scholarly journals New insights into antimalarial chemopreventive activity of antifolates

2021 ◽  
Author(s):  
Chatpong Pethrak ◽  
Navaporn Posayapisit ◽  
Jutharat Pengon ◽  
Nattida Suwanakitti ◽  
Atiporn Saeung ◽  
...  
Keyword(s):  
Malaria Parasite ◽  
Developmental Stages ◽  
Cost Effective ◽  
Asexual Blood Stage ◽  
New Class ◽  
Cost Effective Treatment ◽  
Quadruple Mutant ◽  
Stage Development ◽  
Chemopreventive Activity ◽  
Hepatic Development

Antifolates targeting dihydrofolate reductase (DHFR) are antimalarial compounds that have long been used for malaria treatment and chemoprevention (inhibition of infection from mosquitoes to humans). Despite their extensive applications, the thorough understanding of antifolate activity against hepatic malaria parasites, especially resistant parasites, have yet to be achieved. Using a transgenic P. berghei harboring quadruple mutant dhfr from P. falciparum (Pb::Pfdhfr -4M ) , we demonstrate that quadruple mutations on Pfdhfr confer complete chemoprevention resistance to pyrimethamine, the previous generation of antifolate, but not to a new class of antifolate designed to overcome the resistance such as P218. Detailed investigation to pin-point stage-specific chemoprevention further demonstrated that it is unnecessary for the drug to be present throughout hepatic development. The drug is most potent against the developmental stages from early hepatic trophozoite to late hepatic trophozoite, but is not effective at inhibiting sporozoite and early hepatic stage development from sporozoite to early trophozoite. Our data shows that P218 also inhibited the late hepatic stage development, from trophozoite to mature schizonts to a lesser extent. With a single dose of 15 mg/kg, P218 prevented infection from up to 25,000 pyrimethamine-resistant sporozoites, a number equal to thousands of infectious mosquito bites. Additionally, the hepatic stage of malaria parasite is much more susceptible to antifolates than the asexual blood stage. This study provides important insights into the activity of antifolates, as a chemopreventive therapeutic which could lead to a more efficient and cost effective treatment regime.

scholarly journals New insights into antimalarial chemopreventive activity of antifolates

2021 ◽  
Author(s):  
Chatpong Pethrak ◽  
Navaporn Posayapisit ◽  
Jutharat Pengon ◽  
Nattida Suwanakitti ◽  
Atiporn Saeung ◽  
...  
Keyword(s):  
Malaria Parasite ◽  
Developmental Stages ◽  
Cost Effective ◽  
Asexual Blood Stage ◽  
New Class ◽  
Cost Effective Treatment ◽  
Quadruple Mutant ◽  
Stage Development ◽  
Chemopreventive Activity ◽  
Hepatic Development

Antifolates targeting dihydrofolate reductase (DHFR) are antimalarial compounds that have long been used for malaria treatment and chemoprevention (inhibition of infection from mosquitoes to humans). Despite their extensive applications, the thorough understanding of antifolate activity against hepatic malaria parasites, especially resistant parasites, have yet to be achieved. Using a transgenic P. berghei harboring quadruple mutant dhfr from P. falciparum (Pb::Pfdhfr-4M), we demonstrate that quadruple mutations on Pfdhfr confer complete chemoprevention resistance to pyrimethamine, the previous generation of antifolate, but not a new class of antifolate designed to overcome the resistance such as P218. Detailed investigation to pin-point stage-specific chemoprevention further demonstrated that it is unnecessary for the drug to be present throughout hepatic development. The drug is most potent against the developmental stages from  early hepatic trophozoite to late hepatic trophozoite, but is not effective at inhibiting sporozoite and early hepatic stage development from sporozoite to early trophozoite. Our data shows that P218 also inhibited the late hepatic stage development, from trophozoite to mature schizonts to a lesser extent. With a single dose of 15 mg/kg, P218 prevented infection from up to 25,000 pyrimentamine-resistant sporozoites, a number equal to thousands of infectious mosquito bites. Additionally, the hepatic stage of malaria parasite is much more susceptible to antifolates than the asexual blood stage. This study provides important insights into the activity of antifolates, as a chemopreventive therapeutic which could lead to a more efficient and cost effective treatment regime.

Physical and Psychological Benefits of Written Emotional Expression

2015 ◽  
Vol 20 (4) ◽  
pp. 242-251 ◽  
Author(s):  
Éva Kállay
Keyword(s):  
Mental Health ◽  
Expressive Writing ◽  
Mental Health Problems ◽  
Cost Effective ◽  
Health Problems ◽  
Future Research ◽  
Psychological Benefits ◽  
Cost Effective Treatment ◽  
Meta Analyses

Abstract. The last several decades have witnessed a substantial increase in the number of individuals suffering from both diagnosable and subsyndromal mental health problems. Consequently, the development of cost-effective treatment methods, accessible to large populations suffering from different forms of mental health problems, became imperative. A very promising intervention is the method of expressive writing (EW), which may be used in both clinically diagnosable cases and subthreshold symptomatology. This method, in which people express their feelings and thoughts related to stressful situations in writing, has been found to improve participants’ long-term psychological, physiological, behavioral, and social functioning. Based on a thorough analysis and synthesis of the published literature (also including most recent meta-analyses), the present paper presents the expressive writing method, its short- and long-term, intra-and interpersonal effects, different situations and conditions in which it has been proven to be effective, the most important mechanisms implied in the process of recovery, advantages, disadvantages, and possible pitfalls of the method, as well as variants of the original technique and future research directions.

Cost-Effectiveness: Cholinesterase Inhibitors and Memantine in Vascular Dementia

2009 ◽  
Vol 36 (6) ◽  
pp. 735-739 ◽  
Author(s):  
Camilla L. Wong ◽  
Nick Bansback ◽  
Philip E. Lee ◽  
Aslam H. Anis
Keyword(s):  
Cost Effectiveness ◽  
Adverse Events ◽  
Incremental Cost ◽  
Vascular Dementia ◽  
Standard Care ◽  
Cholinesterase Inhibitors ◽  
Cost Effective ◽  
Decision Analysis Model ◽  
Physician Visits ◽  
Cost Effective Treatment

Background:Several randomized controlled trials of cholinesterase inhibitors and memantine in mild to moderate vascular dementia have demonstrated the efficacy of these treatments. However, given these drugs incur considerable cost, the economic argument for their use is less clear.Objective:To determine the incremental cost-effectiveness of cholinesterase inhibitors and memantine for mild to moderate vascular dementia.Design:A decision analysis model using a 24-28 week time horizon was developed. Outcomes of cholinesterase inhibitors and memantine and probabilities of adverse events were extracted from a systematic review. Costs of adverse events, medications, and physician visits were obtained from local estimates. Robustness was tested with probabilistic sensitivity analysis using a Monte Carlo simulation.Interventions:Donepezil 5 mg daily, donepezil 10 mg daily, galantamine 16-24 mg daily, rivastigmine flexible dosing up to 6 mg twice daily, or memantine 10 mg twice daily versus standard care.Main Outcome Measures:Incremental cost-effectiveness ratio (ICER) expressed as cost per unit decrease in the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) subscale.Results:Donepezil 10 mg daily was found to be the most cost-effective treatment with an ICER of $400.64 (95%CI, $281.10-$596.35) per unit decline in the ADAS-cog subscale. All other treatments were dominated by donepezil 10 mg, that is, more costly and less effective.Conclusion:From a societal perspective, treatment with cholinesterase inhibitors or memantine was more effective but also more costly than standard care for mild to moderate vascular dementia. The donepezil 10 mg strategy was the most cost-effective and also dominated the other alternatives.

scholarly journals What Is Known and Unknown About Twice-Weekly Hemodialysis

2015 ◽  
Vol 40 (4) ◽  
pp. 298-305 ◽  
Author(s):  
Yoshitsugu Obi ◽  
Rieko Eriguchi ◽  
Shuo-Ming Ou ◽  
Connie M. Rhee ◽  
Kamyar Kalantar-Zadeh
Keyword(s):  
Quality Of Life ◽  
De Novo ◽  
Urine Volume ◽  
Cost Effective ◽  
Standard Of Care ◽  
Treatment Regimens ◽  
Interdialytic Weight Gain ◽  
Cost Effective Treatment ◽  
Incremental Hemodialysis

Background: The 2006 Kidney Disease Outcomes Quality Initiative guidelines suggest twice-weekly or incremental hemodialysis for patients with substantial residual kidney function (RKF). However, in most affluent nations de novo and abrupt transition to thrice-weekly hemodialysis is routinely prescribed for all dialysis-naïve patients regardless of their RKF. We review historical developments in hemodialysis therapy initiation and revisit twice-weekly hemodialysis as an individualized, incremental treatment especially upon first transitioning to hemodialysis therapy. Summary: In the 1960's, hemodialysis treatment was first offered as a life-sustaining treatment in the form of long sessions (≥10 hours) administered every 5 to 7 days. Twice- and then thrice-weekly treatment regimens were subsequently developed to prevent uremic symptoms on a long-term basis. The thrice-weekly regimen has since become the ‘standard of care' despite a lack of comparative studies. Some clinical studies have shown benefits of high hemodialysis dose by more frequent or longer treatment times mainly among patients with limited or no RKF. Conversely, in selected patients with higher levels of RKF and particularly higher urine volume, incremental or twice-weekly hemodialysis may preserve RKF and vascular access longer without compromising clinical outcomes. Proposed criteria for twice-weekly hemodialysis include urine output >500 ml/day, limited interdialytic weight gain, smaller body size relative to RKF, and favorable nutritional status, quality of life, and comorbidity profile. Key Messages: Incremental hemodialysis including twice-weekly regimens may be safe and cost-effective treatment regimens that provide better quality of life for incident dialysis patients who have substantial RKF. These proposed criteria may guide incremental hemodialysis frequency and warrant future randomized controlled trials.

scholarly journals P.028 Global surgery for pediatric hydrocephalus in the developing world: a review of the history, challenges, and future directions

2017 ◽  
Vol 44 (S2) ◽  
pp. S20-S20
Author(s):  
S Wang ◽  
RT Muir ◽  
BC Warf
Keyword(s):  
Low Income ◽  
Developing World ◽  
Pediatric Neurosurgery ◽  
Cost Effective ◽  
Global Surgery ◽  
Low Income Countries ◽  
Global Burden ◽  
Pediatric Hydrocephalus ◽  
Cost Effective Treatment ◽  
Education Gaps

Background: Pediatric hydrocephalus is one of the most common neurosurgical conditions and is a major contributor to the global burden of surgically treatable diseases. Methods: The authors conducted a literature review around the topic of pediatric hydrocephalus in the context of global surgery, the unique challenges to creating access to care in low-income countries, and current international efforts to address the problem. Results: Developing countries face the greatest burden of pediatric hydrocephalus due to high birth rates and greater risk of neonatal infections. This burden is related to more general global health challenges, including malnutrition, infectious diseases, maternal and perinatal risk factors, and education gaps. Unique challenges pertaining to the treatment of hydrocephalus in the developing world include a preponderance of postinfectious hydrocephalus, limited resources, and restricted access to neurosurgical care. In the 21st century, several organizations have established programs that provide hydrocephalus treatment and neurosurgical training in Africa, Central and South America, Haiti, and Southeast Asia. These international efforts have employed various models to achieve the goals of providing safe, sustainable, and cost-effective treatment. Conclusions: Broader commitment from the pediatric neurosurgery community, increased funding, public education, surgeon training, and ongoing surgical innovation will be needed to meaningfully address the global burden of untreated hydrocephalus.

The Offshore Supply Vessel as a Naval Auxiliary

1975 ◽  
Vol 12 (04) ◽  
pp. 405-416
Author(s):  
Salvadore J. Guarino
Keyword(s):  
Cost Effective ◽  
New Class

In the late 1960's the expanded international search for petroleum imposed new and rigorous demands on the offshore supply vessel. These vessels entered a phase of their evolution which has resulted in a class of vessel proven to be remarkably versatile and cost effective. This paper reviews the history and development of the offshore supply boat and describes the features and capabilities of these vessels which the author believes will enable them to serve as a new class of naval auxiliary capable of multimission utilization.

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