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Article ; Online: The Tryp and the Pendulum.

Buckner, Frederick S

2021 Volume 64, Page(s) 103188

Language	English
Publishing date	2021-01-22
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2020.103188
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Article ; Online: Early Stages of Drug Discovery in an Academic Institution and Involvement of Pharma for Advancing Promising Leads.

Gelb, Michael H / Buckner, Frederick S

ACS infectious diseases

2021 Volume 7, Issue 7, Page(s) 1874–1876

Abstract: In this Viewpoint, we provide a brief description of two efforts to develop drugs to treat diseases caused by tropical parasites (Malaria, human African trypanosomiasis and Chagas disease). These efforts are largely based in a University setting but draw ...

Abstract	In this Viewpoint, we provide a brief description of two efforts to develop drugs to treat diseases caused by tropical parasites (Malaria, human African trypanosomiasis and Chagas disease). These efforts are largely based in a University setting but draw heavily on Pharma for a complete progression from drug hit discovery to advancement toward clinical trials. The first case is the development of protein farnesyltransferase inhibitors, and the second case is a series of benzthiazoles, the target of which is being investigated.
MeSH term(s)	Animals ; Chagas Disease ; Drug Discovery ; Humans ; Malaria ; Trypanosomiasis, African/drug therapy ; Universities
Language	English
Publishing date	2021-04-19
Publishing country	United States
Document type	Journal Article
ISSN	2373-8227
ISSN (online)	2373-8227
DOI	10.1021/acsinfecdis.1c00091
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Article ; Online: Case Report: Miltefosine Failure and Spontaneous Resolution of Cutaneous Leishmaniasis braziliensis.

Joseph, Sheridan / Whitman, Timothy J / Buckner, Frederick S / Cogen, Anna L

The American journal of tropical medicine and hygiene

2021 Volume 105, Issue 1, Page(s) 142–143

Abstract: Cutaneous leishmaniasis (CL) is often caused by Leishmania braziliensis (L. braziliensis) in South America. Because of the risk for mucocutaneous leishmaniasis, L. braziliensis is frequently treated with parenteral or oral medications. Here, we present a ...

Abstract	Cutaneous leishmaniasis (CL) is often caused by Leishmania braziliensis (L. braziliensis) in South America. Because of the risk for mucocutaneous leishmaniasis, L. braziliensis is frequently treated with parenteral or oral medications. Here, we present a case of a young woman with L. braziliensis (CL) that did not respond to miltefosine but eventually experienced spontaneous resolution. This case highlights the potential for treatment failure and the importance of clinical monitoring in the setting of cutaneous leishmaniasis caused by L. braziliensis.
MeSH term(s)	Antiprotozoal Agents/therapeutic use ; Female ; Humans ; Leishmania braziliensis ; Leishmaniasis, Cutaneous/drug therapy ; Leishmaniasis, Cutaneous/epidemiology ; Peru/epidemiology ; Phosphorylcholine/analogs & derivatives ; Phosphorylcholine/therapeutic use ; Treatment Failure ; Young Adult
Chemical Substances	Antiprotozoal Agents ; Phosphorylcholine (107-73-3) ; miltefosine (53EY29W7EC)
Language	English
Publishing date	2021-05-10
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	2942-7
ISSN	1476-1645 ; 0002-9637
ISSN (online)	1476-1645
ISSN	0002-9637
DOI	10.4269/ajtmh.20-1642
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Article ; Online: Experimental chemotherapy and approaches to drug discovery for Trypanosoma cruzi infection.

Buckner, Frederick S

Advances in parasitology

2011 Volume 75, Page(s) 89–119

Abstract: In the 100 years since the discovery of Chagas disease, only two drugs have been developed and introduced into clinical practice, and these drugs were introduced over 40 years ago. The tools of drug discovery have improved dramatically in the interim; ... ...

Abstract	In the 100 years since the discovery of Chagas disease, only two drugs have been developed and introduced into clinical practice, and these drugs were introduced over 40 years ago. The tools of drug discovery have improved dramatically in the interim; however, this has not translated into new drugs for Chagas disease. This has been largely because the main practitioners of drug discovery are pharmaceutical companies who are not financially motivated to invest in Chagas disease and other "orphan" diseases. As a result, it has largely been up to academic groups to bring drug candidates through the discovery pipeline and to clinical trials. The difficulty with drug discovery in academia has been the challenge of bringing together the diverse expertise in biology, chemistry, and pharmacology in concerted efforts towards a common goal of developing therapeutics. Funding is often inadequate, but lack of coordination amongst academic investigators with different expertise has also contributed to the slow progress. The purpose of this chapter is to provide an overview of approaches that can be accomplished in academic settings for preclinical drug discovery for Chagas disease. The chapter addresses methods of drug screening against Trypanosoma cruzi cultures and in animal models and includes general topics on compound selection, testing for drug-like properties (including oral bioavailability), investigating the pharmacokinetics and toxicity of compounds, and finally providing parameters to help with triaging compounds.
MeSH term(s)	Animals ; Cell Line ; Chagas Disease/parasitology ; Chagas Disease/therapy ; Drug Discovery ; Drug Evaluation, Preclinical/methods ; Humans ; Inhibitory Concentration 50 ; Mammals ; Mice ; Parasitemia/drug therapy ; Parasitic Sensitivity Tests/methods ; Trypanocidal Agents/chemistry ; Trypanocidal Agents/pharmacology ; Trypanosoma cruzi/drug effects ; Trypanosoma cruzi/growth & development ; Trypanosoma cruzi/pathogenicity
Chemical Substances	Trypanocidal Agents
Language	English
Publishing date	2011-02-03
Publishing country	England
Document type	Journal Article
ZDB-ID	165-x
ISSN	2163-6079 ; 0065-308X
ISSN (online)	2163-6079
ISSN	0065-308X
DOI	10.1016/B978-0-12-385863-4.00005-8
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Article ; Online: Phenotypic Drug Discovery for Human African Trypanosomiasis: A Powerful Approach.

Buckner, Frederick S / Buchynskyy, Andriy / Nagendar, Pendem / Patrick, Donald A / Gillespie, J Robert / Herbst, Zackary / Tidwell, Richard R / Gelb, Michael H

Tropical medicine and infectious disease

2020 Volume 5, Issue 1

Abstract: The work began with the screening of a library of 700,000 small molecules for inhibitors ... ...

Abstract	The work began with the screening of a library of 700,000 small molecules for inhibitors of
Language	English
Publishing date	2020-02-05
Publishing country	Switzerland
Document type	Journal Article
ISSN	2414-6366
ISSN (online)	2414-6366
DOI	10.3390/tropicalmed5010023
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Article ; Online: A 71-year-old man with recurrent pulmonary mycobacterial avium complex infections and lymphopenia.

Al-Shaikhly, Taha / Buckner, Frederick S / Altman, Matthew C / Ochs, Hans D / Ayars, Andrew G

Allergy and asthma proceedings

2019 Volume 41, Issue 1, Page(s) 66–69

Abstract: Mycobacterium avium complex (MAC) infections, generally viewed as opportunistic infections, often trigger an evaluation for an underlying immunodeficiency disorder. However, MAC infections can occur in patients who presumably are immunocompetent, ... ...

Abstract	Mycobacterium avium complex (MAC) infections, generally viewed as opportunistic infections, often trigger an evaluation for an underlying immunodeficiency disorder. However, MAC infections can occur in patients who presumably are immunocompetent, particularly in those with an underlying structural lung disease. T-cell immunity plays a critical role in controlling MAC infection. We presented a case of lymphopenia, which complicated the clinical course of a pulmonary MAC infection in a patient who was negative for human immunodeficiency virus.
MeSH term(s)	Aged ; Diagnosis, Differential ; Humans ; Lung/pathology ; Lymphopenia ; Male ; Mycobacterium avium Complex/physiology ; Mycobacterium avium-intracellulare Infection/diagnosis ; Mycobacterium avium-intracellulare Infection/immunology
Language	English
Publishing date	2019-12-30
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	1312445-6
ISSN	1539-6304 ; 1088-5412
ISSN (online)	1539-6304
ISSN	1088-5412
DOI	10.2500/aap.2020.41.190003
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Article: Sterol 14-demethylase inhibitors for Trypanosoma cruzi infections.

Buckner, Frederick S

Advances in experimental medicine and biology

2008 Volume 625, Page(s) 61–80

Abstract: Chagas disease is caused by infection with the protozoan pathogen, Trypanosoma cruzi. The only approved therapeutics for treating Chagas disease are two nitroheterocyclic compounds (benznidazole and nifurtimox) that are suboptimal due to poor curative ... ...

Abstract	Chagas disease is caused by infection with the protozoan pathogen, Trypanosoma cruzi. The only approved therapeutics for treating Chagas disease are two nitroheterocyclic compounds (benznidazole and nifurtimox) that are suboptimal due to poor curative activity for chronic Chagas disease and high rates of adverse drug reactions. Sterol 14-demethylase inhibitors include azole antifungal drugs such as ketoconazole, fluconazole, itraconazole, and others. The first reports of potent activity of azole antifungal drugs against Trypanosoma cruzi came out about 25 years ago. Since then, a sizeable literature has accumulated on this topic. Newer triazole compounds such as posaconazole and D0870 have been shown to be effective at curing mice with chronic Trypanosoma cruzi infection. Small clinical studies with-ketoconazole or itraconazole in humans with chronic Chagas disease have not demonstrated significant curative activity. However, there is good reason for optimism that newer compounds with greater potency and improved pharmacokinetic properties might be more efficacious. Data have been published demonstrating synergistic activity of azole drugs with various other compounds, indicating that combination chemotherapy may be an effective strategy as this field moves ahead. In light of the near absence of adequate therapeutics for curing patients with chronic Chagas disease, additional effort to develop better drugs needs to be a priority.
MeSH term(s)	Animals ; Antifungal Agents/therapeutic use ; Chagas Disease/drug therapy ; Chagas Disease/enzymology ; Cytochrome P-450 Enzyme Inhibitors ; Enzyme Inhibitors/adverse effects ; Enzyme Inhibitors/pharmacology ; Humans ; Oxidoreductases/antagonists & inhibitors ; Sterol 14-Demethylase ; Trypanocidal Agents/adverse effects ; Trypanocidal Agents/pharmacology ; Trypanosoma cruzi/drug effects ; Trypanosoma cruzi/enzymology
Chemical Substances	Antifungal Agents ; CYP51A1 protein, human ; Cytochrome P-450 Enzyme Inhibitors ; Enzyme Inhibitors ; Trypanocidal Agents ; Oxidoreductases (EC 1.-) ; Sterol 14-Demethylase (EC 1.14.13.70) ; Cyp51 protein, mouse (EC 1.14.14.154)
Language	English
Publishing date	2008-01-30
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-0-387-77570-8_6
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Article: Experimental Chemotherapy and Approaches to Drug Discovery for Trypanosoma cruzi Infection

Buckner, Frederick S

Advances in Parasitology. 2011, v. 75

2011

Abstract	In the 100 years since the discovery of Chagas disease, only two drugs have been developed and introduced into clinical practice, and these drugs were introduced over 40 years ago. The tools of drug discovery have improved dramatically in the interim; however, this has not translated into new drugs for Chagas disease. This has been largely because the main practitioners of drug discovery are pharmaceutical companies who are not financially motivated to invest in Chagas disease and other “orphan” diseases. As a result, it has largely been up to academic groups to bring drug candidates through the discovery pipeline and to clinical trials. The difficulty with drug discovery in academia has been the challenge of bringing together the diverse expertise in biology, chemistry, and pharmacology in concerted efforts towards a common goal of developing therapeutics. Funding is often inadequate, but lack of coordination amongst academic investigators with different expertise has also contributed to the slow progress. The purpose of this chapter is to provide an overview of approaches that can be accomplished in academic settings for preclinical drug discovery for Chagas disease. The chapter addresses methods of drug screening against Trypanosoma cruzi cultures and in animal models and includes general topics on compound selection, testing for drug-like properties (including oral bioavailability), investigating the pharmacokinetics and toxicity of compounds, and finally providing parameters to help with triaging compounds.
Keywords	Chagas disease ; Trypanosoma cruzi ; animal models ; bioavailability ; chemistry ; clinical trials ; drug therapy ; funding ; new drugs ; pharmaceutical industry ; pharmacokinetics ; screening ; toxicity
Language	English
Size	p. 89-119.
Publishing place	Elsevier Science & Technology
Document type	Article
ZDB-ID	165-x
ISSN	0065-308X
ISSN	0065-308X
DOI	10.1016/B978-0-12-385863-4.00005-8
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Article ; Online: Recent Developments in Sterol 14-demethylase Inhibitors for Chagas Disease.

Buckner, Frederick S / Urbina, Julio A

International journal for parasitology. Drugs and drug resistance

2012 Volume 2, Page(s) 236–242

Abstract: The protozoan parasite, Trypanosoma cruzi, causes the most prevalent parasitic infection in the American continent. It gives rise to life-long infection in humans and results in severe cardiomyopathy or other life-threatening manifestations (Chagas ... ...

Abstract	The protozoan parasite, Trypanosoma cruzi, causes the most prevalent parasitic infection in the American continent. It gives rise to life-long infection in humans and results in severe cardiomyopathy or other life-threatening manifestations (Chagas disease) in ~30% of those infected. Animal models and clinical studies indicate that etiological treatment of the infection reduces the risk of developing the disease manifestations. Unfortunately, the existing chemotherapeutics have suboptimal antiparasitic activity and cause significant side effects in many patients, thus better anti-trypanosomal drugs are greatly needed. The sterol biosynthesis pathway has received attention as a target for the development of new drugs for Chagas disease. In particular, inhibitors of sterol 14-demethylase (CYP51) are shown to be extremely active on Trypanosoma cruzi in vitro and in animal models. Antifungal drugs (i.e. azoles) in clinical use or in clinical studies have been extensively tested preclinically on Trypanosoma cruzi with posaconazole and ravuconazole demonstrating the most promising activity. As a result, posaconazole and a pro-drug of ravuconazole (E1224) are currently being evaluated in Phase II studies for Chagas disease. Additional CYP51 inhibitors that are specifically optimized for anti-Trypanosoma cruzi activity are in development by academia. These represent an alternative to proprietary antifungal drugs if the latter fall short in clinical trials or are too expensive for widespread clinical use in disease endemic countries. The research over the next few years will help define the role of CYP51 inhibitors, alone or in combination with other drugs, for managing patients with Chagas disease.
Language	English
Publishing date	2012-10-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2751132-7
ISSN	2211-3207 ; 2211-3207
ISSN (online)	2211-3207
ISSN	2211-3207
DOI	10.1016/j.ijpddr.2011.12.002
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Article ; Online: Advances in Chagas disease drug development: 2009-2010.

Buckner, Frederick S / Navabi, Nazlee

Current opinion in infectious diseases

2010 Volume 23, Issue 6, Page(s) 609–616

Abstract: Purpose of review: The need for better drugs to treat patients with Chagas disease remains urgent. This review summarizes the advancements in drug development over the past 2 years.: Recent findings: Drug development efforts are almost exclusively ... ...

Abstract	Purpose of review: The need for better drugs to treat patients with Chagas disease remains urgent. This review summarizes the advancements in drug development over the past 2 years. Recent findings: Drug development efforts are almost exclusively occurring as preclinical research, although phase II studies for the antifungal drug, posaconazole, and a prodrug of ravuconazole are being planned. Several recent laboratory investigations demonstrate anti-Trypanosoma cruzi activity of novel small molecules in animal models. These include nonpeptidic cruzain inhibitors, novel inhibitors of the sterol 14α-demethylase enzyme, new compounds (arylimidamides) related to pentamidine, derivatives of nifurtimox, compounds using ruthenium complexes, and several natural products. The recent implementation of a high-throughput screen of more than 300 000 compounds against intracellular T. cruzi amastigotes done at the Broad Institute is an important development, yielding approximately 300 selective inhibitors, many of which may serve as leads for medicinal chemistry efforts. Summary: Progress is slow, but recent advancements in both drug development and advocacy for research on neglected diseases are encouraging. Efforts to define a target product profile and to harmonize methodologies for testing drugs for Chagas disease are described herein.
MeSH term(s)	Animals ; Antifungal Agents/chemistry ; Antifungal Agents/pharmacology ; Antifungal Agents/therapeutic use ; Biological Products/chemistry ; Biological Products/pharmacology ; Biological Products/therapeutic use ; Chagas Disease/drug therapy ; Chagas Disease/parasitology ; Disease Models, Animal ; Drug Discovery/methods ; Humans ; Molecular Targeted Therapy ; Neglected Diseases/drug therapy ; Neglected Diseases/parasitology ; Trypanocidal Agents/chemistry ; Trypanocidal Agents/pharmacology ; Trypanocidal Agents/therapeutic use ; Trypanosoma cruzi/drug effects ; Trypanosoma cruzi/enzymology
Chemical Substances	Antifungal Agents ; Biological Products ; Trypanocidal Agents
Language	English
Publishing date	2010-09-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	645085-4
ISSN	1473-6527 ; 1535-3877 ; 0951-7375 ; 1355-834X
ISSN (online)	1473-6527 ; 1535-3877
ISSN	0951-7375 ; 1355-834X
DOI	10.1097/QCO.0b013e3283402956
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