scholarly journals Efficacy of Tecovirimat (ST-246) in Nonhuman Primates Infected with Variola Virus (Smallpox)

2013 ◽  
Vol 57 (12) ◽  
pp. 6246-6253 ◽  
Author(s):  
Eric M. Mucker ◽  
Arthur J. Goff ◽  
Joshua D. Shamblin ◽  
Douglas W. Grosenbach ◽  
Inger K. Damon ◽  
...  
Keyword(s):  
Nonhuman Primates ◽  
Pharmacokinetic Profile ◽  
Therapeutic Benefit ◽  
World Health ◽  
Smallpox Vaccination ◽  
Oral Drug ◽  
Variola Virus ◽  
Content Type ◽  
Virus Shedding ◽  
Dermal Lesion

ABSTRACTNaturally occurring smallpox has been eradicated but remains a considerable threat as a biowarfare/bioterrorist weapon (F. Fleck, Bull. World Health Organ.81:917–918, 2003). While effective, the smallpox vaccine is currently not recommended for routine use in the general public due to safety concerns (http://www.bt.cdc.gov/agent/smallpox/vaccination). Safe and effective countermeasures, particularly those effective after exposure to smallpox, are needed. Currently, SIGA Technologies is developing the small-molecule oral drug, tecovirimat (previously known as ST-246), as a postexposure therapeutic treatment of orthopoxvirus disease, including smallpox. Tecovirimat has been shown to be efficacious in preventing lethal orthopoxviral disease in numerous animal models (G. Yang, D. C. Pevear, M. H. Davies, M. S. Collett, T. Bailey, et al., J. Virol.79:13139–13149, 2005; D. C. Quenelle, R. M. Buller, S. Parker, K. A. Keith, D. E. Hruby, et al., Antimicrob. Agents Chemother.,51:689–695, 2007; E. Sbrana, R. Jordan, D. E. Hruby, R. I. Mateo, S. Y. Xiao, et al., Am. J. Trop. Med. Hyg.76:768–773, 2007). Furthermore, in clinical trials thus far, the drug appears to be safe, with a good pharmacokinetic profile. In this study, the efficacy of tecovirimat was evaluated in both a prelesional and postlesional setting in nonhuman primates challenged intravenously with 1 × 108PFU ofVariola virus(VARV; the causative agent of smallpox), a model for smallpox disease in humans. Following challenge, 50% of placebo-treated controls succumbed to infection, while all tecovirimat-treated animals survived regardless of whether treatment was started at 2 or 4 days postinfection. In addition, tecovirimat treatment resulted in dramatic reductions in dermal lesion counts, oropharyngeal virus shedding, and viral DNA circulating in the blood. Although clinical disease was evident in tecovirimat-treated animals, it was generally very mild and appeared to resolve earlier than in placebo-treated controls that survived infection. Tecovirimat appears to be an effective smallpox therapeutic in nonhuman primates, suggesting that it is reasonably likely to provide therapeutic benefit in smallpox-infected humans.

scholarly journals Tailoring a Pediatric Formulation of Artemether-Lumefantrine for Treatment of Plasmodium falciparum Malaria

2015 ◽  
Vol 59 (8) ◽  
pp. 4366-4374 ◽  
Author(s):  
Quique Bassat ◽  
Bernhards Ogutu ◽  
Abdoulaye Djimde ◽  
Kirstin Stricker ◽  
Kamal Hamed
Keyword(s):  
Plasmodium Falciparum ◽  
Plasma Concentrations ◽  
Plasmodium Falciparum Malaria ◽  
Pharmacokinetic Profile ◽  
World Health ◽  
Maximum Plasma ◽  
Comprehensive Overview ◽  
Content Type ◽  
Pediatric Formulation ◽  
Health Organization

ABSTRACTSpecially created pediatric formulations have the potential to improve the acceptability, effectiveness, and accuracy of dosing of artemisinin-based combination therapy (ACT) in young children, a patient group that is inherently vulnerable to malaria. Artemether-lumefantrine (AL) Dispersible is a pediatric formulation of AL that is specifically tailored for the treatment of children with uncomplicatedPlasmodium falciparummalaria, offering benefits relating to efficacy, convenience and acceptance, accuracy of dosing, safety, sterility, stability, and a pharmacokinetic profile and bioequivalence similar to those of crushed and intact AL tablets. However, despite being the first pediatric antimalarial to meet World Health Organization (WHO) specifications for use in infants and children who are ≥5 kg in body weight and its inclusion in WHO Guidelines, there are few publications that focus on AL Dispersible. Based on a systematic review of the recent literature, this paper provides a comprehensive overview of the clinical experience with AL Dispersible to date. A randomized, phase 3 study that compared the efficacy and safety of AL Dispersible to those of crushed AL tablets in 899 African children reported high PCR-corrected cure rates at day 28 (97.8% and 98.5% for AL Dispersible and crushed tablets, respectively), and the results of several subanalyses of these data indicate that this activity is observed regardless of patient weight, food intake, and maximum plasma concentrations of artemether or its active metabolite, dihydroartemisinin. These and other clinical data support the continued use of pediatric antimalarial formulations in all children <5 years of age with uncomplicated malaria when accompanied by continued monitoring for the emergence of resistance.

scholarly journals COVID-19—The Potential Beneficial Therapeutic Effects of Spironolactone during SARS-CoV-2 Infection

2021 ◽  
Vol 14 (1) ◽  
pp. 71
Author(s):  
Katarzyna Kotfis ◽  
Kacper Lechowicz ◽  
Sylwester Drożdżal ◽  
Paulina Niedźwiedzka-Rystwej ◽  
Tomasz K. Wojdacz ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Therapeutic Potential ◽  
Severe Pneumonia ◽  
Therapeutic Benefit ◽  
World Health ◽  
Therapeutic Effects ◽  
Severe Acute Respiratory Infection ◽  
Dual Action ◽  
Health Organization ◽  
Transmembrane Serine Protease

In March 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was declared a global pandemic by the World Health Organization (WHO). The clinical course of the disease is unpredictable but may lead to severe acute respiratory infection (SARI) and pneumonia leading to acute respiratory distress syndrome (ARDS). It has been shown that pulmonary fibrosis may be one of the major long-term complications of COVID-19. In animal models, the use of spironolactone was proven to be an important drug in the prevention of pulmonary fibrosis. Through its dual action as a mineralocorticoid receptor (MR) antagonist and an androgenic inhibitor, spironolactone can provide significant benefits concerning COVID-19 infection. The primary effect of spironolactone in reducing pulmonary edema may also be beneficial in COVID-19 ARDS. Spironolactone is a well-known, widely used and safe anti-hypertensive and antiandrogenic medication. It has potassium-sparing diuretic action by antagonizing mineralocorticoid receptors (MRs). Spironolactone and potassium canrenoate, exerting combined pleiotropic action, may provide a therapeutic benefit to patients with COVID-19 pneumonia through antiandrogen, MR blocking, antifibrotic and anti-hyperinflammatory action. It has been proposed that spironolactone may prevent acute lung injury in COVID-19 infection due to its pleiotropic effects with favorable renin–angiotensin–aldosterone system (RAAS) and ACE2 expression, reduction in transmembrane serine protease 2 (TMPRSS2) activity and antiandrogenic action, and therefore it may prove to act as additional protection for patients at highest risk of severe pneumonia. Future prospective clinical trials are warranted to evaluate its therapeutic potential.

scholarly journals Efficiency of Conditionally Attenuated Salmonella enterica Serovar Typhimurium in Bacterium-Mediated Tumor Therapy

mBio ◽  
2015 ◽  
Vol 6 (2) ◽  
Author(s):  
Michael Frahm ◽  
Sebastian Felgner ◽  
Dino Kocijancic ◽  
Manfred Rohde ◽  
Michael Hensel ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Tumor Targeting ◽  
Antitumor Effect ◽  
Treatment Options ◽  
Tumor Therapy ◽  
Therapeutic Benefit ◽  
Industrialized Countries ◽  
Content Type ◽  
Serovar Typhimurium ◽  
Therapeutic Molecules

ABSTRACTIncreasing numbers of cancer cases generate a great urge for new treatment options. Applying bacteria likeSalmonella entericaserovar Typhimurium for cancer therapy represents an intensively explored option. These bacteria have been shown not only to colonize solid tumors but also to exhibit an intrinsic antitumor effect. In addition, they could serve as tumor-targeting vectors for therapeutic molecules. However, the pathogenicS. Typhimurium strains used for tumor therapy need to be attenuated for safe application. Here, lipopolysaccharide (LPS) deletion mutants (ΔrfaL, ΔrfaG, ΔrfaH, ΔrfaD, ΔrfaP, and ΔmsbBmutants) ofSalmonellawere investigated for efficiency in tumor therapy. Of such variants, the ΔrfaDand ΔrfaGdeep rough mutants exhibited the best tumor specificity and lowest pathogenicity. However, the intrinsic antitumor effect was found to be weak. To overcome this limitation, conditional attenuation was tested by complementing the mutants with an inducible arabinose promoter. The chromosomal integration of the respective LPS biosynthesis genes into thearaBADlocus exhibited the best balance of attenuation and therapeutic benefit. Thus, the present study establishes a basis for the development of an applicably cancer therapeutic bacterium.IMPORTANCECancer has become the second most frequent cause of death in industrialized countries. This and the drawbacks of routine therapies generate an urgent need for novel treatment options. Applying appropriately modifiedS. Typhimurium for therapy represents the major challenge of bacterium-mediated tumor therapy. In the present study, we demonstrated thatSalmonellabacteria conditionally modified in their LPS phenotype exhibit a safe tumor-targeting phenotype. Moreover, they could represent a suitable vehicle to shuttle therapeutic compounds directly into cancerous tissue without harming the host.

scholarly journals Characterization of T Cells Specific for CFP-10 and ESAT-6 in Mycobacterium tuberculosis-Infected Mauritian Cynomolgus Macaques

2017 ◽  
Vol 85 (4) ◽  
Author(s):  
Amy Ellis ◽  
Alexis Balgeman ◽  
Mark Rodgers ◽  
Cassaundra Updike ◽  
Jaime Tomko ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Mhc Class Ii ◽  
Nonhuman Primates ◽  
Content Type ◽  
Host Immune Responses ◽  
Cell Responses ◽  
Cynomolgus Macaques ◽  
Mhc Haplotype

ABSTRACT Nonhuman primates can be used to study host immune responses to Mycobacterium tuberculosis. Mauritian cynomolgus macaques (MCMs) are a unique group of animals that have limited major histocompatibility complex (MHC) genetic diversity, such that MHC-identical animals can be infected with M. tuberculosis. Two MCMs homozygous for the relatively common M1 MHC haplotype were bronchoscopically infected with 41 CFU of the M. tuberculosis Erdman strain. Four other MCMs, which had at least one copy of the M1 MHC haplotype, were infected with a lower dose of 3 CFU M. tuberculosis. All animals mounted similar T-cell responses to CFP-10 and ESAT-6. Two epitopes in CFP-10 were characterized, and the MHC class II alleles restricting them were determined. A third epitope in CFP-10 was identified but exhibited promiscuous restriction. The CFP-10 and ESAT-6 antigenic regions targeted by T cells in MCMs were comparable to those seen in cases of human M. tuberculosis infection. Our data lay the foundation for generating tetrameric molecules to study epitope-specific CD4 T cells in M. tuberculosis-infected MCMs, which may guide future testing of tuberculosis vaccines in nonhuman primates.

scholarly journals Secretion of Anti-Plasmodium Effector Proteins from a Natural Pantoea agglomerans Isolate by Using PelB and HlyA Secretion Signals

2011 ◽  
Vol 77 (13) ◽  
pp. 4669-4675 ◽  
Author(s):  
Dawn C. Bisi ◽  
David J. Lampe
Keyword(s):  
Control Strategies ◽  
Pectate Lyase ◽  
Erwinia Carotovora ◽  
Individual Characteristics ◽  
Pantoea Agglomerans ◽  
Effector Proteins ◽  
World Health ◽  
Content Type ◽  
E Coli ◽  
The Individual

ABSTRACTThe insect-vectored disease malaria is a major world health problem. New control strategies are needed to supplement the current use of insecticides and medications. A genetic approach can be used to inhibit development of malaria parasites (Plasmodiumspp.) in the mosquito host. We hypothesized thatPantoea agglomerans, a bacterial symbiont ofAnophelesmosquitoes, could be engineered to express and secrete anti-Plasmodiumeffector proteins, a strategy termed paratransgenesis. To this end, plasmids that include thepelBorhlyAsecretion signals from the genes of related species (pectate lyase fromErwinia carotovoraand hemolysin A fromEscherichia coli, respectively) were created and tested for their efficacy in secreting known anti-Plasmodiumeffector proteins (SM1, anti-Pbs21, and PLA2) inP. agglomeransandE. coli.P. agglomeranssuccessfully secreted HlyA fusions of anti-Pbs21 and PLA2, and these strains are under evaluation for anti-Plasmodiumactivity in infected mosquitoes. Varied expression and/or secretion of the effector proteins was observed, suggesting that the individual characteristics of a particular effector may require empirical testing of several secretion signals. Importantly, those strains that secreted efficiently grew as well as wild-type strains under laboratory conditions and, thus, may be expected to be competitive with the native microbiota in the environment of the mosquito midgut.

scholarly journals Monkey Models of Tuberculosis: Lessons Learned

2014 ◽  
Vol 83 (3) ◽  
pp. 852-862 ◽  
Author(s):  
Juliet C. Peña ◽  
Wen-Zhe Ho
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Animal Models ◽  
Nonhuman Primates ◽  
Lessons Learned ◽  
Preclinical Testing ◽  
Content Type ◽  
Cynomolgus Macaques ◽  
Drug Regimens

The use of animal models has been invaluable for studying the pathogenesis ofMycobacterium tuberculosisinfection, as well as for testing the efficacy of vaccines and drug regimens for tuberculosis. Among the applied animal models, nonhuman primates, particularly macaques, share the greatest anatomical and physiological similarities with humans. As such, macaque models have been used for investigating tuberculosis pathogenesis and preclinical testing of drugs and vaccines. This review focuses on published major studies which illustrate how the rhesus and cynomolgus macaques have enriched and may continue to advance the field of global tuberculosis research.

The creative artist support group: a case study

2014 ◽  
Vol 13 (3) ◽  
pp. 142-145 ◽  
Author(s):  
Elliot Benjamin
Keyword(s):  
Mental Health ◽  
Support Group ◽  
Public Mental Health ◽  
Therapeutic Benefit ◽  
Humanistic Psychology ◽  
Content Type ◽  
Therapeutic Benefits ◽  
Artistic Theory ◽  
Creative Artists

Purpose – The purpose of this paper is to describe the therapeutic benefits of a community-based creative artists support group. The author is also the participant/facilitator of the group, which has been ongoing for the past eight months. The relevant experiences of three participants in the group have been chosen, to briefly illustrate the diverse kinds of social and therapeutic value that people with creative artistic inclinations may benefit from. Design/methodology/approach – The philosophy of the author's facilitation of this creative artist support group is based upon the humanistic psychology foundations of Carl Rogers and Abraham Maslow, as well as the author's previous work on the relationship of the creative artist to mental disturbance and mental health. Findings – The pragmatic illustrations of therapeutic benefit from participation in this creative artist support group are directly related to the humanistic supportive atmosphere that is described in this paper as a cornerstone of the Artistic Theory of Psychology. Originality/value – This paper is highly original in the context of the author's description of his Artistic Theory of Psychology, which utilizes the foundation for the “successful creative artist” as being successful in both one's chosen artistic realm as well as making a satisfactory adjustment to day-to-day life. It should also be noted that this paper has been written in the context of a “brief case study” as discussed in August 2013 with the Journal of Public Mental Health editor.

A systematic review of adverse childhood experiences (ACEs) with people with intellectual disabilities: an unsafe gap in the literature

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Chloe Crompton ◽  
Bethany Duncan ◽  
Graham Simpson-Adkins
Keyword(s):  
Systematic Review ◽  
Intellectual Disabilities ◽  
Adverse Childhood Experiences ◽  
World Health ◽  
Inclusion Criteria ◽  
Childhood Experiences ◽  
Content Type ◽  
Adverse Childhood ◽  
People With Intellectual Disabilities ◽  
The Impact

Purpose This paper aims to systematically review the available evidence that explores adverse childhood experiences (ACEs) in people with intellectual disabilities (PwID). It is important to systematically review this literature as, to date, there is little known about the number of studies in this area, despite the World Health Organization declaring ACE prevention and support as a global public health priority. Design/methodology/approach Published studies were identified from electronic database searches. Key journals and reference lists were also hand searched. Findings Two studies met the inclusion criteria and the prevalence and frequency of ACEs experienced by participants of these studies analysed. Overall, due to the small number of studies meeting the inclusion criteria, it is difficult to establish any meaningful conclusions. Originality/value This appears to be the first systematic review to try and identify a research base looking at the prevalence of ACEs within a PwID population. Findings suggest that this is a highly neglected area of research, and the authors hope to have identified that further evidence is required to draw clearer conclusions about the impact of ACEs on PwID.

scholarly journals Death of the King: The Introduction of Vaccination into Nepal in 1816

2018 ◽  
Vol 63 (1) ◽  
pp. 24-43 ◽  
Author(s):  
Susan Heydon
Keyword(s):  
Communicable Disease ◽  
World Health ◽  
Smallpox Vaccination ◽  
Communicable Disease Control ◽  
Eradication Programme ◽  
Early Appearance ◽  
Colonial Authority ◽  
History Of ◽  
Global Eradication ◽  
Health Organization

This article explores the introduction of smallpox vaccination into Nepal in 1816 at the request of the Nepalese government; the king, however, was not vaccinated, contracted the disease and died. British hopes that vaccination would be extended throughout the country did not eventuate. The article examines the significance of this early appearance of vaccination in Nepal for both Nepalese and British, and relates it to the longer history of smallpox control and eventual eradication. When the Nepalese requested World Health Organization (WHO) assistance with communicable disease control in the mid-twentieth century little had changed for most Nepalese. We know about the events in 1816 through the letters of the newly imposed British Resident after Nepal’s military defeat in the Anglo-Nepal War (1814–16). By also drawing on other sources and foregrounding Nepal, it becomes possible to build up a more extensive picture of smallpox in Nepal that shows not only boundaries and limits to colonial authority and influence but also how governments may adopt and use technologies on their own terms and for their own purposes. Linking 1816 to the ultimately successful global eradication programme 150 years later reminds us of the need to think longer term as to why policies and programmes may or may not work as planned.

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