Pharmacology of DB844, an Orally Active aza Analogue of Pafuramidine, in a Monkey Model of Second Stage Human African Trypanosomiasis

Novel drugs to treat human African trypanosomiasis (HAT) are still urgently needed despite the recent addition of nifurtimox-eflornithine combination therapy (NECT) to WHO Model Lists of Essential Medicines against second stage HAT, where parasites have invaded the central nervous system (CNS). The pharmacology of a potential orally available lead compound, N-methoxy-6-{5-[4-(N-methoxyamidino) phenyl]-furan-2-yl}-nicotinamidine (DB844), was evaluated in a vervet monkey model of second stage HAT, following promising results in mice. DB844 was administered orally to vervet monkeys, beginning 28 days post infection (DPI) with Trypanosoma brucei rhodesiense KETRI 2537. DB844 was absorbed and converted to the active metabolite 6-[5-(4-phenylamidinophenyl)-furanyl-2-y​l]-nicotinamide(DB820), exhibiting plasma Cmax values of 430 and 190 nM for DB844 and DB820, respectively, after the 14th dose at 6 mg/kg qd. A 100-fold reduction in blood trypanosome counts was observed within 24 h of the third dose and, at the end of treatment evaluation performed four days post the last drug dose, trypanosomes were not detected in the blood or cerebrospinal fluid of any monkey. However, some animals relapsed during the 300 days of post treatment monitoring, resulting in a cure rate of 3/8 (37.5%) and 3/7 (42.9%) for the 5 mg/kg×10 days and the 6 mg/kg×14 days dose regimens respectively. These DB844 efficacy data were an improvement compared with pentamidine and pafuramidine both of which were previously shown to be non-curative in this model of CNS stage HAT. These data show that synthesis of novel diamidines with improved activity against CNS-stage HAT was possible.This investigation received financial support from the Bill and Melinda Gates Foundation through the Consortium for Parasitic Drug Development

Finite difference calculations of permeability in large domains in a wide porosity range.

Determining effective hydraulic, thermal, mechanical and electrical properties of porous materials by means of classical physical experiments is often time-consuming and expensive. Thus, accurate numerical calculations of material properties are of increasing interest in geophysical, manufacturing, bio-mechanical and environmental applications, among other fields. Characteristic material properties (e.g. intrinsic permeability, thermal conductivity and elastic moduli) depend on morphological details on the porescale such as shape and size of pores and pore throats or cracks. To obtain reliable predictions of these properties it is necessary to perform numerical analyses of sufficiently large unit cells. Such representative volume elements require optimized numerical simulation techniques. Current state-of-the-art simulation tools to calculate effective permeabilities of porous materials are based on various methods, e.g. lattice Boltzmann, finite volumes or explicit jump Stokes methods. All approaches still have limitations in the maximum size of the simulation domain. In response to these deficits of the well-established methods we propose an efficient and reliable numerical method which allows to calculate intrinsic permeabilities directly from voxel-based data obtained from 3D imaging techniques like X-ray microtomography. We present a modelling framework based on a parallel finite differences solver, allowing the calculation of large domains with relative low computing requirements (i.e. desktop computers). The presented method is validated in a diverse selection of materials, obtaining accurate results for a large range of porosities, wider than the ranges previously reported. Ongoing work includes the estimation of other effective properties of porous media

Structure-In Vitro Activity Relationships of Pentamidine Analogues and Dication-Substituted Bis-Benzimidazoles as New Antifungal Agents

Twenty analogues of pentamidine, 7 primary metabolites of pentamidine, and 30 dicationic substituted bis-benzimidazoles were screened for their inhibitory and fungicidal activities against Candida albicans and Cryptococcus neoformans. A majority of the compounds had MICs at which 80% of the strains were inhibited (MIC80s) comparable to those of amphotericin B and fluconazole. Unlike fluconazole, many of these compounds were found to have potent fungicidal activity. The most potent compound against C. albicans had an MIC80 of ≤0.09 μg/ml, and the most potent compound against C. neoformans had an MIC80 of 0.19 μg/ml. Selected compounds were also found to be active against Aspergillus fumigatus, Fusarium solani, Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. It is clear from the data presented here that further studies on the structure-activity relationships, mechanisms of action and toxicities, and in vivo efficacies of these compounds are warranted to determine their clinical potential

Many Labs 5:Testing pre-data collection peer review as an intervention to increase replicability

Replication studies in psychological science sometimes fail to reproduce prior findings. If these studies use methods that are unfaithful to the original study or ineffective in eliciting the phenomenon of interest, then a failure to replicate may be a failure of the protocol rather than a challenge to the original finding. Formal pre-data-collection peer review by experts may address shortcomings and increase replicability rates. We selected 10 replication studies from the Reproducibility Project: Psychology (RP:P; Open Science Collaboration, 2015) for which the original authors had expressed concerns about the replication designs before data collection; only one of these studies had yielded a statistically significant effect (p < .05). Commenters suggested that lack of adherence to expert review and low-powered tests were the reasons that most of these RP:P studies failed to replicate the original effects. We revised the replication protocols and received formal peer review prior to conducting new replication studies. We administered the RP:P and revised protocols in multiple laboratories (median number of laboratories per original study = 6.5, range = 3?9; median total sample = 1,279.5, range = 276?3,512) for high-powered tests of each original finding with both protocols. Overall, following the preregistered analysis plan, we found that the revised protocols produced effect sizes similar to those of the RP:P protocols (?r = .002 or .014, depending on analytic approach). The median effect size for the revised protocols (r = .05) was similar to that of the RP:P protocols (r = .04) and the original RP:P replications (r = .11), and smaller than that of the original studies (r = .37). Analysis of the cumulative evidence across the original studies and the corresponding three replication attempts provided very precise estimates of the 10 tested effects and indicated that their effect sizes (median r = .07, range = .00?.15) were 78% smaller, on average, than the original effect sizes (median r = .37, range = .19?.50)

Sedimentation Patterns and Hydrodynamics of a Wave-Dominated Tidal Inlet: Blind Pass, Florida

Blind Pass, a heavily structured wave-dominated tidal inlet on the west central coast of Florida, has undergone substantial morphologic changes in the past 150 years. Initially Blind Pass was a mixed-energy inlet. In 1848 a hurricane opened a new inlet to the north called Johns Pass, which captured a large portion of the tidal prism of Blind Pass. Since then Blind Pass migrated southward until it was structurally stabilized in 1937. The decreasing tidal prism resulted in significant inlet channel filling. The channel has been dredged 12 times since 1937. The present inlet is stabilized by two jetties and a series of seawalls. Detailed time-series field measurements of bathymetry and tidal flows were conducted between 2001 and 2004, after the last channel dredging in the summer of 2000. The measured depositional rate in the inlet channel approximately equals the net southward longshore transport rate. This suggests that the inlet has served as a trap for the southward longshore transport allowing negligible bypassing to the eroding downdrift beach. Most of the active sedimentation occurs on the northern side of the inlet. The sediment in the thalweg is largely coarse shell lag, indicating adequate sediment flushing by the ebbing tide. The cross-channel flow measurements revealed that ebb flow was approximately twice as high in the channel thalweg as compared with the rest of the channel. The flood flow was largely uniform across the entire inlet and dominated over the northern portion of the inlet due to the weak ebb flow there. This cross-channel flow pattern is crucial to the understanding of the sedimentation patterns in the Blind Pass channel. Two years after the last dredging the mouth has become shallow enough to induce wave breaking across the shoal area. Distinctive seasonal patterns of sedimentation were measured thereafter in the inlet channel, influenced by seasonal wave climate. The sedimentation is event driven from passage of cold fronts bringing elevated wave energy that accelerates the southward longshore transport. During normal conditions the sediment deposited in the mouth area is redistributed further into the inlet by the flood current combined with wave-driven current

Sedimentation Patterns in a Stabilized Migratory Inlet, Blind Pass, Florida

The shoaling rate in Blind Pass entrance channel approximately equals the net southward longshore sediment transport rate. Most of the shoaling occurs along the northern side of the channel. Flow measurements and numerical modeling reveal that the ebb current is approximately twice as strong in the thalweg along the south side as compared to the rest of the channel. In contrast, the flood current is mainly uniform across the inlet and is stronger than the ebb flow over the northern portion. This flow-velocity distribution induced by a nearly 90-deg bend of the channel contributes to the shoaling pattern. Two years after the 2000 dredging, the shoal along the north side became shallow enough to induce wave breaking. Distinctive shoaling patterns influenced by seasonal wave climate were observed. Sediment deposition in the channel is closely related to the passages of cold fronts, which significantly increases the sediment supply by longshore transport

Safety, pharmacokinetic, and efficacy studies of oral DB868 in a first stage vervet monkey model of human African trypanosomiasis

There are no oral drugs for human African trypanosomiasis (HAT, sleeping sickness). A successful oral drug would have the potential to reduce or eliminate the need for patient hospitalization, thus reducing healthcare costs of HAT. The development of oral medications is a key objective of the Consortium for Parasitic Drug Development (CPDD). In this study, we investigated the safety, pharmacokinetics, and efficacy of a new orally administered CPDD diamidine prodrug, 2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868; CPD-007-10), in the vervet monkey model of first stage HAT. DB868 was well tolerated at a dose up to 30 mg/kg/day for 10 days, a cumulative dose of 300 mg/kg. Mean plasma levels of biomarkers indicative of liver injury (alanine aminotransferase, aspartate aminotransferase) were not significantly altered by drug administration. In addition, no kidney-mediated alterations in creatinine and urea concentrations were detected. Pharmacokinetic analysis of plasma confirmed that DB868 was orally available and was converted to the active compound DB829 in both uninfected and infected monkeys. Treatment of infected monkeys with DB868 began 7 days post-infection. In the infected monkeys, DB829 attained a median Cmax (dosing regimen) that was 12-fold (3 mg/kg/day for 7 days), 15-fold (10 mg/kg/day for 7 days), and 31-fold (20 mg/kg/day for 5 days) greater than the IC50 (14 nmol/L) against T. b. rhodesiense STIB900. DB868 cured all infected monkeys, even at the lowest dose tested. In conclusion, oral DB868 cured monkeys with first stage HAT at a cumulative dose 14-fold lower than the maximum tolerated dose and should be considered a lead preclinical candidate in efforts to develop a safe, short course (5-7 days), oral regimen for first stage HAT

In Vitro Antifungal Activities of a Series of Dication-Substituted Carbazoles, Furans, and Benzimidazoles

Aromatic dicationic compounds possess antimicrobial activity against a wide range of eucaryotic pathogens, and in the present study an examination of the structures-functions of a series of compounds against fungi was performed. Sixty-seven dicationic molecules were screened for their inhibitory and fungicidal activities against Candida albicans and Cryptococcus neoformans. The MICs of a large number of compounds were comparable to those of the standard antifungal drugs amphotericin B and fluconazole. Unlike fluconazole, potent inhibitory compounds in this series were found to have excellent fungicidal activities. The MIC of one of the most potent compounds against C. albicans was 0.39 μg/ml, and it was the most potent compound against C. neoformans (MIC, ≤0.09 μg/ml). Selected compounds were also found to be active against Aspergillus fumigatus, Fusarium solani, Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. Since some of these compounds have been safely given to animals, these classes of molecules have the potential to be developed as antifungal agents

Synthesis and antiprotozoal activity of dicationic m-terphenyl and 1,3-dipyridylbenzene derivatives

4,4″-Diamidino-m-terphenyl (1) and 36 analogues were prepared and assayed in vitro against T rypanosoma brucei rhodesiense , Trypanosoma cruzi , Plasmodium falciparum , and Leishmania amazonensis . Twenty-three compounds were highly active against T. b. rhodesiense or P. falciparum. Most noteworthy were amidines 1, 10, and 11 with IC50 of 4 nM against T. b. rhodesiense, and dimethyltetrahydropyrimidinyl analogues 4 and 9 with IC50 values of ≤ 3 nM against P. falciparum. Bis-pyridylimidamide derivative 31 was 25 times more potent than benznidazole against T. cruzi and slightly more potent than amphotericin B against L. amazonensis. Terphenyldiamidine 1 and dipyridylbenzene analogues 23 and 25 each cured 4/4 mice infected with T. b. rhodesiense STIB900 with four daily 5 mg/kg intraperitoneal doses, as well as with single doses of ≤10 mg/kg. Derivatives 5 and 28 (prodrugs of 1 and 25) each cured 3/4 mice with four daily 25 mg/kg oral doses