Oxindole alkaloids in the paraherquamide/marcfortine family exhibit broad-spectrum anthelmintic activity that includes drug-resistant strains of nematodes. Paraherquamide (PHQ), 2-deoxoparaherquamide (2DPHQ), and close structural analogs of these compounds rapidly induce flaccid paralysis in parasitic nematodes in vitro, without affecting adenosine triphosphate (ATP) levels. The mechanism of action of this anthelmintic class was investigated using muscle tension and microelectrode recording techniques in isolated body wall segments of Ascaris suum. None of the compounds altered A. suum muscle tension or membrane potential. However, PHQ blocked (when applied before) or reversed (when applied after) depolarizing contractions induced by acetylcholine (ACh) and the nicotinic agonists levamisole and morantel. These effects were mimicked by the nicotinic ganglionic blocker mecamylamine, suggesting that the anthelmintic activity of PHQ and marcfortines is due to blockade of cholinergic neuromuscular transmission. The effects of these compounds were also examined on subtypes of human nicotinic ACh receptors expressed in mammalian cells with a Ca2+ flux assay. 2DPHQ blocked nicotinic stimulation of cells expressing alpha3 ganglionic (IC50 approximately 9 microm) and muscle-type (IC50 approximately 3 microm) nicotinic cholinergic receptors, but was inactive at 100 microm vs. the alpha7 CNS subtype. PHQ anthelmintics are nicotinic cholinergic antagonists in both nematodes and mammals, and this mechanism appears to underlie both their efficacy and toxicity.
In War and Peace, Leo Tolstoy wrote that “the thoughts that have enormous consequences are always simple.” 1 This essay explains an ambitious idea with enormous consequences that is simple: an International Anti-Corruption Court is needed to diminish the devastating consequences of grand corruption, the abuse of public office for private gain by a nation's leaders. Grand corruption depends on a culture of impunity in countries whose leaders will not permit the enforcement of existing criminal laws against their close colleagues and themselves. An International Anti-Corruption Court would provide a forum to enforce those laws, punish corrupt leaders, and deter and thus diminish grand corruption. The successful prosecution and imprisonment of corrupt leaders would create opportunities for the democratic process to produce successors dedicated to serving their people rather than to enriching themselves.
The inclusion of formal courses in medical ethics as part of standard undergraduate medical education has not led to widespread confidence in the moral and professional development of young physicians. As important as classes on informed consent and other such topics are, alternative approaches to professional moral development are needed. One example can be found in The U.S. Schweitzer Fellows Programs, which now support over 100 health professions students annually in six locations. Fellows participate in activities designed to strengthen the ideals that originally attracted them to medicine and other health care fields. Because Dr. Schweitzer is remembered primarily for the way he translated his ideals of human service into action, the core activity of each program is a direct-service project that addresses an important unmet health need of the local community or individuals in the community, with the support of community-based and school-based mentors. Alumni of these programs report that their experiences as Schweitzer fellows have helped them integrate their own ideals into their professional and career development. Such systematic efforts to recognize and support the latent idealism of young health professionals may strengthen the moral dimensions of professional life in ways that have broad social benefits.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.