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Parasites & Vectors Jul 2023The American Heartworm Society canine guidelines recommend treatment with doxycycline prior to adulticide administration to reduce levels of Wolbachia and its associated...
BACKGROUND
The American Heartworm Society canine guidelines recommend treatment with doxycycline prior to adulticide administration to reduce levels of Wolbachia and its associated metabolites, which are known to be a leading cause of pulmonary pathology. Studies have determined that doxycycline administered at 10 mg/kg BID for 28 days is an effective dose for eliminating Wolbachia, but what has not been determined is the clinical relevance of this elimination. The current guidelines also recommend a 30-day wait period following administration of doxycycline to allow for clearance of metabolites, such as Wolbachia surface protein, and for further reduction in heartworm biomass before administration of adulticide. Reducing the doxycycline dose and eliminating the wait period may carry practical benefits for the animal, client, and practitioner.
METHODS
To investigate these treatment practices, Dirofilaria immitis adults were surgically transplanted into each of 45 dogs, which were divided into nine study groups of five dogs each. Seventy-five days after transplantation, two groups each were administered 5, 7.5, or 10 mg/kg BID doxycycline orally for 28 days and 6 µg/kg ivermectin monthly, with three untreated groups serving as controls. Study animals were necropsied and examined prior to treatment as well as 30 and 60 days post-treatment.
RESULTS
Mean worm weight was unaffected by dosage but exhibited a significant increase at 30 days and significant decrease at 60 days post-treatment, including in control groups. Histopathology lesion scores did not significantly differ among groups, with the exception of the lung composite score for one untreated group. Liver enzymes, the levels of which are a concern in doxycycline treatment, were also examined, with no abnormalities in alanine aminotransferase or alkaline phosphatase observed.
CONCLUSIONS
No consistent worsening of tissue lesions was observed with or without the AHS-recommended 30-day wait period, nor did reduced dosages of doxycycline lead to worsening of pathology or any change in efficacy in depleting worm weight. Mean worm weight did significantly increase prior to, and decrease following, the wait period. Future work that also includes adulticide treatment (i.e. melarsomine) will study treatment recommendations that may improve both animal health and owner compliance.
Topics: Animals; Dogs; Dirofilaria immitis; Doxycycline; Dirofilariasis; Filaricides; Dog Diseases; Wolbachia
PubMed: 37491306
DOI: 10.1186/s13071-023-05858-2 -
International Journal of Medical... 2023Multiple myeloma (MM) is an incurable haematological cancer characterized by abnormal proliferation of plasma cells. The promising therapeutic effect of selective...
Multiple myeloma (MM) is an incurable haematological cancer characterized by abnormal proliferation of plasma cells. The promising therapeutic effect of selective inhibitors of nuclear export in MM reveals the broad therapeutic prospects of nuclear localization intervention. Sterol regulatory element binding protein 2 (SREBP2) is a lipid regulatory molecule that has been implicated in the effect of drug therapy for MM. SREBP2 has been reported to be regulated by the antimalarial drug artesunate (ART) through alteration of its nuclear localization and has been shown to inhibit ferroptosis in other tumours. However, the mechanism through which this might occur has not been clarified in MM. Our study aimed to explore whether ART can induce ferroptosis in MM through nuclear localization of SREBP2. To evaluate whether ferroptosis is induced by treatment with ART in myeloma, we used two types of myeloma cell lines. We first used a series of molecular approaches and other techniques to investigate the impact of ART on cell growth, production of reactive oxygen species (ROS), Fe levels, lipid peroxidation and expression of genes related to ferroptosis. Then, we further explored the mechanism through which ferroptosis may occur in these cells and the relationship between ferroptosis and the nuclear localization of SREBP2. Upregulation of ROS, Fe, and lipid peroxidation as well as inhibition of cell growth were observed in myeloma cells after treatment with ART. Expression of acyl CoA synthase long chain family member 4 (ACSL4) was increased, while glutathione peroxidase 4 (GPX4) expression was reduced in cells treated with ART. ART-induced cell death could be reversed by ferropstatin-1 (Fer-1) and deferoxamine mesylate (DFO). Nuclear localization of SREBP2 in myeloma cells was inhibited, accompanied by downregulation of isopentenyl pyrophosphate (IPP) and GPX4, after treatment with ART. In conclusion, our study demonstrated that the antimalarial drug ART can inhibit nuclear localization of SREBP2, downregulate IPP and GPX4, and eventually trigger ferroptosis in myeloma cells. Through this study, we hope to establish a correlation between nuclear localization pathways and mediation of ferroptosis in myeloma cells and provide an innovative direction for exploration-related therapy.
Topics: Humans; Antimalarials; Artesunate; Ferroptosis; Multiple Myeloma; Phospholipid Hydroperoxide Glutathione Peroxidase; Reactive Oxygen Species; Sterol Regulatory Element Binding Protein 2
PubMed: 37859702
DOI: 10.7150/ijms.86409 -
Frontiers in Public Health 2023Thermal health concerns have gained significant attention due to the heightened health risks faced by workers who are exposed to extreme thermal environments for... (Review)
Review
Thermal health concerns have gained significant attention due to the heightened health risks faced by workers who are exposed to extreme thermal environments for prolonged periods. To ensure the occupational health and safety of such workers, and to enhance work efficiency, it is imperative to examine the characteristics of thermal health in the working environment. This study proposes three key elements of thermal health in the working environment, namely thermal health states, absence of heat-related illnesses, and heat adaptability, which can be used to develop a safety management framework for thermal health. By exploring the interconnections between these elements, the study summarizes their features and outlines the necessary precautions to safeguard them. The PDCA (plan/do/check/action) cycle management mode is utilized as a framework, with the three components of thermal health forming the core, to establish a safety management mode for thermal health. To ensure that employees work in a safe, healthy, comfortable, and productive environment, the assessment and control objectives of the thermal environment are regularly revised through the use of labor protection technology and thermal environment control technology. This paper presents a PDCA cycle safety management mode based on the characteristics of thermal health, which offers novel insights and approaches for assessing and managing workers' thermal health.
Topics: Humans; Working Conditions; Fenbendazole; Health Status; Hot Temperature; Safety Management
PubMed: 37670839
DOI: 10.3389/fpubh.2023.1227630 -
Parasitology Research Apr 2024Because of recent reports of praziquantel resistance in schistosome infections, there have been suggestions to employ ivermectin as a possible alternative, especially as...
Because of recent reports of praziquantel resistance in schistosome infections, there have been suggestions to employ ivermectin as a possible alternative, especially as its chemical composition is different from that of praziquantel, so cross-resistance is not expected. In order to ascertain possible damage and elimination of worms, we used ivermectin by oral gavage in infected mice, at a high dose (30.1 mg/kg, bordering toxicity). We also tested the efficacy of the drug at various times postinfection (PI), to check on possible effect on young and mature stages of the parasites. Thus, we treated mice on days 21 and 22 or on days 41 and 42 and even on days 21, 22, 41, and 42 PI. None of the treatment regimens resulted in cure rates or signs of lessened pathology in the mice. We also compared the effect of ivermectin to that of artemisone, an artemisinin derivative which had served us in the past as an effective anti-schistosome drug, and there was a stark difference in the artemisone's efficacy compared to that of ivermectin; while ivermectin was not effective, artemisone eliminated most of the worms, prevented egg production and granulomatous inflammatory response. We assume that the reported lack of activity of ivermectin, in comparison with praziquantel and artemisinins, originates from the difference in their mode of action. In wake of our results, we suggest that ivermectin is not a suitable drug for treatment of schistosomiasis.
Topics: Animals; Mice; Praziquantel; Ivermectin; Schistosomiasis; Artemisinins; Schistosomatidae
PubMed: 38592544
DOI: 10.1007/s00436-024-08178-1 -
Molecules (Basel, Switzerland) Mar 2024Over the years, several new medicinal substances have been introduced for the treatment of diseases caused by bacteria and parasites. Unfortunately, due to the...
Over the years, several new medicinal substances have been introduced for the treatment of diseases caused by bacteria and parasites. Unfortunately, due to the production of numerous defense mechanisms by microorganisms and parasites, they still pose a serious threat to humanity around the world. Therefore, laboratories all over the world are still working on finding new, effective methods of pharmacotherapy. This research work aimed to synthesize new compounds derived from 3-trifluoromethylbenzoic acid hydrazide and to determine their biological activity. The first stage of the research was to obtain seven new compounds, including six linear compounds and one derivative of 1,2,4-triazole. The PASS software was used to estimate the potential probabilities of biological activity of the newly obtained derivatives. Next, studies were carried out to determine the nematocidal potential of the compounds with the use of nematodes of the genus sp. and antibacterial activity using the ACCT standard strains. To determine the lack of cytotoxicity, tests were performed on two cell lines. Additionally, an antioxidant activity test was performed due to the importance of scavenging free radicals in infections with pathogenic microorganisms. The conducted research proved the anthelmintic and antibacterial potential of the newly obtained compounds. The most effective were two compounds with a 3-chlorophenyl substituent, both linear and cyclic derivatives. They demonstrated higher efficacy than the drugs used in treatment.
Topics: Anti-Bacterial Agents; Antinematodal Agents; Cell Line; Hydrazines; Semicarbazides
PubMed: 38611813
DOI: 10.3390/molecules29071529 -
PLoS Neglected Tropical Diseases Oct 2023Parasitic nematodes infect billions of people and are mainly controlled by anthelmintic mass drug administration (MDA). While there are growing efforts to better...
Parasitic nematodes infect billions of people and are mainly controlled by anthelmintic mass drug administration (MDA). While there are growing efforts to better understand mechanisms of anthelmintic resistance in human and animal populations, it is unclear how resistance mechanisms that alter susceptibility to one drug affect the interactions and efficacy of drugs used in combination. Mutations that alter drug permeability across primary nematode barriers have been identified as potential resistance mechanisms using the model nematode Caenorhabditis elegans. We leveraged high-throughput assays in this model system to measure altered anthelmintic susceptibility in response to genetic perturbations of potential cuticular, amphidial, and alimentary routes of drug entry. Mutations in genes associated with these tissue barriers differentially altered susceptibility to the major anthelmintic classes (macrocyclic lactones, benzimidazoles, and nicotinic acetylcholine receptor agonists) as measured by animal development. We investigated two-way anthelmintic interactions across C. elegans genetic backgrounds that confer resistance or hypersensitivity to one or more drugs. We observe that genetic perturbations that alter susceptibility to a single drug can shift the drug interaction landscape and lead to the appearance of novel synergistic and antagonistic interactions. This work establishes a framework for investigating combinatorial therapies in model nematodes that can potentially be translated to amenable parasite species.
Topics: Animals; Humans; Caenorhabditis elegans; Anthelmintics; Nematoda; Benzimidazoles; Drug Interactions; Drug Resistance
PubMed: 37883578
DOI: 10.1371/journal.pntd.0011705 -
Parasitology Oct 2023Helminth infections are ubiquitous in grazing ruminants and cause significant costs due to production losses. Moreover, anthelmintic resistance (AR) in parasites is now... (Review)
Review
Helminth infections are ubiquitous in grazing ruminants and cause significant costs due to production losses. Moreover, anthelmintic resistance (AR) in parasites is now widespread throughout Europe and poses a major threat to the sustainability of modern ruminant livestock farming. Epidemiological data on the prevalence and distribution of gastrointestinal nematodes, cestodes and liver- and rumen-flukes in Italian small ruminants are outdated and fragmentary. However, anthelmintics are commonly used to control these infections and often without prior diagnosis. Compared to other European countries, few reports of AR in small ruminants against levamisole, ivermectin and benzimidazoles have been published in Italy, but recent studies suggest that this phenomenon is spreading. Increased and integrated research efforts in developing innovative approaches to control helminth infections and AR are needed and must be tailored to the peculiarities of each context in order to be effectively implemented. This manuscript provides an overview on helminth prevalence and distribution, sustainable treatment strategies and integrated control approaches in small ruminants in Italy. The implementation of targeted treatments and targeted selective treatments is discussed based on different parameters, such as fecal egg count, degree of anaemia (FAMACHA method), milk production and body condition score. In addition, several Italian studies have also investigated the implementation of alternative strategies such as the use of different natural bioactive compounds or genetic selection for resistance and resilience to helminth infections. These concrete solutions for helminth management in small ruminant farms in the country are reported and discussed, representing a valid example for other Mediterranean countries.
Topics: Animals; Drug Resistance; Anthelmintics; Ruminants; Helminths; Nematoda; Nematode Infections
PubMed: 37039466
DOI: 10.1017/S0031182023000343 -
Journal of Advanced Research Jun 2024Intestinal parasitic infections are neglected diseases and, due to the increasing resistance of parasites to available drugs, they pose an increasing therapeutic...
INTRODUCTION
Intestinal parasitic infections are neglected diseases and, due to the increasing resistance of parasites to available drugs, they pose an increasing therapeutic challenge. Therefore, there is a great need for finding new compounds with antiparasitic activity.
OBJECTIVES
In this work, new thiosemicarbazide and 1,2,4-triazole derivatives were synthesized and tested for their anthelmintic activity.
METHODS
The synthesis was carried out by classical methods of organic chemistry. Anthelmintic activity tests were carried out in vitro (Rhabditis sp., Haemonchus contortus, Strongylidae sp.) in vivo (Heligmosomoides polygyrus/bakeri), and in silico analysis was performed.
RESULTS
Quinoline-6-carboxylic acid derivative compounds were designed and synthesized. The highest activity in the screening tests in the Rhabditis model was demonstrated by compound II-1 with a methoxyphenyl substituent LC = 0.3 mg/mL. In the next stage of the research, compound II-1 was analyzed in the H. contortus model. The results showed that compound II-1 was active and had ovicidal (percentage of dead eggs > 45 %) and larvicidal (percentage of dead larvae > 75 %) properties. Studies in the Strongylidae sp. model confirmed the ovicidal activity of compound II-1 (percentage of dead eggs ≥ 55 %). In vivo studies conducted in the H. polygyrus/bakeri nematode model showed that the number of nematodes decreased by an average of 30 % under the influence of compound II-1. In silico studies have shown two possible modes of action of compound II-1, i.e. inhibition of tubulin polymerization and SDH. The test compound did not show any systemic toxic effects. Its influence on drug metabolism related to the activity of cytochrome CYP450 enzymes was also investigated.
CONCLUSION
The results obtained in the in vitro, in vivo, and in silico studies indicate that the test compound can be described as a HIT, which in the future may be used in the treatment of parasitic diseases in humans and animals.
Topics: Animals; Anthelmintics; Triazoles; Semicarbazides; Computer Simulation; Mice; Haemonchus; Structure-Activity Relationship; Molecular Docking Simulation
PubMed: 37467960
DOI: 10.1016/j.jare.2023.07.004 -
BMC Veterinary Research May 2024As an orally effective benzimidazole anthelmintic agent, fenbendazole was not only widely used in agriculture and animal husbandry to prevent and treat parasites, but...
As an orally effective benzimidazole anthelmintic agent, fenbendazole was not only widely used in agriculture and animal husbandry to prevent and treat parasites, but also shows anti-cancer effects against several types of cancer, exhibits anti-cancer effects in paclitaxel and doxorubicin-resistant cancer cells. However, fenbendazole's poor in water solubility (0.3 µg/mL), limits its clinical applications. Even great efforts were made toward increasing its water solubility, the results were not significant to reach anti-cancer drug delivery requirement (5-10 mg/mL). Through single factor and orthogonal strategy, many complex conditions were designed and used to prepare the complexes, the inclusion complex with methyl-β-cyclodextrin with 29.2 % of inclusion rate and 89.5% of inclusion yield can increase drug's water solubility to 20.21 mg/mL, which is the best result so far. Its structure was confirmed by differential scanning calorimetry, scanning electron microscopic image, 1D and 2D NMR spectra in DO. In its in vitro pharmacokinetic study, fenbendazole was 75% released in 15 min., in its in vivo pharmacokinetic study, the bio-availabilities of fenbendazole, its major metabolic anthelmintic agent oxfendazole and its minor metabolic anthelmintic agent oxfendazole were increased to 138%, 149% and 169% respectively, which would allow for fewer drug doses to achieve the same therapeutic effect and suggest that the complex can be used as a potential anticancer agent.
Topics: Fenbendazole; Animals; beta-Cyclodextrins; Solubility; Antineoplastic Agents; Male; Anthelmintics
PubMed: 38769544
DOI: 10.1186/s12917-024-04056-1 -
Veterinary World Aug 2023Anthelmintic resistance (AR) and acaricide resistance (ACR) pose great economic threat to communal livestock raised by rural communities, limiting sustainable...
Assessment of gastrointestinal nematode anthelmintic resistance and acaricidal efficacy of fluazuron-flumethrin on sheep and goat ticks in the North West province of South Africa.
BACKGROUND AND AIM
Anthelmintic resistance (AR) and acaricide resistance (ACR) pose great economic threat to communal livestock raised by rural communities, limiting sustainable production. This study was conducted to assess the occurrence of AR and ACR against nematodes and ticks that infest small ruminants (sheep and goats) from small-scale farming communities in the North West Province of South Africa, as well as document the associated risk factors.
MATERIALS AND METHODS
The study was conducted on small-scale farming locations in two districts of the North West Province, namely, Dr. Ruth Segomotsi Mompati district and Dr. Kenneth Kaunda district, from November 2019 to March 2020. A questionnaire survey based specifically on antiparasitic treatment and related management practices was administered to 86 small-scale farmers. A fecal egg count reduction test (FECRT) was used to determine AR in small ruminants against benzimidazole (BZD), levamisole, and macrocyclic lactone on nine ruminant farms. Then, deoxyribonucleic acid was extracted from L3 larvae and resistant nematodes were identified using a polymerase chain reaction, targeting the internal transcribed spacer 2 gene. An egg hatch assay (EHA) and a larval mortality assay (LMA) were used to determine AR against thiabendazole (TBZ and BZD) in the same farms. Acaricide resistance against fluazuron-flumethrin (Drastic Deadline eXtreme) pour-on was assessed using an adult immersion test (AIT) on .
RESULTS
Questionnaire results indicated that most farmers (89%) relied solely on anthelmintics. Farmers used visual appraisal to estimate the dosage, which is the primary cause of resistance. The FECRT revealed AR in all the farms. Egg hatch assay results revealed AR development against TBZ in all districts, with >95% of the eggs hatching at variable doses. Larval mortality assay results revealed the development of resistance against BZD, with 50% of L3 larvae surviving at different doses in all farms. Adult immersion test results indicated that fluazuron-flumethrin (>99%) exhibited high acaricidal efficacy against . by inhibiting tick oviposition.
CONCLUSION
This investigation found that sheep and goats in the studied areas are developing AR to gastrointestinal parasites. The findings of tests showed resistance with fecal egg count reduction percentage of <95% or lower confidence limit of <90%. The results of EHA and LMA revealed no evidence of inhibition of egg development and larval mortality, indicating the development of resistance. Acaricide resistance was not detected against fluazuron-flumethrin, which is commonly used in the study areas. Thus, developing management methods for these economically significant livestock nematodes, including teaching small-scale farmers how to properly administer anthelmintics and acaricides to their livestock, is urgently needed.
PubMed: 37766712
DOI: 10.14202/vetworld.2023.1615-1626