Preclinical and clinical investigations of anthelmintics for rat lungworm disease (Neuroangiostrongyliasis)

Jacob, John
Jarvi, Susan
Pharmaceutical Sciences
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Angiostrongylus cantonensis, otherwise known as rat lungworm, is an obligate, digenetic, parasitic nematode, and the causative agent for the clinical condition known as neuroangiostrongyliasis, that ultimately may result in eosinophilic meningitis. It is considered as the leading cause of eosinophilic meningitis worldwide. The treatment aspects of neuroangiostrongyliasis have historically been controversial, especially the use of anthelmintics. This is primarily due to the lack of thorough evaluation of anthelmintic efficacy against A. cantonensis. In addition, there exists a provocative theory amongst clinicians that the use of anthelmintics would kill the larvae that have migrated to the brain, and the dying larvae would induce a severe inflammatory response causing even further complications. There are few reported cases where it is thought that the use of anthelmintics has brought adverse outcomes, but in contrast, there are numerous reports describing successful treatments with anthelmintics. This ambiguity has perplexed the health care system regarding the use of anthelmintics for the management of neuroangiostrongyliasis. Although numerous researchers have investigated the specific question of using anthelmintics for the management of neuroangiostrongyliasis, their findings are scattered among multiple in vitro studies, experimental animal studies and clinical reports, across a wide variety of geographical locations, by multiple authors, and thus, a decisive conclusion has never been established. Therefore, I postulated that through a series of systematic and progressive in vitro, in vivo, and clinical investigations on anthelmintic safety, efficacy, and potency against A. cantonensis, an effective treatment algorithm could be developed for neuroangiostrongyliasis. Previous in vitro studies on anthelmintics efficacy were based on the muscular contractility patterns of adult female A. cantonensis worms using isotonic transductors. However, these results may be clinically irrelevant, since not all anthelmintics affect the motor system. Additionally, anthelmintics with vermicidal properties may not necessarily have larvicidal activity against the same species. Therefore, to determine the absolute death of the parasite after exposure to an anthelmintic, a differential staining technique using propidium iodide penetration as the indicator of death, combined with the natural autofluorescence from the collagenous cuticle of the parasite, was developed. Using this assay, the in vitro efficacy of nine clinically established anthelmintics, which included albendazole, diethylcarbamazine, levamisole, pyrantel, praziquantel, niclosamide, piperazine ivermectin and moxidectin, were evaluated. I concluded that, based on our results and the current United States FDA anthelmintic prescribing guidelines, albendazole, avermectins, and pyrantel pamoate appear to be promising candidates for the management and or prevention of neuroangiostrongyliasis. Albendazole is considered as the anthelmintic of choice for the management of rat lungworm disease (neuroangiostrongyliasis), due to its broad spectrum of nematocidal activity and its ability to cross the blood-brain barrier. While the antimitotic mechanism of albendazole has been explicated in other parasitic and non-parasitic nematodes, it has never been evaluated in A. cantonensis. Hence, I evaluated its mechanism on the microtubules of adult A. cantonensis using the tubulin polymerization assay. Statistically significant dose-dependent reduction in the band intensity of polymerized tubulins (or microtubules) was observed (P = 0.019), suggesting that albendazole imparts its antimitotic effect in a dose-dependent manner.Our in vitro studies suggested pyrantel pamoate as a potential post-exposure prophylactic for rat lungworm. Pyrantel pamoate is readily available over-the-counter in most pharmacies in the USA and possesses anthelmintic activity exclusive to the gastrointestinal tract (GIT). Since its efficacy has never been evaluated in vivo, I conducted an animal study where pharmaceutical grade pyrantel pamoate (11 mg/kg) was orally administered to experimentally infected rats at 0, 2-, 4-, 6-, or 8-hours post-infection. The rats were euthanized six weeks post-infection, and worm burden was evaluated from the heart-lung complex. This study showed that pyrantel pamoate can significantly reduce worm burden by 53-72% (P = 0.004), and I concluded that pyrantel pamoate may help reduce the severity of infection associated with worm burden. Though there are numerous animal studies and clinical reports on the efficacy and safety of benzimidazole anthelmintics, particularly albendazole for neuroangiostrongyliasis, a consensual agreement has never been established. A multilinguistic comprehensive search of databases, for clinical reports and experimental animal studies associated with neuroangiostrongyliasis and benzimidazole anthelmintic treatments, was conducted. I found and evaluated 40 experimental animals and 104 clinical studies. Among those clinical reports that described a confirmed diagnosis of neuroangiostrongyliasis in which albendazole monotherapy was used, 100% reported high efficacy (743 patients, 479 animals). In those where albendazole- corticosteroid co-therapy was used, 97.87% reported it to be effective (323 patients, 130 animals). I concluded that there is insufficient evidence-based data supporting any exacerbation of condition associated with the use of albendazole. Finally, I reviewed a cluster case of neuroangiostrongyliasis involving six individuals associated with the consumption of kava contaminated with at least one slug, presumably infected with A. cantonensis. Five out of six patients were treated with albendazole- corticosteroid co-therapy for at least two weeks, while the remaining one patient received albendazole only for two days, due to lack of insurance. Symptoms in this patient recurred on two separate occasions, requiring additional courses of corticosteroids, but eventually recovered. This suggests that albendazole-corticosteroid co-therapy is safe and beneficial in reducing the symptoms of neuroangiostrongyliasis along with shortening the duration of illness.This series of pre-clinical and clinical investigations provide evidence for the safe and effective use of albendazole for the management of neuroangiostrongyliasis. Considering its safety, early empirical treatment with albendazole-corticosteroid co-therapy based on patient history should be promoted rather than delaying the treatment by waiting for diagnostic confirmation. Our in vitro and in vivo studies show that early administration of pyrantel pamoate after a known exposure could significantly reduce the worm burden and the potentially associated severity of symptoms, giving rise to a new post-exposure prophylactic for the early management of neuroangiostrongyliasis.
Pharmaceutical sciences, Anthelmintics, Management, Neuroangiostrongyliasis, Prophylaxis, Rat lungworm, Treatment
215 pages
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