ABSTRACT
A esquistossomose, uma importante doença no Brasil, é causada por trematódeo pertencente ao gênero Schistosoma, atingindo milhões de pessoas, numa das maiores regiões endêmicas dessa doença em todo globo. O principal objetivo desse trabalho foi sintetizar o derivado 6-formil-oxamniquina e avaliar sua atividade biológica. O derivado 6-formil- oxamniquina foi obtido por oxidação da oxamniquina com dióxido de manganês empregando diclorometano como solvente, à temperatura ambiente, por 24 horas. Sua obtenção foi confirmada por espectrometria na região de infravermelho e espectroscopia de RMN 13C e ÕH, apresentando atividade similar quando comparada à oxamniquina comercial (Mansil®).
Schistosomiasis, an important disease in Brazil, is caused by a trematode of the genus Schistosoma, reaching millions of person in one of the most endemic region of this disease in the whole globe. The main goal of this work was to syntetize the 6-formyl-oxamniquine derivative and evaluate its biological activity. The 6-formyl-oxamniquine derivative was obtained by the oxidation of oxamniquine with MnO2, applying CH2Cl2 as solvent at room temperature for 24 hours. The obtaintion of 6-formyl-oxamniquine derivative compound was confirmed by IR spectroscopy and 13C NMR and ÕH NMR, presenting similar activity when compared to the commercial oxamniquine (Mansil®).
Subject(s)
Animals , Male , Female , Mice , Drug Evaluation , Oxamniquine/pharmacology , Schistosomiasis , Spectrum Analysis/methods , Schistosomiasis mansoniABSTRACT
The antischistosomal activity of clonazepam, when administered alone or in association with oxamniquine and praziquantel, was experimentally evaluated in mice infected with Schistosoma mansoni. The animals were treated 45 days post-infection with a single dose, by oral route, according to three treatment schedules: clonazepam 25 mg/kg and sacrificed 15 min, 1h or 4 h after treatment; clonazepam 1.0, 2.5 or 10.0 mg/kg and sacrificed 15 days post-treatment or with the dose of 10 mg/kg in association with oxamniquine 50 mg/kg or praziquantel 200 mg/kg, single dose, orally, every schedule with a control group. The efficacy of the drugs in vivo was assessed by means of worm counts and their distribution in mesentery and liver, mortality and oogram changes. In the chemotherapeutic schedules used, clonazepam did not present antischistosomal activity and the result of the association of this drug with oxamniquine or praziquantel was not significantly different from the one obtained when these two last drugs were administered alone. In the in vitro experiments, the worms exposed to 0.6 mg/mL clonazepam remained motionless throughout the 8-day-period of observation, without egg-laying, whereas the worms of the control group showed normal movements, egg-laying and hatching of miracidia on the last day of observation. The results obtained in the present study confirm the action of clonazepam on S. mansoni adult worm, in vitro, causing total paralysis of males and females. However, no additive or synergistic effects were observed when clonazepam were used in association with oxamniquine or praziquantel.
Subject(s)
Animals , Female , Male , Mice , Clonazepam/pharmacology , Schistosoma mansoni/drug effects , Schistosomiasis mansoni/drug therapy , Schistosomicides/pharmacology , Clonazepam/administration & dosage , Drug Evaluation, Preclinical , Drug Therapy, Combination , Liver/parasitology , Mesentery/parasitology , Oxamniquine/administration & dosage , Oxamniquine/pharmacology , Praziquantel/administration & dosage , Praziquantel/pharmacology , Schistosomicides/administration & dosage , Time FactorsABSTRACT
Available evidence suggests that the antischistosomal drug oxamniquine is converted to a reactive ester by a schistosome enzyme that is missing in drug-resistant parasites. This study presents data supporting the idea that the active ester is a sulfate and the activating enzyme is a sulfotransferase. Evidence comes from the fact that the parasite extract loses its activating capability upon dialysis, implying the requirement of some dialyzable cofactor. The addition of the sulfate donor 3'-phosphoadenosine 5'-phosphosulfate (PAPS) restored activity of the dialyzate, a strong indication that a sulfotransferase is probably involved. Classical sulfotransferase substrates like beta-estradiol and quercetin competitively inhibited the activation of oxamniquine. Furthermore, these substrates could be sulfonated in vitro using an extract of sensitive (but not resistant) schistosomes. Gel filtration analysis showed that the activating factor eluted in a fraction corresponding to a molecular mass of about 32 kDa, which is the average size of typical sulfotransferase subunits. Ion exchange and affinity chromatography confirmed the sulfotransferase nature of the enzyme. Putative sulfotransferases present in schistosome databases are being examined for their possible role as oxamniquine activators.
Subject(s)
Animals , Oxamniquine/pharmacology , Schistosoma/drug effects , Schistosoma/enzymology , Schistosomicides/pharmacology , Sulfotransferases/metabolism , Drug Resistance , Enzyme Activation/drug effects , Sulfotransferases/administration & dosageABSTRACT
Oxamniquina (OXA) foi encapsulada em vesiculas unilamelares pequenas de distearoilfosfatidilcolina usando-se tecnica de encapsulacao ativa em gradiante de pH. Este procedimento produziu uma alta eficiencia de encapsulacao (> 85 por cento) com uma razao molar de 1/10, alem de reter, eficientemente, a droga encapsulada sob condicoes de dialise a 37 graus centigrados. OXA encapsulada (LOXA), OXA livre (OXA), (10 mg/kg respectivamente) ou lipossomas vazios foram testados durante o curso da infeccao experimental pelo Schistosoma mansoni...
Subject(s)
Animals , Schistosoma mansoni/parasitology , Schistosomiasis/therapy , Liposomes/therapeutic use , Oxamniquine/pharmacology , Oxamniquine/therapeutic useABSTRACT
Ten inhabitants of Itaquara, Bahia, Brazil treated with oxamniquine and subsequently praziquantel were not cured. Schistosoma mansoni isolates derived from these patients were studied. Snails were infected with miracidia derived from the feces of these patients and the cercariae produced used to infect albino mice. The animals were then treated with a single oral dose of oxamniquine (25, 50 and 100mg/kg) or praziquantel (100, 200 and 400 mg/kg). The response to chemotherapy was significantly different in some of the isolates although it was not possible to characterize any of them as resistant. In addition, DNA analysis of the isolates by means of ®Random Amplified Polymorphic DNA® indicated a low degree of variability as compared with a laboratory strain, LE. Thus, it was not possible to characterize these organisms at a genetic level as a distinct strain.
Subject(s)
Adolescent , Animals , Child , Humans , Mice , Antiprotozoal Agents/pharmacology , Oxamniquine/pharmacology , Praziquantel/pharmacology , Schistosoma mansoni/drug effects , Schistosomiasis mansoni/parasitology , Antiprotozoal Agents/therapeutic use , Schistosomiasis mansoni/pharmacologyABSTRACT
Pesquisou-se a letalidade causada por administracao de drogas (oxamniquina e praziquantel) em camundongos infectados por Schistosoma mansoni e seus respectivos controles nao infectados. Os resultados indicam que os animais infectados apresentam claramente taxas de mortalidade mais altas, quando foi utilizado o praziquantel...
Subject(s)
Animals , Female , Mice , Oxamniquine/toxicity , Praziquantel/toxicity , Schistosoma mansoni/drug effects , Case-Control Studies , Oxamniquine/pharmacology , Praziquantel/pharmacologyABSTRACT
Os autores relatam um caso raro de granuloma esquistossomótico no cerebelo removido completamente através de técnicas microcirúrgicas e tratado ulteriormente com oxaminiquine. Alguns aspectos etiopatogênicos assim como clínicos, neuradiológicos e cirúrgicos säo comentados
Subject(s)
Adult , Humans , Male , Cerebellum/parasitology , Granuloma/diagnosis , Oxamniquine/pharmacology , Schistosomiasis , Granuloma/surgeryABSTRACT
Camundongos infectados com 350 cercarias de Schistosoma mansoni (cepa LE) foram tratados com oxamniquina, em dose unica de 400 mg/kg, 24, 48, 72 e 96 horas apos a infeccao. Quarenta dias apos o tratamento, os animais foram submetidos a uma infeccao desafio com 80 cercarias, atraves da pele abdominal e da orelha. O numero de vermes imaturos nos grupos de animais tratados 24 e 96 horas apos a primeira infeccao foi menor do que no grupo controle, evidenciando que a morte de esquistossomulos por quimioterapia, durante as fases da pele e do pulmao, causa um estado de resistencia adquirida.
Subject(s)
Animals , Mice , Lung/parasitology , Mice/immunology , Oxamniquine/pharmacology , Schistosoma mansoni/drug effects , Skin/parasitology , Administration, Oral , Immunity, Active , Larva/drug effects , Oxamniquine/administration & dosage , Schistosomiasis mansoni/immunology , Schistosomiasis mansoni/parasitologyABSTRACT
A administraçäo de praziquantel a camundongos infectados pelo Schistosoma mansoni(50 cercarias/8 semanas) causou necrose de coagulaçäo e/ou lítica, e por vezes calcificaçäo dos miracídios nos tecidos a partir do 4§ dia do início do tratamento. A administraçäo conjugada de oxamniquine/hycanthone, embora muito efetiva para eliminar os vermes adultos, näo teve açäo sobre os miracídios no interior dos granulomas, tendo os testes de eclosäo sido positivos até o 15§ dia após o tratamento curativo. A açäo do praziquantel sobre os ovos do S. mansoni pode ter repercussäo sorológica ou patogênica, facilitando uma mais rápida reabsorçäo dos granulomas pelos tecidos do hospedeiro
Subject(s)
Mice , Animals , Male , Female , Hycanthone/pharmacology , Ovum/drug effects , Oxamniquine/pharmacology , Praziquantel/pharmacology , Schistosoma mansoni/physiology , Schistosomiasis mansoni/drug therapy , Drug Therapy, Combination , Hycanthone/therapeutic use , Oxamniquine/therapeutic use , Praziquantel/therapeutic useABSTRACT
The effects of a single dose (100 mg/kg-body weight of mouse) of oxamniquine on the worm's tegument and paranchyma in relation to the process of immunological granulomatous reaction of the host's liver are described under light and electron microscopy (EM). The lesions caused by the drug are sequentially and simultaneously described in form of swelling, surface bulble and disruption with erosions. Ulceration in the tubercules with loss of spines is often more extensive and severe in male worms and concentration of host's mononuclear cells is observed. The possible role of host's immune response is discussed.
Subject(s)
Schistosoma mansoni/drug effects , Schistosoma mansoni/ultrastructure , Nitroquinolines/pharmacology , Oxamniquine/pharmacology , Microscopy, ElectronABSTRACT
O retardo, induzido pela oxamniquine, no processo de transformaçäo da cercária-esquistossômulo, foi utilizado para verificar a sensibilidade de diferentes estágios larvares à resposta celular do hospedeiro, in vivo. A cavidade peritoneal do camundongo, um modelo utilizado para observaçöes in vivo, foi escolhida para estes experimentos.Esquistossômulos, cercárias e larvas no processo de transformaçäo foram sequestrados pelas células do hospedeiro, näo sendo recuperados através de perfusäo da cavidade peritoneal com salina. As larvas somente foram liberadas vivas e com movimentos após o uso de 10**-2 M de EDTA em salina. Os diferentes estádios larvares, no processo de adaptaçäo ao hospedeiro, säo intensamente recobertos por células que, entretanto, näo conseguem matar os organismos invasores, pelo menos nas primeiras horas após a invasäo
Subject(s)
Mice , Animals , Male , Oxamniquine/pharmacology , Schistosoma mansoni/drug effects , Schistosomiasis mansoni/parasitology , Edetic Acid/pharmacology , Host-Parasite Interactions , Schistosomiasis mansoni/immunologyABSTRACT
No presente estudo, realizou-se uma tentativa de induçäo de resistência a 3 drogas esquistossomicidas em uma cepa brasileira de S. mansoni, segundo o esquema de induçäo de resistência tipo II preconizado por Jansma et al. em 1977. Houve insucesso nas 3 tentativas realizadas. A geraçäo parental tratada com a droga durante o estágio imaturo do verme mostrou-se menos suscetível aos quimioterápicos do que as geraçöes F1 e F2 do verme. Uma hipótese é levantada para a explicaçäo do fato
Subject(s)
Mice , Animals , Female , Schistosoma mansoni/drug effects , Schistosomicides/pharmacology , Drug Resistance, Microbial , Microbial Sensitivity Tests , Oxamniquine/pharmacology , Praziquantel/pharmacology , Pyrazines/pharmacologyABSTRACT
Para estudar a transformaçäo da cercária em esquistossômulo in vivo, sob a influência de um composto ativo contra o Schistosoma mansoni, foi escolhida a técnica da inoculaçäo de cercárias na cavidade peritoneal de camundongos. Este procedimento se mostrou reproduzível e promoveu uma rápida e fácil recuperaçäo das larvas após a lavagem das vísceras abdominais com soluçäo apropriada. Os resultados obtidos sugerem que altas doses de oxamniquine(via intramuscular), uma hora antes da infecçäo, produzem um evidente atraso na cinética do processo de transformaçäo da cercária em esquistossômulo. Cercárias, corpos cercarianos e esquistossômulos foram recuperados da cavidade peritoneal de camundongos tratados em números diferentes daqueles recuperados dos animais controles