The Use of Systemically Absorbed Drugs to Explore An In Vitro Bioequivalence Approach For Comparing Non-Systemically Absorbed Active Pharmaceutical Ingredients in Drug Products For Use in Dogs.

PURPOSE: Currently, for veterinary oral formulations containing one or more active pharmaceutical ingredient (API) that are not systemically absorbed and act locally within the gastrointestinal (GI) tract, the use of terminal clinical endpoint bioequivalence (BE) studies is the only option for evaluating product BE. This investigation explored the use of a totality of evidence approach as an alternative to these terminal studies. METHODS: Three formulations of tablets containing ivermectin plus praziquantel were manufactured to exhibit distinctly different in vitro release characteristics. Because these APIs are highly permeable, plasma drug concentrations served as a biomarker of in vivo dissolution. Tablets were administered to 27 healthy Beagle dogs (3-way crossover) and the rate and extent of exposure of each API for each formulation was compared in a pairwise manner. These results were compared to product relative in vitro dissolution profiles in 3 media. In vivo and in vitro BE predictions were compared. RESULTS: In vivo/in vitro inconsistencies in product relative performance were observed with both compounds when considering product performance across the 3 dissolution media. Formulation comparisons flagged major differences that could explain this outcome. CONCLUSIONS: The finding of an inconsistent in vivo/in vitro relationship confirmed that in vitro dissolution alone cannot assure product BE for veterinary locally acting GI products. However, when combined with a comparison of product composition and manufacturing method, this totality of evidence approach can successfully alert scientists to potential therapeutic inequivalence, thereby supporting FDA's efforts to Replace, Reduce, and/or Refine terminal animal studies.

Combined interventions for the testing and treatment of HIV and schistosomiasis among fishermen in Malawi: a three-arm, cluster-randomised trial.

BACKGROUND: Undiagnosed HIV and schistosomiasis are highly prevalent among fishermen in the African Great Lakes region. We aimed to evaluate the efficacy of lakeside interventions integrating services for HIV and male genital schistosomiasis on the prevalence of schistosomiasis, uptake of antiretroviral therapy (ART) for HIV, and voluntary male medical circumcision (VMMC) among fishermen in Malawi. METHODS: We conducted a three-arm, cluster-randomised trial in 45 lakeshore fishing communities (clusters) in Mangochi, Malawi. Clusters were defined geographically by their home community as the place where fishermen leave their boats (ie, a landing site). Eligible participants were male fishermen (aged ≥18 years) who resided in a cluster. Clusters were randomly allocated (1:1:1) through computer-generated random numbers to either enhanced standard of care (SOC), which offered invitation with information leaflets to a beach clinic offering HIV testing and referral, and presumptive treatment for schistosomiasis with praziquantel; peer education (PE), in which a nominated fisherman was responsible for explaining the study leaflet to promote services to his boat crew; or peer distribution education (PDE), in which the peer educator explained the leaflet and distributed HIV self-test kits to his boat crew. The beach clinic team and fishermen were not masked to intervention allocation; however, investigators were masked until the final analysis. Coprimary composite outcomes were the proportion of participants who had at least one Schistosoma haematobium egg observed on light microscopy from 10 mL of urine filtrate and the proportion who had self-reported initiating ART or scheduling VMMC by day 28. Outcomes were analysed by intention to treat; multiple imputation for missing outcomes was done; random-effect binomial models adjusting for baseline imbalance and clustering were used to compute unadjusted and adjusted risk differences, risk ratios (RRs) and 95% CIs, and intracluster correlation coefficients for each outcome. This trial is registered with ISRCTN, ISRCTN14354324. FINDINGS: Between March 1, 2022, and Jan 29, 2023, 45 (65·2%) of 69 clusters assessed for eligibility were enrolled in the trial, with 15 clusters per arm. Of the 6036 fishermen screened at baseline, 5207 (86·3%) were eligible for participation: 1745 (87·6%) of 1991 in the enhanced SOC group, 1687 (81·9%) of 2061 in the PE group, and 1775 (89·5%) of 1984 in the PDE group. Compared with the prevalence of active schistosomiasis in the enhanced SOC group (292 [16·7%] of 1745), 241 (13·6%) of 1775 fishermen in the PDE group (adjusted RR 0·80 [95% CI 0·69-0·94]; p=0·0054) and 263 (15·6%) of 1687 fishermen in the PE group (0·92 [0·79-1·07]; p=0·28) had schistosomiasis at day 28. 230 (13·2%) in the enhanced SOC group, 281 (16·7%) in the PE group, and 215 (12·1%) in the PDE group initiated ART or were scheduled for VMMC. ART initiation or VMMC scheduling was not significantly increased with the PDE intervention (0·88 [0·74-1·05); p=0·15) and was marginally increased with the PE intervention (1·16 [0·99-1·37]; p=0·069) when compared with the enhanced SOC group. No serious adverse events were reported in this trial. INTERPRETATION: We found weak evidence for the use of peer education to increase uptake of ART and VMMC, but strong evidence for the added distribution of HIV self-test kits to promote high engagement with services and reduce the prevalence of active schistosomiasis, suggesting a high potential for scale-up in hard-to-reach communities across Malawi. FUNDING: Wellcome Trust and the UK National Institute for Health Research.

Crossroad between the sylvatic and domestic cycles of Mesocestoides litteratus: mesocestodiasis in dogs adopted from shelters in Türkiye.

This study aimed to report the presence of Mesocestoides litteratus in dogs adopted from shelters in Türkiye. Gravid segments were examined microscopically in the faeces of dogs from different shelters located in Ankara and Kirikkale provinces in the central region of Türkiye. Then, genomic DNA obtained from these segments, a 446-bp fragment of the mitochondrial cytochrome C oxidase subunit 1 gene, and a 350-bp fragment of mitochondrial 12S rRNA were amplified and sequenced. BLASTn search was performed. During light microscopic examination, an egg-filled paruterine organ was observed in the middle part of the segment. Thin-shelled, oval, 35-µm-diameter parasite eggs containing an oncosphere with three pairs of hooklets were observed. The gravid segments were determined as Mesocestoides spp. based on the appearance of the typical paruterine organ. PCR results supported our diagnosis; moreover, according to the BLAST results, it was detected that the species infecting two dogs was 98.01-100% similar to M. litteratus. Praziquantel-containing medication was administered to the infected dogs at a dosage of 5 mg/kg. Foxes act as the final host of M. litteratus and the parasite is prevalent in wildlife; however, these animals may disperse the parasite in urban life. Veterinarians need to be made more aware of this parasite, especially if the dogs are owned from shelters.

Clinical efficacy of a parasiticide formulation containing eprinomectin, esafoxolaner and praziquantel (NexGard® Combo) in the treatment of natural feline aelurostrongylosis and troglostrongylosis.

The metastrongyloids Aelurostrongylus abstrusus and Troglostrongylus brevior are primary causes of feline clinical respiratory disease. The present field trial evaluated the clinical efficacy of a spot-on formulation containing eprinomectin, esafoxolaner and praziquantel (NexGard® Combo) administered per label recommendations to cats affected with aelurostrongylosis and/or troglostrongylosis. Overall, 36 naturally infected cats were randomly assigned to Group 1 (G1) or Group 2 (G2) of 18 cats each. The two groups included 6 cats with A. abstrusus, T. brevior and mixed infection, each. All cats completed the study. Cats in G1 were treated on study Days (SDs) 0 and 28±2. Cats in G2 served as negative control until SD 56±2 and were then treated on SD 56±2 and 84±2. On SD 0/-7, 28±2 and SD 56±2 all cats were subjected to parasitological (quali-quantitative Baermann) and clinical examinations (physical exams and thoracic X-rays). Hematology and biochemistry analyses were performed on SD 0/-7 and SD 56±2. On SD 84±2 quali-quantitative Baermann, clinical examination and thorax radiography were performed on all G2 cats and on two G1 cats that still had radiographic alterations on SD 56±2. On SD 112±2 all G2 cats were subjected to parasitological and clinical evaluations and one cat from G1 that still had radiographic signs at SD 84±2 was clinically and radiographically evaluated. Efficacy criteria were the reduction of larval shedding in faeces and the clinical response in terms of pathological and radiographic scores after treatment compared to the baseline. An efficacy of 100 % based on LPG reduction was recorded after one (20/24 cats) or two (all 24 cats) treatments in cats with single infection by A. abstrusus or T. brevior. For cats with mixed infections, larval shedding was stopped after one (11/12 cats) or two (all 12 cats) treatments. Statistically significant clinical and radiographic improvement was evident in all study cats after 2 treatments. The present data show that two monthly treatments with NexGard® Combo stopped larval shedding and led to a significant clinical recovery and a complete resolution of radiographic abnormalities in cats infected with A. abstrusus and/or T. brevior.

Schistosomiasis in migrant children and adolescents in a paediatric tropical referral unit in Spain: diagnosis and long-term management challenges.

Globalisation and population movement have led to an increasing number of migrant children residing in areas non-endemic for schistosomiasis. However, diagnosing and managing schistosomiasis in children remain controversial. This study aims to investigate the prevalence of schistosomiasis in migrant children and to describe the diagnostic approach and management strategies, including long-term follow-up, to explore the potential role of serological tests in evaluating treatment response. We conducted a retrospective descriptive study spanning from January 2014-July 2021 at a referral unit for Paediatric Tropical Diseases in Madrid (Spain). The study included patients under 18 years diagnosed with schistosomiasis. Of 679 children screened for schistosomiasis, 73 (10.8%) tested positive. The median age was 16.3 years [IQR 9-17.6], 74% male. The majority originated from Sub-Saharan Africa (47%) and Asia (47%). Only 40% presented with symptoms, with gastrointestinal (18%) and cutaneous (17%) manifestations being the most common. Eosinophilia was observed in 43% (median [IQR]: 1103/mm3 [671-1536]), and ova were visualised in the urine of 2/50 (4.0%). Praziquantel treatment was administered to 92%, and 5 patients required retreatment. Follow-up data were available for 58 (80%) over a median period of 9 months [IQR 6-19.8], revealing a progressive decline in eosinophil count, IgE titres, and ELISA optical density.    Conclusion: In this series, the prevalence of schistosomiasis among migrant children was significant (10%), highlighting the importance of including serological tests in migrant health screening. The disease is largely asymptomatic, eosinophilia is often absent, and visualisation of ova in urine is exceedingly rare. Eosinophil count, IgE titres, and ELISA optical density could prove valuable as an initial approach for monitoring inflammation during follow-up assessments. What is Known: • The burden of disease related to schistosomiasis is significant, particulary in children, and it is advisable to screen this vulnerable population. What is New: • Eosinophilia may not be present in parasitic infections, so serological tests are crucial for screening migrant children. • Serological monitoring facilitates long-term management of migrant children with schistosomiasis.

Efficacy of a topical combination of esafoxolaner, eprinomectin and praziquantel against Amblyomma maculatum infestations in cats.

Amblyomma maculatum, the Gulf Coast tick, infests a wide range of vertebrate species including livestock, dogs, cats, and humans. It is a species of significant veterinary and public health importance, especially as a vector of diseases, for instance American canine hepatozoonosis or tidewater spotted fever. An experimental study was conducted to evaluate the efficacy of NexGard® Combo, a topical endectoparasiticide product for cats combining eprinomectin, praziquantel and esafoxolaner, against induced infestations of A. maculatum in cats. This Good Clinical Practice (GCP) study used a randomized, negative controlled, masked design. Ten cats were allocated to an untreated group and ten to a treated group, dosed once on Day 0 at the minimum label dose. On Days -2, 7, 14, 21, 28, 35, and 42, cats were infested with ~50 unfed adult A. maculatum. On Days 3, 10, 17, 24, 31, 38, and 45, i.e., 72 h after treatment and subsequent infestations, ticks were removed, counted and the numbers of live attached tick in each group were used for efficacy calculations. At each time-point, all untreated cats were adequately infested, demonstrating a vigorous tick population and an adequate study model. The curative efficacy after a single application against existing tick infestation, 72 h after treatment, was 98.7%. The preventive efficacy, 72 h after weekly infestations, over the following five weeks ranged from 93.8% to 99.4%.

Title: Efficacité d'une association topique d'esafoxolaner, d'éprinomectine et de praziquantel contre les infestations par Amblyomma maculatum chez le chat. Abstract: Amblyomma maculatum, la tique de la Gulf Coast, infeste un large éventail d'espèces de vertébrés, notamment le bétail, les chiens, les chats et les humains. Il s'agit d'une espèce d'importance significative en médecine vétérinaire et en santé publique, notamment en tant que vecteur de maladies, par exemple l'hépatozoonose canine américaine ou la fièvre pourprée des marées. Une étude expérimentale a été menée pour évaluer l'efficacité de NexGard® Combo, un produit endectoparasiticide topique pour chats associant éprinomectine, praziquantel et esafoxolaner, contre les infestations par A. maculatum provoquées chez le chat. Cette étude de bonnes pratiques cliniques (BPC) a utilisé une conception randomisée, contrôlée négativement et masquée. Dix chats ont été répartis dans un groupe non traité et dix chats dans un groupe traité, traités une fois au jour 0 à la dose minimale indiquée sur l'étiquette. Aux jours −2, 7, 14, 21, 28, 35 et 42, les chats ont été infestés par environ 50 A. maculatum adultes non nourris. Les jours 3, 10, 17, 24, 31, 38 et 45, c'est-à-dire 72 heures après le traitement et les infestations ultérieures, les tiques ont été retirées, comptées et le nombre de tiques vivantes attachées dans chaque groupe a été utilisé pour les calculs d'efficacité. À chaque instant, tous les chats non traités étaient correctement infestés, démontrant une population de tiques vigoureuse et un modèle d'étude adéquat. L'efficacité curative après une seule application contre une infestation de tiques existante, 72 heures après le traitement, était de 98,7%. L'efficacité préventive, 72 heures après les infestations hebdomadaires, au cours des cinq semaines suivantes, variait entre 93,8% et 99,4%.

The synergistic effect of Ficus carica nanoparticles and Praziquantel on mice infected by Schistosoma mansoni cercariae.

Bilharzia is a parasitic flatworm that causes schistosomiasis, a neglected tropical illness worldwide. Praziquantel (PZQ) is a commercial single treatment of schistosomiasis so alternative drugs are needed to get rid of its side effects on the liver. The current study aimed to estimate the effective role of Ficus carica nanoparticles (Fc-NPCs), silver nanoparticles (Ag-NPCs) and Ficus carica nanoparticles loaded on silver nanoparticles (Fc-Ag NPCs) on C57BL/6 black female mice infected by Schistosoma mansoni and treated with PZQ treatment. It was proved that schistosomiasis causes liver damage in addition to the PZQ is ineffective as an anti-schistosomiasis; it is recorded in the infected mice group and PZQ treated group as in liver function tests, oxidative stress markers & anti-oxidants, pro-inflammatory markers, pro-apoptotic and anti-apoptotic markers also in liver cells' DNA damage. The amelioration in all tested parameters has been clarified in nanoparticle-protected mice groups. The Fc-Ag NPCs + PZQ group recorded the best preemptive effects as anti-schistosomiasis. Fc-NPCs, Ag-NPCs and Fc-Ag NPCs could antagonize PZQ effects that were observed in amelioration of all tested parameters. The study showed the phytochemicals' nanoparticles groups have an ameliorated effect on the health of infected mice.

Anthelmintic activity and pathophysiological effect of anthelmintic drugs against carcinogenic liver fluke, Opisthorchis viverrini.

Human liver fluke, Opisthorchis viverrini poses a significant risk for development of cholangiocarcinoma (CCA) in Thailand, primarily attributed to consumption of undercooked cyprinoid fishes. The current use of anthelmintic drug treatment such as praziquantel (PZQ), as the main therapeutic agent against O. viverrini. There is a need to explore the efficacy of alternative anthelmintic drugs for O. viverrini treatment. This study aimed to assess the efficacy of anthelmintic drugs, which are commonly use in endemic areas of Southeast Asian countries; PZQ, albendazole (AL), niclosamide (NI), and mebendazole (ME) at concentrations of 600, 400, 500, and 500 mg/ml. The study included a negative and positive control group treated with roswell park memorial institute (RPMI) and PZQ. Reactive oxygen species (ROS) levels, indicative of oxidative stress, were quantified using 2',7'-dichlorofluorescein diacetate staining. Morphological changes were observed using scanning electron microscopy. Furthermore, motility assessments were conducted at various time points (0, 5, 30 minutes, 1, 3, 6, 12, and 24 hours), calculating relative motility (RM) and survival index (SI). The results revealed a significant increase of ROS levels with the intensity and corrected total worm fluorescence (CTWF) mostly observed in order of PZQ, followed by NI, ME, and AL, respectively. Morphological damage was presented the tegumental swelling, papillae changes, and disruption of microvilli (Mv), particularly in the group treated with the most effective anthelmintics PZQ, NI, ME, and AL, while negative control group did not exhibit such alterations. Also, the most efficacy for suppressing the motility of adult worms were displayed in PZQ treatment group, followed by NI, ME, and AL, respectively. Overall, first novel findings suggest that apart from NI, ME, and AL demonstrate potential as alternative therapeutic options for O. viverrini infection. Furthermore, animal model is needed to investigate the efficacy of NI, ME, and AL compare with standard treatment.

Re- Infection Rate of Opisthorchis Viverrini Five Years After Treatment with Praziquantel in High-Risk Area: A Community-Based Study.

BACKGROUND: Opisthorchis viverrini (OV)  is a significant public health problem in Thailand, and  OV reinfection poses a serious risk of cholangiocarcinoma with little evidence of a decrease.  While numerous studies have explored OV reinfection and prevalence, most have been limited to short study period. Therefore, there is a need for long-term investigations to gather sufficient evidence. OBJECTIVES: This study aimed to access the current status of re-infection rates in high- risk areas and to determine associations between factors of and re-infection of OV at 5 years after treatment  with praziquantel. MATERIALS AND METHODS: In total, this study included 457 participants from a cohort study. Each participant was required to answer a questionnaire and undergo stool examination using the formalin ethyl acetate concentration technique. Data were analyzed using descriptive statistics and multiple logistic regression. RESULT: Out of the total 457 participants, 418 (91.5%) successfully completed the questionnaires and underwent stool examinations. Among the participants, 10.8% showed re-infection with OV. Using multivariate analysis, factors significantly associated with reinfection OV included yearly income (OR adj = 2.14, 95%CI = 1.11- 4.12, p-value = 0.022) and past stool examination five years (OR adj = 2.47, 95%CI = 1.13-5.43, p-value = 0.023), respectively. CONCLUSIONS: Subjects who frequently experience OV reinfection should undergo CCA screening by experts while closely monitoring their raw fish consumption behavior. Moreover, it is essential to implement comprehensive programs aimed at promoting behavioral changes and provide preventive education, with a specific focus on high epidemic areas, to discourage the consumption of raw fish.

Development of non-sedating benzodiazepines with in vivo antischistosomal activity.

The neglected tropical disease schistosomiasis infects over 200 million people worldwide and is treated with just one broad-spectrum antiparasitic drug (praziquantel). Alternative drugs are needed in the event of emerging praziquantel resistance or treatment failure. One promising lead that has shown efficacy in animal models and a human clinical trial is the benzodiazepine meclonazepam, discovered by Roche in the 1970s. Meclonazepam was not brought to market because of dose-limiting sedative side effects. However, the human target of meclonazepam that causes sedation (GABAARs) is not orthologous to the parasite targets that cause worm death. Therefore, we were interested in whether the structure of meclonazepam could be modified to produce antiparasitic benzodiazepines that do not cause host sedation. We synthesized 18 meclonazepam derivatives with modifications at different positions on the benzodiazepine ring system and tested them for in vitro antiparasitic activity. This identified five compounds that progressed to in vivo screening in a murine model, two of which cured parasite infections with comparable potency to meclonazepam. When these two compounds were administered to mice that were run on the rotarod test, both were less sedating than meclonazepam. These findings demonstrate the proof of concept that meclonazepam analogs can be designed with an improved therapeutic index and point to the C3 position of the benzodiazepine ring system as a logical site for further structure-activity exploration to further optimize this chemical series.

Clinical sensitivity and time-to-result of a cascaded pooled testing approach for assessing the prevalence and intensity of Schistosoma haematobium infection.

BACKGROUND: This study compared the clinical sensitivity and the time-to-result of an individual testing (IT) and a cascaded pooled testing approach (CPT; a positive test result in a pooled sample triggers examination of smaller-sized pools or individual samples) for assessing the prevalence and the intensity of Schistosoma haematobium infection. We also compared the sensitivity of the CPT in detecting S. haematobium infection when deploying urine filtration microscopy (UFM) vs. urine reagent strips (URS), and testing 10 mL vs. 15 mL of urine. METHODOLOGY/PRINCIPAL FINDINGS: Between October 2021 and April 2022, S. haematobium eggs were counted in urine samples collected from school-aged children living in the Afar and Gambella Regional States of Ethiopia. Urine samples were collected at baseline (n = 1,288), and one month after administration of praziquantel (n = 118). All urine samples were processed through both an IT and a CPT approach (pools of 5, 10, 20, and 40 individual samples), deploying UFM (10 mL) and URS (10 mL). In addition, 15 mL urine was processed through the CPT deploying UFM. At baseline, the prevalence of S. haematobium infection estimated when using UFM and deploying a CPT approach was significantly lower (17.3%) compared to an IT approach (31.5%). The clinical sensitivity of the CPT in detecting S. haematobium eggs was 51.7%. The sensitivity increased significantly as a function of increasing log transformed urine egg counts (UECs) of the individual samples (OR 2.71, 95%CI 1.63 - 4.52). The sensitivity was comparable when the amount of urine examined was 10 mL (51.7%) vs. 15 ml (50.8%), and when UFM was used for testing vs. URS (51.5%). The mean log UECs estimated following the CPT approach was lower compared to the estimate by the IT (p <0.001). UECs of the individual samples estimated using the IT and CPT approaches were moderately correlated (r = 0.59 when 10 mL and 15 mL urine was examined after pooling). CPT reduced the time needed for processing urine samples and testing for S. haematobium infection by 29% with UFM and by 27.7% with URS. CONCLUSIONS/SIGNIFICANCE: CPT based on UFM and URS techniques may help to rapidly identify areas with higher prevalence of S. haematobium infection (hotspots) in a population. However, the performance of this approach in estimating the prevalence of infection may be compromised, particularly in endemic areas with low intensity infection.

Paediatric schistosomiasis: last mile preparations for deploying paediatric praziquantel.

Schistosomiasis is the second most important parasitic disease of public health importance in Africa, affecting over 50 million children aged <5 years old. Schistosomiasis control has focused on treating school-aged children (>6 years) and adults through mass drug administration (MDA). Following the recent development of a paediatric praziquantel (PZQ) formulation for children aged <5 years, there are now concerted efforts to determine optimal and effective ways to integrate treatment of these children into national schistosomiasis control programmes. In this opinion article we outline the pathway for successful drug access, delivery, and mainstreaming of the new formulation in endemic country health systems. Effective and sustained paediatric schistosomiasis treatment is an important target of the 2030 World Health Organization (WHO) neglected tropical diseases (NTDs) roadmap.

Follow up study of symptomatic human cystic echinococcosis treatment with albendazole and praziquantel, in Uruguay.

BACKGROUND: Cystic echinococcosis (CE) is a chronic disease considered a neglected one. Cystic echinococcosis is endemic in Uruguay and the region. Surgery, using various technical approaches, has the potential to safely remove the cyst(s) and lead to a complete cure in a high number of patients with simple forms of CE. However, surgery may be impractical in patients with multiple cysts in several organs, high surgical risk, or in patients with previous multiple surgeries. In these cases, the pharmacological treatment with the benzimidazolic drug Albendazole (ABZ) alone or combined with Praziquantel (PZQ), has been promising as the best choice to achieve improvement or cure. METHODS: In this study, we analyze the results obtained on the anti-parasitic treatment of 43 patients diagnosed with CE between the years 2003 and 2020. Patients were treated before and/or after surgery with ABZ or the combination ABZ/PZQ. The standardize protocol of the anti-parasitic drug treatment before surgery was 7 days, 15 days or 1 month depending on the urgency and availability of the surgical procedure. All cases that involved confirmed locations on lungs underwent immediate surgery with minimal pre-treatment when possible. After surgery, the standardize protocol of anti-parasitic drug treatment consisted of six cycles of 30 days each and resting intervals of 15 days in between. ABZ was used in all cases, administered orally, twice daily, at a total dosage of 15 mg/kg/day, with food high in fat content for improved absorption. The follow up was carried out according to WHO-IWGE guidelines for 5 years. RESULTS: Of the 43 patients fourteen were ≤ 15 years of age and had a differentiated pre-surgical treatment. From the ≥ 16 years of age, 36 completed the treatments and the 5 years follow up. Four patients changed geographical locations, without a forwarding contact, after the post-surgery treatment. No patient died during the study. Of the 36 patients that completed the study, 32 were treated only with ABZ; 93.75% achieved treatment success as determined by improvement or cure, and 6.25% treatment failure determined by no change or worsening. The last four patients received the ABZ/PZQ combination therapy and achieved 100% treatment success. CONCLUSION: The pharmacological treatment resulted in a good option not only as palliative but also as potentially curative. The main relevance of its use was in cases with previous multiple surgeries or surgeries with potential life-threatening complications due to the number and location of cysts and concurrent comorbidities. A follow-up of at least 5 years would be recommended to assure remission and control of the transmission. More randomized trials are needed to provide clear clinical evidence of different pharmacological treatments for CE.

OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN PRESUMED VETERINARY ANTHELMINTIC DRUG-INDUCED RETINAL TOXICITY: A Glimpse into Underlying Mechanism.

PURPOSE: To report optical coherence tomography findings of presumed veterinary anthelmintic drugs (VADs)-induced retinal toxicity that may aid in understanding potential pathogenic mechanisms. METHODS: This is a retrospective observational case series analysis of patients with vision abnormalities following the accidental or intentional consumption of veterinary anthelmintic drugs. All cases underwent a thorough ophthalmological examination. Moreover, medical records, as well as the initial and follow-up optical coherence tomography images, were thoroughly scrutinized. RESULTS: Four patients were identified (3 men; mean [range] age, 36.5 [22-52] years). Each patient overdosed on one or two of the following VADs: closantel, triclabendazole, praziquantel, pyrantel pamoate, and niclofolan. The most characteristic optical coherence tomography finding was diffuse, granular, hyperreflective lesions throughout the outer retina, which were initially identified in the ellipsoid zone in two cases. At follow-up, optical coherence tomography exhibited regression of hyperreflective lesions and extensive loss of the outer retinal elements in two patients. In addition, the subfoveal outer retinal layers may be partially preserved. CONCLUSION: Some veterinary anthelmintic drugs could be detrimental to the human retina if overdosed, resulting in visual disturbances. Optical coherence tomography revealed the mitochondria-enriched ellipsoid zone where outer retinal damage first appeared on, implying that these medications may harm the retina by inhibiting mitochondrial energy metabolism, as they do to eliminate parasites.

Test-treat-track-test-treat (5T) approach for Schistosoma haematobium elimination on Pemba Island, Tanzania.

BACKGROUND: After decades of praziquantel mass drug administration (MDA), several countries approach schistosomiasis elimination. Continuing MDA in largely uninfected populations no longer seems justified. Alternative interventions to maintain the gains or accelerate interruption of transmission are needed. We report results, strengths, and shortcomings of novel test-treat-track-test-treat (5T) interventions in low Schistosoma haematobium prevalence areas on Pemba, Tanzania. METHODS: School- and household-based surveys were conducted in 2021 and 2022 to monitor the S. haematobium and microhematuria prevalence and assess the impact of interventions. In 2021, 5T interventions were implemented in 15 low-prevalence areas and included: (i) testing schoolchildren in primary and Islamic schools for microhematuria as a proxy for S. haematobium, (ii) treating positive children, (iii) tracking them to their households and to water bodies they frequented, (iv) testing individuals at households and water bodies, and (v) treating positive individuals. Additionally, test-and-treat interventions were implemented in the 22 health facilities of the study area. RESULTS: The S. haematobium prevalence in the school-based survey in 15 low-prevalence implementation units was 0.5% (7/1560) in 2021 and 0.4% (6/1645) in 2022. In the household-based survey, 0.5% (14/2975) and 0.7% (19/2920) of participants were infected with S. haematobium in 2021 and 2022, respectively. The microhematuria prevalence, excluding trace results, in the school-based survey was 1.4% (21/1560) in 2021 and 1.5% (24/1645) in 2022. In the household-based survey, it was 3.3% (98/2975) in 2021 and 5.4% (159/2920) in 2022. During the 5T interventions, the microhaematuria prevalence was 3.8% (140/3700) and 5.8% (34/594) in children in primary and Islamic schools, respectively, 17.1% (44/258) in household members, and 16.7% (10/60) in people at water bodies. In health facilities, 19.8% (70/354) of patients tested microhematuria-positive. CONCLUSIONS: The targeted 5T interventions maintained the very low S. haematobium prevalence and proved straightforward and feasible to identify and treat many of the few S. haematobium-infected individuals. Future research will show whether 5T interventions can maintain gains in the longer-term and expedite elimination. TRIAL REGISTRATION: ISRCTN, ISCRCTN91431493. Registered 11 February 2020, https://www.isrctn.com/ISRCTN91431493 .

Treatment of uncomplicated hepatic cystic echinococcosis (hydatid disease).

BACKGROUND: Cystic echinococcosis is a parasitic infection mainly impacting people living in low- and middle-income countries. Infection may lead to cyst development within organs, pain, non-specific symptoms or complications including abscesses and cyst rupture. Treatment can be difficult and varies by country. Treatments include oral medication, percutaneous techniques and surgery. One Cochrane review previously assessed the benefits and harms of percutaneous treatment compared with other treatments. However, evidence for oral medication, percutaneous techniques and surgery in specific cyst stages has not been systematically investigated and the optimal choice remains uncertain. OBJECTIVES: To assess the benefits and harms of medication, percutaneous and surgical interventions for treating uncomplicated hepatic cystic echinococcosis. SEARCH METHODS: We searched CENTRAL, MEDLINE, two other databases and two trial registries to 4 May 2023. We searched the reference lists of included studies, and contacted experts and researchers in the field for relevant studies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in people with a diagnosis of uncomplicated hepatic cystic echinococcosis of World Health Organization (WHO) cyst stage CE1, CE2, CE3a or CE3b comparing either oral medication (albendazole) to albendazole plus percutaneous interventions, or to surgery plus albendazole. Studies comparing praziquantel plus albendazole to albendazole alone prior to or following an invasive intervention (surgery or percutaneous treatment) were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were symptom improvement, recurrence, inactive cyst at 12 months and all-cause mortality at 30 days. Our secondary outcomes were development of secondary echinococcosis, complications of treatment and duration of hospital stay. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included three RCTs with 180 adults and children with hepatic cystic echinococcosis. Two studies enrolled people aged 5 to 72 years, and one study enrolled children aged 6 to 14 years. One study compared standard catheterization plus albendazole with puncture, aspiration, injection and re-aspiration (PAIR) plus albendazole, and two studies compared laparoscopic surgery plus albendazole with open surgery plus albendazole. The three RCTs were published between 2020 and 2022 and conducted in India, Pakistan and Turkey. There were no other comparisons. Standard catheterization plus albendazole versus PAIR plus albendazole The cyst stages were CE1 and CE3a. The evidence is very uncertain about the effect of standard catheterization plus albendazole compared with PAIR plus albendazole on cyst recurrence (risk ratio (RR) 3.67, 95% confidence interval (CI) 0.16 to 84.66; 1 study, 38 participants; very low-certainty evidence). The evidence is very uncertain about the effects of standard catheterization plus albendazole on 30-day all-cause mortality and development of secondary echinococcosis compared to open surgery plus albendazole. There were no cases of mortality at 30 days or secondary echinococcosis (1 study, 38 participants; very low-certainty evidence). Major complications were reported by cyst and not by participant. Standard catheterization plus albendazole may increase major cyst complications compared with PAIR plus albendazole, but the evidence is very uncertain (RR 10.74, 95% CI 1.39 to 82.67; 1 study, 53 cysts; very low-certainty evidence). Standard catheterization plus albendazole may make little to no difference on minor complications compared with PAIR plus albendazole, but the evidence is very uncertain (RR 1.03, 95% CI 0.60 to 1.77; 1 study, 38 participants; very low-certainty evidence). Standard catheterization plus albendazole may increase the median duration of hospital stay compared with PAIR plus albendazole, but the evidence is very uncertain (4 (range 1 to 52) days versus 1 (range 1 to 15) days; 1 study, 38 participants; very low-certainty evidence). Symptom improvement and inactive cysts at 12 months were not reported. Laparoscopic surgery plus albendazole versus open surgery plus albendazole The cyst stages were CE1, CE2, CE3a and CE3b. The evidence is very uncertain about the effect of laparoscopic surgery plus albendazole on cyst recurrence in participants with CE2 and CE3b cysts compared to open surgery plus albendazole (RR 3.00, 95% CI 0.13 to 71.56; 1 study, 82 participants; very low-certainty evidence). The second study involving 60 participants with CE1, CE2 or CE3a cysts reported no recurrence in either group. The evidence is very uncertain about the effect of laparoscopic surgery plus albendazole on 30-day all-cause mortality in participants with CE1, CE2, CE3a or CE3b cysts compared to open surgery plus albendazole. There was no mortality in either group (2 studies, 142 participants; very low-certainty evidence). The evidence is very uncertain about the effect of laparoscopic surgery plus albendazole on major complications in participants with CE1, CE2, CE3a or CE3b cysts compared to open surgery plus albendazole (RR 0.50, 95% CI 0.13 to 1.92; 2 studies, 142 participants; very low-certainty evidence). Laparoscopic surgery plus albendazole may lead to slightly fewer minor complications in participants with CE1, CE2, CE3a or CE3b cysts compared to open surgery plus albendazole (RR 0.13, 95% CI 0.02 to 0.98; 2 studies, 142 participants; low-certainty evidence). Laparoscopic surgery plus albendazole may reduce the duration of hospital stay compared with open surgery plus albendazole (mean difference (MD) -1.90 days, 95% CI -2.99 to -0.82; 2 studies, 142 participants; low-certainty evidence). Symptom improvement, inactive cyst at 12 months and development of secondary echinococcosis were not reported. AUTHORS' CONCLUSIONS: Percutaneous and surgical interventions combined with albendazole can be used to treat uncomplicated hepatic cystic echinococcosis; however, there is a scarcity of randomised evidence directly comparing these interventions. There is very low-certainty evidence to indicate that standard catheterization plus albendazole may lead to fewer cases of recurrence, more major complications and similar complication rates compared to PAIR plus albendazole in adults and children with CE1 and CE3a cysts. There is very low-certainty evidence to indicate that laparoscopic surgery plus albendazole may result in fewer cases of recurrence or fewer major complications compared to open surgery plus albendazole in adults and children with CE1, CE2, CE3a and CE3b cysts. Laparoscopic surgery plus albendazole may lead to slightly fewer minor complications. Firm conclusions cannot be drawn due to the limited number of studies, small sample size and lack of events for some outcomes.

Impact of species hybridization on the clinical management of schistosomiasis: A prospective study.

BACKGROUND: Species hybridization represents a real concern in terms of parasite transmission, epidemiology and morbidity of schistosomiasis. It is greatly important to better understand the impact of species hybridization for the clinical management. METHODS: A prospective observational study was carried out in sub-Saharan migrants who were diagnosed with confirmed genitourinary schistosomiasis. A tailored protocol was applied, including Schistosoma serology, a specific urine LAMP tests for schistosomiasis and an ultrasound examination before treatment with praziquantel. A scheduled follow-up was performed at 3, 6 and 12 months to monitor treatment response, comparing patients carriers of Schistosoma hybrids with carriers of only genetically pure forms. RESULTS: A total of 31 male patients from West Africa were included in the study with a mean age of 26.5 years. Twelve (38.7 %) of the patients were carriers of Schistosoma hybrids. As compared with patients infected with S. haematobium alone, hybrid carriers had lower haemoglobin levels (13.8 g/dL [SD 1.8] vs 14.8 g/dL [SD 1.4], p = 0.04), a greater frequency of hematuria (100 % vs 52.6 %, p = 0.005), a higher ultrasound score (2.64, SD 2.20 vs 0.89, SD 0.99; p = 0.02). However, the presence of hybrids did not result in differences in clinical and analytical responses after treatment. CONCLUSIONS: The presence of Schistosoma hybrids seems to cause increased morbidity in infected individuals. However, it does not appear to result in differences in diagnostic tests or in clinical and analytical responses after treatment.

Efficacy assessment of miltefosine and curcumin against Clonorchis sinensis infection.

Praziquantel (PZQ) is currently the only approved drug for treating clonorchiasis, but its poor efficacy against Clonorchis sinensis larvae has highlighted the need to develop newer drugs. In this study, to address this challenge, we investigated the anti-parasitic efficacy of miltefosine (MLT), curcumin (CUR), and PZQ against C. sinensis metacercariae (CsMC), newly excysted juvenile worms (CsNEJs), and adults. Larvicidal effects of MLT and CUR surpassed those elicited by PZQ in vitro. These two drugs exerted their effect against both CsMC and CsNEJs in a dose- and time-dependent manner. To confirm the effect of these drugs in vivo, Syrian golden hamsters were orally infected with 100 CsMC and subsequently treated with MLT, CUR, or PZQ at 1 and 4 weeks post-infection (wpi). MLT and CUR reduced the worm recoveries at 1 and 4 wpi, indicating that these drugs were efficacious against both larvae and adult C. sinensis. PZQ was only efficacious against adult worms. Interestingly, both MLT and CUR showed lower levels of C. sinensis-specific IgG responses than the infection control group, implying that worm burden and bile IgG responses could be correlated. These results indicate that MLT and CUR are efficacious against both larval and adult stages of C. sinensis, thereby highlighting their potential for further development as alternative therapeutic options for clonorchiasis.

Imported schistosomiasis in travelers: Experience from a referral tropical medicine unit in Barcelona, Spain.

BACKGROUND: Acute schistosomiasis occurs most often in travelers to endemic regions. The aim of the study is to describe the epidemiological, clinical and parasitological characteristics of patients with schistosomiasis acquired during an international travel. METHODS: Observational retrospective study including all travel-related schistosomiasis cases seen at the International Health Unit Vall d'Hebron-Drassanes (Barcelona, Spain) from 2009 to 2022. Diagnosis of schistosomiasis was defined by the presence of Schistosoma eggs in stools or urine or the positivity of a serological test. We collected demographic, epidemiological, clinical, parasitological, and therapeutic information. RESULTS: 917 cases of schistosomiasis were diagnosed, from whom 96 (10.5 %) were travel-related. Mean age of the patients was 34.9 years, and 53.1 % were women. Median duration of the travel was 72 days, and geographical areas where travelers had contact with fresh water were Africa (82.3 %), Asia (12.5 %), and South America (5.2 %). Twenty (20.8 %) patients reported having had some clinical symptom, being gastrointestinal symptoms the most frequent. Two patients developed the classical Katayama syndrome. In eleven (11.5 %) cases eggs were observed in urine or feces samples, and 85 (88.5 %) cases were diagnosed by a positive serology. Ninety-one (94.8 %) patients received treatment with praziquantel with different therapeutic schemes. The two patients with Katayama syndrome received concomitant treatment with corticosteroids. CONCLUSIONS: Schistosomiasis in travelers represented 10 % of the overall schistosomiasis cases in our center. Increasing the awareness in the pre-travel advice and implementing specific screening in those travelers at risk (long travelers, contact with fresh water) could reduce the incidence and associated morbidity in this group.