, Jun-Hu; Bergquist, Robert; Zhou, Xiao-Nong

2015-12-28

The Millennium Development Goals (MDGs) made a marked transformation for neglected and vulnerable communities in the developing countries from the start, but infectious diseases of poverty (IDoPs) continue to inflict a disproportionate global public health burden with associated consequences, thereby contributing to the vicious cycle of poverty and inequity. However, the effectiveness and large-scale coverage of artemisinin combination therapy (ACT) have revolutionized malaria treatment just as the control of lymphatic filariasis (LF) and onchocerciasis have benefitted from harnessing the broad-spectrum effect of avermectin-based derivatives. The paradigm shift in therapeutic approach, effected by these two drugs and their impact on community-based interventions of parasitic diseases plaguing the endemic low- and middle-income countries (LIMCs), led to the Nobel Prize in Physiology or Medicine in 2015. However, the story would not be complete without mentioning praziquantel. The huge contribution of this drug in modernizing the control of schistosomiasis and also some intestinal helminth infections had already shifted the focus from control to potential elimination of this disease. Together, these new drugs have provided humankind with powerful new tools for the alleviation of infectious diseases that humans have lived with since time immemorial. These drugs all have broad-spectrum effects, yet they are very safe and can even be packaged together in various combinations. The strong effect on so many of the great infectious scourges in the developing countries has not only had a remarkable influence on many endemic diseases, but also contributed to improving the cost structure of healthcare. Significant benefits include improved quality of preventive and curative medicine, promotion of community-based interventions, universal health coverage and the fostering of global partnerships. The laudable progress and benefits achieved are indispensable in championing

Fixed-functional appliance treatment combined with growth hormone therapy.

Science.gov (United States)

Jung, Min-Ho

2017-09-01

The purpose of this study was to illustrate the effects of growth hormone (GH) therapy and fixed functional appliance treatment in a 13-year-old Class II malocclusion patient without GH deficiency. GH has been shown to effectively increase endochondral growth and induce a more prognathic skeletal pattern. Although a major concern in Class II retrognathic patients is chin deficiency, long-term studies have shown that the mandibular growth enhancement effects of functional appliances are clinically insignificant. This case report demonstrates that the mandible grew significantly during fixed functional appliance treatment combined with GH therapy, with stable results during 2 years 11 months of retention. More studies are needed to evaluate GH therapy as a supplement in Class II treatment. Copyright © 2017 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.

Smart Porous Silicon Nanoparticles with Polymeric Coatings for Sequential Combination Therapy.

Science.gov (United States)

Xu, Wujun; Thapa, Rinez; Liu, Dongfei; Nissinen, Tuomo; Granroth, Sari; Närvänen, Ale; Suvanto, Mika; Santos, Hélder A; Lehto, Vesa-Pekka

2015-11-02

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.

FIRST EXPERIENCE OF CYMEVEN IN THE COMBINED THERAPY OF RHEUMATOID ARTHRITIS

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R M Balabanova

2001-01-01

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.

Microbial hara-kiri: Exploiting lysosomal cell death in malaria parasites

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Jun-Hong Ch’ng

2015-01-01

Full Text Available The antimalarial drug chloroquine (CQ has been sidelined in the fight against falciparum malaria due to wide-spread CQ resistance. Replacement drugs like sulfadoxine, pyrimethamine and mefloquine have also since been surpassed with the evolution of multi-drug resistant parasites. Even the currently recommended artemisinin-based combination therapies show signs of compromise due to the recent spread of artemisinin delayed-clearance parasites. Though there have been promising breakthroughs in the pursuit of new effective antimalarials, the development and strategic deployment of such novel chemical entities takes time. We therefore argue that there is a crucial need to re-examine the usefulness of ‘outdated’ drugs like chloroquine, and explore if they might be effective alternative therapies in the interim. We suggest that a novel parasite cell death (pCD pathway may be exploited through the reformulation of CQ to address this need.

Combination cell therapy with mesenchymal stem cells and neural stem cells for brain stroke in rats.

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Hosseini, Seyed Mojtaba; Farahmandnia, Mohammad; Razi, Zahra; Delavari, Somayeh; Shakibajahromi, Benafsheh; Sarvestani, Fatemeh Sabet; Kazemi, Sepehr; Semsar, Maryam

2015-05-01

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.

Combined modality therapy for exsudative form of age-related macular degeneration

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М. V. Budzinskaya

2013-01-01

Full Text Available Treatment outcomes in patients with age-related vascular degeneration due to formation of subretinal neovascular membrane (SNM of two groups: photodynamic therapy (PDT with Photosens alone (18 patients and in combination with anti-VEGF therapy with Lucentis (20 patients. For both groups Photosens was administrated i.v. in single dose of 0.05 mg/kg. The irradiation was performed on the 3rd day (the wave length 675 nm, light dose 120 J/cm2, total light dose did not exceed 500 J/cm2. The number of sessions accounted for 3 to 5 per week according to clinical manifestation of SNM. Patients with multimodality treatment had intravitreal administration of Lucensis in dose 0.05 ml (0.5 mg. The study showed that combination of PDT and anti-VEGF therapy improved vision better and with more stable effect then PDT alone. Thus vision improvement and decrease of SNM activity occurred in 50% of patients with PDT alone and in 60% of patients with multimodality treatment. For 2-year follow-up in the group of PDT alone the vision gradient gradually decreased compared with baseline vision (from 0.11 to 0.06, in the group of multimodality treatment gradual increase of vision gradient was noticed (from 0.03 to 0.155. The superior efficiency of PDT combined with anti-VEGF therapy compared with PDT alone in patients with age-related vascular degeneration was confirmed by study of vision, fundus angiography and average thickness of retina in foveola in both groups.

Two drugs are better than one. A short history of combined therapy of ovarian cancer.

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Bukowska, Barbara; Gajek, Arkadiusz; Marczak, Agnieszka

2015-01-01

Combined therapy of ovarian cancer has a long history. It has been applied for many years. The first drug which was commonly combined with other chemotherapeutics was cisplatin. It turned out to be effective given together with alkylating agents as well as with taxanes. Another drug which is often the basis of first-line therapy is doxorubicin. The use of traditional chemotherapy is often limited due to side effects. This is why new drugs, targeted specifically at cancer cells (e.g. monoclonal antibodies or epidermal growth factor receptor inhibitors), offer a welcome addition when used in combination with conventional anticancer agents. Drugs applied in combination should be synergistic or at least additive. To evaluate the type of interaction between drugs in a plausible sequence, isobolographic analysis is used. This method allows one to assess whether the two agents could make an efficient combination, which might improve the therapy of ovarian cancer.

Nonstent Combination Interventional Therapy for Treatment of Benign Cicatricial Airway Stenosis

OpenAIRE

Xiao-Jian Qiu; Jie Zhang; Ting Wang; Ying-Hua Pei; Min Xu

2015-01-01

Background: Benign cicatricial airway stenosis (BCAS) is a life-threatening disease. While there are numerous therapies, all have their defects, and stenosis can easily become recurrent. This study aimed to investigate the efficacy and complications of nonstent combination interventional therapy (NSCIT) when used for the treatment of BCAS of different causes and types. Methods: This study enrolled a cohort of patients with BCAS resulting from tuberculosis, intubation, tracheotomy, and othe...

Mechanism-based design of parasite-targeted artemisinin derivatives: synthesis and antimalarial activity of new diamine containing analogues.

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Hindley, Stephen; Ward, Stephen A; Storr, Richard C; Searle, Natalie L; Bray, Patrick G; Park, B Kevin; Davies, Jill; O'Neill, Paul M

2002-02-28

The potent antimalarial activity of chloroquine against chloroquine-sensitive strains can be attributed, in part, to its high accumulation in the acidic environment of the heme-rich parasite food vacuole. A key component of this intraparasitic chloroquine accumulation mechanism is a weak base "ion-trapping" effect whereupon the basic drug is concentrated in the acidic food vacuole in its membrane-impermeable diprotonated form. By the incorporation of amino functionality into target artemisinin analogues, we hoped to prepare a new series of analogues that, by virtue of increased accumulation into the ferrous-rich vacuole, would display enhanced antimalarial potency. The initial part of the project focused on the preparation of piperazine-linked analogues (series 1 (7-16)). Antimalarial evaluation of these derivatives demonstrated potent activity versus both chloroquine-sensitive and chloroquine-resistant parasites. On the basis of these observations, we then set about preparing a series of C-10 carba-linked amino derivatives. Optimization of the key synthetic step using a newly developed coupling protocol provided a key intermediate, allyldeoxoartemisinin (17) in 90% yield. Further elaboration, in three steps, provided nine target C-10 carba analogues (series 2 (21-29)) in good overall yields. Antimalarial assessment demonstrated that these compounds were 4-fold more potent than artemisinin and about twice as active as artemether in vitro versus chloroquine-resistant parasites. On the basis of the products obtained from biomimetic Fe(II) degradation of the C-10 carba analogue (23), we propose that these analogues may have a mode of action subtly different from that of the parent drug artemisinin (series 1 (7-16)) and other C-10 ether derivatives such as artemether. Preliminary in vivo testing by the WHO demonstrated that four of these compounds are active orally at doses of less than 10 mg/kg. Since these analogues are available as water-soluble salts and cannot

Preoperative combination therapy of 5-fluorouracil suppository and radiation for carcinoma of the rectum

International Nuclear Information System (INIS)

Mizusawa, Hirokazu; Takahashi, Toshio

1983-01-01

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.)

Curcumin-Artemisinin Coamorphous Solid: Xenograft Model Preclinical Study

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M. K. Chaitanya Mannava

2018-01-01

Full Text Available Curcumin is a natural compound present in Indian spice turmeric. It has diverse pharmacological action but low oral solubility and bioavailability continue to limit its use as a drug. With the aim of improving the bioavailability of Curcumin (CUR, we evaluated Curcumin-Pyrogallol (CUR-PYR cocrystal and Curcumin-Artemisinin (CUR-ART coamorphous solid. Both of these solid forms exhibited superior dissolution and pharmacokinetic behavior compared to pure CUR, which is practically insoluble in water. CUR-ART coamorphous solid showed two fold higher bioavailability than CUR-PYR cocrystal (at 200 mg/kg oral dose. Moreover, in simulated gastric and intestinal fluids (SGF and SIF, CUR-ART is stable up to 3 and 12 h, respectively. In addition, CUR-PYR and CUR-ART showed no adverse effects in toxicology studies (10 times higher dose at 2000 mg/kg. CUR-ART showed higher therapeutic effect and inhibited approximately 62% of tumor growth at 100 mg/kg oral dosage of CUR in xenograft models, which is equal to the positive control drug, doxorubicin (2 mg/kg by i.v. administration.

Myxedema coma associated with combination aripiprazole and sertraline therapy.

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Church, Chelsea O; Callen, Erin C

2009-12-01

To describe a case of myxedema coma (MC) associated with combination aripiprazole and sertraline therapy. A 41-year-old male presented to the emergency department with confusion, right-sided numbness and tingling, slurred speech, dizziness, and facial edema. His blood pressure was 160/113 mm Hg, with a pulse of 56 beats/min and temperature of 35.4 degrees C. Initial abnormal laboratory values included creatine kinase (CK) 439 U/L; serum creatinine 1.6 mg/dL; aspartate aminotransferase 85 U/L; and alanine aminotransferase 35 U/L. Repeat cardiac markers revealed an elevated CK level of 3573 U/L with a CK-MB of 24 ng/mL. Thyroid function tests showed thyroid-stimulating hormone 126.4 microIU/mL and free thyroxine 0.29 ng/dL. Home medications of unknown duration were sertraline 200 mg and aripiprazole 20 mg daily. He was admitted to the intensive care unit and initially treated with intravenous levothyroxine and dexamethasone. By hospital day 4, the patient was clinically stable and discharged to home. Myxedema coma, the most significant form of hypothyroidism (HT), is a rare but potentially fatal condition. The known precipitating causes of MC were ruled out in this patient, which left his home medications as the likely cause. Cases of HT caused by certain atypical antipsychotics and antidepressants are found in the literature, but none was reported with aripiprazole therapy. There are also no reported cases of sertraline or aripiprazole inducing MC. Use of the Naranjo probability scale indicates that the combination of aripiprazole and sertraline was a probable inducer of MC in this patient. Due to the widespread use of psychotropic medications, clinicians should be reminded of the rare, yet life-threatening, occurrence of MC when treating patients, especially with combination therapies such as sertraline and aripiprazole.

Severe Rhabdomyolysis Associated with the Cerivastatin-Gemfibrozil Combination Therapy

Science.gov (United States)

Lau, Theodore K.; Leachman, D. Richard; Lufschanowski, Roberto

2001-01-01

Cerivastatin is the new 3rd-generation of the synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, the 1st drugs of choice for treating hypercholesterolemia. A potent inhibitor of HMG-CoA reductase, it possesses a high affinity for liver tissue and decreases plasma low-density lipoprotein cholesterol at microgram doses. Cerivastatin produces reductions in low-density lipoprotein cholesterol of 31.3% and 36.1% at doses of 0.3 and 0.4 mg/day, respectively. It is an uncomplicated agent with regard to its pharmacokinetic profile, low potential for interaction with other drugs, and suitability for use in those with impaired renal function. Most other statins have been implicated in causing rhabdomyolysis, either as mono-therapy or in combination with other agents. We report what to our knowledge is the most profound case yet in the literature of rhabdomyolysis in association with ceriva-statin-gemfibrozil combination therapy, in regard both to the extreme elevation in serum creatinine kinase and to the patient's near-paralytic weakness. PMID:11453128

Antihistomonal effects of artemisinin and Artemisia annua extracts in vitro could not be confirmed by in vivo experiments in turkeys and chickens

DEFF Research Database (Denmark)

Thøfner, I.C.N.; Liebhart, D.; Hess, M.

2012-01-01

displayed in vitro activity against all tested protozoal clones. Neither the dry plant material, extracts nor artemisinin showed any antibacterial activity against the xenic bacteria accompanying the six H. meleagridis clones at concentration levels identical to the antihistomonal setting...

Effectiveness of combined antyviral therapy in children with chronic hepatitis C

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G. P. Martynova

2013-01-01

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.

The study of combination therapy for arterial infusion chemotherapy and radiation therapy in unresectable gallbladder cancer

International Nuclear Information System (INIS)

Goto, Takuma; Saito, Hiroya; Yanagawa, Nobuyuki; Fujinaga, Akihiro; Saito, Yoshinori

2013-01-01

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)

Combined Functional Voice Therapy in Singers With Muscle Tension Dysphonia in Singing.

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Sielska-Badurek, Ewelina; Osuch-Wójcikiewicz, Ewa; Sobol, Maria; Kazanecka, Ewa; Rzepakowska, Anna; Niemczyk, Kazimierz

2017-07-01

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 singing range obtained from acoustic analysis of glissando (P 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.

Pemetrexed With Platinum Combination as a Backbone for Targeted Therapy in Non-Small-Cell Lung Cancer.

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Stinchcombe, Thomas E; Borghaei, Hossein; Barker, Scott S; Treat, Joseph Anthony; Obasaju, Coleman

2016-01-01

Standard platinum-based chemotherapy combinations for advanced non-small-cell lung cancer (NSCLC) have reached a plateau in terms of the survival benefit they offer for patients. In addition, the emerging clinical trend of tailored treatment based on patient characteristics has led to the development of therapeutic strategies that target specific cancer-related molecular pathways, including epidermal growth factor receptor (EGFR), angiogenesis, and anaplastic lymphoma kinase inhibitors. Current research is focused on combining targeted therapy with platinum-based chemotherapy in an endeavor to achieve an additional benefit in specific patient populations. Currently, pemetrexed is indicated for use in the first-line, maintenance, and second-line settings for the treatment of nonsquamous NSCLC. The combination of pemetrexed and cisplatin is well tolerated and is the approved standard first-line therapy. Thus, the pemetrexed-platinum backbone provides an attractive option for combination with targeted therapies. This review aims to summarize the current knowledge and future prospects of the use of pemetrexed-platinum as a backbone for combination with targeted therapies for NSCLC. Copyright © 2016 Elsevier Inc. All rights reserved.

Dual combination therapy targeting DR5 and EMMPRIN in pancreatic adenocarcinoma.

Science.gov (United States)

Kim, Hyunki; Zhai, Guihua; Samuel, Sharon L; Rigell, Christopher J; Umphrey, Heidi R; Rana, Samir; Stockard, Cecil R; Fineberg, Naomi S; Zinn, Kurt R

2012-02-01

The goal of the study was to assess the efficacy of combined extracellular matrix metalloprotease inducer (EMMPRIN)- and death receptor 5 (DR5)-targeted therapy for pancreatic adenocarcinoma in orthotopic mouse models with multimodal imaging. Cytotoxicity of anti-EMMPRIN antibody and anti-DR5 antibody (TRA-8) in MIA PaCa-2 and PANC-1 cell lines was measured by ATPlite assay in vitro. The distributions of Cy5.5-labeled TRA-8 and Cy3-labeled anti-EMMPRIN antibody in the 2 cell lines were analyzed by fluorescence imaging in vitro. Groups 1 to 12 of severe combined immunodeficient mice bearing orthotopic MIA PaCa-2 (groups 1-8) or PANC-1 (groups 9-12) tumors were used for in vivo studies. Dynamic contrast-enhanced-MRI was applied in group 1 (untreated) or group 2 (anti-EMMPRIN antibody). The tumor uptake of Tc-99m-labeled TRA-8 was measured in group 3 (untreated) and group 4 (anti-EMMPRIN antibody). Positron emission tomography/computed tomography imaging with (18)F-FDG was applied in groups 5 to 12. Groups 5 to 8 (or groups 9 to 12) were untreated or treated with anti-EMMPRIN antibody, TRA-8, and combination, respectively. TRA-8 showed high killing efficacy for both MIA PaCa-2 and PANC-1 cells in vitro, but additional anti-EMMPRIN treatment did not improve the cytotoxicity. Cy5.5-TRA-8 formed cellular caps in both the cell lines, whereas the maximum signal intensity was correlated with TRA-8 cytotoxicity. Anti-EMMPRIN therapy significantly enhanced the tumor delivery of the MR contrast agent, but not Tc-99m-TRA-8. Tumor growth was significantly suppressed by the combination therapy, and the additive effect of the combination was shown in both MIA PaCa-2 and PANC-1 tumor models.

Molecular analysis demonstrates high prevalence of chloroquine resistance but no evidence of artemisinin resistance in Plasmodium falciparum in the Chittagong Hill Tracts of Bangladesh.

Science.gov (United States)

Alam, Mohammad Shafiul; Ley, Benedikt; Nima, Maisha Khair; Johora, Fatema Tuj; Hossain, Mohammad Enayet; Thriemer, Kamala; Auburn, Sarah; Marfurt, Jutta; Price, Ric N; Khan, Wasif A

2017-08-15

Artemisinin resistance is present in the Greater Mekong region and poses a significant threat for current anti-malarial treatment guidelines in Bangladesh. The aim of this molecular study was to assess the current status of drug resistance in the Chittagong Hill Tracts of Bangladesh near the Myanmar border. Samples were obtained from patients enrolled into a Clinical Trial (NCT02389374) conducted in Alikadam, Bandarban between August 2014 and January 2015. Plasmodium falciparum infections were confirmed by PCR and all P. falciparum positive isolates genotyped for the pfcrt K76T and pfmdr1 N86Y markers. The propeller region of the kelch 13 (k13) gene was sequenced from isolates from patients with delayed parasite clearance. In total, 130 P. falciparum isolates were available for analysis. The pfcrt mutation K76T, associated with chloroquine resistance was found in 81.5% (106/130) of cases and the pfmdr1 mutation N86Y in 13.9% (18/130) cases. No single nucleotide polymorphisms were observed in the k13 propeller region. This study provides molecular evidence for the ongoing presence of chloroquine resistant P. falciparum in Bangladesh, but no evidence of mutations in the k13 propeller domain associated with artemisinin resistance. Monitoring for artemisinin susceptibility in Bangladesh is needed to ensure early detection and containment emerging anti-malarial resistance.

Synergy of combined tPA-edaravone therapy in experimental thrombotic stroke.

Science.gov (United States)

Sun, Yu-Yo; Morozov, Yury M; Yang, Dianer; Li, Yikun; Dunn, R Scott; Rakic, Pasko; Chan, Pak H; Abe, Koji; Lindquist, Diana M; Kuan, Chia-Yi

2014-01-01

Edaravone, a potent antioxidant, may improve thrombolytic therapy because it benefits ischemic stroke patients on its own and mitigates adverse effects of tissue plasminogen activator (tPA) in preclinical models. However, whether the combined tPA-edaravone therapy is more effective in reducing infarct size than singular treatment is uncertain. Here we investigated this issue using a transient hypoxia-ischemia (tHI)-induced thrombotic stroke model, in which adult C57BL/6 mice were subjected to reversible ligation of the unilateral common carotid artery plus inhalation of 7.5% oxygen for 30 min. While unilateral occlusion of the common carotid artery suppressed cerebral blood flow transiently, the addition of hypoxia triggered reperfusion deficits, endogenous thrombosis, and attenuated tPA activity, leading up to infarction. We compared the outcomes of vehicle-controls, edaravone treatment, tPA treatment at 0.5, 1, or 4 h post-tHI, and combined tPA-edaravone therapies with mortality rate and infarct size as the primary end-points. The best treatment was further compared with vehicle-controls in behavioral, biochemical, and diffusion tensor imaging (DTI) analyses. We found that application of tPA at 0.5 or 1 h--but not at 4 h post-tHI--significantly decreased infarct size and showed synergistic (pedaravone treatment, respectively. The acute tPA-edaravone treatment conferred >50% reduction of mortality, ∼ 80% decline in infarct size, and strong white-matter protection. It also improved vascular reperfusion and decreased oxidative stress, inflammatory cytokines, and matrix metalloproteinase activities. In conclusion, edaravone synergizes with acute tPA treatment in experimental thrombotic stroke, suggesting that clinical application of the combined tPA-edaravone therapy merits investigation.

Synergy of combined tPA-edaravone therapy in experimental thrombotic stroke.

Directory of Open Access Journals (Sweden)

Yu-Yo Sun

Full Text Available Edaravone, a potent antioxidant, may improve thrombolytic therapy because it benefits ischemic stroke patients on its own and mitigates adverse effects of tissue plasminogen activator (tPA in preclinical models. However, whether the combined tPA-edaravone therapy is more effective in reducing infarct size than singular treatment is uncertain. Here we investigated this issue using a transient hypoxia-ischemia (tHI-induced thrombotic stroke model, in which adult C57BL/6 mice were subjected to reversible ligation of the unilateral common carotid artery plus inhalation of 7.5% oxygen for 30 min. While unilateral occlusion of the common carotid artery suppressed cerebral blood flow transiently, the addition of hypoxia triggered reperfusion deficits, endogenous thrombosis, and attenuated tPA activity, leading up to infarction. We compared the outcomes of vehicle-controls, edaravone treatment, tPA treatment at 0.5, 1, or 4 h post-tHI, and combined tPA-edaravone therapies with mortality rate and infarct size as the primary end-points. The best treatment was further compared with vehicle-controls in behavioral, biochemical, and diffusion tensor imaging (DTI analyses. We found that application of tPA at 0.5 or 1 h--but not at 4 h post-tHI--significantly decreased infarct size and showed synergistic (p50% reduction of mortality, ∼ 80% decline in infarct size, and strong white-matter protection. It also improved vascular reperfusion and decreased oxidative stress, inflammatory cytokines, and matrix metalloproteinase activities. In conclusion, edaravone synergizes with acute tPA treatment in experimental thrombotic stroke, suggesting that clinical application of the combined tPA-edaravone therapy merits investigation.

A clinical study on combined modality therapy, radio-hyperthermo-chemotherapy, for pancreatic cancer

International Nuclear Information System (INIS)

Yamamoto, Yoshikazu

1989-01-01

A new multimodality therapy, radio-hyperthermo-chemotherapy, has been performed in a total of 31 pancreatic cancer patients with the purpose of improving treatment outcome. Combination of hyperthermia and chemotherapy was given as a pre-irradiation therapy in 7 resectable cancer patients. Among 24 unresectable cancer patients, 17 had irradiation in combination with hyperthermia and chemotherpay. Although both degeneration and necrosis of cancer cells were observed in all resectable cases at biopsy, these were not predictive of a better outcome. Of evaluable 17 patients with unresectable cancer, tumor regression was observed in 5 (29.4%). Although 22 patients had pain before therapy, 8 and 5 patients had remarkable and moderate pain relief, respectively, with therapy. Performance status was improved in 7 patients (29.2%). Survival rate at 12 months was still low (8.3%). However, the radio-hyperthermo-chemotherapy appears to help in increasing the quality of life in view of pain relief. (N.K.)

[Tadalafil combined with behavior therapy for semen collection from infertile males in whom masturbation fails].

Science.gov (United States)

Tang, Wen-Hao; Jiang, Hui; Ma, Lu-Lin; Hong, Kai; Zhao, Lian-Ming; Liu, De-Feng; Mao, Jia-Ming; Yang, Yi; Zhang, Ju; Gao, Ling; Qiao, Jie

2013-05-01

To study the effect of Tadalafil combined with behavior therapy in helping obtain semen from infertile men in whom masturbation has failed. Sixty male infertile patients from whom masturbation had failed to obtain semen were equally assigned to receive Tadalafil combined with behavior therapy (combination group) or Tadalafil only (control group). All the patients took Tadalafil 20 mg orally the night before the day of semen collection by masturbation. Before this procedure, the patients of the combination group practiced masturbation 16 - 24 times at home. The average ages of the patients were (37.0 +/- 5.1) yr and (37.5 +/- 5.2) yr and their IIEF-5 scores were 16.50 +/- 1.25 and 16.90 +/- 1.09 in the combination and the control group, respectively, neither with statistically significant difference between the two groups. Semen was successfully obtained from 9 patients (30.0%) of the combination group and 1 patient (3.33%) of the control group, with statistically significant difference between the two groups (chi2 = 7.680, P masturbation, Tadalafil combined with behavior therapy can significantly increase the success rate of semen collection from the male infertile patients in whom masturbation fails.

Polymorphisms in pfdhfr and pfdhps genes after five years of artemisinin combination therapy (ACT) implementation from urban Kolkata, India.

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Chatterjee, Moytrey; Ganguly, Swagata; Saha, Pabitra; Guha, Subhasish K; Maji, Ardhendu Kumar

2017-09-01

In India, sulphadoxine-pyrimethamine (SP) is now in use as a partner drug of ACT (AS+SP) to treat uncomplicated falciparum malaria since 2010. Declined trend of AS+SP efficacy has been reported from north-eastern states of the country. It is not possible to determine the efficacy of SP alone from any study with ACT. So, this work was designed to study the pattern of polymorphisms in pfdhfr and pfdhps genes to predict the SP resistance status among parasite population of urban Kolkata after five years of ACT implementation. A total of 125 P. falciparum positive patients were enrolled in the study during December 2014 to July 2016 and treated with AS+SP. Parasitic DNA was isolated and subjected to sequencing of pfdhfr and pfdhps genes directly from purified PCR products. Genotyping of both the genes was successfully done in 113 isolates. In pfdhfr, 94.69% (107/113) isolates showed mutations at codon 59 and 108. A double mutant genotype ANRNI was mostly prevalent (107/113, 94.69%), while wild-type genotype ANCSI was found only in 5.3% (6/113) isolates. In pfdhps, mutations were recorded at codon 436 and 437 in 65.49% (74/113) and 23.01% (26/113) isolates, respectively. In combined pfdhfr-pfdhps genes, triple mutant ANRNI-FAKAA was most prevalent (45/113, 39.82%) followed by double mutant ANRNI-SAKAA (37/113, 32.74%) and quadruple mutant ANRNI-FGKAA (24/113, 21.24%). SP resistance hallmark mutations i.e., quadruple (AIRNI-SAEAA) or quintuple (AIRNI-SGEAA) genotype in pfdhfr and pfdhps was absent which indicates that SP components of used ACT is still effective in the study area. It is also evident by the clinical response of AS+SP. Monitoring the efficacy of this combination (both by therapeutic and molecular marker study) at a regular interval is highly suggested to record any development of SP resistance in near future. Copyright © 2017 Elsevier B.V. All rights reserved.

Accelerating cancer therapy development: the importance of combination strategies and collaboration. Summary of an Institute of Medicine workshop.

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LoRusso, Patricia M; Canetta, Renzo; Wagner, John A; Balogh, Erin P; Nass, Sharyl J; Boerner, Scott A; Hohneker, John

2012-11-15

Cancer cells contain multiple genetic changes in cell signaling pathways that drive abnormal cell survival, proliferation, invasion, and metastasis. Unfortunately, patients treated with single agents inhibiting only one of these pathways--even if showing an initial response--often develop resistance with subsequent relapse or progression of their cancer, typically via the activation of an alternative uninhibited pathway. Combination therapies offer the potential for inhibiting multiple targets and pathways simultaneously to more effectively kill cancer cells and prevent or delay the emergence of drug resistance. However, there are many unique challenges to developing combination therapies, including devising and applying appropriate preclinical tests and clinical trial designs, prioritizing which combination therapies to test, avoiding overlapping toxicity of multiple agents, and overcoming legal, cultural, and regulatory barriers that impede collaboration among multiple companies, organizations, and/or institutions. More effective strategies to efficiently develop combination cancer therapies are urgently needed. Thus, the Institute of Medicine's National Cancer Policy Forum recently convened a workshop with the goal of identifying barriers that may be impeding the development of combination investigational cancer therapies, as well as potential solutions to overcome those barriers, improve collaboration, and ultimately accelerate the development of promising combinations of investigational cancer therapies. ©2012 AACR.

Phase II study of bevacizumab and temsirolimus combination therapy for recurrent glioblastoma multiforme

DEFF Research Database (Denmark)

Lassen, Ulrik; Sorensen, Morten; Gaziel, Tine Bernhardtsen

2013-01-01

standard temozolomide chemoradiotherapy and bevacizumab-containing second-line therapy, received temsirolimus (25 mg i.v.) on days 1 and 8 and bevacizumab (10 mg/kg) on day 8, every two weeks. Assessments were performed every eight weeks. Blood samples for biomarkers were collected weekly for the first...... eight weeks and at progression. The primary end-point was median progression-free survival (PFS) and secondary end-points were radiographic response, overall survival (OS), and safety of the bevacizumab-temsirolimus combination. RESULTS: Thirteen patients were included, whereof three went off....../10), infection (1/10), hypertension (1/10), and hyperglycemia (1/10). CONCLUSION: Temsirolimus can be safely administered in combination with bevacizumab. This study failed to detect activity of such a combination in patients with progressive GBM beyond bevacizumab therapy....

Role of olmesartan in combination therapy in blood pressure control and vascular function

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Carlos M Ferrario

2010-08-01

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

Combination phenylbutyrate/gemcitabine therapy effectively inhibits in vitro and in vivo growth of NSCLC by intrinsic apoptotic pathways

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Schniewind Bodo

2006-11-01

Full Text Available Abstract Background Standard chemotherapy protocols in NSCLC are of limited clinical benefit. Histone deacetylase (HDAC inhibitors represent a new strategy in human cancer therapy. In this study the combination of the HDAC inhibitor phenylbutyrate (PB and the nucleoside analogue gemcitabine (GEM was evaluated and the mechanisms underlying increased cell death were analyzed. Methods Dose escalation studies evaluating the cytotoxicity of PB (0.01–100 mM, GEM (0.01–100 μg/ml and a combination of the two were performed on two NSCLC cell lines (BEN and KNS62. Apoptotic cell death was quantified. The involvement of caspase-dependent cell death and MAP-kinase activation was analyzed. Additionally, mitochondrial damage was determined. In an orthotopic animal model the combined effect of PB and GEM on therapy was analyzed. Results Applied as a single drug both GEM and PB revealed limited potential to induce apoptosis in KNS62 and Ben cells. Combination therapy was 50–80% (p = 0.012 more effective than either agent alone. On the caspase level, combination therapy significantly increased cleavage of the pro-forms compared to single chemotherapy. The broad spectrum caspase-inhibitor zVAD was able to inhibit caspase cleavage completely, but reduced the frequency of apoptotic cells only by 30%. Combination therapy significantly increased changes in MTP and the release of cyto-c, AIF and Smac/Diabolo into the cytoplasm. Furthermore, the inhibitors of apoptosis c-IAP1 and c-IAP2 were downregulated and it was shown that in combination therapy JNK activation contributed significantly to induction of apoptosis. The size of the primary tumors growing orthotopically in SCID mice treated for 4 weeks with GEM and PB was significantly reduced (2.2–2.7 fold compared to GEM therapy alone. The Ki-67 (KNS62: p = 0.015; Ben: p = 0.093 and topoisomerase IIα (KNS62: p = 0.008; Ben: p = 0.064 proliferation indices were clearly reduced in tumors treated by combination

Combination use of lentinan with x-ray therapy in mouse experimental tumor system, (3)

International Nuclear Information System (INIS)

Shiio, Tsuyoshi; Ohishi, Kazuo; Niitsu, Iwayasu; Hayashibara, Hiromi; Tsuchiya, Yoshiharu; Yoshihama, Takashi; Moriyuki, Hirobumi

1988-01-01

Combination effect of lentinan with X-ray irradiation on the metastatic mouse tumors, L1210, KLN205 and Lewis lung carcinoma were studied. Combination use of lentinan with X-ray therapy prolonged the life of BDF 1 mice bearing L1210 leukemia in the suitable combination conditions. Combination effects of lentinan with X-ray therapy were also observed on the suppression of the growth of KLN205 squamus cell carcinoma and on the suppression of the metastasis of Lewis lung carcinoma. Especially, in the case that lentinan was administered before or after X-ray local irradiation in the pulmorary metastasis system of Lewis lung carcinoma, a marked suppressin of pulmonary metastasis was observed and 2 to 4 mice among 8 tested mice were tumor free. (author)

A retrospective claims analysis of combination therapy in the treatment of adult attention-deficit/hyperactivity disorder (ADHD

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Pohl Gerhardt M

2009-06-01

Full Text Available Abstract Background Combination therapy in managing psychiatric disorders is not uncommon. While combination therapy has been documented for depression and schizophrenia, little is known about combination therapy practices in managing attention-deficit/hyperactivity disorder (ADHD. This study seeks to quantify the combination use of ADHD medications and to understand predictors of combination therapy. Methods Prescription dispensing events were drawn from a U.S. national claims database including over 80 managed-care plans. Patients studied were age 18 or over with at least 1 medical claim with a diagnosis of ADHD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 314.0, a pharmacy claim for ADHD medication during the study period July2003 to June2004, and continuous enrollment 6 months prior to and throughout the study period. Dispensing events were grouped into 6 categories: atomoxetine (ATX, long-acting stimulants (LAS, intermediate-acting stimulants (IAS, short-acting stimulants (SAS, bupropion (BUP, and Alpha-2 Adrenergic Agonists (A2A. Events were assigned to calendar months, and months with combined use from multiple categories within patient were identified. Predictors of combination therapy for LAS and for ATX were modeled for patients covered by commercial plans using logistic regression in a generalized estimating equations framework to adjust for within-patient correlation between months of observation. Factors included age, gender, presence of the hyperactive component of ADHD, prior diagnoses for psychiatric disorders, claims history of recent psychiatric visit, insurance plan type, and geographic region. Results There were 18,609 patients identified representing a total of 11,886 months of therapy with ATX; 40,949 months with LAS; 13,622 months with IAS; 38,141 months with SAS; 22,087 months with BUP; and 1,916 months with A2A. Combination therapy was present in 19.7% of continuing

A retrospective claims analysis of combination therapy in the treatment of adult attention-deficit/hyperactivity disorder (ADHD).

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Pohl, Gerhardt M; Van Brunt, David L; Ye, Wenyu; Stoops, William W; Johnston, Joseph A

2009-06-08

Combination therapy in managing psychiatric disorders is not uncommon. While combination therapy has been documented for depression and schizophrenia, little is known about combination therapy practices in managing attention-deficit/hyperactivity disorder (ADHD). This study seeks to quantify the combination use of ADHD medications and to understand predictors of combination therapy. Prescription dispensing events were drawn from a U.S. national claims database including over 80 managed-care plans. Patients studied were age 18 or over with at least 1 medical claim with a diagnosis of ADHD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 314.0), a pharmacy claim for ADHD medication during the study period July 2003 to June 2004, and continuous enrollment 6 months prior to and throughout the study period. Dispensing events were grouped into 6 categories: atomoxetine (ATX), long-acting stimulants (LAS), intermediate-acting stimulants (IAS), short-acting stimulants (SAS), bupropion (BUP), and Alpha-2 Adrenergic Agonists (A2A). Events were assigned to calendar months, and months with combined use from multiple categories within patient were identified. Predictors of combination therapy for LAS and for ATX were modeled for patients covered by commercial plans using logistic regression in a generalized estimating equations framework to adjust for within-patient correlation between months of observation. Factors included age, gender, presence of the hyperactive component of ADHD, prior diagnoses for psychiatric disorders, claims history of recent psychiatric visit, insurance plan type, and geographic region. There were 18,609 patients identified representing a total of 11,886 months of therapy with ATX; 40,949 months with LAS; 13,622 months with IAS; 38,141 months with SAS; 22,087 months with BUP; and 1,916 months with A2A. Combination therapy was present in 19.7% of continuing months (months after the first month of therapy

Accepting the Invitation to Open Innovation in Malaria Drug Discovery: Synthesis, Biological Evaluation, and Investigation on the Structure-Activity Relationships of Benzo[b]thiophene-2-carboxamides as Antimalarial Agents.

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Pieroni, Marco; Azzali, Elisa; Basilico, Nicoletta; Parapini, Silvia; Zolkiewski, Michal; Beato, Claudia; Annunziato, Giannamaria; Bruno, Agostino; Vacondio, Federica; Costantino, Gabriele

2017-03-09

Malaria eradication is a global health priority, but current therapies are not always suitable for providing a radical cure. Artemisinin has paved the way for the current malaria treatment, the so-called Artemisinin-based Combination Therapy (ACT). However, with the detection of resistance to ACT, innovative compounds active against multiple parasite species and at multiple life stages are needed. GlaxoSmithKline has recently disclosed the results of a phenotypic screening of an internal library, publishing a collection of 400 antimalarial chemotypes, termed the "Malaria Box". After analysis of the data set, we have carried out a medicinal chemistry campaign in order to define the structure-activity relationships for one of the released compounds, which embodies a benzothiophene-2-carboxamide core. Thirty-five compounds were prepared, and a description of the structural features responsible for the in vitro activity against different strains of P. falciparum, the toxicity, and the metabolic stability is herein reported.

Efficacy and safety of statin and fibrate combination therapy in lipid management.

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Kota, Sunil Kumar; Meher, Lalit Kumar; Rao, Epari Sanjeeva; Jammula, Sruti; Modi, Kirtikumar D

2012-01-01

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.

Sustained long-term immune responses after in situ gene therapy combined with radiotherapy and hormonal therapy in prostate cancer patients

International Nuclear Information System (INIS)

Fujita, Tetsuo; Teh, Bin S.; Timme, Terry L.; Mai, W.-Y.; Satoh, Takefumi; Kusaka, Nobuyuki; Naruishi, Koji; Fattah, Elmoataz Abdel; Aguilar-Cordova, Estuardo; Butler, E. Brian; Thompson, Timothy C.

2006-01-01

Purpose: To explore long-term immune responses after combined radio-gene-hormonal therapy. Methods and Materials: Thirty-three patients with prostate specific antigen 10 or higher or Gleason score of 7 or higher or clinical stage T2b to T3 were treated with gene therapy that consisted of 3 separate intraprostatic injections of AdHSV-tk on Days 0, 56, and 70. Each injection was followed by 2 weeks of valacyclovir. Intensity-modulated radiation therapy was delivered 2 days after the second AdHSV-tk injection for 7 weeks. Hormonal therapy was initiated on Day 0 and continued for 4 months or 2.3 years. Blood samples were taken before, during, and after treatment. Lymphocytes were analyzed by fluorescent antibody cell sorting (FACS). Results: Median follow-up was 26 months (range, 4-48 months). The mean percentages of DR + CD8 + T cells were increased at all timepoints up to 8 months. The mean percentages of DR + CD4 + T cells were increased later and sustained longer until 12 months. Long-term (2.3 years) use of hormonal therapy did not affect the percentage of any lymphocyte population. Conclusions: Sustained long-term (up to 8 to 12 months) systemic T-cell responses were noted after combined radio-gene-hormonal therapy for prostate cancer. Prolonged use of hormonal therapy does not suppress this response. These results suggest the potential for sustained activation of cell-mediated immune responses against cancer

[Flying needling therapy combined with clomiphene for ovulation failure in polycystic ovary syndrome:a randomized controlled trial].

Science.gov (United States)

Ma, Hong; Quan, Xiaohong; Chen, Xiuhua; Dong, Ying

2016-11-12

To compare the efficacy among the combined treatment of flying needling therapy and clomiphene, the simple application of flying needling therapy and simple clomiphene in the treatment of ovulation failure in polycystic ovary syndrome (PCOS). Ninety patients of PCOS were randomized into a flying needling therapy group, a medication group and a combined treatment group, 30 cases in each one. In the flying needling therapy group, the flying needling therapy was simply applied to Ganshu (BL 18), Shenshu (BL 23), Zhongwan (CV 12), Shuifen (CV 9), Guanyuan (CV 4) and Zhongji (CV 3). The unilateral back- shu points were used alternatively in each treatment. The needles were inserted rapidly with rotation technique and even-needling manipulation. The needles were retained for 30 min. The treatment was given once every two days, 3 times a week. In the medication group, clomiphene was taken orally on the 5th day of menstruation, continuously for 5 days. In the combined treatment group, the flying needling therapy and clomiphene were used in combination. All of the patients were treated for 3 months and followed up for 1 month. The ovulation rates were compared among the three groups. The levels of androgen testosterone were compared before and after treatment. In the combined treatment group, the ovulation rate was 86.2% (100/116), better than 66.7% (80/120) in the flying needling therapy group and 69.6% (78/112) in the medication group (both P medication group ( P >0.05). After treatment, the level of testosterone was reduced in the three groups (all P medication group (both P medication group ( P >0.05). The adverse reactions in the combined treatment group and the flying needling therapy group were lower than those in the medication group (both P <0.05). The flying needling therapy effectively improves in the ovulation failure of PCOS and its effect is similar to clomiphene. The allied treatment of them apparently improves the clinical efficacy and alleviates the adverse

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

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Halasa, Salaheldin; Dickinson, Eva

2014-02-01

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.

The combined effects of cold therapy and music therapy on pain following chest tube removal among patients with cardiac bypass surgery.

Science.gov (United States)

Yarahmadi, Sajad; Mohammadi, Nooredin; Ardalan, Arash; Najafizadeh, Hassan; Gholami, Mohammad

2018-05-01

Chest tube removal is an extremely painful procedure and patients may not respond well to palliative therapies. This study aimed to examine the effect of cold and music therapy individually, as well as a combination of these interventions on reducing pain following chest tube removal. A factorial randomized-controlled clinical trial was performed on 180 patients who underwent cardiac surgery. Patients were randomized into four groups of 45. Group A used ice packs for 20 minutes prior to chest tube removal. Group B was assigned to listen to music for a total length of 30 minutes which started 15 minutes prior to chest tube removal. Group C received a combination of both interventions; and Group D received no interventions. Pain intensity was measured in each group every 15 minutes for a total of 3 readings. Analysis of variance, Tukey and Bonferroni post hoc tests, as well as repeated measures ANOVA were employed for data analysis. Cold therapy and combined method intervention effectively reduced the pain caused by chest tube removal (P < 0.001). Additionally, there were no statistically significant difference in pain intensity scores between groups at 15 minutes following chest tube removal (P = 0.07). Cold and music therapy can be used by nursing staff in clinical practice as a combined approach to provide effective pain control following chest tube removal. Copyright © 2018 Elsevier Ltd. All rights reserved.

A study on radiation therapy combined with superselective intraarterial infusion therapy for maxillary sinus carcinoma

International Nuclear Information System (INIS)

Okamoto, Isaku; Ito, Hiroyuki; Shimizu, Akira; Shimizu, Shigetaka; Suzuki, Mamoru; Yoshida, Tomoyuki; Nakamura, Kazuhiro; Tsukahara, Kiyoaki

2010-01-01

The data of 14 patients with squamous cell carcinoma of the maxillary sinus who were admitted to our hospital and received radiation therapy and concurrent superselective intraarterial infusion therapy between 1998 and 2008 were analyzed to determine the effect of the primary treatment and the adverse events. The subjects were between 43 and 79 years old (median, 61 years old), and there were 10 male and 4 female patients. Superselective intraarterial infusion therapy was administered using the Seldinger method, and cisplatin (CDDP) was administered by intraarterial infusion at a total of 200 mg/m 2 . 5-fluorouracil (FU) was systemically administered by intravenous infusion at the dose of 800 mg/m 2 from day 2 to day 5. In addition, radiation therapy was given concurrently, beginning on day 2. At 4 weeks after completion of the scheduled radiation therapy combined with superselective intraarterial infusion therapy, the treatment effect was judged based on macroscopic, radiological and histopathological findings. The response rates to the primary treatment were as follows: 57.1%, complete response (CR) (8 patients) and 42.9%, partial response (PR) (6 patients). Thus, the overall response rate was 100%. As for the adverse events, while grade 4 cerebral infarction occurred in one patient, all of the other adverse events were reversible and not serious. The safety of the treatment was therefore considered to be acceptable. We are planning to investigate the long-term outcomes in a future study. (author)

Combination therapy with hormonal, radiation and chemotherapy for stage C prostate cancer

International Nuclear Information System (INIS)

Iwasawa, Toshihisa; Matsumoto, Hidetsugu

1996-01-01

To improve the effectiveness of treatment for patients with stage C prostate cancer, therapy in combination with hormonal, radiation and chemotherapy was given for the initial period, and there after, hormonal therapy was continuously administered to 18 patients with chemotherapy and three patients without it. At the Social Health Insurance Medical Center, between May 1988 and August 1991, 21 patients were diagnosed to have stage C histologically confirmed adenocarcinoma of the prostate. The average age of the patients was 69.0 years. The tumor was well, moderate and poorly differentiated in 5, 6 and 10 patients, respectively. As hormonal therapy, orchiectomy was performed on 19 of the 21 patients. Furthermore, 11 patients were administered estramustine phosphate, 9 chlormadinone acetate, and one diethylstilbesterol diphosphate. As, radiation therapy, all patients were treated with AP-PA parallel opposing technique to small pelvis with a 12 cm x 12 cm treatment field (44-45 Gy) combined with conformation radiotherapy to prostate (20-26 Gy). Chemotherapy was performed using either one or a combination of the following; cis-diamminedichloroplatinum, adriamycin, cyclophosphamide, 5-fluorouracil, methotrexate and etoposide. The observation period was 54.5 months on the average. Recurrence was observed in 3 patients, for all of which the sites were at bone. The 5-year non-recurrence rate was 90.4% by Kaplan-Meier's method. There were 4 deaths, three were due to prostate cancer and one to gastric cancer. The 5-year cumulative survival rate by Kaplan-Meier's method was 90.5%. In conclusion, this treatment was effective for stage C cases of prostate cancer. (author)

Radiotherapy combined with hormonal therapy in prostate cancer: the state of the art

Directory of Open Access Journals (Sweden)

Piotr Milecki

2010-10-01

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

Anti-tumor effects of Egr-IFN γ gene therapy combined with 125I-UdR radionuclide therapy

International Nuclear Information System (INIS)

Zhao Jingguo; Ni Yanjun; Song Xiangfu; Li Yanyi; Yang Wei; Sun Ting; Ma Qingjie; Gao Fengtong

2008-01-01

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)

Effect of hyperthermia in combination with radiation therapy in a rat glioma model

International Nuclear Information System (INIS)

Tamura, Masaru; Zama, Akira; Kunimine, Hideo; Tamaki, Yoshio; Niibe, Hideo

1988-01-01

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)

Efficacy of Artemisinin-Naphtoquine and Dihydroartemisinin-Piperaquine for uncomplicated malaria patient at primary health care

Directory of Open Access Journals (Sweden)

Hadjar Siswantoro

2015-01-01

Full Text Available AbstrakLatar belakang: Hasil uji klinik terdahulu terhadap artemisinin-naftokuin (ANT dosis sekali minum pada pengobatan pasien dewasa dengan malaria tanpa komplikasi menunjukkan aman, dapat ditoleransi, dan sangat efektif. Data tambahan dibutuhkan untuk verifikasi keamanan dan efikasi dari kelompok umur lainnya sebelum obat baru ini dapat digunakan secara luas di Puskesmas di Indonesia. Metode: Pada penelitian ini, kami menggunakan modifikasi pedoman uji klinis WHO 2009. Studi kuasi- eksperimental ini membandingkan dua paralel grup, subjek dengan ANT di 5 puskesmas rawat inap, dan subjek dengan obat kontrol dihidroartemisinin-piperakuin (DHP minum obatnya di 5 puskesmas rawat jalan. Hasil: Dari total 182 subjek yang direkrut, 168 kasus malaria yang dianalisis dalam uji klinik ini. Mereka adalah 71 kasus dalam ANT grup dan 97 kasus dalam DHP grup. Karakteristik subjek yang mendapat ANT dan DHP saat rekrutmen adalah Sama kecuali proporsi subjek dengan suhu aksila ≥37.50C, dan proporsi subjek dengan anemia (Hb <11 g/dl di ANT grup lebih tinggi dibanding DHP grup (61.8% vs23.8%, and 83.1% vs 48.5%. Subjek ANT grup juga lebih rendah proporsi parasite asexualnya pada hari ke-3 dibanding DHP grup (1.4% vs 10.3%. Efikasi terapetik ANT dan DHP adalah 95.1% (95% CI: 88.8-99.1 dan 91.9% (95% CI:84.3-96.0 pada hari 42. Kedua obat memiliki kejadian sampingan ringan.Kesimpulan: Penggunaan ANT adalah aman dan memiliki efikasi yang sama dengan DHP untuk pengobatan pasien dewasa dan anak dengan malaria tanpa komplikasi di Puskesmas. (Health Science Indones 2014;2:100-5.Kata kunci: semua umur, malaria, artemisinin-naftokuin, dihidroartemisinin-piperakuin, puskesmas.AbstractBackground: Our previous study of single dose artemisinin-naphthoquine (ANT in adult majority male patients showed it as a safe, tolerable, and very effective treatment for uncomplicated malaria. More data is required to verify safety and efficacy from other age groups before this new drug

Combination treatment with T4 and T3: toward personalized replacement therapy in hypothyroidism?

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Biondi, Bernadette; Wartofsky, Leonard

2012-07-01

Levothyroxine therapy is the traditional lifelong replacement therapy for hypothyroid patients. Over the last several years, new evidence has led clinicians to evaluate the option of combined T(3) and T(4) treatment to improve the quality of life, cognition, and peripheral parameters of thyroid hormone action in hypothyroidism. The aim of this review is to assess the physiological basis and the results of current studies on this topic. We searched Medline for reports published with the following search terms: hypothyroidism, levothyroxine, triiodothyronine, thyroid, guidelines, treatment, deiodinases, clinical symptoms, quality of life, cognition, mood, depression, body weight, heart rate, cholesterol, bone markers, SHBG, and patient preference for combined therapy. The search was restricted to reports published in English since 1970, but some reports published before 1970 were also incorporated. We supplemented the search with records from personal files and references of relevant articles and textbooks. Parameters analyzed included the rationale for combination treatment, the type of patients to be selected, the optimal T(4)/T(3) ratio, and the potential benefits of this therapy on symptoms of hypothyroidism, quality of life, mood, cognition, and peripheral parameters of thyroid hormone action. The outcome of our analysis suggests that it may be time to consider a personalized regimen of thyroid hormone replacement therapy in hypothyroid patients. Further prospective randomized controlled studies are needed to clarify this important issue. Innovative formulations of the thyroid hormones will be required to mimic a more perfect thyroid hormone replacement therapy than is currently available.

COMPARISON OF EFFECTS OF MASSAGE THERAPY ALONE AND IN COMBINATION WITH GREEN COCONUT WATER THERAPY ON Β-ENDORPHIN LEVEL IN TEENAGE GIRLS WITH DYSMENORRHEA

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Fitria Hikmatul Ulya

2017-08-01

Full Text Available Background: Dysmenorrhea is pain during menstruation in lower abdomen, and is not due to other diseases. Effleurage massage and consuming green coconut water are considered able to reduce menstrual pain. However, little is known about the effect of the combination between the two interventions. Objective: To compare the effectiveness of effleurage massage and in combination with green coconut water on pain, anxiety, and ß-endorphin level in teenage girls with menstrual pain (dysmenorrhea. Design: A quasy experiment with pretest-posttest approach design with control group. There were 36 samples recruited in this study by purposive sampling, which were divided into a massage therapy group, the combination therapy group, and a control group. Menstrual pain was measured using Numeric Rating Scale, while anxiety was measured using Zung Self rating Anxiety Scale (ZSAS, and endorphin level using ELISA (Enzyme-Linked Immunosorbent Assay. One way anova test and repeated anova were performed as a bivariate analysis. Mancova and post hoc anova were used for multivariate analysis. Result: The combination of massage and green coconut water was more effective in reducing pain (p 0.013 and anxiety levels (p 0.000, and in increasing β-endorphin (p 0.029 with significant value of <0.05 compared to the massage therapy alone. Conclusion: The combination of effleurage massage and green coconut water had significant effect in decreasing anxiety and pain levels, and increasing β-endorphin levels in teenage girls with painful periods (dysmenorrhea; and more effective than performing effleurage massage only. It is suggested that this combination therapy could be used as an alternative therapy for women with dysmenrrohea.

Poor quality vital anti-malarials in Africa - an urgent neglected public health priority

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Newton Paul N

2011-12-01

Full Text Available Abstract Background Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa. Methods Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African countries and in Asia en route to Africa. Packaging, chemical composition (high performance liquid chromatography, direct ionization mass spectrometry, X-ray diffractometry, stable isotope analysis and botanical investigations were performed. Results Counterfeit artesunate containing chloroquine, counterfeit dihydroartemisinin (DHA containing paracetamol (acetaminophen, counterfeit DHA-piperaquine containing sildenafil, counterfeit artemether-lumefantrine containing pyrimethamine, counterfeit halofantrine containing artemisinin, and substandard/counterfeit or degraded artesunate and artesunate+amodiaquine in eight countries are described. Pollen analysis was consistent with manufacture of counterfeits in eastern Asia. These data do not allow estimation of the frequency of poor quality anti-malarials in Africa. Conclusions Criminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACTs and removal of artemisinin monotherapies. The International Health Regulations may need to be invoked to counter these serious public health problems.

Manual therapy, exercise therapy or combined treatment in the management of adult neck pain - A systematic review and meta-analysis.

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Fredin, Ken; Lorås, Håvard

2017-10-01

Neck pain is a common and often disabling musculoskeletal condition. Two therapies frequently prescribed for its management are manual therapy (MT) and exercise therapy (ET), and combining these treatment approaches are common. To assess whether or not combined treatment consisting of MT and ET is more effective than either therapy alone in relieving pain and improving function in adult patients with grade I-II neck pain. Systematic review with meta-analysis. A systematic search on EMBASE, MEDLINE, AMED, CENTRAL and PEDro were performed until June 2017. Randomized controlled trials with adult grade I-II neck pain patients were included if they investigated the combined effect of MT and ET to the same ET or MT alone, and reported pain intensity or disability on numerical scales. Quality of life was assessed as a secondary outcome. Quality of the included trials was assessed with the PEDro scale, and the quality of evidence was assessed with GRADE. 1169 articles were screened, and 7 studies were included, all of which investigated the addition of ET to MT. Only very small and non-significant between group differences was found on pain intensity at rest, neck disability, and quality of life at immediate post-treatment, 6 months, and 12 months follow-up. The quality of evidence was moderate for pain-at-rest outcomes and moderate too low for neck disability and quality of life outcomes. Combined treatment consisting of MT and ET does not seem to be more effective in reducing neck pain intensity at rest, neck disability or improving quality of life in adult patients with grade I-II neck pain, than ET alone. Copyright © 2017 Elsevier Ltd. All rights reserved.