Chemotherapy Of Trypanosomiasis Research Articles

The Correlation between Chemical Structures and Antioxidant, Prooxidant, and Antitrypanosomatid Properties of Flavonoids.

Flavonoids have demonstrated in vivo and in vitro leishmanicidal, trypanocidal, antioxidant, and prooxidant properties. The chemotherapy of trypanosomiasis and leishmaniasis lacks efficacy, presents high toxicity, and is related to the development of drug resistance. Thus, a series of 40 flavonoids were investigated with the purpose of correlating these properties via structure and activity analyses based on integrated networks and QSAR models. The classical groups for the antioxidant activity of flavonoids were combined in order to explain the influence of antioxidant and prooxidant activities on the antiparasitic properties. These analyses become useful for the development of efficient treatments for leishmaniasis and trypanosomiasis. Finally, the dual activity of flavonoids presenting both anti- and prooxidant activities revealed that the existence of a balance between these two features could be important to the development of adequate therapeutic strategies.

Biogenic trypanocidal sesquiterpenes: lead compounds to design future trypanocidal drugs - a mini review

Human trypanosomiasis is a parasitic disease among poor people in Africa and Latin America. Therapy against African and American trypanosomiasis is based on a few drugs that often cause severe side-effects. Therefore, it is essential to develop drug discovery especially from natural origins. Sesquiterpenes, a diverse group of natural terpenoids, are found in essential oils of many plants and show a broad range of bioactivities. They act through multiple mechanisms in the chemotherapy of trypanosomiasis. Some of these active compounds contain hydroperoxides, aldehydes, alcohols, α,β-unsaturated γ-lactone and even halogenated moieties. Among the compounds reported, sesquiterpene lactones showed a potent anti-trypanosoma effect comparable with commercial trypanocidal drugs. Trypanocidal activity of sesquiterpene lactones mostly depends on the reaction between γ-lactone moieties and nucleophile groups of trypanithione, which is essential for Trypanosoma defense against the oxidative stresses. Elatol is a sesquiterpenoid from marine algae, with a different structure and considerable trypanocidal activity which could be an interesting candidate for further antiprotozoal investigations. To develop novel drugs with higher efficacy and lower toxicity from natural products, this review summarizes the more recent information on trypanocidal activities of various sesquiterpenes.

Parasitic Diseases, Diagnostic Approaches, and Therapies

The diagnosis and treatment of parasitic diseases has undergone major changes because of increased awareness and technological advances that now allow for more rapid and accurate diagnosis of parasitic diseases. These advances are critically important for the continuing diagnosis of these infections as there has been a steady decline in the quantity and quality of laboratory technicians who are expert in the classical techniques of examining stool and blood smears for parasites. The majority of laboratories have an increased reliance on nonclassical parasitological techniques for the accurate diagnosis of these infections. Dr. Ndao from McGill University has given an overview of many of these newer diagnostic methods. Malaria is a major pathogen in most of the world, and Drs Murray and Bennett from the US Army provide a timely review of the current status of rapid diagnosis of malaria using nontraditional methods. These rapid techniques have been a great advance since, in many laboratories; there are now few individuals that are expert in examining smears. In addition, these rapid techniques can be used by field workers and military personnel. These new methods make the diagnosis more rapid and accurate leading to a more rapid institution of appropriate treatment. Amebiasis continues to be an important cause of morbidity and mortality worldwide. Drs. Singh, Haupt, and Petri, in their review provide an update on the rapid diagnosis of Entamoeba histolytica. Diseases caused by Microsporidia are found in both immune-competent and immune-compromised hosts such as those with HIV/AIDS. The diagnosis is often difficult to make. In their article, Drs. Ghosh and Weiss review the state of molecular diagnostics for microsporidian infections. Human infections caused by free-living amoebas have not received sufficient attention in literature despite the fact that they may cause disabilities and death. Dr. Marciano-Cabral's group has reviewed the current state of the diagnosis of these important organisms. The review by Vannier and Krause provides an excellent update on the status of the diagnosis and treatment of babesiosis. Importantly, this infection still poses a threat not only from natural infection via the bite of a tick but also through blood transfusion. New diagnostic techniques have been developed for metazoan as well as protozoan infections. Neurocysticercosis has received increasing attention as a cause of seizures worldwide. There has also been an awareness of this disease because of the immigration of individuals from endemic areas to non-endemic areas of the world. Drs. Coyle and Tanowitz provide a review of the diagnostic and therapeutic options for management of this infection. Another helmintic disease of humans with complex management issues is that caused by Echinococcus and this is reviewed by Siracusano and colleagues. The articles by Dr. Baccchi and Dr. de Souza deal with the chemotherapy of trypanosomiasis, both African and American. Drs. Hochman and Kim explore the recent data on the HIV-malaria interaction. Since both HIV and malaria coexist in sub-saharan Africa, this review is timely. Dr. Petersen examines canine leishmaniasis and it implications for human disease. This year 2009 marks the 100th anniversary of the discovery of Chagas disease. This disease caused by the parasite Trypanosoma cruzi continues to be an important cause of cardiomyopathic heart disease in endemic areas of Latin America and is being increasingly recognized in non-endemic areas such as North America and Europe. The article by Dr. Gupta et al. from the Garg group in the University of Texas has offered a unique insight into the role of oxidative stress in the pathogenesis of chagasic cardiomyopathy. Adipose tissue is the largest endocrine organ in the body and its role in infection has only recently been appreciated. The laboratory group at the Albert Einstein College of Medicine offers a review of the role of adipose tissue in the pathogenesis of Chagas diseases, providing a new perspective on this overlooked facet of pathogen host interaction. There has been little success in changing the chronic manifestations of Chagas Disease by using antiparasitic therapy. A new approach to this problem is discussed in the article by Dr. Campos de Carvalho et al. who provide data suggesting that stem cell therapy may be useful in the treatment of the cardiomyopathy caused by T. cruzi infection. We have obtained articles on a range of topics which highlight many of the new issues in the field of parasitological diagnosis and treatment. It is our belief that this collection of articles provides an important summary of these issues and will be of use to both clinicians and researchers working on parasitic diseases. Herbert B. Tanowitz Louis M. Weiss

Molecular properties of cationic antitrypanosomal drugs: a Principal Component Analysis study of 2-phenylimidazo[1,2- a]pyridinium salts

Bis-cationic amidines and guanylhydrazones show some activity in the chemotherapy of trypanosomiasis. The AM1 hamiltonian was employed to calculate a set of molecular descriptors for 34 derivatives of 2-phenylimidazo[1,2- a]pyridinium salts. The descriptors are further analyzed by the Principal Component Analysis method. This classifies the set of molecules into groups that can be correlated to their activity. Molecular parameters like orbital energy, polarizability and basicity are dominant in the classification.

Synthesis of 1-Arylazo-3-acetyl-1H-cinnolin-4-one Derivatives

The biological activity of azocinnoline derivatives especially in the chemotherapy of Trypanosomiasis was already reported. Considering the foregoing and in continuation of our previous work, 3-acetyl-1H-cinnolin-4-one (I) has been well exploited as a coupling component.

5'-Alkyl-substituted analogs of 5'-methylthioadenosine as trypanocides

5'-Deoxy-5'-(methylthio)adenosine (MTA) is a by-product of polyamine metabolism and is phosphoryolytically cleaved to adenine and 5-deoxy-5-(methylthio)ribose-1-phosphate (MTR-1-P) by MTA phosphorylase. In eukaryotes, adenine is subsequently salvaged and converted to nucleotides, while MTR-1-P is converted to methionine. We examined 5'-deoxy-5'-substituted analogs of MTA for trypanocidal activity in vitro and in vivo. 5'-Deoxy-5'-(hydroxyethyl)thioadenosine (HETA) and its 5'-bromo,5'-chloro and 5'-fluoro derivatives were cleaved by extracts of the African trypanosome Trypanosoma brucei brucei (Km for MTA, 11.5 microM; Km for HETA, 13.2 microM) in a phosphate-dependent reaction. HETA and the three halo analogs were 50% inhibitory to growth at 0.5 to 5.0 microM in vitro. Inhibition of growth was reversible by exogenous methionine and 2-keto-4-methylthiobutyric acid, an intermediate in methionine synthesis from MTR-1-P. HETA was selected for further study in vivo. When administered by miniosmotic pump (25 to 150 mg/kg/day for 7 days) to mice infected with T. brucei brucei, HETA effected 70 to 90% cure rates. Results of this study indicate that these analogs of MTA are converted to trypanocidal MTR-1-P analogs and that this approach deserves further consideration in the development of novel chemotherapy of trypanosomiasis.

Biochemical approaches to chemotherapy of trypanosomiasis.

Biochemical approaches to chemotherapy of trypanosomiasis.

Chemotherapy of trypanosomiasis: the potentiation of melarsoprol by concurrent difluoromethylornithine (DFMO) treatment

Chemotherapy of trypanosomiasis: the potentiation of melarsoprol by concurrent difluoromethylornithine (DFMO) treatment

Cinnolines and other heterocyclic types in relation to the chemotherapy of trypanosomiasis. Part VII. Intermediates

The first page of this article is displayed as the abstract.

Cinnolines and other heterocyclic types in relation to the chemotherapy of trypanosomiasis. Part IX. Synthesis of azoquinoxaline derivatives

Cinnolines and other heterocyclic types in relation to the chemotherapy of trypanosomiasis. Part IX. Synthesis of azoquinoxaline derivatives

493. Cinnolines and other heterocyclic types in relation to the chemotherapy of trypanosomiasis. Part IV. Synthesis of azocinnoline derivatives

The first page of this article is displayed as the abstract.

‘Antrycide' : A New Trypanocidal Drug

THE discovery of a new drug, ‘Antrycide'*, showing great promise in comprehensive field trials as a trypanocide, has already been referred to in an announcement from the Colonial Office. This new drug resulted from a systematic study of the chemotherapy of trypanosomiasis in these Laboratories, and although a full account of our researches must await later publication, a few preliminary observations may be of interest.

THE EXPERIMENTAL PRODUCTION OF AN ARSENIC RESISTANT STRAIN OF SPIROCHAETA PALLIDA IN RABBITS

In the chemotherapy of trypanosomiasis of man and animals, it is possible to produce arsenic-fast strains of various trypanosomes after these organisms have been subjected a few times to the action of certain arsenic compounds short of the sterilizing dose. Experiments of this nature have been conducted with atoxyl, arsacetin and other arsenic compounds. If the organisms are not all destroyed after the initial injection, the offspring of the remaining ones are more resistant to the action of the drug than the preceding generation. A larger dose of the arsenical compound is required to destroy the organism and to overcome this increased resistance. This increased resistance may be developed to such an extent that the amount of the arsenic compound required to exert a parasitotropic action is in excess of its organotropic action. Indeed, the production of drug-fast strains of various trypanosomes is an admitted failure of chemotherapy of trypanosomiasis

Mercury saligenin, a new antiseptic

The early studies of G. Cohn on saligenin and homosaligenin and the recent investigations of D. I. Macht on benzyl alcohol have demonstrated that these substances are mild antiseptics. We have studied the action of saligenin, and have found that all of these substances are weak antiseptics. One or two per cent. solutions kill the bacillus coli, staphylococcus albus, streptococcus hemolyticus pneumococcus and gonococcus after 60 minutes exposure. Piperonyl alcohol, whose sodium salt is water soluble. Solutions of this compound possess about the the same antiseptic power as HgCl2, i.e., I :10,000 solutions kill staphylococcus, bacillus coli and gonococcus in five minutes and streptococcus hemolyticus in ten minutes in bouillon cultures, while in beef serum bouillon I :500 solutions kill in five minutes. Mercury saligenin is not a dye, and it is much less irritant to mucous membranes than is HgC12, so that a I :I000 soluion can be held in the urethra for five minutes without burning or subsequent irritation. We are therefore testing it clinically in anterior gonorrheal urethritis with encouraging results. has also been prepared. Its water soluble sodium salt has the same antiseptic action as that of the mercury saligenin, but no greater. We have also prepared the mercury compound of parahydroxymetanitrophenylcarbinol which yields a monomercury derivative, probably The sodium salt of this compound has the same antiseptic strength as to the other two mercury compounds. Attempts at the chemotherapy of trypanosomiasis (brucei) and spirillosis (obermeyeri) in rats by the use of saligenin, piperonyl alcohol and mercury saligenin have thus far yielded only negative results.