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Ravis W.R.,Auburn University | Llanos-Cuentas A.,Cayetano Heredia Peruvian University | Sosa N.,Instituto Conmemorativo Gorgas Of Estudios Of La Salud | Kreishman-Deitrick M.,U.S. Army | And 7 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2013

This study evaluated the pharmacokinetics of topical creams containing 15% paromomycin ("paromomycin alone") and 15% paromomycin plus 0.5% gentamicin (WR 279,396) in patients with cutaneous leishmaniasis. The investigational creams were applied topically to all lesions once daily for 20 days. Plasma samples were analyzed for simultaneous quantitation of paromomycin and gentamicin isomers and total gentamicin. Pharmacokinetic parameters for gentamicin could not be calculated because detectable levels were rarely evident. After one application, the paromomycin area under the concentration-time curve from 0 to 24 h (AUC0-24) was 2,180±2,621 ng h/ml (mean±standard deviation [SD]) for the paromomycin-alone group and 975.6±1,078 ng h/ml for the WR 279,396 group. After 20 days of application, the paromomycin AUC0-24 and maximum concentration of drug (Cmax) were 5 to 6 times greater than those on day 1 for both treatment groups. For the paromomycin-alone group, the AUC0-24 was 8,575±7,268 ng h/ml and the Cmax was 1,000±750 ng/ml, compared with 6,037±3,956 ng h/ml and 660±486 ng/ml for the WR 279,396 group, respectively. Possibly due to large intersubject variability, no differences (P >0.05) in the AUC0-24 or Cmax were noted between treatment or between sites on day 1 or 20. The percentage of dose absorbed on day 20 was 12.0%±6.26% and 9.68%±6.05% for paromomycin alone and WR 279,396, respectively. Paromomycin concentrations in plasma after 20 days of application were 5 to 9% of those after intramuscular administration of 15 mg/kg of body weight/day to adults for the systemic treatment of visceral leishmaniasis. Effective topical treatment of cutaneous leishmaniasis appears to be possible with limited paromomycin and gentamicin systemic absorption, thus avoiding drug accumulation and toxicity. (The work described here has been registered at ClinicalTrials.gov under registration no. NCT01032382 and NCT01083576.) Copyright © 2013, American Society for Microbiology. All Rights Reserved. Source


Rynkiewicz D.,University of Texas Health Science Center at San Antonio | Rathkopf M.,U.S. Air force | Sim I.,Coley Pharmaceutical Group | Waytes A.T.,Emergent BioSolutions | And 8 more authors.
Vaccine | Year: 2011

Immunization with BioThrax ® (Anthrax Vaccine Adsorbed) is a safe and effective means of preventing anthrax. Animal studies have demonstrated that the addition of CpG DNA adjuvants to BioThrax can markedly increase the immunogenicity of the vaccine, increasing both serum anti-protective antigen (PA) antibody and anthrax toxin-neutralizing antibody (TNA) concentrations. The immune response to CpG-adjuvanted BioThrax in animals was not only stronger, but was also more rapid and led to higher levels of protection in spore challenge models. The B-class CpG DNA adjuvant CPG 7909, a 24-base synthetic, single-strand oligodeoxynucleotide, was evaluated for its safety profile and adjuvant properties in a Phase 1 clinical trial. A double-blind study was performed in which 69 healthy subjects, age 18-45 years, were randomized to receive three doses of either: (1) BioThrax alone, (2) 1mg of CPG 7909 alone or (3) BioThrax plus 1mg of CPG 7909, all given intramuscularly on study days 0, 14 and 28. Subjects were monitored for IgG to PA by ELISA and for TNA titers through study day 56 and for safety through month 6. CPG 7909 increased the antibody response by 6-8-fold at peak, and accelerated the response by 3 weeks compared to the response seen in subjects vaccinated with BioThrax alone. No serious adverse events related to study agents were reported, and the combination was considered to be reasonably well tolerated. The marked acceleration and enhancement of the immune response seen by combining BioThrax and CPG 7909 offers the potential to shorten the course of immunization and reduce the time to protection, and may be particularly useful in the setting of post-exposure prophylaxis. © 2011 Elsevier Ltd. Source


Sundar S.,Banaras Hindu University | Sinha P.K.,Rajendra Memorial Research Institute of Medical Sciences | Verma D.K.,Banaras Hindu University | Kumar N.,Rajendra Memorial Research Institute of Medical Sciences | And 9 more authors.
Transactions of the Royal Society of Tropical Medicine and Hygiene | Year: 2011

The combination of one intravenous administration of 5. mg/kg Ambisome and oral administration of miltefosine, 2.5. mg/kg/day for 14 days, was evaluated in 135 Indian patients with kala-azar. The Intent-to-Treat cure rate at 6 months was 124 of the 135 enrolled patients (91.9%: 95% CI = 86-96%), and the per protocol cure rate was 124 of 127 evaluable patients (97.6%: 95% CI = 93-100%). Side effects could be attributed to each drug separately: fevers, rigors and back pain due to Ambisome; gastrointestinal side effects due to miltefosine. This combination is attractive for reasons of efficacy, tolerance, and feasibility of administration, although the gastrointestinal side effects of miltefosine require medical vigilance. Clinical Trials.gov identification number: NCT00371995. © 2010 Royal Society of Tropical Medicine and Hygiene. Source


Berman J.,Fast Track Drugs and Biologics
Expert Opinion on Orphan Drugs | Year: 2015

Introduction: Leishmaniasis, and most tropical diseases, are rare/orphan diseases in the developed world but not rare worldwide. Classic treatment is with parenteral agents, namely, pentavalent antimony and amphotericin B deoxycholate. Miltefosine is the first oral agent for all forms of leishmaniasis. The target regimen is 2.5 mg/kg/day for 28 days, with a maximum dose of 150 mg/day (one 50 mg capsule each with breakfast, lunch and dinner).Areas covered: Clinical studies visceral, cutaneous and mucosal leishmaniasis treated with miltefosine.Expert opinion: The 2014 FDA approval of the miltefosine New Drug Application for visceral, cutaneous and mucosal leishmaniasis was a breakthrough in several ways. In a clinical sense, miltefosine was recognized in the US, after previously being approved in Europe and in the developing world, as the first oral treatment for any form of leishmaniasis. In a regulatory sense, miltefosine was the first drug solely developed for leishmaniasis. In a financial sense, the $125 million sale of miltefosine's Tropical Disease Priority Review Voucher created a financial incentive for all tropical disease products. Clinical issues remaining post-approval include generalizability of efficacy data generated against the specific species evaluated in registration documents to the large number of species worldwide and tolerance issues partially addressed pre-registration. © 2015 Informa UK, Ltd. Source


Ben Salah A.,University of Tunis | Ben Messaoud N.,University of Tunis | Guedri E.,University of Tunis | Zaatour A.,University of Tunis | And 29 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: There is a need for a simple and efficacious treatment for cutaneous leishmaniasis with an acceptable side-effect profile. METHODS: We conducted a randomized, vehicle-controlled phase 3 trial of topical treatments containing 15% paromomycin, with and without 0.5% gentamicin, for cutaneous leishmaniasis caused by Leishmania major in Tunisia. We randomly assigned 375 patients with one to five ulcerative lesions from cutaneous leishmaniasis to receive a cream containing 15% paromomycin-0.5% gentamicin (called WR 279,396), 15% paromomycin alone, or vehicle control (with the same base as the other two creams but containing neither paromomycin nor gentamicin). Each lesion was treated once daily for 20 days. The primary end point was the cure of the index lesion. Cure was defined as at least 50% reduction in the size of the index lesion by 42 days, complete reepithelialization by 98 days, and absence of relapse by the end of the trial (168 days). Any withdrawal from the trial was considered a treatment failure. RESULTS: The rate of cure of the index lesion was 81% (95% confidence interval [CI], 73 to 87) for paromomycin-gentamicin, 82% (95% CI, 74 to 87) for paromomycin alone, and 58% (95% CI, 50 to 67) for vehicle control (P<0.001 for each treatment group vs. the vehicle-control group). Cure of the index lesion was accompanied by cure of all other lesions except in five patients, one in each of the paromomycin groups and three in the vehicle-control group. Mild-to-moderate application-site reactions were more frequent in the paromomycin groups than in the vehicle-control group. CONCLUSIONS: This trial provides evidence of the efficacy of paromomycin-gentamicin and paromomycin alone for ulcerative L. major disease. (Funded by the Department of the Army; ClinicalTrials.gov number, NCT00606580.). Copyright © 2013 Massachusetts Medical Society. Source

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