Design and Evaluation of Hydrophilic Matrix System for pH-Independent Sustained Release of Weakly Acidic Poorly Soluble Drug

The aim of this research was to design and evaluate a hydrophilic matrix system for sustained release of glipizide, a weakly acidic poor soluble drug. A combination of inclusion complexation and microenvironmental pH modification techniques was utilized to improve the dissolution and pH-independent release of glipizide. Hydroxypropyl-β-cyclodextrin (HP-β-CD) was used as the complexation agent while sodium citrate and magnesium oxide (MgO) were used as model pH modifiers. The hydrophilic matrix tablets were prepared by powder direct compression and evaluated by in vitro dissolution study respectively in pH 6.8 and pH 1.2 dissolution media. The formulations containing MgO exhibited increased cumulative drug release from less than 40% in the reference formulation to 90% within 24 h in acidic media (pH 1.2). The release profile in acidic media was similar to the alkaline media (pH 6.8) with a similarity factor (f₂) of 55.0, suggesting the weakening of the effect of pH on the dissolution efficiency of glipizide. The release profile fitted well into the Higuchi model and the dominant mechanism of drug release was Fickian diffusion while case II transport/polymer relaxation occurred. In conclusion, combining inclusion complexation agents and pH modifiers had improved the dissolution of glipizide as well as achieved the pH-independent release profile.     

Solid Dispersion of Ursolic Acid in Gelucire 50/13: a Strategy to Enhance Drug Release and Trypanocidal Activity

Solid dispersions (SDs) are an approach to increasing the water solubility and bioavailability of lipophilic drugs such as ursolic acid (UA), a triterpenoid with trypanocidal activity. In this work, Gelucire 50/13, a surfactant compound with permeability-enhancing properties, and silicon dioxide, a drying adjuvant, were employed to produce SDs with UA. SDs and physical mixtures (PMs) in different drug/carrier ratios were characterized and compared using differential scanning calorimetry, hot stage microscopy, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), particle size, water solubility values, and dissolution profiles. Moreover, LLC-MK2 fibroblast cytotoxicity and trypanocidal activity evaluation were performed to determine the potential of SD as a strategy to improve UA efficacy against Chagas disease. The results demonstrated the conversion of UA from the crystalline to the amorphous state through XRD. FTIR experiments provided evidence of intermolecular interactions among the drug and carriers through carbonyl peak broadening in the SDs. These findings helped explain the enhancement of water solubility from 75.98 μg/mL in PMs to 293.43 μg/mL in SDs and the faster drug release into aqueous media compared with pure UA or PMs, which was maintained after 6 months at room temperature. Importantly, improved SD dissolution was accompanied by higher UA activity against trypomastigote forms of Trypanosoma cruzi, but not against mammalian fibroblasts, enhancing the potential of UA for Chagas disease treatment.Key words: Chagas disease, Gelucire 50/13, solid dispersions, solvent evaporation method, ursolic acid     

Controlled Release Hydrophilic Matrix Tablet Formulations of Isoniazid: Design and In Vitro Studies

The aim of the present investigation was to develop oral controlled release matrix tablet formulations of isoniazid using hydroxypropyl methylcellulose (HPMC) as a hydrophilic release retardant polymer and to study the influence of various formulation factors like proportion of the polymer, polymer viscosity grade, compression force, and release media on the in vitro release characteristics of the drug. The formulations were developed using wet granulation technology. The in vitro release studies were performed using US Pharmacopoeia type 1 apparatus (basket method) in 900 ml of pH 7.4 phosphate buffer at 100 rpm. The release kinetics was analyzed using Korsmeyer–Peppas model. The release profiles were also analyzed using statistical method (one-way analysis of variance) and f ₂ metric values. The release profiles found to follow Higuchi’s square root kinetics model irrespective of the polymer ratio and the viscosity grade used. The results in the present investigation confirm that the release rate of the drug from the HPMC matrices is highly influenced by the drug/HPMC ratio and viscosity grade of the HPMC. Also, the effect of compression force and release media was found to be significant on the release profiles of isoniazid from HPMC matrix tablets. The release mechanism was found to be anomalous non-Fickian diffusion in all the cases. In the present investigation, a series of controlled release formulations of isoniazid were developed with different release rates and duration so that these formulations could further be assessed from the in vivo bioavailability studies. The formulations were found to be stable and reproducible.     

A Drug Delivery Strategy: Binding Enkephalin to Asialoglycoprotein Receptor by Enzymatic Galactosylation

Glycosylation of biopharmaceuticals can mediate cell specific delivery by targeting carbohydrate receptors. Additionally, glycosylation can improve the physico-chemical (drug-like) properties of peptide based drug candidates. The main purpose of this study was to examine if glycosylation of the peptide enkephalin could facilitate its binding to the carbohydrate receptor, asialoglycoprotein. Firstly, we described the one-pot enzymatic galactosylation of lactose modified enkephalin in the presence of uridine-5′-diphosphogalactose 4-epimerase and lipopolysaccharyl α-1,4-galactosyltransferase. Stability experiments using human plasma and Caco-2 cell homogenates showed that glycosylation considerably improved the stability of enkephalin (at least 60% remained stable after a 2 hr incubation at 37°C). In vitro permeability experiments using Caco-2 cells revealed that the permeability of mono- and trisaccharide conjugated enkephalins was 14 and 28 times higher, respectively, than that of enkephalin alone (Papp 3.1×10⁻⁸ cm/s). By the methods of surface plasmon resonance and molecular modeling, we demonstrated that the enzymatic glycosylation of enkephalin enabled binding the asialoglycoprotein receptor. The addition of a trisaccharide moiety to enkephalin improved the binding of enkephalin to the asialoglycoprotein receptor two fold (K_D = 91 µM). The docking scores from molecular modeling showed that the binding modes and affinities of the glycosylated enkephalin derivatives to the asialoglycoprotein receptor complemented the results from the surface plasmon resonance experiments.     

Leishmaniasis Direct Agglutination Test: Using Pictorials as Training Materials to Reduce Inter-Reader Variability and Improve Accuracy

Background

The Direct Agglutination Test (DAT) has a high diagnostic accuracy and remains, in some geographical areas, part of the diagnostic algorithm for Visceral Leishmaniasis (VL). However, subjective interpretation of results introduces potential for inter-reader variation. We report an assessment of inter-laboratory agreement and propose a pictorial-based approach to standardize reading of the DAT.

Methodology

In preparation for a comparative evaluation of immunochromatographic diagnostics for VL, a proficiency panel of 15 well-characterized sera, DAT-antigen from a single batch and common protocol was sent to nine laboratories in Latin-America, East-Africa and Asia. Agreement (i.e., equal titre or within 1 titer) with the reading by the reference laboratory was computed. Due to significant inter-laboratory disagreement on-site refresher training was provided to all technicians performing DAT. Photos of training plates were made, and end-titres agreed upon by experienced users of DAT within the Visceral-Leishmaniasis Laboratory-Network (VL-LN).

Results

Pre-training, concordance in DAT results with reference laboratories was only 50%, although agreement on negative sera was high (94%). After refresher training concordance increased to 84%; agreement on negative controls increased to 98%. Variance in readings significantly decreased after training from 3.3 titres to an average of 1.0 titre (two-sample Wilcoxon rank-sum (Mann-Whitney) test (z = −3,624 and p = 0.0003)).

Conclusion

The most probable explanation for disagreement was subjective endpoint reading. Using pictorials as training materials may be a useful tool to reduce disparity in results and promote more standardized reading of DAT, without compromising diagnostic sensitivity.     

Fish Oil and Antipsychotic Drug Risperidone Modulate Oxidative Stress in PC12 Cell Membranes Through Regulation of Cytosolic Calcium Ion Release and Antioxidant System

Oxidative stress is a critical route of damage in various psychological disorders such as schizophrenia, although fish oil and risperidone (RISP) induce antioxidant effects in the human body. However, the mechanisms behind these effects remain elusive. We investigated the effects of fish oil and RISP in the PC12 cell line by evaluating Ca²⁺ mobilization, lipid peroxidation (LP) and antioxidant levels. PC12 cells were divided into eight flasks: control, fish oil, RISP, H₂O₂, fish oil + H₂O₂, RISP + H₂O₂, fish oil + RISP and fish oil + RISP + H₂O₂. Cells were incubated with fish oil and RISP for 24 and 48 h, respectively. Then, cells were exposed to H₂O₂ for 15 min before analysis. Ca²⁺ release and LP levels were higher in the H₂O₂ group than in the control, RISP and fish oil groups, although their levels were decreased by incubation of cells in fish oil and RISP. Glutathione peroxidase activity, reduced glutathione and vitamin C levels in the cells were lower in the H₂O₂ group than in the control, RISP and fish oil groups, although levels were higher in cells incubated with fish oil and RISP than in those in the H₂O₂ groups. In conclusion, these results indicate that RISP and fish oil induced protective effects on oxidative stress in PC12 cells by modulating cytosolic Ca²⁺ release and antioxidant levels.     

Assessing the In Vitro Drug Release from Lipid-Core Nanocapsules: a New Strategy Combining Dialysis Sac and a Continuous-Flow System

The in vitro assessment of drug release from polymeric nanocapsules suspensions is one of the most studied parameters in the development of drug-loaded nanoparticles. Nevertheless, official methods for the evaluation of drug release from submicrometric carriers are not available. In this work, a new approach to assess the in vitro drug release profile from drug-loaded lipid-core nanocapsules (LNC) was proposed. A continuous-flow system (open system) was designed to evaluate the in vitro drug release profiles from different LNC formulations containing prednisolone or clobetasol propionate (LNC-CP) as drug model (LNC-PD) using a homemade apparatus. The release medium was constantly renewed throughout the experiment. A dialysis bag containing 5 mL of formulation (0.5 mg mL⁻¹) was maintained inside the apparatus, under magnetic stirring and controlled temperature (37°C). In parallel, studies based on the conventional dialysis sac technique (closed system) were performed. It was possible to discriminate the in vitro drug release profile of different formulations using the open system. The proposed strategy improved the sink condition, by constantly renewing the release medium, thus maintaining the drug concentration farther from the saturated concentration in the release medium. Moreover, problems due to sampling errors can be easily overcome using this semi-automated system, since the collection is done automatically without interference from the analyst. The system proposed in this paper brings important methodological and analytical advantages, becoming a promising prototype semi-automated apparatus for performing in vitro drug release studies from drug-loaded lipid-core nanocapsules and other related nanoparticle drug delivery systems.KEY WORDS: dialysis sac technique, flow-through cell apparatus, in vitro drug release, lipid-core nanocapsules, sink condition     

Evaluation of Colloidal Solid Dispersions: Physiochemical Considerations and In Vitro Release Profile

Colloidal solid dispersion is an innovative breakthrough in the pharmaceutical industry that overcomes the solubility-related issue of poorly soluble drugs by using an amorphous approach and also the stability-related issue by means of a complex formation phenomenon using different carrier materials. In the present study, a newly developed adsorption method is introduced to incorporate a high-energy sulfathiazole–polyvinylpyrrolidone (Plasdone® K-29/32) solid dispersion on porous silicon dioxide (Syloid® 244FP). Different ternary systems of sulfathiazole–Plasdone® K-29/32–Syloid® 244FP were prepared (1:1:2, 1:1:3, and 1:2:2) and categorized depending on the mechanism by which Syloid® 244FP was incorporated. Modulated differential scanning calorimetry (MDSC), X-ray diffraction, Fourier transform infrared spectroscopy, and in vitro dissolution studies were conducted to characterize the ternary systems. The X-ray diffraction and MDSC data showed a lack of crystallinity in all internal and external ternary systems, suggesting a loss of the crystallinity of sulfathiazole compared to the physical mixtures. USP apparatus II was used to measure the in vitro dissolution rate of the prepared systems at 75 rpm in different media. The dissolution rate of the optimum ratio (1:2:2) containing an internal ternary solid dispersion system was found to be three times higher than that of the external and physical systems. Thus, the porous silicon dioxide incorporated into the conventional binary solid dispersion acted as a carrier to disperse the complex and increase the dissolution rate.     

Trends of Mycobacterium bovis Isolation and First-Line Anti-tuberculosis Drug Susceptibility Profile: A Fifteen-Year Laboratory-Based Surveillance

Background Mycobacterium tuberculosis causes the majority of tuberculosis (TB) cases in humans; however, in developing countries, human TB caused by M. bovis may be frequent but undetected. Human TB caused by M. bovis is considered a zoonosis; transmission is mainly through consumption of unpasteurized dairy products, and it is less frequently attributed to animal-to-human or human-to-human contact. We describe the trends of M. bovis isolation from human samples and first-line drug susceptibility during a 15-year period in a referral laboratory located in a tertiary care hospital in Mexico City.Conclusions/SignificanceThere is a high prevalence and a rising trend of M. bovis isolates in our region. The proportion of pulmonary M. bovis isolates is higher than in previous reports. Additionally, we report high rates of primary anti-tuberculosis resistance and secondary MDR in both M. tuberculosis and M. bovis. This is one of the largest reports on drug susceptibility of M. bovis from human samples and shows a significant proportion of first-line anti-tuberculosis drug resistance.     

Tuning the Hydrophilic/Hydrophobic Balance to Control the Structure of Chitosan Films and Their Protein Release Behavior

The control over the crystallinity of chitosan and chitosan/ovalbumin films can be achieved via an appropriate balance of the hydrophilic/hydrophobic interactions during the film formation process, which then controls the release kinetics of ovalbumin. Chitosan films were prepared by solvent casting. The presence of the anhydrous allomorph can be viewed as a probe of the hydrophobic conditions at the neutralization step. The semicrystalline structure, the swelling behavior of the films, the protein/chitosan interactions, and the release behavior of the films were impacted by the DA and the film processing parameters. At low DAs, the chitosan films neutralized in the solid state corresponded to the most hydrophobic environment, inducing the crystallization of the anhydrous allomorph with and without protein. The most hydrophilic conditions, leading to the hydrated allomorph, corresponded to non-neutralized films for the highest DAs. For the non-neutralized chitosan acetate (amorphous) films, the swelling increased when the DA decreased, whereas for the neutralized chitosan films, the swelling decreased. The in vitro release of ovalbumin (model protein) from chitosan films was controlled by their swelling behavior. For fast swelling films (DA?=?45%), a burst effect was observed. On the contrary, a lag time was evidenced for DA?=?2.5% with a limited release of the protein. Furthermore, by blending chitosans (DA?=?2.5% and 45%), the release behavior was improved by reducing the burst effect and the lag time. The secondary structure of ovalbumin was partially maintained in the solid state, and the ovalbumin was released under its native form.     

Bio-Dis and the Paddle Dissolution Apparatuses Applied to the Release Characterization of Ketoprofen from Hypromellose Matrices

The purposes of this work were: (1) to comparatively evaluate the effects of hypromellose viscosity grade and content on ketoprofen release from matrix tablets, using Bio-Dis and the paddle apparatuses, (2) to investigate the influence of the pH of the dissolution medium on drug release. Furthermore, since direct compression had not shown to be appropriate to obtain the matrices under study, it was also an objective (3) to evaluate the impact of granulation on drug release process. Six formulations of ketoprofen matrix tablets were obtained by compression, with or without previous granulation, varying the content and viscosity grade of hypromellose. Dissolution tests were carried out at a fixed pH, in each experiment, with the paddle method (pH 4.5, 6.0, 6.8, or 7.2), while a pH gradient was used in Bio-Dis (pH 1.2 to 7.2). The higher the hypromellose viscosity grade and content were, the lower the amount of ketoprofen released was in both apparatuses, the content effect being more expressive. Drug dissolution enhanced with the increase of the pH of the medium due to its pH-dependent solubility. Granulation caused an increase in drug dissolution and modified the mechanism of the release process.Key words: apparatus 3, Bio-Dis, dissolution, hypromellose matrix, ketoprofen     

A Statistical Approach to Optimize the Spray Drying of Starch Particles: Application to Dry Powder Coating

This article describes the preparation of starch particles, by spray drying, for possible application to a dry powder coating process. Dry powder coating consists of spraying a fine powder and a plasticizer on particles. The efficiency of the coating is linked to the powder morphological and dimensional characteristics. Different experimental parameters of the spray-drying process were analyzed, including type of solvent, starch concentration, rate of polymer feeding, pressure of the atomizing air, drying air flow, and temperature of drying air. An optimization and screening of the experimental parameters by a design of the experiment (DOE) approach have been done. Finally, the produced spray-dried starch particles were conveniently tested in a dry coating process, in comparison to the commercial initial starch. The obtained results, in terms of coating efficiency, demonstrated that the spray-dried particles led to a sharp increase of coating efficiency value.     

A Reduce and Replace Strategy for Suppressing Vector-Borne Diseases: Insights from a Stochastic,Spatial Model

Two basic strategies have been proposed for using transgenic Aedes aegypti mosquitoes to decrease dengue virus transmission: population reduction and population replacement. Here we model releases of a strain of Ae. aegypti carrying both a gene causing conditional adult female mortality and a gene blocking virus transmission into a wild population to assess whether such releases could reduce the number of competent vectors. We find this “reduce and replace” strategy can decrease the frequency of competent vectors below 50% two years after releases end. Therefore, this combined approach appears preferable to releasing a strain carrying only a female-killing gene, which is likely to merely result in temporary population suppression. However, the fixation of anti-pathogen genes in the population is unlikely. Genetic drift at small population sizes and the spatially heterogeneous nature of the population recovery after releases end prevent complete replacement of the competent vector population. Furthermore, releasing more individuals can be counter-productive in the face of immigration by wild-type mosquitoes, as greater population reduction amplifies the impact wild-type migrants have on the long-term frequency of the anti-pathogen gene. We expect the results presented here to give pause to expectations for driving an anti-pathogen construct to fixation by relying on releasing individuals carrying this two-gene construct. Nevertheless, in some dengue-endemic environments, a spatially heterogeneous decrease in competent vectors may still facilitate decreasing disease incidence.     

Methotrexate-Loaded Chitosan- and Glycolchitosan-Based Nanoparticles: A Promising Strategy for the Administration of the Anticancer Drug to Brain Tumors

Brain tumor treatment employing methotrexate (MTX) is limited by the efflux mechanism of Pg-p on the blood–brain barrier. We aimed to investigate MTX-loaded chitosan or glycol chitosan (GCS) nanoparticles (NPs) in the presence and in the absence of a coating layer of Tween 80 for brain delivery of MTX. The effect of a low Tween 80 concentration was evaluated. MTX NPs were formulated following the ionic gelation technique and size and zeta potential measurements were acquired. Transport across MDCKII-MDR1 monolayer and cytotoxicity studies against C6 glioma cell line were also performed. Cell/particles interaction was visualized by confocal microscopy. The particles were shown to be cytotoxic against C6 cells line and able to overcome MDCKII-MDR1 cell barrier. GCS-based NPs were the most cytotoxic NPs. Confocal observations highlighted the internalization of Tween 80-coated fluorescent NPs more than Tween 80-uncoated NPs. The results suggest that even a low concentration of Tween 80 is sufficient for enhancing the transport of MTX from the NPs across MDCKII-MDR1 cells. The nanocarriers represent a promising strategy for the administration of MTX to brain tumors which merits further investigations under in vivo conditions.     

Carbohydrate Modified Diet & Insulin Sensitizers Reduce Body Weight & Modulate Metabolic Syndrome Measures in EMPOWIR (Enhance the Metabolic Profile of Women with Insulin Resistance): A Randomized Trial of Normoglycemic Women with Midlife Weight Gain

Rationale

Progressive midlife weight gain is associated with multiple adverse health outcomes and may represent an early manifestation of insulin resistance in a distinct subset of women. Emerging data implicate hyperinsulinema as a proximate cause of weight gain and support strategies that attenuate insulin secretion.

Objective

To assess a previously reported novel hypocaloric carbohydrate modified diet alone (D), and in combination with metformin (M) and metformin plus low-dose rosiglitazone (MR), in diverse women with midlife weight gain (defined as >20lbs since the twenties), normal glucose tolerance, and hyperinsulinemia.

Participants

46 women, mean age 46.6±1.0, BMI 30.5±0.04 kg/m², 54.5% white, 22.7% black, 15.9% Hispanic, at 2 university medical centers.

Methods

A dietary intervention designed to reduce insulin excursions was implemented in 4 weekly nutritional group workshops prior to randomization.

Main Outcome Measure

Change in 6-month fasting insulin. Pre-specified secondary outcomes were changes in body weight, HOMA-IR, metabolic syndrome (MS) measures, leptin, and adiponectin.

Results

Six-month fasting insulin declined significantly in the M group: 12.5 to 8.0 µU/ml, p = .026. Mean 6-month weight decreased significantly and comparably in D, M, and MR groups: 4.7, 5.4, and 5.5% (p’s.049, .002, and.032). HOMA–IR decreased in M and MR groups (2.5 to 1.6 and 1.9 to 1.3, p’s = .054, .013). Additional improvement in MS measures included reduced waist circumference in D and MR groups and increased HDL in the D and M groups. Notably, mean fasting leptin did not decline in a subset of subjects with weight loss (26.15±2.01 ng/ml to 25.99±2.61 ng/ml, p = .907. Adiponectin increased significantly in the MR group (11.1±1.0 to 18.5±7.4, p<.001) Study medications were well tolerated.

Conclusions

These findings suggest that EMPOWIR’s easily implemented dietary interventions, alone and in combination with pharmacotherapies that target hyperinsulinemia, merit additional investigation in larger, long-term studies.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00618072","term_id":"NCT00618072"}}NCT00618072     

A Systematic Approach of Employing Quality by Design Principles: Risk Assessment and Design of Experiments to Demonstrate Process Understanding and Identify the Critical Process Parameters for Coating of the Ethylcellulose Pseudolatex Dispersion Using Non-Conventional Fluid Bed Process

The goal of this study was to utilize risk assessment techniques and statistical design of experiments (DoE) to gain process understanding and to identify critical process parameters for the manufacture of controlled release multiparticulate beads using a novel disk-jet fluid bed technology. The material attributes and process parameters were systematically assessed using the Ishikawa fish bone diagram and failure mode and effect analysis (FMEA) risk assessment methods. The high risk attributes identified by the FMEA analysis were further explored using resolution V fractional factorial design. To gain an understanding of the processing parameters, a resolution V fractional factorial study was conducted. Using knowledge gained from the resolution V study, a resolution IV fractional factorial study was conducted; the purpose of this IV study was to identify the critical process parameters (CPP) that impact the critical quality attributes and understand the influence of these parameters on film formation. For both studies, the microclimate, atomization pressure, inlet air volume, product temperature (during spraying and curing), curing time, and percent solids in the coating solutions were studied. The responses evaluated were percent agglomeration, percent fines, percent yield, bead aspect ratio, median particle size diameter (d50), assay, and drug release rate. Pyrobuttons® were used to record real-time temperature and humidity changes in the fluid bed. The risk assessment methods and process analytical tools helped to understand the novel disk-jet technology and to systematically develop models of the coating process parameters like process efficiency and the extent of curing during the coating process.     

A Pilot Study of Brief Heart Rate Variability Biofeedback to Reduce Craving in Young Adult Men Receiving Inpatient Treatment for Substance Use Disorders

The present pilot study investigated the implementation feasibility, and efficacy for reducing alcohol and drug craving, of a brief, 3-session heart rate variability biofeedback (HRV BFB) intervention added to a traditional 28-day substance abuse disorder inpatient treatment program. Forty-eight young adult men received either treatment as usual (TAU) plus three sessions of HRV BFB training over 3 weeks, or TAU only. Participants receiving HRV BFB training were instructed to practice daily using a hand-held HRV BFB device. HRV BFB training was well tolerated by participants and supported by treatment staff. Men receiving TAU + HRV BFB demonstrated a greater, medium effect size reduction in alcohol and drug craving compared to those receiving TAU only, although this difference did not reach statistical significance. In addition, an interaction effect was observed in analyses that accounted for baseline craving levels, wherein heart rate variability (HRV) levels at treatment entry were predictive of changes in craving in the TAU group only. Low baseline levels of HRV were associated with increases in craving, whereas higher baseline HRV levels were associated with greater decreases in craving from start to end of treatment. In the TAU + HRV BFB group, however, there was no such association. That is, HRV BFB appeared to dissociate individual differences in baseline HRV levels from changes in craving. Given that alcohol and drug craving often precipitates relapse, HRV BFB merits further study as an adjunct treatment to ameliorate craving experienced by persons with substance use disorders.     

Prioritizing Countries for Interventions to Reduce Child Mortality: Tools for Maximizing the Impact of Mass Drug Administration of Azithromycin

Background

As new interventions to reduce childhood mortality are identified, careful consideration must be given to identifying populations that could benefit most from them. Promising reductions in childhood mortality reported in a large cluster randomized trial of mass drug administration (MDA) of azithromycin (AZM) prompted the development of visually compelling, easy-to-use tools that synthesize country-specific data on factors that would influence both potential AZM benefit and MDA implementation success.

Methodology/Principal Findings

We assessed the opportunity to reduce mortality and the feasibility of implementing such a program, creating Opportunity and Feasibility Indices, respectively. Countries with high childhood mortality were included. A Country Ranking Index combined key variables from the previous two Indices and applied a scoring system to identify high-priority countries. We compared four scenarios with varying weights given to each variable.Twenty-five countries met inclusion criteria. We created easily visualized tools to display the results of the Opportunity and Feasibility Indices. The Opportunity Index revealed substantial variation in the opportunity for an MDA of AZM program to reduce mortality, even among countries with high overall childhood mortality. The Feasibility Index demonstrated that implementing such a program would be most challenging in the countries that could see greatest benefit. Based on the Country Ranking Index, Equatorial Guinea would benefit the most from the MZA of AZM in three of the four scenarios we tested.

Conclusions/Significance

These visually accessible tools can be adapted or refined to include other metrics deemed important by stakeholders, and provide a quantitative approach to prioritization for intervention implementation. The need to explicitly state metrics and their weighting encourages thoughtful and transparent decision making. The objective and data-driven approach promoted by the three Indices may foster more efficient use of resources.