Antiparasitic Research Articles

Antileishmanial and Antitrypanosomal Trends of Synthetic Tetralone Derivatives.

Leishmaniasis and trypanosomiasis are parasitic diseases that are closely linked to poverty, pose significant local burdens, and are common in tropical and subtropical regions. Various synthetic tetralone derivatives were studied as potential scaffolds for antileishmanial and antitrypanosomal activities. The compounds were studied for their effectiveness against multiple kinetoplastid protozoan pathogens: Leishmania major, Leishmania mexicana, and bloodstream trypomastigotes of Trypanosoma brucei brucei. Two different strains of T. b. brucei were used. The first strain was the wild-type Trypanosoma brucei (s427-WT), and the second strain was the multidrug resistant (MDR) strain B48, which was produced by deleting the TbAT1 gene from s427WT and subsequent adaptation to high levels of resistance to diamidines and organo-arsenical drugs. Compounds 4c, 7c, 9b, and 11b showed activity against two strains of Trypanosoma and two different Leishmania species, establishing them as versatile leads with broad anti-kinetoplastid activity. Compound 4c, a tetralone derivative with a bromo-containing trimethoxybenzylidene moiety and methyl-substituted cyclohexanone ring, was identified as the most potent inhibitor for both T. b. brucei strains, with EC50 values of 0.19 and 0.22 µM for WT and B48, respectively, showing the absence of cross-resistance with the diamidine and arsenical trypanocide classes. In addition, compound 4c exhibited more potency than both controls, eflornithine and pentamidine, against the MDR strain. We conclude that tetralone derivates could be a valuable starting point for the discovery of new antiparasitic drugs.

ВЛИЯНИЕ КОНТАМИНИРОВАННОГО МИКОТОКСИНАМИ КОРМА И ПРОТИВОПАРАЗИТАРНОЙ ОБРАБОТКИ ЭПРИНОМЕКТИНОМ НА КИШЕЧНУЮ МИКРОБИОТУ ЖИВОТНЫХ В УСЛОВИЯХ ЭКСПЕРИМЕНТА

Animals are exposed to numerous stress factors in industrial conditions. The greatest danger is posed by mycotoxins that change the composition of the microbiota in animals, which is one of the reasons for the development of immunosuppression. The purpose of the study is to establish changes in the composition of the intestinal microbiota in laboratory animals with combined contamination of feed with mycotoxins and antiparasitic treatment with eprinomectin. The study was conducted on laboratory rats (five groups of 10 rats each). Animals of the 1st group received a standardized diet and were not exposed to mycotoxins and eprinomectin, the 2nd, 3rd, 4th and 5th groups of animals received food containing mycotoxins (DON – 0.93, T-2 – 0.025; ZEA – less than 0.02 mg/kg). Additionally, animals of the 3rd and 5th groups were subjected to a single antiparasitic treatment with the drug Veteprin (active ingredient – eprinomectin). Enterosorbent modified with polyarginine was administered daily with food to animals of groups 4 and 5 at a dose of 0.2 g/kg for 12 days at the final stage of the experiment lasting 50 days. The material for bacteriological research was samples of the contents of the cecum. The luminal microflora of the cecum in all animals is dominated by Bifidobactererium spp. and Lactobacillus spp. However, a noticeable decrease in their number is observed with the combined effect of eprinomectin and mycotoxins on the animal body, which indicates a decrease in colonization resistance and inhibition of parietal digestion. Against the background of a decrease in the proportion of obligate anaerobic microflora in the intestine, the number of facultative opportunistic microorganisms increases. Increased growth of yeast-like fungi in the intestine indicates decreased immune reactivity and impaired intestinal barrier function. The use of a sorbent modified with polyarginine normalizes and stabilizes the intestinal microflora.

АНАЛИЗ АНТИГЕЛЬМИНТНЫХ СРЕДСТВ ДЛЯ ВЕТЕРИНАРНОГО ПРИМЕНЕНИЯ

The paper presents the assortment trend and marketing analysis of veterinary medicinal products for the prevention and treatment of helminthic infestations in horses registered in the Russian Federation. Anthelmintics are antiparasitic drugs for the fight against helminths. The analysis of these drugs was carried out on the example of the veterinary pharmacies "Horsevet" and "Vetlek". According to the data obtained, it was established that the Russian market has a significant range of medicinal anthelmintic drugs (41 names) used for the prevention and treatment of helminth infections in horses. The domestic manufacturer occupies a leading position among the presented range of products – 34.1±1.87 %. On the market of veterinary drugs, there are imported anthelmintic drugs represented by such manufacturing countries as Belarus, Argentina, Brazil, Holland, Spain, Canada, etc. In the study of drugs by the number of pharmacologically active substances, it was found that monocomponent drugs account for 63.4±0.38 %, and multicomponent drugs – 36.6±0.85 %. The most common are soft dosage forms – 63.4±3.78 % (26 trade names in the form of flavored pastes and gels), which makes it easier to give the drug. Anthelmintic drugs in most cases are potent drugs, so most of them have a number of contraindications for use (85.4±4.95 %). 14.6±0.95 % of drugs have no contraindications. The use of all registered anthelmintic drugs for horses at the recommended doses does not cause changes in vital functions in the animal body.

Anthelmintic Potential of Annona muricata Leaf Extract against Parasitic Nematode Haemonchus contortus

Gastrointestinal infections caused by the parasitic worm Haemoncus contortus are the main cause of economic losses in the agricultural sector. H. contortus causes small ruminants such as goats to experience acute anemia and diarrhea, weight loss, decreased productivity, and eventually mortality, which impacts economic losses. Synthetic antiparasitics have been used extensively around the world to combat haemonchosis. However, the emergence of resistance to anthelmintics, accompanied by the unavailability of an effective vaccine, results in difficulties in controlling this disease. Because of the high cost of treatment and the emergence of resistance and toxicity due to the residue of antiparasitic drugs, it is necessary to develop natural anthelmintics that are easy to obtain, economical, and have minimal risk. This study aims to determine the anthelmintic effect of Annona muricata leaf extract on mice infected with H. contortus larvae. First, an in vitro study was conducted to see if the soursop leaf extract from Lombok would show a different effect from the previous research. In the in vivo test, the impact of A. muricata leaf extract was measured from the number of H. contortus eggs found in the feces and the percent reduction of adult worms collected from mice's stomachs. The result shows that the higher the concentration of soursop leaf extract, the higher the inhibition effect on larvae motility. The combination of A. muricata and albendazole had the strongest antiparasitic effect, shown by the lowest amount of eggs in feces and the highest reduction of adult worms in the stomach. However, administering A. muricata leaf extract can also reduce the number of eggs and adult worms in the stomach. Therefore, it can be concluded that A. muricata is a potential anthelmintic candidate for overcoming the H. contortus infection.

Knowledge, attitudes and practices of Australian dairy goat farmers towards the control of gastrointestinal parasites

BackgroundGastrointestinal parasites such as nematodes and coccidia are responsible for significant economic losses in the goat industry globally. An indiscriminate use of antiparasitic drugs, primarily registered for use in sheep and cattle, in goats has resulted in drug-resistant gastrointestinal parasites. Very little is known about the gastrointestinal parasite control practices used by Australian dairy goat farmers that are pivotal for achieving sustainable control of economically important parasites. The study reported here provides insights into gastrointestinal parasite control practices of Australian dairy goat farmers based on responses to an online survey.MethodsThe questionnaire comprised 58 questions on farm demography, husbandry and grazing management, knowledge of gastrointestinal parasites and their importance in dairy goats, diagnosis of infections, antiparasitic drugs and alternate control options. After a pilot survey (n = 15 respondents), a link to the questionnaire was available to all (n = 456) registered members of the Dairy Goat Society of Australia Ltd from 17 April to 16 June 2023. Multiple correspondence analyses (MCA) were performed to explore the association between selected parasite control practices.ResultsA total of 66 (14%) respondents completed the questionnaire. Of these, 74% (49/66) observed parasite-related illnesses in their goats; two-thirds of them assessed worms burden using faecal egg counts (FECs), with 26% (39/149) deworming their goats based on the results of the FECs. Most respondents (97%; 183/188) perceived that gastrointestinal parasites caused production losses and ranked Haemonchus contortus as the most important parasite. Anitparasitic drugs were used by 94% (62/66) of respondents, with the most frequently used anthelmintics being a commercial combination of four anthelmintics (levamisole, closantel, albendazole and abamectin), benzimidazoles and macrocyclic lactones. Most respondents (77%; 51/66) were unaware of anthelmintic resistance on their property. MCA results delineated two clusters of gastrointestinal parasites management.ConclusionsThis study provides insights into the demography of Australian dairy goat farms, the husbandry and grazing practices used by dairy goat farmers, their knowledge regarding gastrointestinal parasites and their practices for internal parasite control, thereby paving the way for tackling drug resistance in gastrointestinal parasites in dairy goats.Graphical

In vitro evaluation of anthelmintic activity of biocompatibile carbon quantum dot nanocomposite against egg and larval stages of equine strongyles

BackgroundStrongyle nematodes pose a major challenge in veterinary parasitology, causing significant economic losses in livestock due to resistance to conventional treatments. Current anthelmintics, like Ivermectin, often encounter resistance issues. This study aims to address these gaps by synthesizing Carbon Quantum Dots (CQDs) and Copper-Doped CQDs (Cu@CQDs) using glucose extract, and evaluating their nematicidal properties against strongyles in vitro. We assessed the nematicidal effects of CQDs and Cu@CQDs through larval feeding inhibition of first-stage larvae (L1), egg hatch inhibition (EHI), and the mobility and mortality of infectious larvae (L3s). Additionally, we conducted ultrastructural examinations of eggs and larvae and evaluated oxidative/nitrosative stress indicators, including total antioxidant status (TAS), protein carbonylation (PCO), lipid peroxidation (MDA), and oxidative DNA damage in homogenized samples of L3s.ResultsThe synthesized CQDs displayed semi-spherical morphology with diameters under 30 nm. Cu@CQDs at 12.5 µg/ml achieved over 90% EHI and larval motility inhibition. Fluorescence microscopy confirmed over 90% larval feeding inhibition at the same concentration. Both CQDs and Cu@CQDs induced oxidative stress, indicated by decreased TAS and increased MDA, PCO, and oxidative DNA damage. Scanning Electron Microscopy showed that CQDs and Cu@CQDs penetrated the larvae cuticle, altered the tegument, caused larval mortality, and resulted in egg deformities.ConclusionsGiven the potential for resistance to Ivermectin, seeking suitable alternatives is essential. Cu@CQDs exhibit effects similar to Ivermectin, indicating their potential as novel antiparasitic agents against strongyles. These findings emphasize the importance of exploring alternative treatments to address resistance and enhance nematode control efficacy.Graphical

Zinc from an Essential Element to an Antiparasitic Therapeutic Agent

Zinc from an Essential Element to an Antiparasitic Therapeutic Agent

Biosafety and Withdrawal Period of In-Feed Administered Antiparasitic Drug Emamectin Benzoate in Cirrhinus mrigala (Hamilton, 1822).

Parasitic infestations are one of the most economically important disease conditions in the Indian major carps including mrigal, Cirrhinus mrigala. This study reported the biosafety and tissue withdrawal of in-feed administered antiparasitic drug, emamectin benzoate (EMB). To evaluate the biosafety of the drug, behaviour, growth and tissue changes in Cirrhinus mrigala was recorded the following in-feed administration of EMB up to 10 times (T1-50 μg kg-1 fish day-1 (1×), T2-125 μg kg-1 fish day-1 (2.5×), T3-250 μg kg-1 fish day-1 (5×), T4-375 μg kg-1 fish day-1 (7.5×) and T5-500 μg kg-1 fish day-1 (10×)) for the period of three times the recommended duration (7 days). The withdrawal period was calculated by feeding EMB at 50 μg kg-1 fish day-1 for consecutive 10 days followed by EMB-free feed. The results revealed that the drug is safe to mrigal up to ten times the recommended dose, while the fish fed with the highest dose (500 μg kg-1 fish day-1) showed transient histological alterations. The feeding behaviour is affected with poor acceptability beyond 5× dosages. The drug residue at the concentration below the MRL (1.0 μg g-1) in the muscle tissue on the day of cessation of medicated feed administration indicates no requirement of the withdrawal period. The study suggests that EMB can be safely used at 50 μg kg-1 fish day-1 for 7 consecutive days, and no withdrawal period is required without affecting the feeding behaviour and tissue histological alterations.

Classification and Mechanism of Action of Anti-Parasitic Drugs: A Review Article

The action of antiparasitic drugs is critical in the treatment of infections caused by parasites and that have devastating effects on millions of individuals worldwide. This paper consolidates different research findings on the classification and mechanisms of action of these drugs, highlighting new therapies and natural products. In particular, this special class of heterocyclic compounds, known as Benzimidazoles, has garnered a wide interest in medicinal chemistry due to their broad pharmacological activities. It recognizes the important contribution normally made by these drugs in the treatment of a wide range of different diseases, including cancer, bacterial infection, and parasitic disease. Drug-resistant parasites are now increasingly prevalent and have greatly impeded the management of parasitic infections; thus, there is an increasing demand for new therapeutic approaches. Anti-parasitic metallodrugs have emerged as another auspicious mode of intervention that carefully exploits the unique chemical features of metal ions and their complexes to affect the biological pathways important for the survival of the parasite. In this paper, we will draw up a range of knowledge gaps identified up-to-date and propose future research directions that would enhance the understanding and, what is more important, the efficiency of anti-parasitic therapies.

Does intranasal demodex infestation play a role in chronic allergic rhinitis?

Aims: The aim of this study is to evaluate the prevalence of Demodex mites in the intranasal follicles of patients with allergic rhinitis and investigate their potential role in the etiology of allergic rhinitis. Methods: The study involved 50 patients diagnosed with allergic rhinitis and 50 healthy controls matched for age and gender. The severity of the disease was evaluated using the Score for Allergic Rhinitis and the Total Nasal Symptom Score (TNSS). To evaluate the presence of Demodex in nasal follicles, a total of 8 terminal follicles, 4 from each of the right and left nasal vestibules, were epilated using sterile forceps. The samples were examined under a light microscope at 10x, 40x, and 100x magnification by two dermatologists. Results: Demodex mites were found in the intranasal follicles of 3 (6%) individuals from the healthy control group. Intranasal Demodex mites were found in 3 (6%) patients with allergic rhinitis, showing no statistically significant difference between the two groups (p=1). The mean total nasal symptom score was 7.66±1.52 in the 3 allergic rhinitis patients with Demodex positivity, and 7.61±1.13 in the 47 patients without Demodex infestation, with no statistically significant difference between the two groups (p>0.05). No significant correlation was observed between Demodex positivity, disease severity, and TNSS in patients with allergic rhinitis (p>0.05). Conclusion: Based on our study results, we think that intranasal antiparasitic treatments may be unnecessary in patients with allergic rhinitis.

Reproductive management: conditioning, spawning and development of Peruvian grunt Anisotremus scapularis in southern Peru.

The Peruvian grunt, Anisotremus scapularis, is beginning its domestication as a candidate species for marine aquaculture. The optimal management of fingerling production requires precise knowledge on early development. Herein, we report the methodology for capturing and conditioning wild specimens to find a viable broodstock. The speed of capture and transportation (about 30 min), the post capture preventive treatment (60 min with tetracycline), and the 6-days preventive antiparasitic treatment (29 ppm formalin) maximized survival and a rapid feeding adaptation. Progressive diets based on the copepod Emerita analoga, fish meal, pellets and processed feedstuff prompted the spontaneous broodstock spawning 7 months post-capture. The interannual spawning of this broodstock since September 2016 indicated the optimal control of its reproduction in captivity. The morphogenetic process of the embryo lasted 42 h at 18 °C compared to (31-41) h at 19 °C in northern Peruvian latitudes. The knowledge generated allowed us to work out broodstock and egg management protocols in southern Pacific latitudes (southern Peru and northern Chile). Such protocols would help to escalate larval and juvenile production and to alleviate fishing pressure on the overexploited Peruvian grunt population.

The Ivermectin Related Compound Moxidectin Can Target Apicomplexan Importin α and Limit Growth of Malarial Parasites.

Signal-dependent transport into and out of the nucleus mediated by members of the importin (IMP) superfamily is crucial for eukaryotic function, with inhibitors targeting IMPα being of key interest as anti-infectious agents, including against the apicomplexan Plasmodium species and Toxoplasma gondii, causative agents of malaria and toxoplasmosis, respectively. We recently showed that the FDA-approved macrocyclic lactone ivermectin, as well as several other different small molecule inhibitors, can specifically bind to and inhibit P. falciparum and T. gondii IMPα functions, as well as limit parasite growth. Here we focus on the FDA-approved antiparasitic moxidectin, a structural analogue of ivermectin, for its IMPα-targeting and anti-apicomplexan properties for the first time. We use circular dichroism and intrinsic tryptophan fluorescence measurements to show that moxidectin can bind directly to apicomplexan IMPαs, thereby inhibiting their key binding functions at low μM concentrations, as well as possessing anti-parasitic activity against P. falciparum in culture. The results imply a class effect in terms of IMPα's ability to be targeted by macrocyclic lactone compounds. Importantly, in the face of rising global emergence of resistance to approved anti-parasitic agents, the findings highlight the potential of moxidectin and possibly other macrocyclic lactone compounds as antimalarial agents.

Impact of antiparasitic therapy on cardiovascular outcomes in chronic Chagas disease. A systematic review and meta-analysis

Endemic in more than 20 countries, Chagas disease affects 6.3 million people worldwide, leading to 28,000 new infections and 7700 deaths each year. Previous meta-analyses on antiparasitic treatment need updates to encompass recent studies and to assess key clinically meaningful endpoints. This study aims to evaluate the impact of antitrypanosomal therapy in preventing or reducing disease progression and mortality in chronic Chagas disease. We performed a systematic review and meta-analysis of studies reporting the cardiovascular outcomes of antitrypanosomal therapy in patients with chronic Chagas disease. We searched Ovid Embase, Ovid MEDLINE, Ovid Global Health, Scopus, Web of Science Core Collection, Cochrane Library, PubMed, Google Scholar, and Virtual Health Library databases from inception to May 18, 2024. We included aggregated data from randomized controlled studies and observational reports (full articles and abstracts) featuring antiparasitic interventions with benznidazole or nifurtimox compared to a control group. Primary outcomes were electrocardiogram (ECG) changes, disease progression, cardiovascular death, and overall mortality. A customized risk of bias scale assessed the methodological quality of studies, and a random-effects model estimated the pooled risk ratios. This investigation was registered in PROSPERO (CRD42023495755). Out of 4666 reports screened, 23 met the pre-specified inclusion criteria (8972 participants). Compared to no treatment or placebo, antiparasitic treatment led to a reduction in i) ECG changes (17 studies, 4994 participants: risk ratio (RR): 0.48, 95% CI 0.36-0.66, p<0.001; I 2=76.4%) with a number needed to treat (NNT) of 5; ii) disease progression (12 studies, 5722 participants: RR: 0.35, 95% CI 0.23-0.51, p<0.001; I 2=72.4%) NNT of 6; iii) cardiovascular death (7 studies, 5662 participants: RR: 0.44, 95% CI 0.21-0.95, p=0.04; I 2=50.5%) NNT of 22; and iv) overall mortality (10 studies, 7694 participants: RR: 0.54, 95% CI 0.34-0.87, p<0.001; I 2=60%) NNT of23. We found compelling evidence that antiparasitic treatment significantly reduces the risk of ECG changes, disease progression, cardiovascular death, and overall mortality in chronic Chagas disease. Although the quality of evidence ranges from low to intermediate, with considerable heterogeneity across studies, the potential benefits are substantial. These findings support the broader use of trypanocidal therapy in the management of Chagas disease, though further research remains necessary. This study had no funding source.

Thiourea as a Promising Scaffold for Development of Agents Toward TriTryp Diseases

AbstractThiourea has emerged as a versatile scaffold and a promising candidate for developing novel therapeutics against TriTryp diseases. This review explores the medicinal chemistry aspects of thiourea derivatives, highlighting their potential for Chagas Disease, African trypanosomiasis/sleeping sickness, and leishmaniasis. The discussion encompasses general synthetic approaches, physicochemical properties, and updates readers on the diverse structural substitutions on the thiourea scaffold governing potent molecules. The thiourea derivatives reviewed here demonstrated equipotent or superior activities compared to current chemotherapeutic agents. Early preclinical in silico assessments suggest favorable pharmacokinetic profiles and low toxicological potential. However, elucidating the molecular mechanisms and targets of these compounds remains a critical knowledge gap. Expanding the use of in silico tools is proposed as an effective strategy for designing novel antiparasitic drugs. Leveraging existing knowledge on thiourea derivatives holds promise in addressing TriTryp diseases more effectively.

In-vivo implementation of the HPTLC methodology to rat plasma for the concurrent determination of a novel combination therapy for the management of COVID-19 (favipiravir and nitazoxanide).

The 2019 coronavirus outbreak has prompted scientists to investigate pharmaceuticals to prevent the spread of the disease. Favipiravir (FAV) has received Food and Drug Administration FDA approval for the treatment of various viral infections with notable efficacy in clinical trials for COVID-19. Nitazoxanide (NTZ) is a broad-spectrum antiparasitic and antiviral agent used for the treatment of parasitic illnesses. Recently, the antiviral medications FAV and NTZ have been utilized therapeutically as early antiviral combination therapy for COVID-19, highlighting their safety, efficacy, and immunomodulatory effects. Despite several clinical studies on both FAV and NTZ, no analytical method has been developed for their concurrent detection. The objective of this study is to develop a TLC-densitometric method for their assessment and application to rat plasma. FAV, NTZ, and tizoxanide (the active metabolite of nitazoxanide (TZM)) were simultaneously determined using an HPTLC method embracing sulfasalazine as an internal standard (IS). Silica gel 60 F254 used as the stationary phase for chromatographic separation, the mobile phase consisted of chloroform-methanol-formic acid (9.5:0.5:0.2, v/v/v), with UV detection at 230 nm demonstrating linearity within the range of 0.5-5 μg/band. The proposed methodology has been shown to effectively measure the analyzed elements in both pure form and in-vivo rat plasma.

Platinum Group Metals against Parasites: State of the Art and Future Perspectives

Background: Globally, parasitic diseases are considered among the neglected diseases. Clinically, several drugs are used in treatment, however due to drug resistance and multidrug resistance and the low investment in new research lines, there has been a failure in the treatment of parasitic illnesses. Objectives: The present mini-review is a comprehensive review of the use of platinum group metals as biological agents. It aims to establish the actual state of the art of these metal elements in the antiparasitic activity-specific area and define the future possibilities of action. Methods: The review comprises more than 100 research works done in this field. The differences between platinum group metals chemistry and their use as metal complexes with biological activity have been discussed. Results: This review highlighted the platinum group metal's potential as an antiparasitic agent for different diseases. Conclusion: The review will be helpful for the researchers involved in targeted drugs for parasitic disease therapy.

Increased Medication Utilization Precedes Incidentally Diagnosed Inflammatory Bowel Disease: A Multicenter, Case-Control Study.

This study investigates whether subclinical inflammation in asymptomatic patients with inflammatory bowel disease (IBD) leads to increased medication use. In a multicenter, retrospective analysis of patients diagnosed with incidental ulcerative colitis or Crohn's disease during colorectal cancer screening (2010-2021), medication use was compared with symptomatic patients and healthy non-IBD controls. Asymptomatic patients showed a higher use of cardiovascular, antiparasitic, musculoskeletal, respiratory, and sensory organ medications up to 5 years before diagnosis. This trend suggests that a systemic inflammatory process occurs years before clinical onset of IBD, suggesting the potential for earlier diagnosis and intervention.

Discovery and Characterization of Two Selective Inhibitors for a Mu-Class Glutathione S-Transferase of 25 kDa from Taenia solium Using Computational and Bioinformatics Tools.

Glutathione S-transferases (GSTs) are promising pharmacological targets for developing antiparasitic agents against helminths, as they play a key role in detoxifying cytotoxic xenobiotics and managing oxidative stress. Inhibiting GST activity can compromise parasite viability. This study reports the successful identification of two selective inhibitors for the mu-class glutathione S-transferase of 25 kDa (Ts25GST) from Taenia solium, named i11 and i15, using a computationally guided approach. The workflow involved modeling and refining the 3D structure from the sequence using the AlphaFold algorithm and all-atom molecular dynamics simulations with an explicit solvent. Representative structures from these simulations and a putative binding site with low conservation relative to human GSTs, identified via the SILCS methodology, were employed for virtual screening through ensemble docking against a commercial compound library. The two compounds were found to reduce the enzyme's activity by 50-70% under assay conditions, while showing a reduction of only 30-35% for human mu-class GSTM1, demonstrating selectivity for Ts25GST. Notable, i11 displayed competitive inhibition with CDNB, while i15 exhibited a non-competitive inhibition type.

Case report: C57BL/6NTac and C57BL/6NCrl mice displaying neurological signs after deworming with ivermectin

For over 40 years, ivermectin has served as an effective anti-parasitic drug used in human and veterinary medicine. In laboratory animal facilities it is used prophylactically or therapeutically to maintain the health status of the colony or experimentally in studies. Although ivermectin is generally safe to use, there are reports of neurotoxicity associated with ivermectin crossing the blood–brain barrier due to overdosing or blood–brain barrier dysfunction. In mice, P-glycoprotein maintains the blood–brain barrier and mice with a mutation in the P-glycoprotein encoding gene mdr1a are 50–100 times more sensitive to ivermectin. Signs of neurotoxicity include ataxia, bradypnea, recumbency, tremor, and death. We report neurotoxicity after ivermectin administration was used for the purpose of eradicating the murine-specific intestinal nematode Heligmosomoides polygyrus in C57BL/6NTac and C57BL/6NCrl mice. The mice were dewormed by subcutaneous administration of 10 or 20 mg/kg ivermectin to eradicate all stages of Heligmosomoides polygyrus. At 24–48h after deworming, 5% ( n = 4) of the mice presented with tremor, ataxia, and/or head tilt. The affected mice were euthanised and gross pathological findings were found in one of the four mice (left-sided hydronephrosis). We assume that the observed neurological effects were due to defects in the blood–brain barrier, overdosing or individual sensitivity. This report provides a reason for caution when deworming laboratory mice subcutaneously with ivermectin at doses of 10 mg/kg or higher.

Management of adult sepsis in resource-limited settings: global expert consensus statements using a Delphi method.

To generate consensus and provide expert clinical practice statements for the management of adult sepsis in resource-limited settings. An international multidisciplinary Steering Committee with expertisein sepsis management and including a Delphi methodologist was convened by the Asia Pacific Sepsis Alliance (APSA). The committee selected an international panel of clinicians and researchers with expertise in sepsis management. A Delphi process based on an iterative approach was used to obtain the final consensus statements. A stable consensus was achieved for 30 (94%) of the statements by 41 experts after four survey rounds. These include consensus on managing patients with sepsis outside a designated critical care area, triggers for escalating clinical management and criteria for safe transfer to another facility. The experts agreed on the following: in the absence of serum lactate, clinical parameters such as altered mental status, capillary refill time and urine output may be used to guide resuscitation; special considerations regarding the volume of fluid used for resuscitation, especially in tropical infections, including the use of simple tests to assess fluid responsiveness when facilities for advanced hemodynamic monitoring are limited; use of Ringer's lactate or Hartmann's solution as balanced salt solutions; epinephrine when norepinephrine or vasopressin are unavailable; and the administration of vasopressors via a peripheral vein if central venous access is unavailable or not feasible. Similarly, where facilities for investigation are unavailable, there was consensus for empirical antimicrobial administration without delay when sepsis was strongly suspected, as was the empirical use of antiparasitic agents in patients with suspicion of parasitic infections. Using a Delphi method, international experts reached consensus to generate expert clinical practice statements providing guidance to clinicians worldwide on the management of sepsis in resource-limited settings. These statements complement existing guidelines where evidence is lacking and add relevant aspects of sepsis management that are not addressed by current international guidelines. Future studies are needed to assess the effects of these practice statements and address remaining uncertainties.