An open label,block randomized,community study of the safety and efficacy of co-administered ivermectin,diethylcarbamazine plus albendazole vs. diethylcarbamazine plus albendazole for lymphatic filariasis in India

BackgroundBetter drug regimens for mass drug administration (MDA) could accelerate the Global Programme to Eliminate Lymphatic Filariasis (LF). This community study was designed to compare the safety and efficacy of MDA with IDA (ivermectin, diethylcarbamazine and albendazole) or DA (diethylcarbamazine and albendazole) in India.Methodology/Principal findingsThis two-armed, open-labelled, block randomised, community study was conducted in LF endemic villages in Yadgir district, Karnataka, India. Consenting participants ≥5 years of age were tested for circulating filarial antigenemia (CFA) and microfilaremia (Mf) before treatment with a single oral dose of IDA or DA. Adverse events (AEs) were monitored actively for two days and passively for five more days. Persons with positive CFA or Mf tests at baseline were retested 12-months post-treatment to assess treatment efficacy.Baseline CFA and Mf-rates were 26.4% and 6.9% in IDA and 24.5% and 6.4% in DA villages respectively. 4758 and 4160 participants received IDA and DA. Most AEs were mild after both treatments; fewer than 0.1% of participants experienced AEs with severity > grade 1. No serious AEs were observed. Fever, headache and dizziness were the most common AEs. AE rates were slightly higher after IDA than DA (8.3% vs. 6.4%, P<0.01). AEs were more frequent in females and Mf-positives after either treatment, but significantly more frequent after IDA (40.5% vs 20.2%, P < 0.001).IDA was more effective for clearing Mf than DA (84% vs. 61.8%, P < 0.001). Geometric mean Mf counts per 60μl in retested Mf-positives decreased by 96.4% from 11.8 after IDA and by 90.0% from 9.5 after DA. Neither treatment was effective for clearing CFA.Conclusions/SignificanceIDA had an acceptable safety profile and was more effective for clearing Mf than DA. With adequate compliance and medical support to manage AEs, IDA has the potential to accelerate LF elimination in India.Trial registrationClinical Trial Registry of India (CTRI No/2016/10/007399)     

Controlling Schistosomiasis: Significant Decrease of Anaemia Prevalence One Year after a Single Dose of Praziquantel in Nigerien Schoolchildren

Background

In the framework of the monitoring and evaluation of the Nigerien schistosomiasis and soil-transmitted helminth control programme, a follow-up of children took place in eight sentinel sites. The objective of the study was to assess the evolution of Schistosoma haematobium infection and anaemia in schoolchildren after a single administration of praziquantel (PZQ) and albendazole.

Methods/Principal Findings

Pre-treatment examination and follow-up at one year post-treatment of schoolchildren aged 7, 8, and 11 years, including interview, urine examination, ultrasound examination of the urinary tract, and measurement of haemoglobin. Before treatment, the overall prevalence of S. heamatobium infection was 75.4% of the 1,642 enrolled children, and 21.8% of children excreted more than 50 eggs/10 ml urine. Prevalence increased with age. The overall prevalence of anaemia (haemoglobin <11.5 g/dl) was 61.6%, decreasing significantly with increasing age. The mean haemoglobinemia was 11 g/dl. In bivariate analysis, anaemia was significantly more frequent in children infected with S. haematobium, although it was not correlated to the intensity of infection. Anaemia was also associated with micro-haematuria and to kidney distensions. In a sub-sample of 636 children tested for P. falciparum infection, anaemia was significantly more frequent in malaria-infected children. In multivariate analysis, significant predictors of anaemia were P. falciparum infection, kidney distension, and the village. One year after a single-dose praziquantel treatment (administered using the WHO PZQ dose pole) co-administered with albendazole (400 mg single dose) for de-worming, the prevalence of S. haematobium infection was 38%, while the prevalence of anaemia fell to 50.4%. The mean haemoglobinemia showed a statistically significant increase of 0.39 g/dl to reach 11.4 g/dl. Anaemia was no longer associated with S. haematobium or to P. falciparum infections, or to haematuria or ultrasound abnormalities of the urinary tract.

Conclusions

The high prevalence of anaemia in Nigerien children is clearly a result of many factors and not of schistosomiasis alone. Nevertheless, treatment of schistosomiasis and de-worming were followed by a partial, but significant, reduction of anaemia in schoolchildren, not explainable by any other obvious intervention.     

An open label,randomized clinical trial to compare the tolerability and efficacy of ivermectin plus diethylcarbamazine and albendazole vs. diethylcarbamazine plus albendazole for treatment of brugian filariasis in Indonesia

Improved treatments for lymphatic filariasis (LF) could accelerate the global elimination program for this disease. A triple drug combination of the anti-filarial drugs ivermectin, diethylcarbamazine (DEC) and albendazole (IDA) has been shown to be safe and effective for achieving sustained clearance of microfilariae (Mf) of the filarial parasite Wuchereria bancrofti from human blood. However, the triple drug combination has not been previously been evaluated for treatment of brugian filariasis, which accounts for about 10% of the global LF burden. This hospital-based clinical trial compared the safety and efficacy of IDA with that of the standard treatment (DEC plus albendazole, DA) in persons with Brugia timori infections on Sumba island, Indonesia. Fifty-five asymptomatic persons with B. timori Mf were treated with either a single oral dose of IDA (28 subjects) or with DEC plus albendazole (DA, 27 subjects). Participants were actively monitored for adverse events (AE) for two days after treatment by nurses and physicians who were masked regarding treatment assignments. Passive monitoring was performed by clinical teams that visited participant’s home villages for an additional five days. Microfilaremia was assessed by membrane filtration of 1 ml night blood at baseline, at 24h and one year after treatment. IDA was more effective than DA for completely clearing Mf at 24 hours (25/28, 89% vs. 8/27, 30%, P < 0.001). By 12 months after treatment, only one of 27 IDA recipients had Mf in their blood (4%) vs. 10 of 25 (40%) in persons treated with DA (P = 0.002). Approximately 90% of participants had antibodies to recombinant filarial antigen BmR1 at baseline. Antibody prevalence decreased to approximately 30% in both treatment groups at 12 months. About 45% of persons in both treatment groups experienced AE such as fever, muscle aches, lower back, joint and abdominal pain. These were mostly mild and most common during the first two days after treatment. No participant experienced a severe or serious AE. This study showed that IDA was well-tolerated and significantly more effective for clearing B. timori Mf from the blood than DA. Larger studies should be performed to further assess the safety and efficacy of IDA as a mass drug administration regimen to eliminate brugian filariasis.Trial Registration: {"type":"clinical-trial","attrs":{"text":"NCT02899936","term_id":"NCT02899936"}}NCT02899936.     

Control of lymphatic filariasis by annual single-dose diethylcarbamazine treatments

It has long been stressed that diethylcarbamazine citrate must be given at a total dosage of 72 mg per kilogram of body weight in 12 divided doses of 6 mg kg(-1) to obtain maximum effect against Wuchereria bancrofti. However, recent studies revealed that only a single dose at 6 mg kg(-1) could reduce microfilaria (Mf) counts by 90%, and that the effect would persist for 12-18 months. The annual repeat of the single-dose mass treatment was shown to be effective in reducing Mf prevalence and density in large-scale, long-term field trials. The scheme is simple and economic, and could be sustainable in many endemic areas, where health manpower and resources are often not sufficient. Annual single-dose mass treatments can be an effective weapon against human lymphatic filariasis, as discussed here by Eisaku Kimura and Jona Mataika.     

Safety and efficacy of mass drug administration with a single-dose triple-drug regimen of albendazole + diethylcarbamazine + ivermectin for lymphatic filariasis in Papua New Guinea: An open-label,cluster-randomised trial

BackgroundPapua New Guinea (PNG) has a high burden of lymphatic filariasis (LF) caused by Wuchereria bancrofti, with an estimated 4.2 million people at risk of infection. A single co-administered dose of ivermectin, diethylcarbamazine and albendazole (IDA) has been shown to have superior efficacy in sustained clearance of microfilariae compared to diethylcarbamazine and albendazole (DA) in small clinical trials. A community-based cluster-randomised trial of DA versus IDA was conducted to compare the safety and efficacy of IDA and DA for LF in a moderately endemic, treatment-naive area in PNG.MethodologyAll consenting, eligible residents of 24 villages in Bogia district, Madang Province, PNG were enrolled, screened for W. bancrofti antigenemia and microfilaria (Mf) and randomised to receive IDA (N = 2382) or DA (N = 2181) according to their village of residence. Adverse events (AE) were assessed by active follow-up for 2 days and passive follow-up for an additional 5 days. Antigen-positive participants were re-tested one year after MDA to assess treatment efficacy.Principal findingsOf the 4,563 participants enrolled, 96% were assessed for AEs within 2 days after treatment. The overall frequency of AEs were similar after either DA (18%) or IDA (20%) treatment. For those individuals with AEs, 87% were mild (Grade 1), 13% were moderate (Grade 2) and there were no Grade 3, Grade 4, or serious AEs (SAEs). The frequency of AEs was greater in Mf-positive than Mf-negative individuals receiving IDA (39% vs 20% p<0.001) and in Mf-positive participants treated with IDA (39%), compared to those treated with DA (24%, p = 0.023). One year after treatment, 64% (645/1013) of participants who were antigen-positive at baseline were re-screened and 74% of these participants (475/645) remained antigen positive. Clearance of Mf was achieved in 96% (52/54) of infected individuals in the IDA arm versus 84% (56/67) of infected individuals in the DA arm (relative risk (RR) 1.15; 95% CI, 1.02 to 1.30; p = 0.019). Participants receiving DA treatment had a 4-fold higher likelihood of failing to clear Mf (RR 4.67 (95% CI: 1.05 to 20.67; p = 0.043). In the DA arm, a significant predictor of failure to clear was baseline Mf density (RR 1.54; 95% CI, 1.09 to 2.88; p = 0.007).ConclusionIDA was well tolerated and more effective than DA for clearing Mf. Widespread use of this regimen could accelerate LF elimination in PNG.Trial registrationRegistration number {"type":"clinical-trial","attrs":{"text":"NCT02899936","term_id":"NCT02899936"}}NCT02899936; https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT02899936","term_id":"NCT02899936"}}NCT02899936.     

Assessing density dependence in the transmission of lymphatic filariasis: uptake and development of Wuchereria bancrofti microfilariae in the vector mosquitoes

Understanding density dependence in the transmission of lymphatic filariasis is essential for assessing the prospects of elimination. This study seeks to quantify the relationship between microfilaria (Mf) density in human blood and the number of third stage (L3) larvae developing in the mosquito vectors Aedes polynesiensis Marks and Culex quinquefasciatus Say (Diptera: Culicidae) after blood-feeding. Two types of curves are fitted to previously published data. Fitting a linearized power curve through the data allows for correction for measurement error in human Mf counts. Ignoring measurement error leads to overestimation of the strength of density dependence; the degree of overestimation depends on the accuracy of measurement of Mf density. For use in mathematical models of transmission of lymphatic filariasis, a hyperbolic saturating function is preferable. This curve explicitly estimates the Mf uptake and development at lowest Mf densities and the average maximum number of L3 that can develop in mosquitoes. This maximum was estimated at 23 and 4 for Ae. polynesiensis and Cx. quinquefasciatus, respectively.     

A multicenter,community-based,mixed methods assessment of the acceptability of a triple drug regimen for elimination of lymphatic filariasis

BackgroundMany countries will not reach elimination targets for lymphatic filariasis in 2020 using the two-drug treatment regimen (diethylcarbamazine citrate [DEC] and albendazole [DA]). A cluster-randomized, community-based safety study performed in Fiji, Haiti, India, Indonesia and Papua New Guinea tested the safety and efficacy of a new regimen of ivermectin, DEC and albendazole (IDA).Methodology/Principal findingsTo assess acceptability of IDA and DA, a mixed methods study was embedded within this community-based safety study. The study objective was to assess the acceptability of IDA versus DA. Community surveys were performed in each country with randomly selected participants (>14 years) from the safety study participant list in both DA and IDA arms. In depth interviews (IDI) and focus group discussions (FGD) assessed acceptability-related themes. In 1919 individuals, distribution of sex, microfilariae (Mf) presence and circulating filarial antigenemia (CFA), adverse events (AE) and age were similar across arms. A composite acceptability score summed the values from nine indicators (range 9–36). The median (22.5) score indicated threshold of acceptability. There was no difference in scores for IDA and DA regimens. Mean acceptability scores across both treatment arms were: Fiji 33.7 (95% CI: 33.1–34.3); Papua New Guinea 32.9 (95% CI: 31.9–33.8); Indonesia 30.6 (95% CI: 29.8–31.3); Haiti 28.6 (95% CI: 27.8–29.4); India 26.8 (95% CI: 25.6–28) (P<0.001). AE, Mf or CFA were not associated with acceptability. Qualitative research (27 FGD; 42 IDI) highlighted professionalism and appreciation for AE support. No major concerns were detected about number of tablets. Increased uptake of LF treatment by individuals who had never complied with MDA was observed.Conclusions/SignificanceIDA and DA regimens for LF elimination were highly and equally acceptable in individuals participating in the community-based safety study in Fiji, Haiti, India, Indonesia, and Papua New Guinea. Country variation in acceptability was significant. Acceptability of the professionalism of the treatment delivery was highlighted.     

Pharmacological and Host Considerations Surrounding Dose Selection and Duration of Therapy with Echinocandins

Caspofungin, micafungin and anidulafungin are antifungal drugs with excellent safety profiles. Dosing regimens and treatment durations must be appropriate for optimal patient outcomes. Overall, factors that affect dosing of all three drugs are similar. Drug-specific properties, including in vitro concentration-dependent antifungal activity, activity against fungal biofilms, and pharmacokinetic and pharmacodynamic parameters influence dose selection and duration of therapy. Dosing strategies that provide “unbound” plasma drug concentrations exceeding the minimum inhibitory concentration (or minimum effective concentration) of the fungus are essential. Patient weight, age and illness severity are also important considerations for adequate exposure to drug: individuals >66 kg, pediatric patients and the critically-ill clear drug at higher rates although drug product information guidelines do not recommend for these populations to receive doses higher than those currently used. Clinical studies of treatment of, and prophylaxis against, Candida and Aspergillus infection indicate that currently recommended dosing regimens are adequate in most instances.     

Protective efficacy of a filarial surface antigen in experimental filariasis

A water-insoluble, detergent-soluble, surface-associated glycoprotein, designated as Dssd1, was found to induce microfilaria clearance in Mastomys coucha implanted with Setaria digitata. Intraperitoneal implantation of adult female worms of S. digitata in M. coucha could induce microfilaraemia lasting about 165 days in circulation. Immunization of M. coucha with Dssd1 antigen either before or after implantation of worms resulted in a significant reduction in microfilaria density. Complete clearance of circulating microfilaria was achieved by immunization (before and after implantation) in animals by 95 and 105 days post-implantation, respectively, indicating the efficacy of Dssd1 antigen in the clearance of microfilaraemia in infected M. coucha.     

Albendazole induces apoptosis in adults and microfilariae of Setaria cervi

Setaria cervi, a filarial nematode of cattle, inhabits in the peritoneal cavity and has been used as a suitable model for screening antifilarial agents. Albendazole (ABZ), a tubulin-disrupting benzimidazole (BZ) and a potent microfilaricide binds to β-tubulin, is causing structural impairment of cytoskeleton and worm death. Our present study has revealed that exposure of microfilaria (Mf) and adult to gradually increasing concentration of ABZ leads to a dose-dependent gradual impairment of their motility followed by early death in vitro. We found extreme cellular disturbances in ABZ-treated worms characterized by nucleosomal DNA laddering and chromatin condensation. However, in the treated Mf no nucleosomal DNA laddering was found although presence of TUNEL reactive DNA was evident, thus indicating an apoptotic pathway independent of DNA fragmentation. We present data from molecular studies to provide evidence for ABZ-induced apoptosis in Mf and adult worms of S. cervi.     

Risk of Recrudescence of Lymphatic Filariasis after Post-MDA Surveillance in Brugia malayi Endemic Belitung District,Indonesia

Belitung district in Bangka-Belitung Province, Indonesia with a population of 0.27 million is endemic for Brugia malayi and 5 rounds of mass drug administration (MDA) were completed by 2010. Based on the results of 3 transmission assessment surveys (TAS), the district is declared as achieving elimination of lymphatic filariasis (LF) in 2017. The findings of an independent survey conducted by the National Institute of Health Research and Development (NIHRD) in the same year showed microfilaria (Mf) prevalence of 1.3% in this district. In 2019, NIHRD conducted microfilaria survey in 2 villages in Belitung district. Screening of 311 and 360 individuals in Lasar and Suak Gual villages showed Mf prevalence of 5.1% and 2.2% with mean Mf density of 120 and 354 mf/ml in the respective villages. Mf prevalence was significantly higher among farmers and fishermen compared to others and the gender specific difference was not significant. The results of a questionnaire based interview showed that 62.4% of the respondents reported to have participated in MDA in Lasar while it was 57.7% in Suak Gual village. About 42% of the Mf positive cases did not participate in MDA. Environmental surveys identified many swampy areas supporting the breeding of Mansonia vector species. Persistence of infection is evident and in the event of successful TAS3 it is necessary to monitor the situation and plan for focal MDA. Appropriate surveillance strategies including xenomonitoring in post-MDA situations need to be developed to prevent resurgence of infection. Possible role of animal reservoirs is discussed.     

A Multi-Compartment Single and Multiple Dose Pharmacokinetic Comparison of Rectally Applied Tenofovir 1% Gel and Oral Tenofovir Disoproxil Fumarate

This Phase 1, randomized, two-site (United States), double-blind, placebo-controlled study enrolled 18 sexually abstinent men and women. All received a single 300-mg dose of oral tenofovir disoproxil fumarate (TDF) and were then randomized 2∶1 to receive single and then seven daily rectal exposures of vaginally-formulated tenofovir (TFV) 1% gel or a hydroxyethyl cellulose (HEC) placebo gel. Blood, colonic biopsies and rectal and vaginal mucosal fluids were collected after the single oral TDF, the single topical TFV gel dose, and after 7 days of topical TFV gel dosing for extracellular analysis of TFV and intracellular analysis of the active metabolite tenofovir diphosphate (TFVdp) in peripheral blood mononuclear cells (PBMCs) and isolated mucosal mononuclear cells (MMC), including CD4+ and CD4- cell subsets. With a single rectal dose, TFV plasma concentrations were 24–33 fold lower and half-life was 5 h shorter compared to a single oral dose (p = 0.02). TFVdp concentrations were also undetectable in PBMCs with rectal dosing. Rectal tissue exposure to both TFV and TFVdp was 2 to 4-log₁₀ higher after a single rectal dose compared to a single oral dose, and after 7 daily doses, TFVdp accumulated 4.5 fold in tissue. TFVdp in rectal tissue homogenate was predictive (residual standard error, RSE  = 0.47) of tissue MMC intracellular TFVdp concentration, with the CD4+ cells having a 2-fold higher TFVdp concentration than CD4- cells. TFV concentrations from rectal sponges was a modest surrogate indicator for both rectal tissue TFV and TFVdp (RSE  = 0.67, 0.66, respectively) and plasma TFV (RSE  = 0.38). TFV penetrates into the vaginal cavity after oral and rectal dosing, with rectal dosing leading to higher vaginal TFV concentrations (p<0.01).

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00984971","term_id":"NCT00984971"}}NCT00984971     

Efficacy and safety of single and double doses of ivermectin versus 7-day high dose albendazole for chronic strongyloidiasis

Background

Strongyloidiasis, caused by an intestinal helminth Strongyloides stercoralis, is common throughout the tropics. It remains an important health problem due to autoinfection, which may result in hyperinfection and disseminated infection in immunosuppressed patients, especially patients receiving chemotherapy or corticosteroid treatment. Ivermectin and albendazole are effective against strongyloidiasis. However, the efficacy and the most effective dosing regimen are to be determined.

Methods

A prospective, randomized, open study was conducted in which a 7-day course of oral albendazole 800 mg daily was compared with a single dose (200 microgram/kilogram body weight), or double doses, given 2 weeks apart, of ivermectin in Thai patients with chronic strongyloidiasis. Patients were followed-up with 2 weeks after initiation of treatment, then 1 month, 3 months, 6 months, 9 months, and 1 year after treatment. Combination of direct microscopic examination of fecal smear, formol-ether concentration method, and modified Koga agar plate culture were used to detect strongyloides larvae in two consecutive fecal samples in each follow-up visit. The primary endpoint was clearance of strongyloides larvae from feces after treatment and at one year follow-up.

Results

Ninety patients were included in the analysis (30, 31 and 29 patients in albendazole, single dose, and double doses ivermectin group, respectively). All except one patient in this study had at least one concomitant disease. Diabetes mellitus, systemic lupus erythrematosus, nephrotic syndrome, hematologic malignancy, solid tumor and human immunodeficiency virus infection were common concomitant diseases in these patients. The median (range) duration of follow-up were 19 (2–76) weeks in albendazole group, 39 (2–74) weeks in single dose ivermectin group, and 26 (2–74) weeks in double doses ivermectin group. Parasitological cure rate were 63.3%, 96.8% and 93.1% in albendazole, single dose oral ivermectin, and double doses of oral ivermectin respectively (P = 0.006) in modified intention to treat analysis. No serious adverse event associated with treatment was found in any of the groups.

Conclusion/Significance

This study confirms that both a single, and a double dose of oral ivermectin taken two weeks apart, is more effective than a 7-day course of high dose albendazole for patients with chronic infection due to S. stercoralis. Double dose of ivermectin, taken two weeks apart, might be more effective than a single dose in patients with concomitant illness.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00765024","term_id":"NCT00765024"}}NCT00765024     

The role of albendazole in programmes to eliminate lymphatic filariasis.

Citing earlier advances in the treatment of lymphatic filariasis [particularly the effectiveness of single-dose diethylcarbamazine (DEC) in reducing microfilaraemia and its enhanced effectiveness when co-administered with single-dose ivermectin], Eric Ottesen, Mahroof Ismail and John Horton consider recent studies on the antifilarial activity of albendazole that have led to the current recommendations for its use in single-dose regimens in conjunction with either DEC or ivermectin for large-scale control/elimination programmes. Furthermore, the potential of albendazole as a macrofilaricide for treating individual patients with lymphatic filarial infections is emphasized as one of a number of important research questions that remain to be explored.     

Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories

Objective To describe characteristics of dosing history in patients prescribed a once a day antihypertensive medication.Design Longitudinal database study.Setting Clinical studies archived in database for 1989-2006.Participants Patients who participated in the studies whose dosing histories were available through electronic monitoring.Main outcome measures Persistence with prescribed antihypertensive treatment and execution of their once a day drug dosing regimens.Results The database contained dosing histories of 4783 patients with hypertension. The data came from 21 phase IV clinical studies, with lengths ranging from 30 to 330 days and involving 43 different antihypertensive drugs, including angiotensin II receptor blockers (n=2088), calcium channel blockers (n=937), angiotensin converting enzyme inhibitors (n=665), β blockers (n=195), and diuretics (n=155). About half of the patients who were prescribed an antihypertensive drug had stopped taking it within one year. On any day, patients who were still engaged with the drug dosing regimen omitted about 10% of the scheduled doses: 42% of these omissions were of a single day’s dose, whereas 43% were part of a sequence of several days (three or more days—that is, drug “holidays”). Almost half of the patients had at least one drug holiday a year. The likelihood that a patient would discontinue treatment early was inversely related to the quality of his or her daily execution of the dosing regimen.Conclusions Early discontinuation of treatment and suboptimal daily execution of the prescribed regimens are the most common facets of poor adherence with once a day antihypertensive drug treatments. The shortfalls in drug exposure that these dosing errors create might be a common cause of low rates of blood pressure control and high variability in responses to prescribed antihypertensive drugs.     

Consequences of Low Dose Ionizing Radiation Exposure on the Hippocampal Microenvironment

The response of the brain to irradiation is complex, involving a multitude of stress inducible pathways that regulate neurotransmission within a dynamic microenvironment. While significant past work has detailed the consequences of CNS radiotherapy following relatively high doses (≥ 45 Gy), few studies have been conducted at much lower doses (≤ 2 Gy), where the response of the CNS (like many other tissues) may differ substantially from that expected from linear extrapolations of high dose data. Low dose exposure could elicit radioadaptive modulation of critical CNS processes such as neurogenesis, that provide cellular input into hippocampal circuits known to impact learning and memory. Here we show that mice deficient for chemokine signaling through genetic disruption of the CCR2 receptor exhibit a neuroprotective phenotype. Compared to wild type (WT) animals, CCR2 deficiency spared reductions in hippocampal neural progenitor cell survival and stabilized neurogenesis following exposure to low dose irradiation. While radiation-induced changes in microglia levels were not found in WT or CCR2 deficient animals, the number of Iba1+ cells did differ between each genotype at the higher dosing paradigms, suggesting that blockade of this signaling axis could moderate the neuroinflammatory response. Interestingly, changes in proinflammatory gene expression were limited in WT animals, while irradiation caused significant elevations in these markers that were attenuated significantly after radioadaptive dosing paradigms in CCR2 deficient mice. These data point to the importance of chemokine signaling under low dose paradigms, findings of potential significance to those exposed to ionizing radiation under a variety of occupational and/or medical scenarios.     

Corallopyronin A for short-course anti-wolbachial,macrofilaricidal treatment of filarial infections

Current efforts to eliminate the neglected tropical diseases onchocerciasis and lymphatic filariasis, caused by the filarial nematodes Onchocerca volvulus and Wuchereria bancrofti or Brugia spp., respectively, are hampered by lack of a short-course macrofilaricidal–adult-worm killing–treatment. Anti-wolbachial antibiotics, e.g. doxycycline, target the essential Wolbachia endosymbionts of filariae and are a safe prototype adult-worm-sterilizing and macrofilaricidal regimen, in contrast to standard treatments with ivermectin or diethylcarbamazine, which mainly target the microfilariae. However, treatment regimens of 4–5 weeks necessary for doxycycline and contraindications limit its use. Therefore, we tested the preclinical anti-Wolbachia drug candidate Corallopyronin A (CorA) for in vivo efficacy during initial and chronic filarial infections in the Litomosoides sigmodontis rodent model. CorA treatment for 14 days beginning immediately after infection cleared >90% of Wolbachia endosymbionts from filariae and prevented development into adult worms. CorA treatment of patently infected microfilaremic gerbils for 14 days with 30 mg/kg twice a day (BID) achieved a sustained reduction of >99% of Wolbachia endosymbionts from adult filariae and microfilariae, followed by complete inhibition of filarial embryogenesis resulting in clearance of microfilariae. Combined treatment of CorA and albendazole, a drug currently co-administered during mass drug administrations and previously shown to enhance efficacy of anti-Wolbachia drugs, achieved microfilarial clearance after 7 days of treatment at a lower BID dose of 10 mg/kg CorA, a Human Equivalent Dose of 1.4 mg/kg. Importantly, this combination led to a significant reduction in the adult worm burden, which has not yet been published with other anti-Wolbachia candidates tested in this model. In summary, CorA is a preclinical candidate for filariasis, which significantly reduces treatment times required to achieve sustained Wolbachia depletion, clearance of microfilariae, and inhibition of embryogenesis. In combination with albendazole, CorA is robustly macrofilaricidal after 7 days of treatment and fulfills the Target Product Profile for a macrofilaricidal drug.     

The Impact of Repeated Rounds of Mass Drug Administration with Diethylcarbamazine Plus Albendazole on Bancroftian Filariasis in Papua New Guinea

Background

This study employed various monitoring methods to assess the impact of repeated rounds of mass drug administration (MDA) on bancroftian filariasis in Papua New Guinea, which has the largest filariasis problem in the Pacific region.

Methodology/Principal Findings

Residents of rural villages near Madang were studied prior to and one year after each of three rounds of MDA with diethylcarbamazine plus albendazole administered per World Health Organization (WHO) guidelines. The mean MDA compliance rate was 72.9%. Three rounds of MDA decreased microfilaremia rates (Mf, 1 ml night blood by filter) from 18.6% pre-MDA to 1.3% after the third MDA (a 94% decrease). Mf clearance rates in infected persons were 71%, 90.7%, and 98.1% after 1, 2, and 3 rounds of MDA. Rates of filarial antigenemia assessed by card test (a marker for adult worm infection) decreased from 47.5% to 17.1% (a 64% decrease) after 3 rounds of MDA. The filarial antibody rate (IgG₄ antibodies to Bm14, an indicator of filarial infection status and/or exposure to mosquito-borne infective larvae) decreased from 59.3% to 25.1% (a 54.6% decrease). Mf, antigen, and antibody rates decreased more rapidly in children <11 years of age (by 100%, 84.2%, and 76.8%, respectively) relative to older individuals, perhaps reflecting their lighter infections and shorter durations of exposure/infection prior to MDA. Incidence rates for microfilaremia, filarial antigenemia, and antifilarial antibodies also decreased significantly after MDA. Filarial DNA rates in Anopheles punctulatus mosquitoes that had recently taken a blood meal decreased from 15.1% to 1.0% (a 92.3% decrease).

Conclusions/Significance

MDA had dramatic effects on all filariasis parameters in the study area and also reduced incidence rates. Follow-up studies will be needed to determine whether residual infection rates in residents of these villages are sufficient to support sustained transmission by the An. punctulatus vector. Lymphatic filariasis elimination should be feasible in Papua New Guinea if MDA can be effectively delivered to endemic populations.     

Microfluidic Thrombosis under Multiple Shear Rates and Antiplatelet Therapy Doses

The mainstay of treatment for thrombosis, the formation of occlusive platelet aggregates that often lead to heart attack and stroke, is antiplatelet therapy. Antiplatelet therapy dosing and resistance are poorly understood, leading to potential incorrect and ineffective dosing. Shear rate is also suspected to play a major role in thrombosis, but instrumentation to measure its influence has been limited by flow conditions, agonist use, and non-systematic and/or non-quantitative studies.In this work we measured occlusion times and thrombus detachment for a range of initial shear rates (500, 1500, 4000, and 10000 s⁻¹) and therapy concentrations (0–2.4 µM for eptifibatide, 0–2 mM for acetyl-salicylic acid (ASA), 3.5–40 Units/L for heparin) using a microfluidic device. We also measured complete blood counts (CBC) and platelet activity using whole blood impedance aggregometry. Effects of shear rate and dose were analyzed using general linear models, logistic regressions, and Cox proportional hazards models.Shear rates have significant effects on thrombosis/dose-response curves for all tested therapies. ASA has little effect on high shear occlusion times, even at very high doses (up to 20 times the recommended dose). Under ASA therapy, thrombi formed at high shear rates were 4 times more prone to detachment compared to those formed under control conditions. Eptifibatide reduced occlusion when controlling for shear rate and its efficacy increased with dose concentration. In contrast, the hazard of occlusion from ASA was several orders of magnitude higher than that of eptifibatide. Our results show similar dose efficacy to our low shear measurements using whole blood aggregometry. This quantitative and statistically validated study of the effects of a wide range of shear rate and antiplatelet therapy doses on occlusive thrombosis contributes to more accurate understanding of thrombosis and to models for optimizing patient treatment.