10 results on '"Rianna Stefanakis"'
Search Results
2. In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis.
- Author
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Alexandra Ehrens, Christopher S Lunde, Robert T Jacobs, Dominique Struever, Marianne Koschel, Stefan J Frohberger, Franziska Lenz, Martina Fendler, Joseph D Turner, Stephen A Ward, Mark J Taylor, Yvonne R Freund, Rianna Stefanakis, Eric Easom, Xianfeng Li, Jacob J Plattner, Achim Hoerauf, and Marc P Hübner
- Subjects
Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
The elimination of filarial diseases such as onchocerciasis and lymphatic filariasis is hampered by the lack of a macrofilaricidal-adult worm killing-drug. In the present study, we tested the in vivo efficacy of AN11251, a boron-pleuromutilin that targets endosymbiotic Wolbachia bacteria from filarial nematodes and compared its efficacy to doxycycline and rifampicin. Doxycycline and rifampicin were previously shown to deplete Wolbachia endosymbionts leading to a permanent sterilization of the female adult filariae and adult worm death in human clinical studies. Twice-daily oral treatment of Litomosoides sigmodontis-infected mice with 200 mg/kg AN11251 for 10 days achieved a Wolbachia depletion > 99.9% in the adult worms, exceeding the Wolbachia reduction by 10-day treatments with bioequivalent human doses of doxycycline and a similar reduction as high-dose rifampicin (35 mg/kg). Wolbachia reductions of > 99% were also accomplished by 14 days of oral AN11251 at a lower twice-daily dose (50 mg/kg) or once-per-day 200 mg/kg AN11251 treatments. The combinations tested of AN11251 with doxycycline had no clear beneficial impact on Wolbachia depletion, achieving a > 97% Wolbachia reduction with 7 days of treatment. These results indicate that AN11251 is superior to doxycycline and comparable to high-dose rifampicin in the L. sigmodontis mouse model, allowing treatment regimens as short as 10-14 days. Therefore, AN11251 represents a promising pre-clinical candidate that was identified in the L. sigmodontis model, and could be further evaluated and developed as potential clinical candidate for human lymphatic filariasis and onchocerciasis.
- Published
- 2020
- Full Text
- View/download PDF
3. The impact of the US priority review voucher on private-sector investment in global health research and development.
- Author
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Andrew S Robertson, Rianna Stefanakis, Don Joseph, and Melinda Moree
- Subjects
Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Published
- 2012
- Full Text
- View/download PDF
4. Analysis of neglected tropical disease drug and vaccine development pipelines to predict issuance of FDA priority review vouchers over the next decade.
- Author
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Rianna Stefanakis, Andrew S Robertson, Elizabeth L Ponder, and Melinda Moree
- Subjects
Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Published
- 2012
- Full Text
- View/download PDF
5. Macrofilaricidal Benzimidazole–Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness: Part 2. Ketone Linked Analogs
- Author
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Robert T. Jacobs, Rianna Stefanakis, Nancy Tricoche, Eric E. Easom, Yvonne Freund, Kee Chong Lim, James H. McKerrow, David S. Carter, Christina A. Bulman, Brian M. Suzuki, Christopher S. Lunde, Pamela Berry, Judy A. Sakanari, Jacob J. Plattner, Chelsea Fischer, Sara Lustigman, Tsutomu Akama, and Fernando Rock
- Subjects
Boron Compounds ,Male ,0301 basic medicine ,Benzimidazole ,Letter ,Ketone ,030106 microbiology ,Administration, Oral ,Flubendazole ,Pharmacology ,03 medical and health sciences ,chemistry.chemical_compound ,Pharmacokinetics ,Onchocerciasis, Ocular ,parasitic diseases ,medicine ,Animals ,lymphatic filariasis ,chemistry.chemical_classification ,flubendazole ,organoboron ,Blindness ,biology ,Chemistry ,onchocerciasis ,Ketones ,medicine.disease ,biology.organism_classification ,Onchocerca volvulus ,Disease Models, Animal ,Filaricides ,030104 developmental biology ,Infectious Diseases ,Nematode ,tubulin ,Benzimidazoles ,Female ,Gerbillinae ,Onchocerciasis - Abstract
The optimization of a series of benzimidazole–benzoxaborole hybrid molecules linked via a ketone that exhibit good activity against Onchocerca volvulus, a filarial nematode responsible for the disease onchocerciasis, also known as river blindness, is described. The lead identified in this series, 21 (AN15470), was found to have acceptable pharmacokinetic properties to enable an evaluation following oral dosing in an animal model of onchocerciasis. Compound 21was effective in killing worms implanted in Mongolian gerbils when dosed orally as a suspension at 100 mg/kg/day for 14 days but not when dosed orally at 100 mg/kg/day for 7 days.
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- 2019
6. Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis
- Author
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Rianna Stefanakis, Eric E. Easom, Jacob J. Plattner, Yvonne Freund, Erin E. Stebbins, Melissa S. Love, Pamela Berry, Jiri Gut, Christopher D. Huston, Rajiv S. Jumani, Case W. McNamara, Philip J. Rosenthal, Peter J. Miller, Christopher S. Lunde, Robert T. Jacobs, John W. Barlow, and Mahmudul Hasan
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Boron Compounds ,Male ,0301 basic medicine ,Parasitic infection ,Phenotypic screening ,Science ,Antiprotozoal Agents ,Drug Evaluation, Preclinical ,Cryptosporidiosis ,Cryptosporidium ,General Physics and Astronomy ,Drug development ,02 engineering and technology ,Disease ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,medicine ,Animals ,Humans ,lcsh:Science ,Multidisciplinary ,biology ,business.industry ,Intracellular parasite ,Isoxazoles ,General Chemistry ,021001 nanoscience & nanotechnology ,biology.organism_classification ,Amides ,Rats ,3. Good health ,Diarrhea ,Drug repositioning ,030104 developmental biology ,Immunology ,Neglected tropical diseases ,Female ,lcsh:Q ,medicine.symptom ,0210 nano-technology ,business - Abstract
Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children and causes chronic diarrhea in AIDS patients, but the only approved treatment is ineffective in malnourished children and immunocompromised people. We here use a drug repositioning strategy and identify a promising anticryptosporidial drug candidate. Screening a library of benzoxaboroles comprised of analogs to four antiprotozoal chemical scaffolds under pre-clinical development for neglected tropical diseases for Cryptosporidium growth inhibitors identifies the 6-carboxamide benzoxaborole AN7973. AN7973 blocks intracellular parasite development, appears to be parasiticidal, and potently inhibits the two Cryptosporidium species most relevant to human health, C. parvum and C. hominis. It is efficacious in murine models of both acute and established infection, and in a neonatal dairy calf model of cryptosporidiosis. AN7973 also possesses favorable safety, stability, and PK parameters, and therefore, is an exciting drug candidate for treating cryptosporidiosis., Cryptosporidium infection can cause severe diarrhea with limited treatment options available. Here, Lunde et al. perform a drug repositioning screen with a library of benzoxaboroles and identify AN7973 as potent inhibitor of intracellular parasite development with good efficacy in murine and neonatal dairy calf disease models.
- Published
- 2019
7. Macrofilaricidal Benzimidazole-Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness: Part 1. Amide Linked Analogs
- Author
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Tsutomu Akama, Yvonne R. Freund, Pamela W. Berry, David S. Carter, Eric E. Easom, Kurt Jarnagin, Christopher S. Lunde, Jacob J. Plattner, Fernando Rock, Rianna Stefanakis, Chelsea Fischer, Christina A. Bulman, Kee Chong Lim, Brian M. Suzuki, Nancy Tricoche, Abdelmoneim Mansour, Utami DiCosty, Scott McCall, Ben Carson, John W. McCall, James McKerrow, Marc P. Hübner, Sabine Specht, Achim Hoerauf, Sara Lustigman, Judy A. Sakanari, and Robert T. Jacobs
- Subjects
Boron Compounds ,Male ,flubendazole ,Letter ,organoboron ,onchocerciasis ,Amides ,Onchocerca volvulus ,Infectious Diseases ,Filaricides ,tubulin ,parasitic diseases ,Brugia ,Animals ,Benzimidazoles ,Female ,Gerbillinae ,lymphatic filariasis - Abstract
A series of benzimidazole–benzoxaborole hybrid molecules linked via an amide linker are described that exhibit good in vitro activity against Onchocerca volvulus, a filarial nematode responsible for the disease onchocerciasis, also known as river blindness. The lead identified in this series, 8a (AN8799), was found to have acceptable pharmacokinetic properties to enable evaluation in animal models of human filariasis. Compound 8a was effective in killing Brugia malayi, B. pahangi, and Litomosoides sigmodontis worms present in Mongolian gerbils when dosed subcutaneously as a suspension at 100 mg/kg/day for 14 days but not when dosed orally at 100 mg/kg/day for 28 days. The measurement of plasma levels of 8a at the end of the dosing period and at the time of sacrifice revealed an interesting dependence of activity on the extended exposure for both 8a and the positive control, flubendazole.
- Published
- 2019
8. In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis
- Author
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Christopher S. Lunde, Martina Fendler, Xianfeng Li, Joseph D. Turner, Mark J. Taylor, Marianne Koschel, Marc P. Hübner, Alexandra Ehrens, Dominique Struever, Robert T. Jacobs, Franziska Lenz, Stefan J. Frohberger, Achim Hoerauf, Eric E. Easom, Yvonne Freund, Stephen A. Ward, Jacob J. Plattner, and Rianna Stefanakis
- Subjects
0301 basic medicine ,RC955-962 ,Onchocerciasis ,0302 clinical medicine ,Antibiotics ,qx_301 ,Oral administration ,Arctic medicine. Tropical medicine ,Medicine and Health Sciences ,Oral Administration ,Routes of Administration ,Lymphatic filariasis ,Doxycycline ,Mice, Inbred BALB C ,Antimicrobials ,Pharmaceutics ,Drugs ,Animal Models ,wc_850 ,Anti-Bacterial Agents ,Filariasis ,Infectious Diseases ,Experimental Organism Systems ,Helminth Infections ,Female ,Wolbachia ,Diterpenes ,Rifampin ,Public aspects of medicine ,RA1-1270 ,Research Article ,Neglected Tropical Diseases ,medicine.drug ,wc_880 ,030231 tropical medicine ,Mouse Models ,Biology ,Research and Analysis Methods ,wc_885 ,Microbiology ,Antimalarials ,03 medical and health sciences ,Model Organisms ,Drug Therapy ,In vivo ,Microbial Control ,parasitic diseases ,Parasitic Diseases ,medicine ,Animals ,Adults ,Polycyclic Compounds ,Symbiosis ,qw_131 ,Filarioidea ,Boron ,Pharmacology ,Bacteria ,Lymphatic Filariasis ,Organisms ,Public Health, Environmental and Occupational Health ,Biology and Life Sciences ,Tropical Diseases ,medicine.disease ,biology.organism_classification ,030104 developmental biology ,Nematode ,Age Groups ,People and Places ,Animal Studies ,Population Groupings ,Rifampicin - Abstract
The elimination of filarial diseases such as onchocerciasis and lymphatic filariasis is hampered by the lack of a macrofilaricidal–adult worm killing–drug. In the present study, we tested the in vivo efficacy of AN11251, a boron-pleuromutilin that targets endosymbiotic Wolbachia bacteria from filarial nematodes and compared its efficacy to doxycycline and rifampicin. Doxycycline and rifampicin were previously shown to deplete Wolbachia endosymbionts leading to a permanent sterilization of the female adult filariae and adult worm death in human clinical studies. Twice-daily oral treatment of Litomosoides sigmodontis-infected mice with 200 mg/kg AN11251 for 10 days achieved a Wolbachia depletion > 99.9% in the adult worms, exceeding the Wolbachia reduction by 10-day treatments with bioequivalent human doses of doxycycline and a similar reduction as high-dose rifampicin (35 mg/kg). Wolbachia reductions of > 99% were also accomplished by 14 days of oral AN11251 at a lower twice-daily dose (50 mg/kg) or once-per-day 200 mg/kg AN11251 treatments. The combinations tested of AN11251 with doxycycline had no clear beneficial impact on Wolbachia depletion, achieving a > 97% Wolbachia reduction with 7 days of treatment. These results indicate that AN11251 is superior to doxycycline and comparable to high-dose rifampicin in the L. sigmodontis mouse model, allowing treatment regimens as short as 10–14 days. Therefore, AN11251 represents a promising pre-clinical candidate that was identified in the L. sigmodontis model, and could be further evaluated and developed as potential clinical candidate for human lymphatic filariasis and onchocerciasis., Author summary Onchocerciasis and lymphatic filariasis are human filarial tropical diseases, which can cause blindness and severe dermatitis (onchocerciasis) or lymphedema and hydrocele (lymphatic filariasis). Current strategies to eliminate these diseases include the mass drug administration (MDA) of drugs that target the progeny of the filariae, the microfilariae, and temporarily inhibit filarial embryogenesis and, therefore, the transmission of the disease. However, MDA has several limitations that delay the goal of elimination including the lack of a drug with a short term regimen and a potent macrofilaricidal effect. As an alternative approach, the antibiotic doxycycline has been proven to be effective in depleting Wolbachia endosymbionts from adult filariae, which then leads to permanent sterilization and death of the adult worms. Due to contraindications for doxycycline and prolonged treatment regimen of at least 4 weeks, there is an urgent need for new anti-filarial drugs with an improved safety profile and shorter regimens. The current study demonstrates that the boron-pleuromutilin derivative AN11251 provides an excellent in vivo anti-Wolbachia depletion in the Litomosoides sigmodontis filarial mouse model that is superior to doxycycline and comparable to rifampicin, allowing for regimens as short as 10–14 days. Combination with doxycycline for 7 days had no significant beneficial effect on efficacy, achieving Wolbachia reductions of more than 97%. Therefore, AN11251 shows potent anti-Wolbachia activity in the L. sigmodontis mouse model and may also present an alternative pre-clinical candidate for filariasis treatment.
- Published
- 2020
9. Leptin is an effective treatment for hypothalamic amenorrhea
- Author
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Huizhi Gong, Giuseppe Matarese, Christos S. Mantzoros, Mary Brinkoetter, Chuanyun Gao, Kalliopi M. Arampatzi, Xiaowen Liu, John P. Chamberland, Sharon H. Chou, Rianna Stefanakis, Chou, Sh, Chamberland, Jp, Liu, X, Matarese, Giuseppe, Gao, C, Stefanakis, R, Brinkoetter, Mt, Gong, H, Arampatzi, K, and Mantzoros, Cs
- Subjects
Adult ,Leptin ,medicine.medical_specialty ,Hypothalamo-Hypophyseal System ,Time Factors ,Adolescent ,Pituitary-Adrenal System ,030209 endocrinology & metabolism ,Hypothalamic disease ,Bone remodeling ,Feeding and Eating Disorders ,03 medical and health sciences ,Metreleptin ,chemistry.chemical_compound ,Eating ,0302 clinical medicine ,Internal medicine ,medicine ,Endocrine system ,Humans ,Amenorrhea ,030304 developmental biology ,2. Zero hunger ,Bone mineral ,0303 health sciences ,Multidisciplinary ,business.industry ,Thyroid ,Biological Sciences ,medicine.disease ,3. Good health ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Female ,medicine.symptom ,business ,Hypothalamic Diseases - Abstract
Hypothalamic amenorrhea (HA) is associated with dysfunction of the hypothalamic-pituitary-peripheral endocrine axes, leading to infertility and bone loss, and usually is caused by chronic energy deficiency secondary to strenuous exercise and/or decreased food intake. Energy deficiency also leads to hypoleptinemia, which has been proposed, on the basis of observational studies as well as an open-label study, to mediate the neuroendocrine abnormalities associated with this condition. To prove definitively a causal role of leptin in the pathogenesis of HA, we performed a randomized, double-blinded, placebo-controlled trial of human recombinant leptin (metreleptin) in replacement doses over 36 wk in women with HA. We assessed its effects on reproductive outcomes, neuroendocrine function, and bone metabolism. Leptin replacement resulted in recovery of menstruation and corrected the abnormalities in the gonadal, thyroid, growth hormone, and adrenal axes. We also demonstrated changes in markers of bone metabolism suggestive of bone formation, but no changes in bone mineral density were detected over the short duration of this study. If these data are confirmed, metreleptin administration in replacement doses to normalize circulating leptin levels may prove to be a safe and effective therapy for women with HA.
- Published
- 2011
10. Analysis of Neglected Tropical Disease Drug and Vaccine Development Pipelines to Predict Issuance of FDA Priority Review Vouchers over the Next Decade
- Author
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Elizabeth L. Ponder, Melinda Moree, Rianna Stefanakis, and Andrew S. Robertson
- Subjects
lcsh:Arctic medicine. Tropical medicine ,lcsh:RC955-962 ,Science Policy ,Communicable Diseases ,Approved drug ,Tropical Medicine ,Drug Discovery ,Humans ,Medicine ,Market value ,Drug Approval ,New drug application ,Finance ,Vaccines ,Policy Platform ,United States Food and Drug Administration ,business.industry ,lcsh:Public aspects of medicine ,Public Health, Environmental and Occupational Health ,Neglected Diseases ,lcsh:RA1-1270 ,United States ,Priority review ,Product (business) ,Voucher ,Infectious Diseases ,Incentive ,Neglected tropical diseases ,business - Abstract
The need for new drugs and vaccines for neglected tropical diseases (NTDs) is widely accepted [1]. Yet, encouraging pharmaceutical and biotechnology company investment in developing these much-needed treatments remains a challenge due to a lack of a commercial market driving companies to pursue NTD projects [2]. To address this challenge, economists Ridley, Grabowski, and Moe at Duke University conceived of an incentive to encourage investment in the development of new drugs and vaccines for NTDs: the US Food and Drug Administration's (FDA) priority review voucher (PRV) program [3]. The program was signed into law on September 27, 2007 [4], and went into effect one year later. Under the program, the FDA awards a voucher to the sponsor of a newly approved drug or vaccine that targets an NTD (such as cholera or dengue) or malaria and tuberculosis (TB). The voucher, which can be traded or sold, entitles the holder to a 6-month priority review for a future new drug application that would not otherwise qualify for priority review—potentially shaving between 4 and 12 months from the standard FDA review process [5]. Since the program's inception, only one PRV has been awarded, to Novartis Pharmaceuticals Co. for their 2009 approval of the antimalarial drug Coartem. Novartis used the voucher to accelerate the review of one of its own products, rather than selling it on the marketplace. Because a product resulting from a PRV has not yet been sold in the marketplace, the value remains uncertain. Early economic models estimated that the worth of a PRV could range from US$50 million to US$500 million, with an average value of US$322 million, and a variation in value based on the therapeutic area for which it is used [5], [6]. Part of predicting the value relies on the supply and demand of vouchers; that is, will the number of vouchers awarded be absorbed by the blockbuster products that are likely to be the intended recipients of benefit from accelerated review? The lack of understanding as to how many PRVs may be awarded in the future limits companies from predicting the potential value of a voucher that might be earned. In the absence of a tangible example of a voucher's market value, companies, the FDA, policymakers, and other program stakeholders could benefit from examining NTD product pipelines, understanding when the next PRV(s) are expected to be issued, and ultimately quantifying the supply side of the PRV market. In addition, it is unclear to global health stakeholders whether companies are actively pursuing PRV-eligible products, and if they are, whether the PRV incentive has had an impact on their motivation [5], [6]. Here, we present an analysis of the drug and vaccine development pipeline to a) identify products that meet eligibility criteria to earn a PRV, and b) predict the number of PRVs that will be issued over the next 10 years. Of those products currently in clinical development, standard industry probabilities of success (POS) were applied to predict how many drugs and vaccines will ultimately earn regulatory approval, and therefore a PRV. Presumably, if stakeholders are armed with a supply forecast of the PRV market over the next decade, companies can conduct more informed calculations of value estimates, policymakers can assess whether the demand market for PRVs absorbs those vouchers being awarded, and the FDA can more accurately predict their expected workload increases when the PRVs are used.
- Published
- 2012
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