Current Topics in Medicinal Chemistry - Volume 8, Issue 5, 2008

Parasite infections are common in many developing countries and constitute a public health problem. Taenia solium cysticercosis is still an important parasitosis in rural pigs in many developing countries and affects millions of humans in Asia, Africa and Latin America. The tapeworms produce thousand of embryos in eggs that are infective for humans, causing the human disease neurocysticercosis, and porcine cysticercosis in the natural intermediate host, the pig. Recent reports describe the appearance of neurocysticercosis cases in industrialized countries where the disease has been eradicated. The clinical and radiologic presentation of the disease is highly heterogeneous because of diversity in parasite number, localization, size and stage and intensity of nervous system inflammation. Factors determining this diversity need to be studied. Although the use of cysticidal drugs and a better understanding of the host immune response have had important advances in the last years, neurocysticercosis treatment is not ideal because of adverse drug effects. The inflammation triggered by the parasite can complicate the disease and be the cause of severe sequelae, and the administration of cysticidal drugs frequently increases local inflammation, which can increase the severity of the disease. Hence, research on the biology of the parasite, and search for new treatments, or improvement of the traditional ones continue. The purpose of the current issue of “Current Topics in Medicinal Chemistry” is to review recent developments in cysticercosis. This issue presents review articles from eight groups of researchers who are involved in the investigation of the physio-pathology and treatment of cysticercosis. Aline Aluja opens the issue with a revision on aspects of the swine disease. As stated above the pork is the intermediate host of the parasite, and the ingestion of the undercooked or raw infected meat by humans spreads the parasite. The ingestion of the tapeworm eggs by the pig or humans cause cysticercosis and neurocysticercosis. The chapter reviews the diagnostic procedures in the pig and the macro and microscopic characteristics of the developmental stages of cysticerci. The second review by Kaethe Willms describes the ultrastructure of the Taenia solium tapeworm and metacestode (cysticerci) with special emphasis on the reproductive units of the adult tapeworm called proglottids. The chapter reviews work on the surface characteristics of the larval stage as well as the experimental models developed to study morphological and physiological traits of the adult tapeworm which include descriptions of the tissue localization of glycogen deposits, calcium binding proteins, myosin isoforms and gap junctions and steroid producing enzymes. The next review presented by Luis Terrazas, describes the role of pro- and antinflammatory cytokines in cysticercosis and the host-parasite interactions. The review also emphasizes the importance of STAT-6 mediated signaling. It also describes the dual role of macrophages in the pathology of the infection and the immunomodulatory effect of glucocorticoids in the treatment of cysticercosis. The fourth review presented by Vaca-Paniagua, Torres-Rivera, Parra-Unda and Abraham Landa focused on the role of three antioxidant enzymes in different aspects of the disease. Oxidative damage produced by reactive oxygen species (ROS) such as superoxide anion (O2 .-), hydrogen peroxide (H2O2) and hydroxyl radical are some of the major challenges that the parasite must confront. Some of these enzymes are targets for cestocidal drugs. The review by Morales-Montor, Escobedo, Vargas-Villavicencio and Larralde described the complex neuroimmunoendocrine relationship which develops in the course of the Taenia crassiceps experimental cysticercosis. The role of sex-steroid hormones in the immune profile, changes of c-fos expression in different areas of the nervous system, are relevant points described in the article. The chapter by Romano, Valdez, Hinojosa, Gómez and Jiménez focused on the endocrine capacity of parasites and in the consequences on their own development. It also discusses the result of blocking hormone effects or inhibiting the enzymes involved in sterol synthesis in different parasites and their relevance in the design of antiparasitic drugs. The last two articles are related to the medical treatment and prevention of cysticercosis. “Vaccines against cysticercosis” by Sciutto, Fragoso, Hernández, Rosas and Larralde reviews the current knowledge on vaccines against porcine cysticercosis. It highlights new developments designed to increase effectiveness by novel routes and delivery systems. Finally, Jung, Cárdenas, Sciutto and Fleury revised critical aspects of human cysticidal treatments used today, discussing pharmacological aspects, therapy for the different types of neurocysticercosis, control of associated inflammation, as well as the side effects of medication. I would like to offer my thanks to all the authors of this special issue; this collection could not have been created without their essential input. I also wish to thank Dr. A.B. Reitz and E. Juaristi for the invitation to be the Guest Editor of this special issue.

Taenia solium cysticercosis is still an important parasitosis in rural pigs in many developing countries, Mexico among them. The main causes for the persistence of this condition are lack of hygiene in the rural communities, lack of education of the animal owners, lack of control in the trade of pigs and their meat and lack of conscientious meat inspection. The pig production systems in the marginated areas of Mexico are briefly mentioned and it is stressed that among the important reasons for the persistence of the reproductive cycle of Taenia solium is the fact that appropriate toilet facilities in village dwellings are not mandatory. The diagnostic methods of cysticercosis in the living pigs and in their meat are discussed and the degenerative stages of the larvae as well as methods to test their viability are explained. The treatment of infected pigs and their meat is discussed. Recommendations for control programmes are given.

This chapter describes the life cycle, general morphology and ultrastructure of the larval and adult stages of Taenia solium, a parasitic flatworm of humans found in underdeveloped countries. Experimental results describing the role of proteins and glycoproteins in the host-parasite relationship, as well as the various strategies the larval stage has developed to evade the host immune responses are analyzed. Characteristics of the tapeworm attachment site in the hamster intestine and the host inflammatory reaction are reviewed. The general morphology and ultrastructure of the experimental tapeworm is described, with emphasis on muscle fiber distribution, the abundance of cytoplasmic glycogen and its association with gap junctions, the development of testis, structure of mature spermatids and vas efferens. Recent descriptions of T. solium actin, myosin and calreticulin components, metabolic steroid pathways, apoptosis and glucose uptake of tapeworms in the hamster model are reviewed.

Parasitic helminthes have developed complex mechanisms to evade or modulate hosts responses. Studies on cysticercosis are solid, but scarce. The most studied immunological models of cysticercosis are Taenia crassiceps infecting mice and T. solium infecting pigs. These parasites, despite being widely exposed to the host, are able to modulate the host immune system. Taenia metacestodes, much like other helminthes parasites, have developed complicated strategies in order to infect and successfully colonize their hosts. We focus here on the accumulated evidence from experimental models that have been helpful in analyzing and characterizing the host immune response to cysticercosis. Moreover, the mouse model has been used to design rationale vaccine strategies, some of them with promising results. We also discuss recent advances in understanding immune-regulation of cysticercosis. The parasite is able to manipulate the host immune system into supporting its survival by keeping a low inflammatory profile by causing the production of some cysticerci-released products that have immunomodulatory activities, as well as promoting the raise of alternatively activated macrophages. Finally, we delineate, according to recent literature, the likely pathway involved in protection and susceptibility against cysticercosis. As more aspects of the role of different immune and parasite-derived molecules are elucidated, better therapeutic targets may be identified to help treat cysticercosis.

This review focuses in the role that antioxidant enzymes play in protection and other important physiological functions such as signal transduction, cell differentiation, growth and apoptosis. Parasites use these enzymes to evade ROS produced by the host immune response and for development inside the host. In the cestoda Taenia solium, three antioxidant enzymes have been studied: a cystosolic Cu,Zn superoxide dismutase that is a target of cestocidal drugs (bencimidazoles); a 2-Cys peroxiredoxin that is a regulatory enzyme of H2O2, molecule essential for several physiological functions; and two isoforms of glutathione transferases that are immunological targets, since they protect immunized mice against cysticercosis. Moreover, all these enzymes are present in all stages of the parasite. These findings suggest that antioxidant enzymes have an important role in T. solium physiology and infection, therefore they might represent the Achilles' heel of the parasite.

We review here the role that sex steroids play in experimental intraperitoneal Taenia crassiceps cysticercosis of male and female BalbC/AnN mice. Briefly, estrogens favour and androgens hinder the reproduction of cysticerci by at least two main mechanisms: 1) through estradiol tilting the TH2/TH1 immune system balance towards parasite-permissive TH2 response,which is IL-6 dependent mediating P450-aromatase over expression, shunting testosterone towards estradiol and thus creating a positive feed-back loop which progressively favours TH2 response, blocking in turns TH1 and furthers parasite growth; and 2) estrogens and androgens acting directly upon the cysticercus reproductive system, favoring or hindering, respectively, its asexual reproduction. Later infection, when parasite loads are for milliars, male mice become estrogenized, deandrogenized and diminish their copulative, aggressive and social behaviors in association with P450-aromatase testis overexpression. Changes in c-fos expression in different areas of the infected mice brain point to the additional connection of the central nervous system with the infection driven events, which senses and perhaps reacts to infection with behavioral changes. This complex immune-neuro-endocrine network management of parasite loads in murine cysticercosis, and its physiological and behavioral consequences upon the host, may be operative in other infections of mammals. Such complexity may also help to explain the often conflicting results, observed between infections with respect to the role of the host sex, and hints to other avenues of research and strategies for their treatment and control.

Over the last years the biology of many parasites that infect humans and domestic animals has been intensively studied. Considerable efforts were addressed to obtain information on the parasite-host immune relationship. However, the knowledge of the endocrine physiology of parasites and the consequences of the local hormone production on the host tissues needs further investigation. We review here literature and our own studies on endocrine parasite capacities with special emphasis on cysticercosis. Besides the biological interest, these investigations may contribute to identify in the future alternative treatments for the disease.

Taenia solium cysticercosis is a major parasitic disease that seriously and frequently affects human health and economy in undeveloped countries. Since pigs are an indispensable intermediate host, it is conceivable to curb transmission by reducing pig cysticercosis through their effective vaccination. This article reviews current knowledge on the development vaccines against porcine cysticercosis. It highlights the development of several versions of S3Pvac aimed to increase effectiveness, reduce costs and increase feasibility by novel delivery systems and alternative routes of administration.

Neurocysticercosis is one of the most frequent parasitic diseases affecting the central nervous system. The introduction of anticysticidal therapy in the early 80's and the concomitant improvement of the radiological techniques have lead to apparently significant progress in patient prognosis. However, due to the specificity of the disease, a great debate has been generated on the real usefulness of cysticidal drugs. This article revises and discusses the pharmacological aspects of cysticidal treatment and summarizes current indications for the different types of the disease.

Is Zetia™ a A ‘Do Nothing’ Drug? After months of delays and on the eve of meetings with congressional investigators, results from the much anticpated ENHANCE clinical trial for Vytorin™ were finally disclosed (January 15, 2008) to the dismay of pharmacuetical giants Merck and Schering- Plough, with the announcement that VytorinTM conferred no medical benefit over Zocor™ alone [1-4]. The ENHANCE trial was launched to demomstrate superior cardiovascular protection (fewer heart attacks and strokes) with Vytorin™ versus Zocor™ and enrolled 720 patients with heterozygous familiar hypercholesterolemia, a rare condition that predisposes them to abnormally high blood cholesterol. The two year study measured the amount of artery-clogging plagues in three areas and compared patients taking Vytorin ™ versus high dose Zocor™ [1-4]. Vytroin™, approved by the FDA in 2004, is a combination drug consisting of Merck's Zocor™, an HMG-CoA reductase inhibitor (statin) that inhibits cholesterol production in the liver, and Zetia™, the first cholesterol absorption inhibitor (works in digestive track). These complimentary cholesterol lowering strategies in a single pill where touted to treat the two sources of cholesterol - heredity and diet and provide superior protection from heart attack and stroke versus stain alone therapy. Zocor™ has proven to be a safe and effective statin which lowers cholesterol and decreases the risk of adverse cardiovascular events. Zetia™, was shown to lower LDL (bad cholesterol) 15-20% in a surrogate goal trial, with no clinical support that its effects on LDL confer cardioprotection - the chief concern of patients [1-4]. These data raised questions about aggressive marketing tactics, the delays to announce negative clinical data and the issue of Brand versus cheaper Generic medications with Vytorin™ [2-4]. Many physicians and clinicians voiced their displeasure and referred to Zetia™ and Vytorin™ as ‘Do Nothing’ drugs [2-4]. Moreover, both Vytroin™ and Zetia™ had achieved blockbuster status with billions in sales/year and provided additional sales for Merck's Zocor™, which is now facing billion dollar generic competition, and a major component of Schering-Plough's annual revenue. Merck's Zocor™ is an excellent example of the impact of the loss of patent protection and generic competition. In 2005, the statins LipitorTM and ZocorTM were ranked No.1 ($7.6 billion) and No.2 ($4.5 billion) in sales, and No. 1 and No. 11 in prescriptions dispensed, respectively. After generic variants of Zocor™ entered the market mid-year 2006, Pfizer's Lipitor™ remained No. 1 in terms of both sales ($ 8.6 billion) and prescriptions dispensed (74,020) while Zocor™ slid to No.7 in sales ($3.2 billion) and No. 25 in prescriptions dispensed [5-7]. With an increasing market share in each quarter of 2007, Vytorin™ was poised to recoupe much of Zocor's™ lost revenues for Merck, but the ENHANCE trial may derail this rally and drive more patients to request cheaper, generic simvastatin [1-7]. However, three larger clinical trials are underway, including the 10,000 patient IMPROVE IT trial, which Merck and Schering-Plough hope will conclusively demonstrate that Vytorin™ can reduce the number of detahs and major, adverse cardiac events versus Zocor™ alone [1-4]. Unfortunately, data from these trials will not be available for ∼ three years and the moniker of ‘Do Nothing’ drug may linger until conclusive data proves otherwise. REFERENCES [1] For information on the ENHANCE trial see: www.merck.com, www.sherng-plough.com [2] For information on the ENHANCE trial in the popular media see: www.cnn.com, keyword Vytorin and www. Healthrevolution.com, search Vytorin. [3] Sternberg, S. ‘Drug Trials Under Pressure’ USA Today, D1, January 17, 2008. [4] Rubin, R. ‘Surrogtae goals can defuddle patients’ USA Today, D2, January 17, 2008. [5] Lamb, E. Top 200 prescription drugs of 2006. Pharmacy Times, May 2007, pp.1-4, and reference therein. [6] IMS Health. Press release. March 8, 2007, www.imshealth.com. [7] For more information on generic drug approvals and impact on sales see the US Food and Drug [8] Adminstration: www.fda.gov.