Safety of an oral combination of moxidectin, afoxolaner, and pyrantel pamoate in dogs.

NexGard®PLUS (moxidectin, afoxolaner, and pyrantel pamoate), is an oral combination product for dogs indicated for the prevention of heartworm disease, the treatment and prevention of flea and tick infestations, and the treatment of gastro-intestinal nematode infections. The safety of this product in dogs was evaluated in three studies. Study #1 was a margin-of-safety study conducted in puppies, dosed six times at 28-day intervals at 1X, 3X, or 5X multiples of the maximum exposure dose (equivalent to 24 µg/kg moxidectin, 5 mg/kg afoxolaner, and 10 mg/kg pyrantel). In Study #2, the product was administered to ABCB1-deficient collie dogs at a 1X dose twice at a 28-day interval, and at a 3X or 5X dose once. Study #3 evaluated the safety of the product at 1X and 3X doses administered three times at 4-week intervals, to dogs harboring adult Dirofilaria immitis. In the three studies, the safety was evaluated on the basis of multiple clinical observations and physical examinations, including a complete assessment of toxicity to macrocyclic lactones, and on comprehensive clinical and anatomical pathology evaluations in Study #1. No clinically significant combination product-related effects were observed in any of the three studies. No signs of macrocyclic lactone toxicity were observed in the ABCB1-deficient collie dogs. Some mild and self-resolving instances of emesis or diarrhea were occasionally observed in the 3X and 5X dosed dogs. NexGard® PLUS was demonstrated to be safe following multiple administrations in puppies, in ABCB1-deficient collie dogs, and in microfilaremic dogs infected with adult D. immitis.

Demonstration of reduced efficacy against cyathostomins without change in species composition after pyrantel embonate treatment in Swedish equine establishments.

Consisting of approximately 50 different species, the cyathostomin parasites are ubiquitous in grazing horses. Co-infection with several species is common, and large burdens can cause the fatal disease of larval cyathostominosis. Due to intense anthelmintic drug use, cyathostomin resistance has developed to all available anthelmintic drug groups. Resistance to the anthelmintic drug pyrantel (PYR) has been documented in over 90% of studies published over the past two decades. In Sweden, a study performed in the early 2000s only confirmed resistance in 4.5% of farms. Further, prescription-only administration of equine anthelmintic drugs was enforced in Sweden in 2007. However, it is unknown if this conservative drug use has maintained PYR efficacy in cyathostomins. The aim of the present study was to investigate the effect of PYR on cyathostomin infection in Sweden using fecal egg count reduction tests (FECRTs). Further, the effect of PYR treatment on cyathostomin species composition was studied using metabarcoding. Sixteen farms with at least six horses excreting a minimum of 100 eggs per gram feces were included. Using the current World Association for the Advancement of Veterinary Parasitology (WAAVP) guidelines, PYR resistance was demonstrated in nine of farms, with seven farms showing full susceptibility. Farms with low biosecurity measures had significantly lower efficacy of PYR treatment. The most common cyathostomin species were Cylicocyclus nassatus, Cyathostomum catinatum, Cylicostephanus longibursatus, Cys. calicatus, Cys. goldi, Cys. minutus, Coronocyclus coronatus and Cya. pateratum, accounting for 97% of all sequence reads prior to treatment. Of these, Cyc. nassatus and Cya. catinatum had the highest occurrence, accounting for 68% of all sequence reads prior to PYR treatment. Treatment did not significantly affect the species composition. The results highlight the importance of drug efficacy testing when using PYR to treat cyathostomin infection, even when selective anthelmintic treatment and thus low treatment intensity, is used on the farm.

Efficacy of an oral combination of moxidectin, afoxolaner, and pyrantel pamoate for the prevention of heartworm disease in dogs.

Dirofilaria immitis, the mosquito-borne agent of dirofilariosis, a chronic and sometimes fatal cardiopulmonary canine disease, is endemic in most warm and temperate regions in the world. The efficacy of an oral endectoparasiticide product (test product or TP) combining moxidectin, afoxolaner, and pyrantel pamoate was evaluated for the prevention of heartworm disease in dogs, in two laboratory and one field studies. In each laboratory study, 20 D. immitis-naïve beagle dogs were experimentally infected with D. immitis. Ten control dogs were sham-treated, and ten dogs were administered the TP targeting the minimum effective dose, six times monthly and starting 30 days post infection. At necropsy seven months after inoculations, no heartworms were found in any of the TP treated dog, whereas 19 to 42 live heartworms were found in the control dogs. In each study, treatment efficacy was 100% and the difference between treated and untreated groups was highly significant (p < 0.0001). A field study was conducted through the full transmission season in several heartworm-endemic regions of the United States. One hundred and twenty client-owned dogs that were negative for D. immitis at enrollment were administered twelve monthly oral doses of the TP at label dose. Blood tests for D. immitis antigen and modified Knott's tests for microfilariae remained negative through the full duration of the study, demonstrating that all dogs were protected from heartworm infection during the full transmission season. These studies demonstrated that TP administered monthly for at least six doses is effective at preventing dirofilariosis.

MANAGEMENT OF A FATAL OUTBREAK OF STRONGYLOIDIASIS IN A CAPTIVE POPULATION OF PANTHER CHAMELEONS (FURCIFER PARDALIS) WITH IVERMECTIN.

An outbreak of the nematode Strongyloides sp. occurred in a population of 18 male and 29 female panther chameleons (Furcifer pardalis) at the Singapore Zoo. The parasite was first detected in one individual during routine microscopic examination of feces using the direct examination and magnesium sulfate flotation methods. The parasite was later found to have a closest match (98.96%) with Strongyloides sp. Okayama by DNA sequencing. Over a period of 6 mon, 97.9% (46/47) of the panther chameleons tested positive for the parasite, and 25.5% (12/47) of the animals died due to the disease. All the animals that died were female. Of the positive tests, magnesium sulfate flotation identified the parasite 98.1% (105/107) of the time, compared to direct fecal microscopy, which identified the parasite only 43.9% (47/107) of the time. Parasite eggs were detected in 100% (105/105) of the positive magnesium sulfate flotation tests but only 66.0% (31/47) of the positive direct fecal microscopy tests. Parasite larvae were detected in 61.7% (29/47) of the positive direct fecal microscopy tests but only 9.5% (10/105) of the magnesium sulfate flotation tests. Treatments with fenbendazole and pyrantel pamoate at published doses were ineffective at eliminating the parasite. Ivermectin (0.2 mg/kg PO q2wk for two doses) was successful at treating the parasite, with all animals testing negative for the parasite at the end of the treatment course without any observed adverse reactions. However, complete eradication of the parasite could not be achieved, as Strongyloides sp. could still be detected in the population on routine coproscopy intermittently over 3 yr. There were no further mortalities due to the disease with prompt treatment with ivermectin. Strongyloidiasis may cause high morbidity in panther chameleons, but severe disease leading to mortality can be prevented with the use of ivermectin.

Apparent treatment failure of praziquantel and pyrantel pamoate against anoplocephalid tapeworms.

Anoplocephalid tapeworms are commonly occurring in grazing horses around the world. Two currently available anthelmintics have documented high efficacy against Anoplocephala perfoliata; praziquantel in various dosages ranging from 1.0 to 2.5 mg/kg and pyrantel pamoate administered at 13.2 mg base/kg. Anthelmintic resistance has not been reported in A. perfoliata, but anecdotal reports made during 2022 have suggested a possible loss of efficacy for both actives. This paper reports fecal egg count data from a Thoroughbred operation in Central Kentucky in 2023. Fifty-six yearlings were first dewormed with a combination of ivermectin (200 µg/kg) and praziquantel (1.5 mg/kg) and subsequently treated with pyrantel pamoate (13.2 mg base/kg). Fecal egg counts were determined at the day of treatment and again 14 days post-treatment. Two groups of mares (n = 39 and 45) were also treated with ivermectin/praziquantel and examined pre- and post-treatment. Low efficacy of ivermectin and pyrantel pamoate was demonstrated against strongylid parasites in the yearlings with mean Fecal Egg Count Reductions (FECRs) at 75.6% or below and upper 95% credible interval (CI) limits below 90% in all cases. Overall anti-cestodal FECR levels in the yearlings were 23.5% (95% CI: 11.2-48.0) for praziquantel and 50.9% (20.5-72.0) for pyrantel pamoate. Praziquantel eliminated anoplocephalid eggs from three of 17 yearlings, but another 5 yearlings went from negative to positive status following treatment. Pyrantel pamoate failed to eliminate anoplocephalid eggs from any of 14 treated tapeworm-positive yearlings. Nine of 84 mares tested positive for anoplocephalid eggs, and seven of these were still positive post praziquantel treatment. These findings sharply contrast data from historic field efficacy studies conducted for both actives and raise concern about anthelmintic resistance having possibly developed. This emphasizes the need for developing and refining antemortem methodologies for evaluating anti-cestodal treatment efficacy and for searching for possible alternative treatment options.

Clinical and Parasitological Evaluation of Ivermectin and Ivermectin + Pyrantel Against Oxyuris Equi in Equines.

The equine pinworm could become an increasingly common problem, as there are reports of failure in the control of this parasite. The aim of this study was to evaluate the effects of ivermectin (IVM) and IVM combined with pyrantel pamoate (PYR). Thirteen parasitological positive equines were treated with oral IVM (200 µg/kg) and therapeutic efficacy, clinical recovery and the egg reappearance period (ERP) were evaluated. In cases for which ERP was shorter than the pre-patent period (PPP), a second treatment was performed with IVM (200 µg/kg) + PYR (6.6 mg/kg), followed by the same evaluation criteria described above. Therapeutic efficacy was 100% with IVM + PYR and 53.84% with IVM. The mean ERP was shorter than the PPP with both formulations, 77.55 days with IVM + PYR and 50 days with IVM. The presence of egg mass was always associated with a least one clinical sign. The reduction in the number of clinical signs per animal from Day 0 to Day 30 was greater in equines treated with IVM + PYR compared to those treated with IVM alone. The animals treated with IVM were 4.5-fold more likely to present clinical signs 30 days after treatment than those treated with IVM+PYR. A negative correlation was found between ERP and the number of clinical signs at 30 days in the animals treated with IVM. This clinical and parasitological evaluation demonstrated that the combination of IVM+PYR was more effective than IVM alone to control Oxyuris equi.

Multiple anthelmintic drug resistance in hookworms (Ancylostoma caninum) in a Labrador breeding and training kennel in Georgia, USA.

OBJECTIVE: To evaluate the efficacy of the 3 major classes of anthelmintics used for the treatment of hookworms in dogs in the US and an extralabel treatment with an FDA-approved product for use in cats in a Labrador kennel with a history of persistent hookworm infections. ANIMALS: 22 dogs housed in a single kennel comprised of the following breeds: 19 Labrador Retrievers, 1 English Cocker Spaniel, 1 Chesapeake Bay Retriever, and 1 Boykin Spaniel. PROCEDURES: We performed a fecal egg count (FEC) reduction test using 22 dogs that were allocated randomly to 1 of 5 treatment groups: pyrantel pamoate (Pyrantel pamoate suspension), fenbendazole (Safe-Guard suspension 10%), milbemycin oxime (Interceptor), moxidectin plus imidacloprid (Advantage Multi), and emodepside plus praziquantel (Profender topical solution for cats). FEC was performed on samples collected on days 0 and 11. RESULTS: FEC reductions for the milbemycin oxime, moxidectin plus imidacloprid, and emodepside plus praziquantel groups were 43.9%, 57.4%, and 100%, respectively. The FEC increased following treatment for the pyrantel and fenbendazole groups. CLINICAL RELEVANCE: These data demonstrate that the Ancylostoma caninum infecting the dogs in this kennel are highly resistant to all major anthelmintic classes approved for use in dogs in the US but are susceptible to emodepside. This was the first report of multiple anthelmintic drug-resistant A caninum in a dog kennel that does not involve Greyhounds.

Gastrointestinal helminths in dogs: occurrence, risk factors, and multiple antiparasitic drug resistance.

Helminth infections are detrimental to the overall health of dogs; therefore, this study aimed to identify antiparasitic-resistant helminths and evaluate the infection rate and risk factors for parasitism in canines. For this purpose, a parasitological evaluation of 38 randomly selected animals was performed, followed by the evaluation of the anthelminthic efficacy of three drugs: pyrantel pamoate with praziquantel (Canex Composto®), fenbendazole (Fenzol Pet®), and milbemycin oxime with praziquantel (Milbemax C®). Among the evaluated animals, 22/38 (57.89%) tested negative and 16/38 (42.71%) tested positive for Ancylostoma caninum infection. Evaluation of the efficacy of antiparasitic drugs showed that 12/16 (75%) dogs were infected with helminths that were susceptible to pyrantel pamoate with praziquantel. Among those for which pyrantel pamoate with praziquantel was not effective, 3/4 (75%) were susceptible to fenbendazole, while the remaining case resistant to both pyrantel pamoate with praziquantel and fenbendazole was sensitive to milbemycin oxime with praziquantel (100%). The odds ratio of infection in dogs inhabiting environments containing soil or grass was 6.67 times higher than that in dogs inhabiting impermeable environments. Mixed-breed dogs (SRD) were 6.54 times more likely to be infected compared to purebred dogs. A. caninum resistant to pyrantel pamoate with praziquantel (4/16, 25%) and fenbendazole (1/4, 25%) were detected. The results of this study demonstrated the importance of coproparasitological monitoring by professionals before and after treatments to assess antiparasitic drug effectiveness, ensure animal health and welfare, and minimize animal exposure to risk factors.

In vivo efficacy of pyrantel pamoate as a post-exposure prophylactic for rat lungworm (Angiostrongylus cantonensis).

Rat lungworm (Angiostrongylus cantonensis) is a neurotropic nematode, and the leading cause of eosinophilic meningitis worldwide. The parasite is usually contracted through ingestion of infected gastropods, often hidden in raw or partially cooked produce. Pharmaceutical grade pyrantel pamoate was evaluated as a post-exposure prophylactic against A. cantonensis. Pyrantel pamoate is readily available over-the-counter in most pharmacies in the USA and possesses anthelmintic activity exclusive to the gastrointestinal tract (GIT). Administering pyrantel pamoate immediately after exposure should theoretically paralyze the larvae in the GIT, causing the larvae to be expelled via peristalsis without entering the systemic circulation. In this study, pyrantel pamoate (11 mg/kg) was orally administered to experimentally infected rats at 0, 2-, 4-, 6-, or 8-h post-infection. The rats were euthanized six weeks post-infection, and worm burden was evaluated from the heart-lung complex. This is the first in vivo study to evaluate its efficacy against A. cantonensis. This study demonstrates that pyrantel pamoate can significantly reduce worm burden by 53-72% (P = 0.004), and thus likely reduce the severity of infection that is known to be associated with worm burden. This paralyzing effect of pyrantel pamoate on the parasite may also be beneficial for delaying the establishment of infection until a more suitable anthelmintic such as albendazole is made available to the patient.

Preclinical and Clinical Characteristics of the Trichuricidal Drug Oxantel Pamoate and Clinical Development Plans: A Review.

Soil-transmitted helminths (Ascaris lumbricoides, hookworm and Trichuris trichiura) infect about one-fifth of the world's population. The currently available drugs are all highly efficacious against A. lumbricoides. However, they are only moderately efficacious against hookworm and poorly efficacious against T. trichiura. Oxantel, a tetrahydropyrimidine derivative discovered in the 1970s, has recently been brought back to our attention given its high efficacy against T. trichiura infections (estimated 76% cure rate and 85% egg reduction rate at a 20 mg/kg dose). This review summarizes the current knowledge on oxantel pamoate and its use against T. trichiura infections in humans. Oxantel pamoate acts locally in the human gastrointestinal tract and binds to the parasite's nicotinic acetylcholine receptor (nAChR), leading to a spastic paralysis of the worm and subsequent expulsion. The drug is metabolically stable, shows low permeability and low systemic bioavailability after oral use. Oxantel pamoate was found to be safe in humans, with only a few mild adverse events reported. Several clinical trials have investigated the efficacy of this drug against T. trichiura and suggest that oxantel pamoate is more efficacious against T. trichiura than the currently recommended drugs, which makes it a strong asset to the depleted drug armamentarium and could help delay or even prevent the development of resistance to existing drugs. We highlight existing data to support the use of oxantel pamoate against T. trichiura infections.

Evaluation of Commercially Available Anthelminthics in Laboratory Models of Human Intestinal Nematode Infections.

Drug repurposing from veterinary to human medicine has been the main strategy to develop the four recommended human anthelminthics, albendazole, mebendazole, levamisole, and pyrantel pamoate, for the treatment of soil-transmitted helminthiasis. A systematic, head-to-head comparison of the anthelminthic activity profile of derivatives of these drugs and other anthelminthics developed in succession has not been conducted to date. We studied eight benzimidazoles, five macrocyclic lactones, tribendimidine, levamisole, and pyrantel pamoate in laboratory models of human intestinal nematode infections. In vitro studies were performed on Trichuris muris L1 larval stage and adults, as well as Ancylostoma ceylanicum, Necator americanus, Heligmosomoides polygyrus, and Strongyloides ratti L3 larvae and adults. The benzimidazoles showed pronounced differences against larval and adult stages, with low activity against larvae and the highest activity observed against adult N. americanus (IC50 of flubendazole 1.1 µM). The macrocyclic lactones, on the other hand, revealed a higher activity on the larval stages, with the lowest IC50 values observed against N. americanus L3 (IC50 values of 0.03-3 µM). In vivo studies were performed in the T. muris and H. polygyrus mice models, with moxidectin and milbemycin oxime showing the highest activity against H. polygyrus (ED50 values of 0.009 and 0.006 mg/kg, respectively) and moxidectin and abamectin being the most effective drugs against T. muris (ED50 values of 0.2 and 0.5 mg/kg, respectively). Laboratory models for soil-transmitted helminthiasis can assist characterizing potential drug candidates. Drugs should be evaluated against different species, and both the adult and larval stages as activities could differ considerably.

Comparison of real-time PCR and the Kato-Katz method for the diagnosis of soil-transmitted helminthiasis and assessment of cure in a randomized controlled trial.

BACKGROUND: Diagnosis of soil-transmitted helminths (STHs) in developing countries is commonly based on microscopic detection of eggs in stool samples, using the Kato-Katz (KK) method, which has a poor sensitivity for detecting light intensity infections. We compared the performance of the KK method and real-time PCR in the framework of a randomized trial, which evaluated four novel treatments against Trichuris trichiura and concomitant STH infections. RESULTS: Two stool samples obtained from 320 participants were examined at baseline and follow-up with quadruplicate KK and PCR analyses of one of the two samples using "bead-beating" for DNA extraction. At follow-up, 80 samples were negative according to both PCR and KK and 173 were positive with both methods for any of the STHs. Relative to PCR, the calculated sensitivity of KK at follow-up was 83.6%, 43.0% and 53.8% for T. trichiura, for hookworm and for Ascaris lumbricoides, respectively. The sensitivity of PCR compared with KK at this time point was 89.1% for T. trichiura, 72.7% for hookworm and 87.5% for A. lumbricoides. Cure rates (CRs) for T. trichiura and A. lumbricoides were slightly lower with the PCR method. For hookworm CRs with KK were mostly significantly lower, namely 36.7%, 91.1%, 72.2% and 77.8% for moxidectin, moxidectin in combination with tribendimidine, moxidectin in combination with albendazole and albendazole in combination with oxantel pamoate, respectively, whereas with PCR the CRs were 8.3%, 82.6%, 37.1% and 57.1%, respectively. CONCLUSIONS: In conclusion, a single real-time PCR is as sensitive as quadruplicate KK for T. trichiura and A. lumbricoides detection but more sensitive for hookworm, which has an influence on the estimated treatment efficacy. PCR method with DNA extraction using the "bead-beating protocol" should be further promoted in endemic areas and laboratories that can afford the needed equipment. The study is registered at ISRCTN (no. 20398469).

Effects of anthelmintics on the pinworm Blatticola blattae in laboratory-reared German cockroaches Blattella germanica.

The efficacy of pyrantel pamoate, pyrvinium pamoate, ivermectin, and piperazine citrate against pinworm in cockroach was evaluated. Laboratory-reared German cockroaches naturally infected with Blatticola blattae were treated with the anthelmintics and necropsied at 3 to 35 days after treatment. Ivermectin at over 5 ppm and piperazine citrate at over 2000 ppm killed all the treated cockroaches. Pinworms were still detected in cockroaches given lower concentration of the aforementioned drugs. Administration of pyrantel pamoate (100-1000 ppm) and pyrvinium pamoate (2000 ppm) did not kill the cockroaches, and no pinworms were detected at 3 and 17 days after treatment. Thus, pyrantel pamoate and pyrvinium pamoate were found to be effective for deworming B. blattae in the German cockroaches, without causing mortality for the host. Our results showed that anthelmintics selection is essential for eradication of pinworms in cockroaches because of the toxicity for the host such as ivermectin or piperazine citrate. This is the first report of piperazine citrate toxicity in cockroaches.

Risk factors for equine intestinal parasite infections and reduced efficacy of pyrantel embonate against Parascaris sp.

Gastrointestinal parasites, Parascaris sp. and strongyles, are common in young horses worldwide and control of these parasites is challenged by increasing anthelmintic resistance. Our aim was to identify risk factors for these infections as well as to assess the efficacy of fenbendazole (dose 7.5 mg/kg) and pyrantel embonate (dose 19 mg/kg) against Parascaris sp. We also evaluated association between owner observed symptoms and patent infections with these parasites. Fecal samples were collected from 367 young horses in Finland and a questionnaire study was conducted. Fecal egg counts were performed by Mini-FLOTAC® method. Univariable logistic regression models using patent infection status (Yes/No), separately for Parascaris sp. and strongyle infections as an outcome were run initially to screen potential risk factors collected by the questionnaire. After the initial screening, multiple logistic regression models were constructed and run to account for correlated data structure, risk factors and potential confounders simultaneously. Two significant risk factors for a patent Parascaris sp. infection were found: breeding farm size (p = 0.028) and frequency of horse movements (p = 0.010). Horses originating from large breeding farms were more likely (OR = 2.47, 95% confidence interval (CI) 1.10-5.51) to shed Parascaris sp. eggs upon relocation to training stables compared to horses originating from small breeding farms. Horses living in farms with frequent horse movements to other premises had higher odds (OR = 3.56, 95% CI: 1.35-9.39) of a patent Parascaris sp. infection compared to farms with less frequent horse movements. Risk factors for patent strongyle infection included age (p < 0.001) and season (p = 0.017). Horses were less likely (OR = 0.27, 95% CI: 0.10 - 0.66) to shed strongylid eggs during the spring compared to the winter. Horses excreting over 200 ascarid eggs per gram were included in the anthelmintic efficacy trial. A mean FECR less than 90% was interpreted as presence of anthelmintic resistance. The mean FECR was 98.5% (95% CI: 95.8-100) and 68.0% (95% CI: 52.7-83.3) in the fenbendazole (n = 31) and pyrantel (n = 26) treatment groups, respectively. In conclusion, we identified two new risk factors for patent Parascaris sp. infection; breeding farm size and frequency of horse movements. Reduced efficacy of pyrantel against Parascaris sp. was observed for the second time in Europe. A relatively high Parascaris sp. prevalence in yearlings (34%) and two-year-olds (20%) was observed, which has not been reported earlier. An association between symptoms and a patent Parascaris sp. infection was observed in foals.

The importance of anthelmintic efficacy monitoring: results of an outreach effort.

Anthelmintic resistance in equine cyathostomin parasites is widespread. A surveillance-based parasite control program using fecal egg counts (FECs) and fecal egg count reduction tests (FECRTs) to decrease anthelmintic use and monitor treatment efficacy is recommended. The purpose of this study was to examine shifts in equine parasite control program management practices via a short course presented by the Penn State Extension, and to highlight how data collected from these programs is useful for monitoring anthelmintic efficacy on a large scale. Horse owners were enrolled after participating in a short course and filled out questionnaire surveys about their parasite management programs pre and post study, horse information, and farm information. FECs were performed at three time points, and horses above a 300 strongyle eggs per gram cut-off were treated with pyrantel pamoate, fenbendazole, or ivermectin. Two weeks post-treatment, FECRTs were performed to determine treatment efficacy, which included 29 farms with 513 individual treatments. Prior to the study, only 30.6% of farms used FECs, but after the study, 97.3% of farms said they would use FECs in the future. Horses were given an average of 4.1 anthelmintic treatments per year before the study, and post study 89.2% of farms were able to reduce the number of anthelmintic treatments used. Fenbendazole was effective on zero farms, pyrantel pamoate on 7.4% of farms, and ivermectin on 92.9% of farms. This outreach project helped generate information about anthelmintic efficacy levels, causing a shift in practices on participating farms, and collected useful anthelmintic resistance data.

Variation in Local and Systemic Pro-Inflammatory Immune Markers of Wild Wood Mice after Anthelmintic Treatment.

The immune system represents a host's main defense against infection to parasites and pathogens. In the wild, a host's response to immune challenges can vary due to physiological condition, demography (age, sex), and coinfection by other parasites or pathogens. These sources of variation, which are intrinsic to natural populations, can significantly impact the strength and type of immune responses elicited after parasite exposure and infection. Importantly, but often neglected, a host's immune response can also vary within the individual, across tissues and between local and systemic scales. Consequently, how a host responds at each scale may impact its susceptibility to concurrent and subsequent infections. Here we analyzed how characteristics of hosts and their parasite infections drive variation in the pro-inflammatory immune response in wild wood mice (Apodemus sylvaticus) at both the local and systemic scale by experimentally manipulating within-host parasite communities through anthelmintic drug treatment. We measured concentrations of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) produced in vitro in response to a panel of toll-like receptor agonists at the local (mesenteric lymph nodes [MLNs]) and systemic (spleen) scales of individuals naturally infected with two gastrointestinal parasites, the nematode Heligmosomoides polygyrus and the protozoan Eimeria hungaryensis. Anthelmintic-treated mice had a 20-fold lower worm burden compared to control mice, as well as a four-fold higher intensity of the non-drug targeted parasite E. hungaryensis. Anthelmintic treatment differentially impacted levels of TNF-α expression in males and females at the systemic and local scales, with treated males producing higher, and treated females lower, levels of TNF-α, compared to control mice. Also, TNF-α was affected by host age, at the local scale, with MLN cells of young, treated mice producing higher levels of TNF-α than those of old, treated mice. Using complementary, but distinct, measures of inflammation measured across within-host scales allowed us to better assess the wood mouse immune response to changes in parasite infection dynamics after anthelmintic treatment. This same approach could be used to understand helminth infections and responses to parasite control measures in other systems in order to gain a broader view of how variation impacts the immune response.

An ocular myasthenia gravis attack after oral pyrantel pamoate: An unusual case report.

RATIONALE: Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction that can be triggered by anticholinergic agents. PATIENT CONCERNS: We present a 4-year-old female patient who was admitted to the outpatient clinic. She complained of drooped eyelids, which first appeared 2 days after taking a 200 mg dose of pyrantel pamoate. Past medical history is negative. DIAGNOSES AND TREATMENT: She was hospitalized with a diagnosis of ocular type MG, and pyridostigmine (40 mg/day) treatment was started. OUTCOMES: The patient recovered, and subsequently, the treatment dose was tapered. CONCLUSION: Pyrantel is an antihelminthic that acts as an agonist of nicotinic acetylcholine receptors (AChRs) of nematodes and exerts its therapeutic effects by depolarizing their muscle membranes. Consequently, there may be an association between pyrantel pamoate and MG.

Diagnóstico de las infecciones por geohelmintos. Un problema sin resolver en la era de las ómicas / Diagnosis of soil-transmitted helminth infections. An unsolved problemin the omics era

Las infecciones producidas por Strongyloides stercoralis y otros geohelmintos, como las uncinarias (Necator americanus y Ancylostoma duodenale), representan un importante problema a nivel mundial, especialmente en áreas en vías de desarrollo. Clínicamente son difíciles de sospechar ya que producen cuadros inespecíficos y muchas veces solapados entre ellos. Asimismo, los largos períodos prepatentes que presentan dificultan la detección de las formas parasitarias. El diagnóstico microscópico continúa siendo la herramienta más utilizada en los laboratorios asistenciales, pero aún dista mucho de ser la herramienta ideal para detectarlos debido a su baja sensibilidad. Además, morfológicamente estos nematodos presentan similitudes importantes, por lo que el diagnóstico microbiológico aún es un reto. La serología ha permitido avanzar en cuanto al diagnóstico de la infección por S. stercoralis, pero esta opción no está disponible todavía para las uncinarias. Las técnicas de biología molecular han demostrado aumentar discretamente esta falta de sensibilidad, pero al igual que en otras infecciones parasitarias, actualmente no están disponibles para su uso en los laboratorios de microbiología clínica. Información sobre el suplemento: este artículo forma parte del suplemento titulado "Programa de Control de Calidad Externo SEIMC. Año 2016", que ha sido patrocinado por Roche, Vircell Microbiologists, Abbott Molecular y Francisco Soria Melguizo, S.A

Infections caused by Strongyloides stercoralis and other soil-transmitted worms such as hookworms (Necator americanus and Ancylostoma duodenale) represent a major problem worldwide, especially in developing areas. They are difficult to suspect clinically since they produce non-specific and often overlapping signs and symptoms. Likewise, their long prepatent periods hamper the detection of parasitic structures. Microscopic diagnosis is still the most commonly used tool in healthcare laboratories but it is still far from being the ideal technique to detect these infections due to its low sensitivity. In addition, these nematodes have strong morphologic similarities and consequently microbiological diagnosis remains a challenge. Serology has made progress in the diagnosis of S. stercoralis infection but this option is not yet available for hookworms. Molecular biology techniques have been shown to slightly increase this lack of sensitivity, but as with other parasitic infections, they are not currently available for use in clinical microbiology laboratories. Supplement information: This article is part of a supplement entitled "SEIMC External Quality Control Programme. Year 2016", which is sponsored by Roche, Vircell Microbiologists, Abbott Molecular and Francisco Soria Melguizo, S.A

Pharmacokinetics of Albendazole, Albendazole Sulfoxide, and Albendazole Sulfone Determined from Plasma, Blood, Dried-Blood Spots, and Mitra Samples of Hookworm-Infected Adolescents.

Albendazole is an effective anthelmintic intensively used for decades. However, profound pharmacokinetic (PK) characterization is missing in children, the population mostly affected by helminth infections. Blood microsampling would facilitate PK studies in pediatric populations but has not been applied to quantify albendazole's disposition. Quantification methods were developed and validated using liquid chromatography-tandem mass spectrometry to analyze albendazole and its metabolites albendazole sulfoxide and albendazole sulfone in wet samples (plasma and blood) and blood microsamples (dried-blood spots [DBS]; Mitra). The use of DBS was limited by a matrix effect and poor recovery, but the extraction efficiency was constant throughout the concentration range. Hookworm-infected adolescents were venous and capillary blood sampled posttreatment with 400 mg albendazole and 25 mg/kg oxantel pamoate. Similar half-life (t1/2 = ∼1.5 h), time to reach the maximum concentration (tmax = ∼2 h), and maximum concentration (Cmax = 12.5 to 26.5 ng/ml) of albendazole were observed in the four matrices. The metabolites reached Cmax after ∼4 h with a t1/2 of ca. 7 to 8 h. A statistically significant difference in albendazole sulfone's t1/2 as determined by using DBS and wet samples was detected. Cmax of albendazole sulfoxide (288 to 380 ng/ml) did not differ among the matrices, but higher Cmax of albendazole sulfone were obtained in the two microsampling devices (22 ng/ml) versus the wet matrices (14 ng/ml). In conclusion, time-concentration profiles and PK results of the four matrices were similar, and the direct comparison of the two microsampling devices indicates that Mitra extraction was more robust during validation and can be recommended for future albendazole PK studies.

In Vitro and In Vivo Drug-Drug Interaction Study of the Effects of Ivermectin and Oxantel Pamoate on Tribendimidine.

Soil-transmitted helminth (STH) infections still remain a major health problem in poor rural settings. The lack of efficacious drugs against all STH species raises interest in drug combinations. Drug-drug interactions (DDIs) are, however, of major concern, so careful in vitro and in vivo characterization is needed. The combination of tribendimidine with either ivermectin or oxantel pamoate targets a broad range of STHs and thus represents a promising treatment alternative. Drug-drug interactions, however, have not yet been investigated. Therefore, the effects of combinations of ivermectin, oxantel pamoate, and tribendimidine's active metabolite deacylated amidantel (dADT) on cytochrome P450 (CYP450) metabolism were evaluated, followed by a pharmacokinetic analysis of tribendimidine and ivermectin alone and in combination in healthy rats. Oxantel pamoate is only poorly absorbed and was therefore excluded from pharmacokinetic analysis. No evident effect was observed for tribendimidine-oxantel pamoate at the CYP450 metabolism level, whereas a combination of tribendimidine and ivermectin led to moderately increased CYP2D6 inhibition compared to ivermectin or tribendimidine alone. Coadministration of tribendimidine with ivermectin altered neither the time to maximum concentration of drug in plasma (Tmax) nor the elimination half-lives of dADT, the acetylated derivative of amidantel (adADT), and ivermectin. While the area under the concentration-versus-time curve (AUC) and maximum concentration of drug in plasma (Cmax) values of dADT, adADT, and ivermectin are reduced by coadministration, the change is insufficient to declare that a DDI has been detected. Further studies are necessary to understand the observed interaction of tribendimidine and ivermectin, which is not related to P450 metabolism, and its significance for the situation in humans.