Relative Efficacies Research Articles

Real-Time PCR Assay for Detection of Sphacelotheca reiliana Infection in Maize (Zea mays) Seedlings and Evaluation of Seed Treatment Efficacy.

Head smut of maize, caused by the fungus Sphacelotheca reiliana, is an economically important disease in all major maize-producing countries. Although seed treatments are commonly used for management purposes, evaluating these treatments for efficacy is both time consuming and inefficient. Therefore, in order to improve the capacity for evaluating seed treatment fungicides, we developed a real-time PCR-based seedling assay for S. reiliana infection. We optimized growth chamber conditions and inoculation methods to achieve infection incidence of 60 to 80% in inoculated, nontreated controls. The effects of five commercially available fungicidal seed treatment formulations on seedling infection incidence were compared by PCR analysis of root and mesocotyl tissues. Tebuconazole, fludioxonil, sedaxane, and Maxim Quattro (fludioxonil+mefenoxam+azoxystrobin+thiabendazole) reduced the incidence of infection (P < 0.05) compared with the control, but no difference was found between the azoxystrobin treatment and the control. All rates tested for both sedaxane and tebuconazole were equally effective for seeds coated with 106 teliospores∙seed-1. Sedaxane, at a rate of 0.1 mg/kernel, eliminated seedling infection if seeds were infested with a low inoculum concentration (101 teliospores∙seed-1). The assay developed here is a valuable tool not only for the detection of fungal infection at the seedling stage, but also for testing the relative efficacies of seed treatments for reducing incidence of infection.

Effectiveness and Implications of Alternative Placebo Treatments: A Systematic Review and Network Meta-analysis of Osteoarthritis Trials.

Placebo controls are essential in evaluating the effectiveness of medical treatments. Although it is unclear whether different placebo interventions for osteoarthritis vary in efficacy, systematic differences would substantially affect interpretation of the results of placebo-controlled trials. To evaluate the effects of alternative placebo types on pain outcomes in knee osteoarthritis. MEDLINE, EMBASE, Web of Science, Google Scholar, and Cochrane Database from inception through 1 June 2015 and unpublished data. 149 randomized trials of adults with knee osteoarthritis that reported pain outcomes and compared widely used pharmaceuticals against oral, intra-articular, topical, and oral plus topical placebos. Study data were independently double-extracted; study quality was assessed by using the Cochrane risk of bias tool. Placebo effects that were evaluated by using a network meta-analysis with 4 separate placebo nodes (differential model) showed that intra-articular placebo (effect size, 0.29 [95% credible interval, 0.09 to 0.49]) and topical placebo (effect size, 0.20 [credible interval, 0.02 to 0.38]) had significantly greater effect sizes than did oral placebo. This differential model showed marked differences in the relative efficacies and hierarchy of the active treatments compared with a network model that considered all placebos equivalent. In the model accounting for differential effects, intra-articular and topical therapies were superior to oral treatments in reducing pain. When these differential effects were ignored, oral nonsteroidal anti-inflammatory drugs were superior. Few studies compared different placebos directly. The study could not decisively conclude whether disease severity and co-interventions systematically differed between trials evaluating different placebos. All placebos are not equal, and some can trigger clinically relevant responses. Differential placebo effects can substantially alter estimates of the relative efficacies of active treatments, an important consideration for the design of clinical trials and interpretation of their results. Agency for Healthcare Research and Quality.

Meglumine antimoniate is more effective than sodium stibogluconate in the treatment of cutaneous leishmaniasis

Sodium stibogluconate (SSG, Pentostam) and meglumine antimoniate (MA, Glucantime) are two antimonials that are widely used to treat cutaneous leishmaniasis (CL), but the relative efficacies of these treatments are not clear. The aim of this study is to compare the efficacy of intralesional SSG with intralesional MA therapy in the treatment of CL. One month after completion of the therapy, 1431 of 1728 patients (82%) who received intralesional MA showed complete clinical cure compared to 1157 of 1728 patients (67%) in the SSG group. Patients who did not respond to the first round of therapy were re-administered the same treatment but with twice weekly injections. Following completion of the second course of therapy, 237 of 297 patients (80%) in the MA group and 407 of 561 patients (72%) in the SSG group healed their lesions by 1-month post-treatment. At both times, the differences in cure rates between MA and SSG groups were statistically significant (p < 0.05). Cure rates in the MA group were always significantly higher than SSG groups irrespective of other parameters including age, gender, lesion site and type of lesion. Intralesional MA is more effective than intralesional SSG in the treatment of CL.

Controlling honeybee pathogen by using neem and Barbaka plant extracts

The honeybees (Apis mellifera) population is declining. The involved causes may be pathogens (mites, viruses and bacteria) and parasites, due to honeybee's compromised immune system, leading to various bee-associated infections. Therefore, the present study assessed the comparative efficacy of plant extracts, including neem (Azadirachta indica) and Barbaka (Vitex trifolia) against gut bacteria and ectoparasitic mite Varroa destructor of honeybee A. mellifera (Hymenoptera: Apidae). The in vitro activities of the plant extracts were determined by using standard methods against five bee gut bacterial isolates, including the well-known bee pathogenic bacteria Paenibacillus larvae. Miticides were also assessed in field against honeybee mites. The obtained results from the phytochemical screening of Barbaka and neem extracts efficiency showed inhibitory zones with diameters of 23 mm with 60 mg/mL against P. larvae and 14 mm with 60 mg/mL against Escherichia coli, respectively. None of the extracts proved to be effective against Salmonella enterica and the neem extract showed intermediate activity against Bacillus subtilis and Staphylococcus hominis. Likewise, Barbaka plant extracts were not effective against B. subtilis. Similarly, the relative treatment efficacies of neem and Barbaka extracts, together with conventional miticides against honeybee Varroa mites, varied significantly. However, the effect of Barbaka and neem extracts on the mite-infested colonies was lower than the effect of other treatments, but it was also higher than in the control colonies. This study concluded that Barbaka and neem extracts have antibacterial and miticidal activity and are reasonably safe. However, more trials have to be conducted, in order to validate these results.

Effect of Concession‐Timing Strategies in Auditor–Client Negotiations: It Matters Who Is Using Them

AbstractIn this study, we examine how norms about the use of negotiation strategies by different parties in an auditor–client negotiation influence the relative efficacies of these negotiation strategies. We conduct an experiment with experienced auditors/financial managers as participants, who enter into a negotiation on an income‐decreasing audit adjustment with a hypothetical client/auditor who uses a strategy where the same concessions are given either at the start, gradually, or the end of the negotiation. We find that the concession‐end strategy is more effective than the concession‐start strategy when used by auditors; however, the reverse is true when these same strategies are used by financial managers. The concession‐gradual strategy leads to superior outcomes when used by either auditors or clients. We also provide evidence that auditors’ and financial managers’ perceptions of the norms relating to the use of these strategies correspond to what we propose in our theory.

RX-P873, a Novel Protein Synthesis Inhibitor, Accumulates in Human THP-1 Monocytes and Is Active against Intracellular Infections by Gram-Positive (Staphylococcus aureus) and Gram-Negative (Pseudomonas aeruginosa) Bacteria.

The pyrrolocytosine RX-P873, a new broad-spectrum antibiotic in preclinical development, inhibits protein synthesis at the translation step. The aims of this work were to study RX-P873's ability to accumulate in eukaryotic cells, together with its activity against extracellular and intracellular forms of infection by Staphylococcus aureus and Pseudomonas aeruginosa, using a pharmacodynamic approach allowing the determination of maximal relative efficacies (Emax values) and bacteriostatic concentrations (Cs values) on the basis of Hill equations of the concentration-response curves. RX-P873's apparent concentration in human THP-1 monocytes was about 6-fold higher than the extracellular one. In broth, MICs ranged from 0.125 to 0.5 mg/liter (S. aureus) and 2 to 8 mg/liter (P. aeruginosa), with no significant shift in these values against strains resistant to currently used antibiotics being noted. In concentration-dependent experiments, the pharmacodynamic profile of RX-P873 was not influenced by the resistance phenotype of the strains. Emax values (expressed as the decrease in the number of CFU from that in the initial inoculum) against S. aureus and P. aeruginosa reached more than 4 log units and 5 log units in broth, respectively, and 0.7 log unit and 2.7 log units in infected THP-1 cells, respectively, after 24 h. Cs values remained close to the MIC in all cases, making RX-P873 more potent than antibiotics to which the strains were resistant (moxifloxacin, vancomycin, and daptomycin for S. aureus; ciprofloxacin and ceftazidime for P. aeruginosa). Kill curves in broth showed that RX-P873 was more rapidly bactericidal against P. aeruginosa than against S. aureus. Taken together, these data suggest that RX-P873 may constitute a useful alternative for infections involving intracellular bacteria, especially Gram-negative species.

Cost-effectiveness of ranibizumab versus aflibercept in the treatment of visual impairment due to diabetic macular edema: a UK healthcare perspective.

BackgroundRanibizumab and aflibercept are alternative anti-vascular endothelial growth factor agents approved for the treatment of visual impairment (VI) due to diabetic macular edema (DME).ObjectiveTo estimate, from a UK healthcare perspective, the cost-effectiveness of ranibizumab 0.5 mg pro re nata (PRN) and ranibizumab 0.5 mg treat and extend (T&E) compared with aflibercept 2 mg every 8 weeks after five initial monthly doses (2q8) in the treatment of VI due to DME.MethodsA Markov model previously reviewed by the National Institute for Health and Care Excellence was used to simulate the long-term outcomes and costs of treating DME. Health states were defined by increments of ten letters in best-corrected visual acuity (BCVA), with a 3-month cycle length. Patients could gain (or lose) a maximum of two health states between cycles. A 3-year treatment time frame and a lifetime horizon were used. Future costs and health outcomes were discounted at 3.5% per annum. Patient baseline characteristics and the efficacy of ranibizumab PRN were derived using data from the RESTORE study. The relative efficacies of ranibizumab PRN, ranibizumab T&E, and aflibercept were assessed with a network meta-analysis. Different utilities were assigned based on BCVA and whether the treated eye was the better- or the worse-seeing eye. Sensitivity analyses tested the robustness of the model.ResultsLifetime costs per patient of treating DME were £20,019 for ranibizumab PRN, £22,930 for ranibizumab T&E, and £25,859 for aflibercept 2q8. Ranibizumab was dominant over aflibercept, with an incremental gain of 0.05 quality-adjusted life-years (QALYs) and cost savings of £5,841 (PRN) and £2,930 (T&E) compared with aflibercept. Ranibizumab PRN and ranibizumab T&E had 79% and 67% probability, respectively, of being cost-effective relative to aflibercept at a willingness-to-pay threshold of £20,000/QALY. When assuming the higher end of PRN injection frequency (15.9 over 3 years), the cost savings associated with ranibizumab were £3,969.ConclusionFrom a UK healthcare perspective, ranibizumab provides greater health gains with lower overall costs than aflibercept in patients with VI due to DME.

Relative unisensory strength and timing predict their multisensory product.

Understanding the principles by which the brain combines information from different senses provides us with insight into the computational strategies used to maximize their utility. Prior studies of the superior colliculus (SC) neuron as a model suggest that the relative timing with which sensory cues appear is an important factor in this context. Cross-modal cues that are near-simultaneous are likely to be derived from the same event, and the neural inputs they generate are integrated more strongly than those from cues that are temporally displaced from one another. However, the present results from studies of cat SC neurons show that this "temporal principle" of multisensory integration is more nuanced than previously thought and reveal that the integration of temporally displaced sensory responses is also highly dependent on the relative efficacies with which they drive their common target neuron. Larger multisensory responses were achieved when stronger responses were advanced in time relative to weaker responses. This new temporal principle of integration suggests an inhibitory mechanism that better accounts for the sensitivity of the multisensory product to differences in the timing of cross-modal cues than do earlier mechanistic hypotheses based on response onset alignment or response overlap.

SMT19969 for Clostridium difficile infection (CDI): in vivo efficacy compared with fidaxomicin and vancomycin in the hamster model of CDI.

ObjectivesSMT19969 is a novel narrow-spectrum antimicrobial under development for the treatment of Clostridium difficile infection (CDI). The objectives were to assess the relative efficacies of SMT19969, vancomycin and fidaxomicin in the hamster model of CDI.MethodsHamsters were infected with either C. difficile BI1 (ribotype 027) or C. difficile 630 (ribotype 012) prior to treatment with vehicle, SMT19969, fidaxomicin or vancomycin for 5 days. Animals were further monitored through to day 28 and survival recorded. Plasma and gastrointestinal concentrations of SMT19969 following single and repeat administration in infected hamsters were determined.ResultsFollowing infection with C. difficile BI1, treatment with SMT19969, vancomycin and fidaxomicin resulted in 100% survival during the 5 day dosing period, with 90%–100% of animals receiving SMT19969 and fidaxomicin surviving during the post-dosing follow-up period. Whilst protective during treatment, onset of mortality was observed on day 11 in animals treated with vancomycin, with a 10% survival recorded by day 28. Similar results were observed for SMT19969 and vancomycin following infection with C. difficile 630, with day 28 survival rates of 80%–100% and 0%, respectively. Fidaxomicin protected animals infected with C. difficile 630 from mortality during dosing, although day 28 survival rates varied from 0% to 40% depending on dose. Plasma levels of SMT19969 were typically below the limit of quantification, but levels in the gastrointestinal tract remained far in excess of the MIC.ConclusionsThese data show that SMT19969 is highly effective at treating both acute infection and preventing recurrent disease and support continued investigation of SMT19969 as a potential therapy for CDI.

Intercropping influenced the occurrence of stripe rust and powdery mildew in wheat

The intercropping of three susceptible winter wheat varieties, Lantian 13, Lantian 6, and Tian 94-3, with potato, chili, maize, sunflower, benne or soybean was tested for efficacy in controlling stripe rust and powdery mildew and increasing yields in the field under different ecological conditions in Tianshui, Gansu Province, China, from 2007 to 2009. The relative control efficacies of the intercropping between wheat and maize were 16.7%–45.7% for stripe rust and 14.7%–37.0% for powdery mildew compared to the pure stands of wheat. The yield increased by 52.4%–140.0%. The relative control efficacies of intercropping between wheat and sunflower were 5.9%–28.9% for stripe rust and 11.7%–18.4% for powdery mildew. The yield increased by −1.4%–24.8%. The differences were statistically significant for control efficacy. Therefore, intercropping systems could be used extensively in South Gansu, where machinery is seldom used due to the mountainous landscape, to reduce damage caused by the two major diseases. The intercropping system of wheat with potato or chili did not result in significant differences in disease reduction compared to the pure wheat stands. However, the two crop combinations increased the yield by 150.0% or more. Other intercropping combinations did not result in a significant disease reduction or yield increase.

PET Imaging of Epigenetic Influences on Alzheimer's Disease.

The precise role of environment-gene interactions (epigenetics) in the development and progression of Alzheimer's disease (AD) is unclear. This review focuses on the premise that radiotracer-specific PET imaging allows clinicians to visualize epigenetically influenced events and that such imaging may provide new, valuable insights for preventing, diagnosing, and treating AD. Current understanding of the role of epigenetics in AD and the principles underlying the use of PET radiotracers for in vivo diagnosis are reviewed. The relative efficacies of various PET radiotracers for visualizing the epigenetic influences on AD and their use for diagnosis are discussed. For example, [18F]FAHA demonstrates sites of differential HDAC activity, [18F]FDG indirectly illuminates sites of neuronal hypomethylation, and the carbon-11 isotope-containing Pittsburgh compound B ([11C]PiB) images amyloid-beta plaque deposits. A definitive AD diagnosis is currently achievable only by postmortem histological observation of amyloid-beta plaques and tau neurofibrillary tangles. Therefore, reliable in vivo neuroimaging techniques could provide opportunities for early diagnosis and treatment of AD.

Optimizing therapy for vancomycin-resistant enterococcal bacteremia in children.

Uncertainties exist regarding the optimal treatment for vancomycin-resistant enterococcal (VRE) bloodstream infections, particularly in settings in which ampicillin cannot be used. Quinupristin-dalfopristin, linezolid, and daptomycin, all approved between 1999 and 2003, represent the mainstays of therapy for VRE bacteremia, although only linezolid has been specifically approved by the United States Food and Drug Administration for this indication. The main objective of this review is to compare the relative efficacies, dosing strategies, and side-effect profiles of quinupristin-dalfopristin, linezolid, and daptomycin for VRE bacteremia in the pediatric population. A brief description of recently approved broad-spectrum Gram-positive agents that may have a role in the management of VRE bacteremia in upcoming years is also provided. Linezolid, despite its bacteriostatic activity against VRE, may be the most versatile of the available drugs. It has activity against both Enterococcus faecalis and E. faecium, can be administered orally, and resistance appears to be less of a concern with linezolid compared with the other agents. Additionally, the results of two recent meta-analyses demonstrate more favorable outcomes with linezolid compared with daptomycin for the treatment of VRE bacteremia. The clinical pharmacokinetics of linezolid have been well described in children. The most notable concern with linezolid, however, is toxicities associated with prolonged use. Until more prospective data are available, we favor linezolid as first-line therapy for the treatment of VRE bacteremia in children.

Treating prolonged grief disorder: a randomized clinical trial.

Prolonged grief disorder (PGD) is a potentially disabling condition that affects approximately 10% of bereaved people. Grief-focused cognitive behavior therapy (CBT) has been shown to be effective in treating PGD. Although treatments for PGD have focused on exposure therapy, much debate remains about whether exposure therapy is optimal for PGD. To determine the relative efficacies of CBT with exposure therapy (CBT/exposure) or CBT alone for PGD. A randomized clinical trial of 80 patients with PGD attending the outpatient University of New South Wales Traumatic Stress Clinic from September 17, 2007, through June 7, 2010. All patients received 10 weekly 2-hour group therapy sessions that consisted of CBT techniques. Patients also received 4 individual sessions, in which they were randomized to receive exposure therapy for memories of the death or supportive counseling. Measures of PGD by clinical interview and self-reported measures of depression, cognitive appraisals, and functioning at the 6-month follow-up. Intention-to-treat analyses at follow-up indicated a significant quadratic time×treatment condition interaction effect (B [SE], 0.49 [0.16]; t120.16=3.08 [95% CI, 0.18-0.81]; P=.003), indicating that CBT/exposure led to greater PGD reductions than CBT alone. At follow-up, CBT/exposure led to greater reductions in depression (B [SE], 0.35 [0.12]; t112.65=2.83 [95% CI, 0.11-0.60]; P=.005), negative appraisals (B [SE], 0.68 [0.25]; t109.98=2.66 [95% CI, 0.17-1.18]; P=.009), and functional impairment (B [SE], 0.24 [0.08]; t111.40=3.01 [95% CI, 0.08-0.40]; P=.003) than CBT alone. In terms of treatment completers, fewer patients in the CBT/exposure condition at follow-up (14.8%) met criteria for PGD than those in the CBT condition (37.9%) (odds ratio, 3.51; 95% CI, 0.96-12.89; χ2=3.81; P=.04). Including exposure therapy that promotes emotional processing of memories of the death is an important component to achieve optimal reductions in PGD severity. Facilitating emotional responses to the death may promote greater changes in appraisals about the loss, which are associated with symptom reduction. Promotion of emotional processing techniques in therapies to treat patients with PGD is needed. anzctr.org.au Identifier: ACTRN12609000229279.

Knowledge, attitudes and beliefs of patients and carers regarding medication adherence: a review of qualitative literature.

The aim of this review is to cohere evidence on the knowledge, attitudes and beliefs of patients and carers regarding medication adherence. Medication adherence refers to "the extent to which the patient's action matches the agreed recommendations". Medication adherence is vital in preventing, managing and curing illnesses and, hence, is linked with positive health outcomes. A search was conducted using the following databases: CINAHL, Embase, PubMed and Web of Knowledge from inception to November 2013. Titles and abstracts were screened for inclusion in the review according to pre-defined inclusion and exclusion criteria. Studies were assessed for quality, and data were extracted into a data extraction form. Results were analysed thematically. The final results included 34 articles. Eight analytical themes were identified: (i) beliefs and experiences of medicines, (ii) family support and culture, (iii) role of and relationship with health-care practitioners, (iv) factors related to the disease, (v) self-regulation, (vi) communication, (vii) cost and (viii) access. The theme, "beliefs and experiences of medicines", was present in 33 studies, with many discussing the influence that side effects have on medication adherence. There are a number of variables that impact upon the knowledge, attitudes and beliefs of patients and carers regarding medication adherence. This review presents an overview of the analytical themes which offers the opportunity to examine interventions and their relative efficacies to increase medication adherence.

Enhancing the functional content of eukaryotic protein interaction networks.

Protein interaction networks are a promising type of data for studying complex biological systems. However, despite the rich information embedded in these networks, these networks face important data quality challenges of noise and incompleteness that adversely affect the results obtained from their analysis. Here, we apply a robust measure of local network structure called common neighborhood similarity (CNS) to address these challenges. Although several CNS measures have been proposed in the literature, an understanding of their relative efficacies for the analysis of interaction networks has been lacking. We follow the framework of graph transformation to convert the given interaction network into a transformed network corresponding to a variety of CNS measures evaluated. The effectiveness of each measure is then estimated by comparing the quality of protein function predictions obtained from its corresponding transformed network with those from the original network. Using a large set of human and fly protein interactions, and a set of over GO terms for both, we find that several of the transformed networks produce more accurate predictions than those obtained from the original network. In particular, the measure and other continuous CNS measures perform well this task, especially for large networks. Further investigation reveals that the two major factors contributing to this improvement are the abilities of CNS measures to prune out noisy edges and enhance functional coherence in the transformed networks.

Determining Drug Efficacy Using Plasmonically Enhanced Imaging of the Morphological Changes of Cells upon Death.

Recently, we utilized the optical properties of gold nanoparticles (AuNPs) for plasmonically enhanced Rayleigh scattering imaging spectroscopy (PERSIS), a new technique that enabled the direct observation of AuNP localization. In this study, we employ PERSIS by using AuNPs as light-scattering probes to compare the relative efficacy of three chemotherapeutic drugs on human oral squamous carcinoma cells. Although the drugs induced apoptotic cell death through differing mechanisms, morphological changes including cell membrane blebbing and shrinkage, accompanied by an increase in white light scattering, were visually evident. By utilizing the AuNPs to increase the cells’ inherent Rayleigh scattering, we have obtained the time profile of cell death from the anticancer drugs using a single sample of cells in real time, using inexpensive equipment available in any lab. From this time profile, we calculated cell death enhancement factors to compare the relative efficacies of the different drugs using our technique, which corresponded to those calculated from the commonly used XTT cell viability assay. Although this technique does not impart molecular insights into cell death, the ability to quantitatively correlate cell death to morphological changes suggests the potential use of this technique for the rapid screening of drug analogues to determine the most effective structure against a disease or cell line.

Irrigation solutions in head and neck cancer surgery: a preclinical efficacy study.

It is common practice to irrigate the operative site following tumor resection during major head and neck surgery. A variety of irrigation solutions are used, but there are few data on their relative efficacies in this context. The effect of different irrigation solutions on cell survival was assessed by clonogenic survival assay in 5 head and neck squamous cell carcinoma cell lines at different time points. Saline had no effect on cell survival in any of the cell lines tested. Hydrogen peroxide, povidone-iodine, and a hydrogen peroxide/povidone-iodine mix caused complete cell death in all cell lines. Irrigation with distilled water caused a significant reduction in cell survival in 3 cell lines. Duration of exposure showed no effect on cell survival. These data suggest a significant difference in the cytocidal effect of commonly used irrigation solutions on head and neck cancer cells in an in vitro model.

Correlates of customer loyalty to financial institutions: a case study

Purpose – The purpose of this study is to investigate the relative efficacies of intrinsic and extrinsic cues as drivers of customer loyalty to financial institutions between male and female bank customers. Design/methodology/approach – A large-scale survey of 872 customers of a national bank serves as the study setting. Findings – Results showed that extrinsic cues were the more effective correlates of customer loyalty and that gender does not moderate the relationships between image cues and customer loyalty. Research limitations/implications – The cross-sectional nature of the current study does not allow causal inferences. Therefore, future studies should adopt longitudinal designs. Practical implications – Results suggest that, although transmitting a favorable image through extrinsic cues is critical, nevertheless, intrinsic cues (interactions among customers and bank personnel) should not be ignored. To reinforce this not only among current customers but also among potential customers, banks should use advertisements featuring favorable testimonials. Originality/value – Empirical research in the banking services literature pertaining to the efficacies of intrinsic and extrinsic cues in forming customer loyalty is scarce. This study fills in the void. Also, in determining if the relationships between image and customer loyalty vary by gender, the authors not only looked at male versus female differences on the basis of average construct scores but also examined the structural relationships among the constructs.

Pharmacokinetic comparison to determine the mechanisms underlying the differential efficacies of cationic diamidines against first- and second-stage human African trypanosomiasis.

Human African trypanosomiasis (HAT), a neglected tropical disease, is fatal without treatment. Pentamidine, a cationic diamidine, has been used to treat first-stage (hemolymphatic) HAT since the 1940s, but it is ineffective against second-stage (meningoencephalitic, or central nervous system [CNS]) infection. Novel diamidines (DB75, DB820, and DB829) have shown promising efficacy in both mouse and monkey models of first-stage HAT. However, only DB829 cured animals with second-stage infection. In this study, we aimed to determine the mechanisms underlying the differential efficacies of these diamidines against HAT by conducting a comprehensive pharmacokinetic characterization. This included the determination of metabolic stability in liver microsomes, permeability across MDCK and MDR1-MDCK cell monolayers, interaction with the efflux transporter MDR1 (P-glycoprotein 1 or P-gp), drug binding in plasma and brain, and plasma and brain concentration-time profiles after a single dose in mice. The results showed that DB829, an azadiamidine, had the highest systemic exposure and brain-to-plasma ratio, whereas pentamidine and DB75 had the lowest. None of these diamidines was a P-gp substrate, and the binding of each to plasma proteins and brain differed greatly. The brain-to-plasma ratio best predicted the relative efficacies of these diamidines in mice with second-stage infection. In conclusion, pharmacokinetics and CNS penetration influenced the in vivo efficacies of cationic diamidines against first- and second-stage HAT and should be considered when developing CNS-active antitrypanosomal diamidines.

Relative potency of macrocyclic lactones in in vitro assays with larvae of susceptible and drug-resistant Australian isolates of Haemonchus contortus and H. placei

The present study used in vitro assays to determine the relative potency of commercial macrocyclic lactone (ML) anthelmintics against larvae of drug-susceptible and drug-resistant Australian isolates of important parasites of sheep and cattle, Haemonchus contortus and Haemonchus placei, respectively. Cattle pour-on products containing abamectin, ivermectin, eprinomectin, doramectin or moxidectin were diluted in DMSO and used in larval development assays. Abamectin was the most potent chemical (lowest IC50 value) towards the drug-susceptible H. contortus Kirby isolate. The abamectin IC50 was approximately 2-fold lower than those for ivermectin, moxidectin, eprinomectin and doramectin. Moxidectin and abamectin were the most potent chemicals towards the resistant H. contortus Wallangra isolate. This isolate showed resistance ratios up to 70-fold towards eprinomectin. The resistance ratio for this species was lowest with moxidectin (ratio of 4.0-fold). Abamectin was also the most potent chemical towards both drug-susceptible (Bremner) and drug-resistant (Dayboro) H. placei isolates. The larval development assay only showed low levels of resistance for the drug-resistant H. placei, with resistance ratios ranging from 1.7 to 2.0 fold for moxidectin and abamectin, up to 3.3-fold for eprinomectin. This study examined the readily-accessible larval life stages of these parasites in in vitro assays, and, hence, the relationship between our findings and relative drug efficacies in vivo remains to be determined. Despite this, the study accords with some evidence from the use of these anthelmintics in the field in demonstrating the potency of moxidectin and abamectin against ML-resistant H. contortus. The study also highlights the usefulness of eprinomectin as a readily-available compound which is a more sensitive marker for ML resistance in in vitro larval development assays than the other commercial ML compounds examined.