RESUMO
Etoposide, a nonintercalating antitumor drug, is a potent inhibitor of topoisomerase II activity. When Trypanosoma equiperdum is treated with etoposide, cleavable complexes are stabilized between topoisomerase II and kinetoplast DNA minicircles, a component of trypanosome mitochondrial DNA (T. A. Shapiro, V. A. Klein, and P. T. Englund, J. Biol. Chem. 264:4173-4178, 1989). Etoposide also promotes the time-dependent accumulation of small minicircle catenanes. These catenanes are radiolabeled in vivo with [3H]thymidine. Dimers are most abundant, but novel structures containing up to five noncovalently closed minicircles are detectable. Analysis by two-dimensional gel electrophoresis and electron microscopy indicates that dimers joined by up to six interlocks are late replication intermediates that accumulate when topoisomerase II activity is blocked. The requirement for topoisomerase II is particularly interesting because minicircles do not share the features postulated to make this enzyme essential in other systems: for minicircles, the replication fork is unidirectional, access to the DNA is not blocked by nucleosomes, and daughter circles are extensively nicked and (or) gapped.
Assuntos
DNA Topoisomerases Tipo II/metabolismo , DNA de Cinetoplasto/metabolismo , Mitocôndrias/enzimologia , Trypanosoma/enzimologia , Animais , DNA de Cinetoplasto/biossíntese , DNA de Cinetoplasto/isolamento & purificação , Eletroforese em Gel Bidimensional , Etoposídeo/farmacologia , Microscopia Eletrônica , Oligodesoxirribonucleotídeos/química , Oligodesoxirribonucleotídeos/isolamento & purificação , Timidina/metabolismo , Inibidores da Topoisomerase II , Trypanosoma/genéticaRESUMO
Kinetoplast DNA, the mitochondrial DNA of trypanosomes, is a topologically complex structure composed of interlocked minicircles and maxicircles. We previously reported that etoposide, a potent inhibitor of topoisomerase II, promotes the cleavage of about 20% of network minicircle DNA (T. A. Shapiro, V. A. Klein, and P. T. Englund, J. Biol. Chem. 264:4173-4178, 1989). We now find that virtually all maxicircles are released from kinetoplast DNA networks after trypanosomes are treated with etoposide. As expected for a topoisomerase II cleavage product, the linearized maxicircles have protein bound to both 5' ends. After etoposide treatment, the residual minicircle catenanes have a sedimentation coefficient which is only 70% that of controls, and by electron microscopy the networks are less compact. Double-size networks, the characteristic dumbbell-shape forms that normally arise in the final stages of network replication, are replaced by aberrant unit-size forms.
Assuntos
DNA Topoisomerases Tipo II/metabolismo , DNA de Cinetoplasto/metabolismo , Animais , DNA de Cinetoplasto/efeitos dos fármacos , DNA de Cinetoplasto/ultraestrutura , Etoposídeo/farmacologia , Substâncias Macromoleculares , Microscopia Eletrônica , TrypanosomaRESUMO
The parasitic protozoa are notorious for their bizarre cellular structures and metabolic pathways, a characteristic also true for their nucleic acids. Despite these florid differences from mammalian cells, however, it has proven surprisingly difficult to devise novel chemotherapy against these pathogens. In recent years, the DNA topoisomerases from parasites have been the focus of considerable study, not only because they are intrinsically interesting, but also because they may provide a target for much-needed new antiparasitic chemotherapy.
Assuntos
Antiparasitários/farmacologia , Eucariotos/enzimologia , Inibidores da Topoisomerase I , Inibidores da Topoisomerase II , Animais , DNA Topoisomerases Tipo II/genética , Etoposídeo/farmacologia , Eucariotos/parasitologia , Plasmodium falciparum/enzimologia , Plasmodium falciparum/parasitologia , Trypanosoma/enzimologia , Trypanosoma/parasitologiaRESUMO
There are no safe and effective oral drugs to treat leishmaniasis and Chagas' disease. The safety, pharmacokinetics, and metabolism of single and multiple oral doses of allopurinol riboside, an investigational antiparasitic agent, were evaluated in a randomized, double-blinded, placebo-controlled study in 32 healthy male volunteers, at levels up to 25 mg/kg q.i.d. for 13 doses. No significant toxicity was detected. Allopurinol riboside peaks in plasma 1.6 hours after administration, has an elimination half-life of 3 hours, and steady-state concentrations in the therapeutic range. However, in contrast to preclinical studies in dogs (plasma levels proportional to oral doses up to 200 mg/kg), we found that plasma levels were unexpectedly low and did not rise with increasing dose. Furthermore, allopurinol and oxypurinol (unanticipated metabolites) were detected at levels proportional to the dose of allopurinol riboside. We present a model that includes incomplete absorption, metabolism of residual drug by enteric flora, and absorption of bacterial metabolites to explain these findings in humans.
Assuntos
Alopurinol/análogos & derivados , Antiprotozoários/farmacocinética , Ribonucleosídeos/farmacocinética , Adolescente , Adulto , Alopurinol/efeitos adversos , Alopurinol/sangue , Alopurinol/farmacocinética , Alopurinol/urina , Antiprotozoários/efeitos adversos , Antiprotozoários/sangue , Antiprotozoários/urina , Método Duplo-Cego , Avaliação de Medicamentos , Meia-Vida , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Oxipurinol/sangue , Purinas/sangue , Ribonucleosídeos/efeitos adversos , Ribonucleosídeos/sangue , Ribonucleosídeos/urinaRESUMO
Broccoli sprouts are a rich source of glucosinolates and isothiocyanates that induce phase 2 detoxication enzymes, boost antioxidant status, and protect animals against chemically induced cancer. Glucosinolates are hydrolyzed by myrosinase (an enzyme found in plants and bowel microflora) to form isothiocyanates. In vivo, isothiocyanates are conjugated with glutathione and then sequentially metabolized to mercapturic acids. These metabolites are collectively designated dithiocarbamates. We studied the disposition of broccoli sprout glucosinolates and isothiocyanates in healthy volunteers. Broccoli sprouts were grown, processed, and analyzed for (a) inducer potency; (b) glucosinolate and isothiocyanate concentrations; (c) glucosinolate profiles; and (d) myrosinase activity. Dosing preparations included uncooked fresh sprouts (with active myrosinase) as well as homogenates of boiled sprouts that were devoid of myrosinase activity and contained either glucosinolates only or isothiocyanates only. In a crossover study, urinary dithiocarbamate excretion increased sharply after administration of broccoli sprout glucosinolates or isothiocyanates. Cumulative excretion of dithiocarbamates following 111-micromol doses of isothiocyanates was greater than that after glucosinolates (88.9 +/- 5.5 and 13.1 +/- 1.9 micromol, respectively; P < 0.0003). In subjects fed four repeated 50-micromol doses of isothiocyanates, the intra- and intersubject variation in dithiocarbamate excretion was very small (coefficient of variation, 9%), and after escalating doses, excretion was linear over a 25- to 200-micromol dose range. Dithiocarbamate excretion was higher when intact sprouts were chewed thoroughly rather than swallowed whole (42.4 +/- 7.5 and 28.8 +/- 2.6 micromol; P = 0.049). These studies indicate that isothiocyanates are about six times more bioavailable than glucosinolates, which must first be hydrolyzed. Thorough chewing of fresh sprouts exposes the glucosinolates to plant myrosinase and significantly increases dithiocarbamate excretion. These findings will assist in the design of dosing regimens for clinical studies of broccoli sprout efficacy.
Assuntos
Anticarcinógenos/metabolismo , Anticarcinógenos/farmacocinética , Brassica/química , Dieta , Glucosinolatos/metabolismo , Glucosinolatos/farmacocinética , Isotiocianatos/metabolismo , Isotiocianatos/farmacocinética , Neoplasias/prevenção & controle , Adulto , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Valores de Referência , Sensibilidade e EspecificidadeRESUMO
Isothiocyanates and their naturally occurring glucosinolate precursors are widely consumed as part of a diet rich in cruciferous vegetables. When plant cells are damaged, glucosinolates are released and converted to isothiocyanates by the enzyme myrosinase. Many isothiocyanates inhibit the neoplastic effects of various carcinogens at a number of organ sites. Consequently, these agents are attracting attention as potential chemoprotectors against cancer. As a prerequisite to understanding the mechanism of the protective effects of these compounds, which is thought to involve the modulation of carcinogen metabolism by the induction of phase 2 detoxication enzymes and the inhibition of phase 1 carcinogen-activating enzymes, we examined the fate of ingested isothiocyanates and glucosinolates in humans. Recently developed novel methods for quantifying isothiocyanates (and glucosinolates after their quantitative conversion to isothiocyanates by purified myrosinase) and their urinary metabolites (largely dithiocarbamates) have made possible a detailed examination of the fates of isothiocyanates and glucosinolates of dietary crucifers. In a series of studies in normal volunteers, we made these findings. First, in nonsmokers, urinary dithiocarbamates were detected only after the consumption of cruciferous vegetables and condiments rich in isothiocyanates and/or glucosinolates. In sharp contrast, the consumption of noncrucifers (corn, tomatoes, green beans, and carrots) did not lead to the excretion of dithiocarbamates. Moreover, the quantities of dithiocarbamates excreted were related to the glucosinolate/isothiocyanate profiles of the cruciferous vegetables administered (kale, broccoli, green cabbage, and turnip roots). Second, eating prepared horseradish containing graded doses of isothiocyanates (12.3-74 micromol; mostly allyl isothiocyanate) led to a rapid excretion of proportionate amounts (42-44%) of urinary dithiocarbamates with first-order kinetics. The ingestion of broccoli in which myrosinase had been heat-inactivated also led to proportionate but low (10-20%) recoveries of urinary dithiocarbamates. Broccoli samples subsequently treated with myrosinase to produce the cognate isothiocyanates were much more completely (47%) converted to dithiocarbamates. Finally, when bowel microflora were reduced by mechanical cleansing and antibiotics, the conversion of glucosinolates became negligible. These results establish that humans convert substantial amounts of isothiocyanates and glucosinolates to urinary dithiocarbamates that can be easily quantified, thus paving the way for meaningful studies of phase 2 enzyme induction in humans.
Assuntos
Anticarcinógenos/farmacocinética , Brassicaceae , Glucosinolatos/urina , Glicosídeo Hidrolases/metabolismo , Isotiocianatos/urina , Neoplasias/prevenção & controle , Adulto , Idoso , Estudos Cross-Over , Indução Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/enzimologia , Projetos Piloto , Valores de ReferênciaRESUMO
On the basis of a mechanistic understanding of the mode of action of artemisinin-like antimalarials, a series of structurally simple 3-aryl-1,2,4-trioxanes 5 was designed and was prepared in three to five operations from commercial reactants. The 3-aryl group was attached in each case as a nucleophile. In an electronically complementary fashion, 3-(fluoroalkyl)-trioxanes 6 were prepared via attachment of electrophilic fluoroalkyl esters. Both in vitro and in vivo antimalarial evaluations of these new trioxanes showed 12 beta-methoxy-3-aryltrioxanes 5g, 5j, 5k, and 51 to be highly potent, with crystalline fluorobenzyl ether trioxane 5k especially potent even when administered to rodents orally. As shown by rearrangement of hexamethyl Dewar benzene into hexamethylbenzene, iron-induced degradation of some of these 3-aryltrioxanes 5 involves generation of high-valent iron oxo species that might kill malaria parasites.
Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Administração Oral , Animais , Antimaláricos/administração & dosagem , Antimaláricos/química , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/química , Avaliação Pré-Clínica de Medicamentos , Camundongos , Plasmodium berghei , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Novel C4-(hydroxyalkyl)trioxanes 5d and 5e were designed and synthesized based on an understanding of the molecular mechanism of action of similar 1,2,4-trioxanes structurally related to the antimalarial natural product artemisinin (1). In vitro efficacies of these two new pairs of C4-diastereomers against chloroquine-sensitive Plasmodium falciparum support conclusions about the importance to antimalarial activity of formation of a C4 radical by a 1,5-hydrogen atom abstraction. Derivatives 6, 7, and 21 of C4 beta-substituted trioxane alcohols 4a, 5d, and 5e were prepared, each in a single-step, high-yielding transformation. Four of these new analogues, 6a-c and 7, are potent in vitro antimalarials, having 140 to 50% of the efficacy of the natural trioxane artemisinin (1).
Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Artemisininas , Compostos Heterocíclicos/síntese química , Sesquiterpenos/farmacologia , Animais , Antimaláricos/química , Cloroquina/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Over 20 new, cyclic, peroxy ketals have been prepared via a two-step protocol starting with readily available aryl methyl ketones. Structure-activity correlations using in vitro antimalarial data as a guide for optimization of potency have led to the design and synthesis of seven new peroxides that have IC50 values of 31-85 nM (artemisinin IC50 = 8.4 nM). Some SAR generalizations are discussed.
Assuntos
Antimaláricos , Artemisininas , Desenho de Fármacos , Compostos Heterocíclicos , Animais , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/farmacologia , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Sesquiterpenos/farmacologia , Relação Estrutura-AtividadeRESUMO
A streamlined five-step chemical synthesis of rationally designed, simplified 3-aryltrioxane 8a is described. A noteworthy feature of this synthetic scheme is use of air rather than expensive molecular oxygen as the source of the pharmacologically critical peroxide unit in trioxane 8a. This simplified acetal trioxane carboxylic acid 8a is thermally stable, and it is hydrolytically stable in water even at 40 degrees C and pH 7.4 for at least 7 days. Preclinical evaluation of this water-soluble synthetic trioxane 8a in rodents shows it to have at least as good a therapeutic index (efficacy/toxicity) as that of water-soluble semisynthetic trioxane artelinic acid (5).
Assuntos
Antimaláricos/síntese química , Benzoatos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Antimaláricos/toxicidade , Benzoatos/química , Benzoatos/farmacologia , Benzoatos/toxicidade , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/toxicidade , Avaliação Pré-Clínica de Medicamentos , Armazenamento de Medicamentos , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos com 3 Anéis/toxicidade , Masculino , Camundongos , Plasmodium berghei/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
In only three chemical operations, natural trioxane lactone artemisinin (1) was converted into a series of C-10 carbon-substituted 10-deoxoartemisinin compounds 4-9. The three steps involved lactone reduction, replacement of the anomeric lactol OH by F using diethylaminosulfur trifluoride, and finally boron trifluoride-promoted substitution of F by aryl, heteroaryl, and acetylide nucleophiles. All of these C-10 nonacetal, chemically robust, enantiomerically pure compounds 4-9 have high antimalarial potencies in vitro against Plasmodium falciparum malaria parasites, and furans 5a and 5b and pyrrole 7a are antimalarially potent also in vivo even when administered to rodents orally.
Assuntos
Antimaláricos/farmacologia , Artemisininas , Compostos Heterocíclicos/farmacologia , Sesquiterpenos/química , Administração Oral , Antimaláricos/administração & dosagem , Antimaláricos/química , Estabilidade de Medicamentos , Compostos Heterocíclicos/administração & dosagem , Compostos Heterocíclicos/química , Hidrólise , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Espectrofotometria InfravermelhoRESUMO
Nine C-10 non-acetal derivatives of the natural trioxane artemisinin (1) were prepared as dimers using some novel chemistry. As designed, each dimer was stable chemically. C-10 Olefinic dimers 7 and C-10 saturated dimers 8-13 all showed good to excellent antimalarial and antiproliferative activities in vitro. Dimers 8, 10, and 12 were especially potent and selective at inhibiting growth of some human cancer cell lines in the NCI in vitro 60-cell line assay.
Assuntos
Antimaláricos/síntese química , Antineoplásicos/síntese química , Artemisininas , Lactonas/síntese química , Sesquiterpenos/síntese química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Lactonas/química , Lactonas/farmacologia , Camundongos , Transplante de Neoplasias , Plasmodium falciparum/efeitos dos fármacos , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Relação Estrutura-AtividadeRESUMO
Currently, the treatment of falciparum malaria is seriously compromised by spreading drug resistance. We studied the effects of camptothecin, a potent and specific topoisomerase I inhibitor, on erythrocytic malaria parasites in vitro. In Plasmodium falciparum, camptothecin trapped protein-DNA complexes, inhibited nucleic acid biosynthesis, and was cytotoxic. These results provide proof for the concept that topoisomerase I is a vulnerable target for new antimalarial drug development.
Assuntos
Camptotecina/farmacologia , Inibidores Enzimáticos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Inibidores da Topoisomerase I , Animais , Eritrócitos/parasitologia , Plasmodium falciparum/enzimologiaRESUMO
African trypanosomes (Trypanosoma brucei species) are parasitic protozoa that cause lethal diseases in humans and cattle. Previous studies showed that camptothecin, a potent and specific inhibitor of DNA topoisomerase I, is cytotoxic to African trypanosomes and related pathogenic hemoflagellates (Bodley AL and Shapiro TA, Proc Natl Acad Sci USA 92: 3726-3730, 1995). In this study, a series of camptothecin analogs was tested against axenically cultured, bloodstream form, T. brucei. Modifications to the pentacyclic nucleus of camptothecin ablated antiparasitic activity. In contrast, activity could be increased by substituents added to the parent ring system (e.g. 10,11-methylenedioxy or ethylenedioxy groups; alkyl additions to carbon 7; or 9-amino or 9-chloro substituents). Cytotoxicity was correlated with the level of cleavable complexes in trypanosomes, implicating topoisomerase I as the intracellular target for these compounds. To obtain some indication of selective toxicity, ten compounds were also tested against L1210 mouse leukemia cells. The 9-substituted-10,11-methylenedioxy analogs caused a disproportionate increase in antiparasitic activity, compared with mammalian cell toxicity. These findings provide a basis for designing further structural modifications and for selecting camptothecin analogs to test in animal models of trypanosomiasis.
Assuntos
Camptotecina/análogos & derivados , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Animais , Camptotecina/síntese química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Camundongos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Trypanosoma brucei brucei/isolamento & purificação , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Diseases caused by parasitic protozoa present a health problem of immense magnitude, and there is an urgent need for safe and effective new therapies. DNA topoisomerases are clinically relevant targets for anti-cancer and anti-bacterial agents. Inhibitor studies on parasite topoisomerases have revealed that these enzymes have great promise as molecular targets for anti-parasitics, and have helped to dissect the basic biology of DNA topoisomerases in these organisms. This review provides a brief introduction to DNA topoisomerases and anti-topoisomerase drugs, and an overview of studies on protozoal DNA topoisomerases and their inhibitors.
Assuntos
Antiprotozoários/uso terapêutico , Eucariotos/efeitos dos fármacos , Infecções por Protozoários/tratamento farmacológico , Inibidores da Topoisomerase , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Antiprotozoários/química , Antiprotozoários/farmacologia , DNA Topoisomerases/metabolismo , DNA de Protozoário/efeitos dos fármacos , DNA de Protozoário/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Eucariotos/enzimologia , Humanos , Infecções por Protozoários/parasitologiaRESUMO
The prophylactic antimalarial activity of atovaquone was determined in a randomized, double-blind, placebo-controlled study of healthy volunteers who were challenged by the bite of Plasmodium falciparum-infected Anopheles stephensi. Subjects were randomly assigned to one of three groups: six received seven daily doses of 750 mg of atovaquone, starting the day before challenge; six received a single dose of 250 mg of atovaquone the day before challenge; and four received placebo. Polymerase chain reaction- and culture-confirmed parasitemia developed in all four placebo recipients, but in none of the drug recipients, indicating that either of the atovaquone regimens provides effective prophylaxis (P = 0.005). However, in low-dose recipients, the drug levels by day 6.5 were profoundly subtherapeutic, indicating that parasites were eliminated prior to the establishment of erythrocytic infection. Atovaquone thus protects non-immune subjects against mosquito-transmitted falciparum malaria, and has causal prophylactic activity.
Assuntos
Antimaláricos/uso terapêutico , Malária Falciparum/prevenção & controle , Naftoquinonas/uso terapêutico , Adolescente , Adulto , Animais , Anopheles/parasitologia , Anopheles/fisiologia , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Atovaquona , Método Duplo-Cego , Humanos , Mordeduras e Picadas de Insetos , Malária Falciparum/imunologia , Pessoa de Meia-Idade , Naftoquinonas/efeitos adversos , Naftoquinonas/farmacocinética , Parasitemia/parasitologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Plasmodium falciparum/isolamento & purificação , Reação em Cadeia da Polimerase/métodosRESUMO
Single oral doses of amoscanate (4-isothiocyanato-4'-nitrodiphenylamine), an experimental antiparasitic agent, are highly effective in animals against the four major species of schistosomes which infect humans. Two prospective, randomized, double blinded, placebo controlled Phase I studies were designed to evaluate the tolerance and safety of the 5% aqueous suspension of 2-mu particles of amoscanate administered to healthy male volunteers. In addition to routine safety monitoring, particular attention was directed toward detecting hepatic, neurological, cardiovascular or ocular toxicity. Three of four men who received 3.5 mg/kg of amoscanate developed mild, reversible hepatotoxicity, which could not be unequivocably attributed to the drug. In the second study, of 1 mg/kg amoscanate, there was no statistically significant evidence of hepatotoxicity, although 1 of 12 drug recipients developed transient liver chemistry changes. Despite intensive monitoring, there was no evidence in either study of significant symptomatic complaints, or of neurological, cardiovascular or ocular toxicity. No mutagenic activity attributable to amoscanate was detectable in the urine. These results suggest that this formulation of amoscanate, at 1 mg/kg, is sufficiently well tolerated and safe to justify evaluation for efficacy in patients with schistosomiasis.
Assuntos
Compostos de Anilina/efeitos adversos , Anti-Helmínticos/efeitos adversos , Difenilamina/efeitos adversos , Isotiocianatos , Tiocianatos/efeitos adversos , Adulto , Anti-Helmínticos/uso terapêutico , Sistema Cardiovascular/efeitos dos fármacos , Difenilamina/análogos & derivados , Difenilamina/uso terapêutico , Método Duplo-Cego , Avaliação de Medicamentos , Eletroencefalografia , Humanos , Fígado/efeitos dos fármacos , Testes de Função Hepática , Masculino , Testes de Mutagenicidade , Sistema Nervoso/efeitos dos fármacos , Estudos Prospectivos , Distribuição Aleatória , Tiocianatos/uso terapêuticoRESUMO
African trypanosomiasis continues to pose a challenge for the development of new chemotherapy. Type II topoisomerases, essential enzymes in nucleic acid metabolism, have proven highly suitable as targets for antibacterial and antitumor therapy. Well-characterized topoisomerase II inhibitors affect the cognate nuclear and mitochondrial enzymes in Trypanosoma equiperdum. Inhibition is accompanied by extensive fragmentation and structural alteration in nuclear and mitochondrial DNA. Some clinically important antitrypanosomal drugs bind to DNA (i.e., pentamidine, isometamidium, diminazene). These agents inhibit the mitochondrial, but not nuclear, topoisomerase II of trypanosomes. These studies suggest that type II topoisomerase inhibitors may prove to be effective and safe new antitrypanosomal drugs.
Assuntos
Isomerases/antagonistas & inibidores , Tripanossomicidas/farmacologia , Trypanosoma/enzimologia , Animais , DNA de Cinetoplasto/efeitos dos fármacos , DNA de Cinetoplasto/ultraestrutura , Tripanossomíase Africana/enzimologia , Tripanossomíase Africana/parasitologiaRESUMO
BACKGROUND: The spread of drug-resistant malaria and appreciation of side effects associated with existing antimalarial drugs emphasize the need for new drugs to prevent malaria. The combination of atovaquone and proguanil hydrochloride was previously shown to be safe and highly effective for treatment of malaria, including multi-drug-resistant Plasmodium falciparum. METHODS: We reviewed results of clinical trials that evaluated either a fixed-dose combination of atovaquone and proguanil hydrochloride for malaria prophylaxis or atovaquone alone for causal prophylactic activity against P. falciparum. RESULTS: In three placebo-controlled trials, 331 subjects received 250 mg atovaquone and 100 mg proguanil hydrochloride (or an equivalent dose based on body weight in children) once daily for 10 to 12 weeks. The overall efficacy for preventing parasitemia was 98%. Among 175 nonimmune volunteers taking the same dose of atovaquone/proguanil once daily for 10 weeks while temporarily residing in a malaria-endemic area, malaria developed in one patient who was noncompliant with therapy. Results of volunteer challenge studies indicate that both atovaquone and proguanil have causal prophylactic activity directed against the liver stages of P. falciparum. Adverse events occurred with similar or lower frequencies in subjects treated with atovaquone/proguanil compared to placebo. Less than 1% of patients discontinued from these studies due to a treatment-related adverse event. CONCLUSION: A fixed-dose combination of atovaquone and proguanil hydrocloride is a promising new alternative for malaria prophylaxis.
Assuntos
Antimaláricos/uso terapêutico , Atovaquona/uso terapêutico , Quimioprevenção/métodos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Proguanil/uso terapêutico , Animais , Antimaláricos/efeitos adversos , Antimaláricos/farmacologia , Atovaquona/efeitos adversos , Atovaquona/farmacologia , Combinação de Medicamentos , Humanos , Malária Falciparum/prevenção & controle , Proguanil/efeitos adversos , Proguanil/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Viagem , Resultado do TratamentoRESUMO
Long-term spinal cord injury (SCI) profoundly alters skeletal structure and function. In this study, the biomechanical properties of tibias from persons with SCI and from individuals closely matched in age and size but without SCI were quantified at both the structural and material levels. Nondestructive torsion tests were performed to determine apparent shear moduli for the tibia. The cortical thicknesses and polar moment of inertia were determined numerically. Four-point bending tests were performed to determine flexural modulus of elasticity on cortical bone specimens of the tibia. The apparent shear moduli of the SCI tibias were found to be lower than the non-SCI tibias (p < 0.05). The cortical thicknesses of the SCI tibias were significantly thinner than the control tibias (p < 0.05), while the polar moment of inertia showed no significant differences between control and SCI tibial cross sections (p > 0.05). The flexural modulus of elasticity of the cortical bone specimens were lower in the SCI tibias than the controls (p < 0.05). These differences suggest that tibias may undergo micro-structural changes as well as structural adaptation following SCI, which alter their mechanical properties.