Codelivery of ivermectin and methyl dihydrojasmonate in nanostructured lipid carrier for synergistic antileukemia therapy.

Chronic myeloid leukemia is a life-threatening blood-cancer prevalent among children and adolescents. Research for innovative therapeutics combine drug-repurposing, phytotherapeutics and nanodrug-delivery. Ivermectin (Ivn) is a potent anthelmintic, repurposed for antileukemic-activity. However, Ivn exerts off-target toxicity. Methyl-dihydrojasmonate (MJ) is a phytochemical of known antileukemic potential. Herein, we developed for the first-time Ivn/MJ-coloaded nanostructured-lipid-carrier (Ivn@MJ-NLC) for leveraging the antileukemic-activity of the novel Ivn/MJ-combination while ameliorating possible adverse-effects. The developed Ivn@MJ-NLC possessed optimum-nanosize (97 ± 12.70 nm), PDI (0.33 ± 0.02), entrapment for Ivn (97.48 ± 1.48 %) and MJ (99.48 ± 0.57 %) and controlled-release of Ivn (83 % after 140 h) and MJ (80.98 ± 2.45 % after 48 h). In-vitro K562 studies verified Ivn@MJ-NLC prominent cytotoxicity (IC50 = 35.01 ± 2.23 µg/mL) with pronounced Ivn/MJ-synergism (combination-index = 0.59) at low-concentrations (5-10 µg/mL Ivn). Superior Ivn@MJ-NLC cytocompatibility was established on oral-epithelial-cells (OEC) with high OEC/K562 viability-ratio (1.49-1.85). The innovative Ivn@MJ-NLC enhanced K562-nuclear-fragmentation and afforded upregulation of caspase-3 and BAX (1.71 ± 0.07 and 1.45 ± 0.07-fold-increase, respectively) compared to control. Ex-vivo hemocompatibility and in-vivo-biocompatibility of parenteral-Ivn@MJ-NLC, compared to Ivn-solution, was verified via biochemical-blood analysis, histological and histomorphometric studies of liver and kidney tissues. Our findings highlight Ivn@MJ-NLC as an Ivn/MJ synergistic antileukemic platform, ameliorating possible adverse-effects.

Effect of a combination of nitazoxanide, ribavirin, and ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance of mild COVID-19.

This trial compared the rate and time of viral clearance in subjects receiving a combination of nitazoxanide, ribavirin, and ivermectin plus Zinc versus those receiving supportive treatment. This non-randomized controlled trial included 62 patients on the triple combination treatment versus 51 age- and sex-matched patients on routine supportive treatment. all of them confirmed cases by positive reverse-transcription polymerase chain reaction of a nasopharyngeal swab. Trial results showed that the clearance rates were 0% and 58.1% on the 7th day and 13.7% and 73.1% on the 15th day in the supportive treatment and combined antiviral groups, respectively. The cumulative clearance rates on the 15th day are 13.7% and 88.7% in the supportive treatment and combined antiviral groups, respectively. This trial concluded by stating that the combined use of nitazoxanide, ribavirin, and ivermectin plus zinc supplement effectively cleared the SARS-COV2 from the nasopharynx in a shorter time than symptomatic therapy.

Treatment of sarcoptic and chorioptic mange in an alpaca (Vicugna pacos) herd with a combination of topical amitraz and subcutaneous ivermectin.

Clinical history: An outbreak of intense pruritus and weight loss in a herd of 40 alpacas (Vicugna pacos) in the south-west of France was investigated after the death of 14 adults. One alpaca was referred to a veterinary teaching hospital for diagnosis and treatment but died soon after and one of the dead alpacas was submitted for necropsy. Clinical findings: The remaining alpacas were intensely pruritic with variably severe and extensive alopecia, erythema, lichenification and crusting on the face, ventral abdomen and distal limbs. Superficial skin scrapes from five animals revealed large numbers of Sarcoptes scabiei mites, and less frequent and numerous Chorioptes bovis mites. Coproscopic examinations revealed a median of 1,350 (min 500, max 8800) strongyle epg. The alpaca admitted for treatment was anaemic and hypoalbuminaemic. Skin scrapes revealed copious S. scabiei and C. bovis mites. The two alpacas examined post-mortem had similar skin lesions to those examined on-farm and were cachexic. One had lung lesions attributed to protostrongylid infestation and its liver contained numerous Dicrocoelium spp. adults. Diagnosis: Sarcoptic and chorioptic mange with secondary superficial bacterial skin infection, associated with severe internal parasitism and underfeeding. Treatment and outcome: All 25 alpacas were treated topically with a 3% chlorhexidine shampoo followed by a 0.025% amitraz wash at the initial visit and then 1, 2, 3, 7 and 9 weeks later. A systemic treatment with S/C 500 µg/kg ivermectin was administered at the initial visit and then 2, 7 and 9 weeks later. The alpacas were treated orally with 50 mg/kg praziquantel to control dicrocoeliosis. Nutritional measures, including increased pasture area and supplemental feeding were simultaneously implemented. Pruritus was reduced 1 week after the start of treatment and had resolved after 2 weeks. After 9 weeks, skin lesions were markedly improved. Six months after the initial visit, skin lesions entirely resolved and superficial skin scrapes, taken from half of the animals, were negative for mites. Clinical relevance: This is the first report of the use of two acaricides combined with a chlorhexidine shampoo to successfully treat simultaneous sarcoptic and chorioptic mange in alpacas.

Efficacy of Topical Ivermectin for the Treatment of Cutaneous and Ocular Rosacea.

Purpose: To investigate the efficacy of once-daily topical treatment of ocular and cutaneous rosacea with ivermectin 1% cream (Soolantra®, Galderma).Methods: Ten patients with rosacea were evaluated in a retrospective monocentric pilot study. Subjective symptoms (measured with the Ocular Surface Disease Index), skin findings, and ocular changes (blepharitis with telangiectasia and meibomian gland dysfunction, conjunctival redness, tear breakup time (TBUT), and fluorescein staining of the cornea) were evaluated. The follow-up was 8 months (range: 5-12 months).Results: The OSDI score decreased in the 8th week of treatment (38.5 ± 21.7, P = .004). After 16 weeks, blepharitis (P = .004), and conjunctival redness (P = .008) had strongly improved, and grade 1 was seen in all patients until the end of follow-up. Fluorescein staining of the cornea (P = .001) and TBUT (P = .016) showed significant improvement until the last follow-up visit. No side effects were observed. Conclusion: Topical ivermectin cream 1% given daily is an effective and safe therapy against rosacea.

Gastrointestinal nematode infections do not hinder the development of Simmental X Nellore crossbred calves raised with a nutritionally enhanced diet.

An evaluation was made of the effect of anthelmintic treatments on the performance of Simmental X Nellore crossbred calves before and after weaning. To this end, the calves were divided into three groups: (1) treated monthly with a low efficacy anthelmintic drug, ivermectin; (2) treated monthly with a highly effective anthelmintic drug, albendazole; and (3) untreated control group. All the groups in this experiment showed an average fecal egg count of less than 400 eggs per gram (EPG), and no clinical signs of parasitic gastroenteritis. The blood variables were within the normal range and no calf presented anemia. In most of the samplings, mean EPGs were significantly lower (P<0.05) in the group treated with albendazole. The calves received dietary supplementation before and after weaning, which enabled them to gain weight in every month of the experiment and reach a body weight of about 250 kg on the last sampling date, before turning one year old. The anthelmintic treatments did not affect body weight gain, leading to the conclusion that, when fed with suitable dietary supplements, Simmental X Nellore crossbred calves are not affected by gastrointestinal nematode parasites acquired by grazing.

Vitamin E and selenium administration synergistically mitigates ivermectin and doramectin-induced testicular dysfunction in male Wistar albino rats.

Avermectins are broad-spectrum antiparasitic drugs in veterinary and human medication. The current study aimed to examine the toxic effects of ivermectin (IVM) and doramectin (DRM), with or without co-treatment of vitamin E (Vit.E) and selenium (Se) on apoptosis, oxidative stress and male fertility in Wistar rats. Twenty five adult male animals were divided into five groups; G1; was control (CTL) received saline, G2; IVM (0.2 mg/kg b.w), G3; IVM plus Vit.E/Se (80/1.6 mg/kg b.w, respectively), G4; DRM (0.2 mg/kg b.w), and G5; DRM plus Vit.E/Se. Both IVM and DRM were given by subcutaneous (s.c) injections while Vit.E/Se was orally given. All treatments were administered once weekly for four consecutive weeks. By 24 h after the last treatment, the animals were sacrificed. Blood and tissue samples were collected for hematology, serobiochemistry, histopathology, and molecular assays for hepatic/ renal toxicities, oxidative stress, cell viability and fertility parameters. Apoptosis of the hepatic cells obtained from the treated rats was assayed by detection of annexin-V using the flow cytometric assay (FCA). The proliferating cellular nuclear antigen (PCNA) and DNA fragmentation in the treated rats' testicular tissues were also assayed. Moreover, the direct effects of IVM or DRM with or without concomitant administration of Vit.E/Se on testicular cells isolated from adult rat were also performed in vitro. Apoptosis of those cultured testicular cells in response to the different treatments was assayed by detection of the inhibition-concentration fifty (IC50) using the SRB method, and evaluating the viable versus apoptotic cells microscopically after staining with acridine orange-ethidium bromide (AO/EB). In conclusion, both avermectins induced apoptosis in the living and cultured cells, while those antioxidants; Vit.E and Se, reduced the oxidative stress and cytotoxicity both in vivo and in vitro, either. Furthermore, the reprotoxicity and reduced male fertility were seriously evoked by IVM, but not DRM with dramatic ameliorative effect of Vit.E/Se if concomitantly administered. Avermectins, especially ivermectin, should be given according to the dose recommended by the manufacturer company and repeated dosages should be given with Vit.E/Se.

Case Report: Nasal Myiasis in an Elderly Patient with Atrophic Rhinitis and Facial Sequelae of Leprosy.

We describe a case of nasal myiasis in an 89-year-old Brazilian patient affected by leprosy with severe nasal sequelae. An initial treatment comprising sinusectomy combined with nasal endoscopy removed more than 300 larvae, supplemented by systemic treatment using oral and topical ivermectin and levofloxacin. Infestation recurred after 2 months, was treated similarly, and resolved completely. The case could be attributed to severe nasal leprosy sequelae, with a lack of sneezing reflex, painless ulceration, atrophic rhinitis (ozena), and inability to clean the nose properly due to hand and nose impairment. This case illustrates the importance of long-term medical follow-up of patients with leprosy sequelae.

Efficacy of topical ivermectin and impact on quality of life in patients with papulopustular rosacea: A systematic review and meta-analysis.

Rosacea is a chronic dermatosis which affects negatively patients' quality of life (QoL). There is shortage of high-quality evidence comparing the efficacy of ivermectin cream (IVM) 1% with other available topical choices. Besides, the well-documented impaired of self-esteem and stigmatization of rosacea patients make essential to address which treatment provides the greatest psychological and social benefit. Our objective is to critically review and appraise the efficacy of IVM 1% in PPR and the impact in patients' QoL against other options. We carried out a literature search from PubMed, MEDLINE, EMBASE, Cochrane, and clinicaltrials.gov using the following descriptors: "rosacea" AND "ivermectin." Efficacy was assessed with the Investigator Global Assessment (IGA), and the impact on QoL was based on the DLQI score. Six studies from four published articles were included. The meta-analysis estimated that more participants achieved "success" (IGA ≤ 1) and "complete clearance" (IGA = 0) with IVM1%. The overall effect estimate for IGA ≤ 1 was: 1.56 [1.23-1.97], whereas for IGA = 0, it was: 1.72 [1.40-2.11]. The rate of participants achieving lower DLQI score, and thus, better QoL was with IVM 1%. The overall effect estimate was: 1.71 [1.34-2.18] at week 16# and 1.64 [1.38-1.94] at week 52#. This meta-analysis confirms IVM 1% cream as the most effective topical treatment and it satisfies the impairment of social life with sustained better QoL. Further studies extending this period of remission are warranted, as well as researches about the potential application of this agent combined with other agents. KEY POINTS: Question: What is the current efficacy of ivermectin versus other choices in papulopustular rosacea and its impact on patients' quality of life? Findings: In this meta-analysis, ivermectin showed higher efficacy than metronidazol, azelaic acid, and placebo measured by Investigator Global Assessment. Parallely, the DLQI score highlighted that this agent was more beneficious in both short and long-term. Meaning: This meta-analysis gives strong evidence that ivermectin is the most effective topical treatment. Besides, this agent provides the greatest psychological benefit as it satisfies the stigmatization of rosacea patients as well as the impairment of social and working life with a sustained better QoL above other alternatives.

Gastrointestinal nematode infections do not hinder the development of Simmental X Nellore crossbred calves raised with a nutritionally enhanced diet / Infecções por nematódeos gastrintestinais não prejudicam o desenvolvimento de bezerros Simental x Nelore criados em plano nutricional elevado

Abstract An evaluation was made of the effect of anthelmintic treatments on the performance of Simmental X Nellore crossbred calves before and after weaning. To this end, the calves were divided into three groups: (1) treated monthly with a low efficacy anthelmintic drug, ivermectin; (2) treated monthly with a highly effective anthelmintic drug, albendazole; and (3) untreated control group. All the groups in this experiment showed an average fecal egg count of less than 400 eggs per gram (EPG), and no clinical signs of parasitic gastroenteritis. The blood variables were within the normal range and no calf presented anemia. In most of the samplings, mean EPGs were significantly lower (P<0.05) in the group treated with albendazole. The calves received dietary supplementation before and after weaning, which enabled them to gain weight in every month of the experiment and reach a body weight of about 250 kg on the last sampling date, before turning one year old. The anthelmintic treatments did not affect body weight gain, leading to the conclusion that, when fed with suitable dietary supplements, Simmental X Nellore crossbred calves are not affected by gastrointestinal nematode parasites acquired by grazing.

Resumo O objetivo do experimento foi avaliar o efeito de tratamentos anti-helmínticos no desempenho de bezerros Simental x Nelore antes e após o desmame. Os bezerros foram alocados em três grupos: (1) tratado mensalmente com anti-helmínticos de baixa eficácia, ivermectina; (2) tratado mensalmente com anti-helmíntico de alta eficácia, albendazol e (3) controle não tratado. A média das contagens de ovos de nematoides durante o experimento foi inferior a 400 ovos por grama (OPG) em todos os grupos sem manifestação clínica de gastroenterite parasitária. As variáveis ​​sanguíneas mantiveram-se dentro dos limites de normalidade e nenhum bezerro apresentou anemia. Na maioria das coletas, as médias de OPG foram significativamente inferiores (P<0,05) no grupo tratado com albendazol. Os bezerros receberam suplementação antes e depois do desmame, o que lhes permitiu ganhar peso em todos os meses do experimento, atingindo peso corporal em torno de 250 kg, ao final do experimento, antes de completarem um ano de idade. Não houve efeito dos tratamentos anti-helmínticos no ganho em peso, o que permitiu concluir que bezerros Nelore x Simental não são afetados pelo parasitismo por nematoides gastrintestinais sob condições de pastejo, quando devidamente suplementados com concentrado.

Production responses and cost-benefit of long-acting pre-lambing anthelmintic treatment of yearling ewes in two commercial flocks in New Zealand.

AIMS: To investigate the production responses and cost-benefit of administering a controlled-release anthelmintic capsule (CRC) to pregnant yearling ewes prior to lambing. METHODS: Yearling ewes from two commercial sheep flocks (A, n=489; B, n=248) in the North Island of New Zealand were enrolled in the study. Prior to lambing, CRC containing albendazole and abamectin were administered to half the ewes while the other half remained untreated. Ewe liveweights and body condition scores were measured prior to lambing, at weaning and, for Flock B, prior to subsequent mating. Lambs were matched to dams shortly after birth and the weight and number of lamb weaned per ewe were determined. A cost-benefit analysis was undertaken for Flock B considering the increased weight of lamb weaned per ewe, and the weight of ewes at the next mating and the benefit in terms of lambs born. RESULTS: The mean weight at weaning of treated ewes was greater for treated than untreated ewes by 2.76 (95% CI 0.64-4.88) kg in Flock A (p<0.001) and 2.35 (95% CI -0.41-5.12) kg in Flock B (p=0.003); the weight of lamb weaned per ewe was greater for treated than untreated ewes by 1.43 (95% CI -0.71 to -3.49) kg in Flock A (p=0.041) and 3.97 (95% CI 1.59-6.37) kg in Flock B (p<0.001), and ewe liveweight prior to subsequent mating was greater for treated than untreated ewes in Flock B by 4.60 (95% CI 3.6-5.6) kg (p<0.001). There was no difference in the percentage of lambs reared to weaning between treated and untreated ewes in either flock (p>0.8). The overall cost-benefit of treatment for Flock B was NZ$9.44 per treated ewe. CONCLUSIONS AND CLINICAL RELEVANCE: Pre-lambing CRC administration to yearling ewes resulted in increased ewe weaning weights and weight of lamb weaned in both the flocks studied. There was an economic benefit in the one flock where this was assessed.

Self-implanted tiny needles as alternative to traditional parenteral administrations for controlled transdermal drug delivery.

Controlled drug-delivery systems have potential as substitutes for traditional medication systems due to the advantages in safety, efficacy, and patient compliance that these long-acting dosage forms provide. In this context, the present study focus on the development of self-implanted hyaluronic acid (HA) tiny needles that encapsulate ivermectin (IVM)-poly (lactic-co-glycolic acid) (PLGA) microparticles for controlled transdermal IVM release to treat parasitic diseases. The fabricated tiny needles involved matching portable applicator have potentially able for self-administration by patients without intense pain or complexity of current controlled-release devices. The biodegradable IVM-loaded PLGA microparticles were prepared and encapsulated within the tip of dissolving HA tiny needles to achieve high delivery efficiency. The drug loading of tiny needles might be controlled by varying the repeat time of filling or pressing processes. In-vitro tests showed that the tiny needles have sufficient mechanical strength to be inserted into skin within seconds and, next rapidly dissolved to release the loaded drug carriers into subcutaneous tissues for intradermal sustained IVM release. With the in-vivo test in rats, the insertion site recovered barrier property within 3 h. In comparison to traditional hypodermic injection or implantation of controlled-release systems, the proposed polymer tiny needles can be considered as a promising device for controlled transdermal drug delivery.

In vivo combined treatment of rats with ivermectin and aged garlic extract attenuates ivermectin-induced cytogenotoxicity in bone marrow cells.

Ivermectin (IVM) is widely used in human and veterinary medicine for the control of parasitic infections. Researches revealed new avenues of medicinal applications of IVM as an antiviral and an anticancer agent. Very little is known about the genotoxic potential of IVM and the available literature is contradictory. The objective of this study was to evaluate the possible genetic damage caused by IVM. Male Sprague Dawley rats were intraperitoneally given IVM at doses between 0.2 mg and 3.2 mg/kg body weight (b. w). Percentages of mitotic and aberrant bone marrow cells were followed. The results indicated that IVM by itself, at doses higher than the recommended dose, induced significant levels of cytogenetic toxicity. To this end, we decided to investigate the potential use of combination of varying doses of aged garlic extract (AGE); 300, 600 and 1200 mg/kg b w and the minimum detectable toxic (MDT) dose of IVM; 0.4 mg/kg. A powerful capacity of AGE to reduce IVM cytogenetic effects was demonstrated. Overall, the data prove the safety of IVM at the recommended dose and provide a strong scientific evidence for superior protection of AGE against possible cytogenotoxic side effects of IVM, confirming the existence of a meaningful therapeutic window.

Formulation Studies of Solid Self-Emulsifying Drug Delivery System of Ivermectin.

BACKGROUND: The suggested dose of ivermectin is 300 µG/kg/day for onchocerciasis but it has low water solubility and poor oral bioavailability. AIM: To prepare and evaluate a solid lipid-based self-emulsifying drug delivery system of ivermectin. MATERIALS AND METHODS: Based on supersaturated solubility study, oil, surfactant, and co-surfactant were selected. On the basis of ternary phase diagrams and simplex-lattice design, self-emulsifying, drug delivery formulations had been developed and optimized. Ivermectin-excipients compatibility studies were performed using differential scanning calorimetry and Fourier transform infrared spectroscopy. Solid self-emulsifying drug delivery formulation was formulated from the optimized batch by surface assimilation method and filled into hard gelatin capsules. In vitro release rate and in vivo pharmacokinetic parameters of ivermectin from the capsules were determined. Two-tailed paired t-test/Dunnett multiple comparison tests were performed for in vivo pharmacokinetic parameter at 95 % of confidence level. RESULTS: Soybeans oil, tween 80, and span 80 were selected as oil, surfactant, and co-surfactant respectively. The ternary diagrams were shown the maximum area for emulsion in 1:2 surfactant/co-surfactant ratio. The optimized batch had found with 30 mg ivermectin, 6.17 g soybeans oil, 0.30 g tween 80, and 3.50 g span 80. All differential scanning calorimetry and Fourier transform infrared characteristic peaks of the optimized formulation were identical with that of pure ivermectin. The area under the curve of ivermectin from the capsule was about two-fold higher than that of ivermectin suspension. CONCLUSIONS: Solid self-emulsifying drug delivery system was an effective oral solid dosage form to improve the oral bioavailability of ivermectin.

Sustained release ivermectin-loaded solid lipid dispersion for subcutaneous delivery: in vitro and in vivo evaluation.

This work aimed to develop a sustained release solid dispersion of ivermectin (IVM-SD) in a lipid matrix (hydrogenated castor oil, HCO) for subcutaneous delivery. Solvent-melting technology was employed to prepare IVM-SDs using HCO. The physicochemical properties of the IVM-SDs were evaluated by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), and Fourier transform infrared spectroscopy (FTIR). The release of IVM from IVM-SDs was evaluated with HPLC in vitro. Pharmacokinetics of IVM was studied in rabbits following a single subcutaneous administration of IVM-SD formulations. The efficacy of IVM-SD against the ear mange mite was evaluated in rabbits. IVM was completely dispersed in HCO in an amorphous state at a drug:carrier ratio lower than 1:3. No chemical interactions between drug and carrier were found besides hydrogen bonding for the amorphous IVM-SDs. The amorphous IVM-SDs formulations exhibited a sustained release of IVM versus physical mixtures (PMs) of IVM and HCO. The drug release decreased as the drug:carrier ratios decreased, and the release kinetics of IVM were controlled via diffusion. Cytotoxicity of IVM-SD to MDCK cells was lower than native IVM. The IVM plasma concentration of SD1:3 remained above 1 ng/mL for 49 d. Higher AUC, MRT, and Tmax values were obtained at a SD1:3 relative to the IVM group. The IVM-SD improved almost 1.1-fold bioavailability of drug compared with IVM in rabbits. IVM-SD could provide longer persistence against rabbit's ear mites than a commercial IVM injection. This study shows that these solid lipid dispersions are a promising approach for the development of subcutaneous IVM formulations.

Preclinical Study of Single-Dose Moxidectin, a New Oral Treatment for Scabies: Efficacy, Safety, and Pharmacokinetics Compared to Two-Dose Ivermectin in a Porcine Model.

BACKGROUND: Scabies is one of the commonest dermatological conditions globally; however it is a largely underexplored and truly neglected infectious disease. Foremost, improvement in the management of this public health burden is imperative. Current treatments with topical agents and/or oral ivermectin (IVM) are insufficient and drug resistance is emerging. Moxidectin (MOX), with more advantageous pharmacological profiles may be a promising alternative. METHODOLOGY/PRINCIPAL FINDINGS: Using a porcine scabies model, 12 pigs were randomly assigned to receive orally either MOX (0.3 mg/kg once), IVM (0.2 mg/kg twice) or no treatment. We evaluated treatment efficacies by assessing mite count, clinical lesions, pruritus and ELISA-determined anti-S. scabiei IgG antibodies reductions. Plasma and skin pharmacokinetic profiles were determined. At day 14 post-treatment, all four MOX-treated but only two IVM-treated pigs were mite-free. MOX efficacy was 100% and remained unchanged until study-end (D47), compared to 62% (range 26-100%) for IVM, with one IVM-treated pig remaining infected until D47. Clinical scabies lesions, pruritus and anti-S. scabiei IgG antibodies had completely disappeared in all MOX-treated but only 75% of IVM-treated pigs. MOX persisted ~9 times longer than IVM in plasma and skin, thereby covering the mite's entire life cycle and enabling long-lasting efficacy. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate that oral single-dose MOX was more effective than two consecutive IVM-doses, supporting MOX as potential therapeutic approach for scabies.

Mathematical modelling of lymphatic filariasis elimination programmes in India: required duration of mass drug administration and post-treatment level of infection indicators.

BACKGROUND: India has made great progress towards the elimination of lymphatic filariasis. By 2015, most endemic districts had completed at least five annual rounds of mass drug administration (MDA). The next challenge is to determine when MDA can be stopped. We performed a simulation study with the individual-based model LYMFASIM to help clarify this. METHODS: We used a model-variant for Indian settings. We considered different hypotheses on detectability of antigenaemia (Ag) in relation to underlying adult worm burden, choosing the most likely hypothesis by comparing the model predicted association between community-level microfilaraemia (Mf) and antigenaemia (Ag) prevalence levels to observed data (collated from literature). Next, we estimated how long MDA must be continued in order to achieve elimination in different transmission settings and what Mf and Ag prevalence may still remain 1 year after the last required MDA round. The robustness of key-outcomes was assessed in a sensitivity analysis. RESULTS: Our model matched observed data qualitatively well when we assumed an Ag detection rate of 50 % for single worm infections, which increases with the number of adult worms (modelled by relating detection to the presence of female worms). The required duration of annual MDA increased with higher baseline endemicity and lower coverage (varying between 2 and 12 rounds), while the remaining residual infection 1 year after the last required treatment declined with transmission intensity. For low and high transmission settings, the median residual infection levels were 1.0 % and 0.4 % (Mf prevalence in the 5+ population), and 3.5 % and 2.0 % (Ag prevalence in 6-7 year-old children). CONCLUSION: To achieve elimination in high transmission settings, MDA must be continued longer and infection levels must be reduced to lower levels than in low-endemic communities. Although our simulations were for Indian settings, qualitatively similar patterns are also expected in other areas. This should be taken into account in decision algorithms to define whether MDA can be interrupted. Transmission assessment surveys should ideally be targeted to communities with the highest pre-control transmission levels, to minimize the risk of programme failure.

Efficacy of sainfoin (Onobrychis viciifolia) pellets against multi resistant Haemonchus contortus and interaction with oral ivermectin: Implications for on-farm control.

The worldwide spread of resistance to anthelmintic (AH) drugs in gastrointestinal nematodes (GINs) imposes to explore alternative solutions. Amongst those, the possible use of tannin-containing nutraceuticals appears as a relevant option to replace (or decrease the frequency of) chemical-based treatments. Our objectives were to test the AH efficacy of sainfoin pellets against a multiresistant strain of Haemonchus contortus in experimentally infected lambs and to examine possible interaction between ivermectin (IVM) and condensed tannins (CT)-rich ressource. In vivo study was performed with twenty-four lambs were inoculated (Day 0) with multiresistant H. contortus infective larvae. On D21 Post-Infection, the lambs were assigned to two dietary treatments (sainfoin vs lucerne control pellets). On D39, half of the animals per group received 0.25ml/kg of an oral ivermectin treatment. On D47, animals were slaughtered to count worms. The consumption of sainfoin was associated with higher packed cell volume (PCV) values (P<0.05) and reduced faecal egg counts (FECs) (P<0.05). For the experimental feeding period, FECs were overall reduced by 50% in the sainfoin group. The diet did not have significant effect on the worm number but sainfoin significantly reduced female fertility. Decrease in plasma IVM concentrations was observed in the sainfoin-fed animals and was associated with a decrease of IVM efficiency when compared with the control group. Incubating tannin in vitro with ivermectin and rumen fluid showed a blocking of ivermectin by the tannins. This suggests that tannins lower the IVM intestinal absorption compromising thereby drug plasma bioavailability and efficacy. Tannin-containing nutraceuticals alter the biology of multiresistant nematodes, thus representing an option for their sustainable control. In vivo and in vitro interactions between nutraceuticals and chemicals impose caution when both tannin-rich diet and drug-based treatments are combined. Further studies are required to clarify the mechanisms that support such interactions.

Accuracy of Coverage Survey Recall following an Integrated Mass Drug Administration for Lymphatic Filariasis, Schistosomiasis, and Soil-Transmitted Helminthiasis.

BACKGROUND: Achieving target coverage levels for mass drug administration (MDA) is essential to elimination and control efforts for several neglected tropical diseases (NTD). To ensure program goals are met, coverage reported by drug distributors may be validated through household coverage surveys that rely on respondent recall. This is the first study to assess accuracy in such surveys. METHODOLOGY/PRINCIPAL FINDINGS: Recall accuracy was tested in a series of coverage surveys conducted at 1, 6, and 12 months after an integrated MDA in Togo during which three drugs (albendazole, ivermectin, and praziquantel) were distributed. Drug distribution was observed during the MDA to ensure accurate recording of persons treated during the MDA. Information was obtained for 506, 1131, and 947 persons surveyed at 1, 6, and 12 months, respectively. Coverage (defined as the percentage of persons taking at least one of the MDA medications) within these groups was respectively 88.3%, 87.4%, and 80.0%, according to the treatment registers; it was 87.9%, 91.4% and 89.4%, according to survey responses. Concordance between respondents and registers on swallowing at least one pill was >95% at 1 month and >86% at 12 months; the lower concordance at 12 months was more likely due to difficulty matching survey respondents with the year-old treatment register rather than inaccurate responses. Respondents generally distinguished between pills similar in appearance; concordance for recall of which pills were taken was over 80% in each survey. SIGNIFICANCE: In this population, coverage surveys provided remarkably consistent coverage estimates for up to one year following an integrated MDA. It is not clear if similar consistency will be seen in other settings, however, these data suggest that in some settings coverage surveys might be conducted as much as one year following an MDA without compromising results. This might enable integration of post-MDA coverage measurement into large, multipurpose, periodic surveys, thereby conserving resources.

Successful management of ivermectin-induced blindness in an African lion (Panthera leo) by intravenous administration of a lipid emulsion.

BACKGROUND: Ivermectin is widely used in veterinary practice for the treatment of ecto- and endo-parasites. In wildlife, an extra-label use this parasiticide is sometimes associated with toxicity. Different treatment regimens have been used in ivermectin toxicosis. The present report describes a successful reversal of ivermectin toxicity by intravenous administration of a commercially available lipid emulsion in a captive African lion (Panthera leo). CASE PRESENTATION: A 2-year old captive African lion (Panthera leo) weighing ~130 kg was presented with acute neurological impairment and bilateral blindness that had developed 24 h after ivermectin exposure. The animal was treated with a commercially available lipid emulsion along with supportive therapy and experienced complete recovery. CONCLUSION: To our knowledge, this is the first case report of the use of lipid emulsion in the management of ivermectin induced blindness in an African lion and it appears that intravenous lipid emulsion may be an effective therapy in ivermectin toxicity in lions. Further testing in expanded clinical trials is clearly warranted.