Caracterização do efeito da dietilcarbazina (DEC) sobre a espermatogênese de camundongos / Characterization of the effect of the diethylcarbazine (DEC) on spermatogenesis of mice

A dietilcarbamazina tem sido altamente efetiva contra filariose linfática, mas seu efeito sobre células de vertebrados permanece controverso. Apesar de ter sido descrita sua ação sobre microtúbulos, a hipótese de que esta droga atue sobre a espermatogênese não havia sido testada. Após o tratamento de camundongos Swiss com 200mg de DEC/kg durante doze dias, as análises ultraestruturais mostraram vacuolização das células de Sertoli e espermatogônias com características morfológicas de apoptose, como condensação do citoplasma e aumento da densidade cromossomal. Algumas espermátides apresentaram mitocôndrias vacuoladas, as quais estavam desorganizadas em relação ao eixo microtubular do flagelo. Além disso, as células de Leydig mostraram numerosas gotículas de lipídio distribuídas no citoplasma, corpos multivesiculares e círculos concêntricos gigantes de retículo endoplasmático liso, alguns dos quais englobando gotículas de lipídio. Algumas células de Leydig não apresentaram núcleo indicando um processo de esteatose. Baixas dosagens de DEC produziram alterações similares nas células de Leydig, entretanto seus efeitos foram diretamente proporcionais à concentração da droga. Os níveis de testosterona no soro foram significativamente menores no grupo tratado com 200mg de DEC/kg quando comparados com o controle. Entretanto, nenhuma mudança significante foi observada nas taxas de gravidez e no número de filhotes quando machos tratados com DEC acasalaram com fêmeas não tratadas, nas doses estudadas. Os resultados do presente estudo indicam que a DEC apresenta um importante efeito sobre a morfologia testicular e esteroidogênese de camundongos provavelmente por afetar tubulina e/ou complexo de microtúbulos. Porém, os presentes dados não excluem a possibilidade desta droga atuar diretamente sobre as vias enzimáticas hormonais.

Dietilcarbamazina no tratamento da filariose bancroftiana / Diethylcarbamazine in the treatment of Bancroft's filariasis

Os autores realizaram uma ampla revisão sobre o tratamento da filariose bancroftiana com a droga dietilcarbamazina. Os aspectos interessantes sobre o histórico de sua descoberta e os conceitos básicos de sua farmacologia foram relatados de forma resumida. Ênfase especial, por outro lado, foi dada às especulações feitas pelos diversos autores sobre os achados intrigantes descritos na literatura. Foram trazidos os novos avanços sobre o conhecimento da doença, como por exemplo, a visualização pela ultra-sonografia do verme vivo de Wuchereria bancrofti, no seu hospedeiro natural, o homem. Isso possibilitou a compreensão de muitos dos achados aparentemente paradoxais encontrados na literatura sobre o tratamento da infeção com a DEC. Assim, devido à inexistência de uma droga sucessora que reunisse efeitos micro e macrofilaricidas ideais e aos novos conhecimentos sobre a bancroftose e sobre a própria dietilcarbamazina, foi-lhe conferido um novo realce. Esses aspectos a colocaram numa posição de destaque no cenário da infecção, à época do seu quase cinqüentenário de existência.

The authors presented a detailed review about the treatment of bancroftian filariasis with diethylcarbamazine. The interesting aspects about the drug discovery and the basic concepts about its pharmacology were reported in a summarised form. On the other hand, emphasis was made about the speculation done by several authors about the intriguing findings regarding its efficacy reported in the literature. Latter, it was brought the new advances about the disease, as for example, the visualization by ultrasound of living Wuchereria bancrofti adult worm on its natural host--the human being. This made possible the comprehension of several paradoxical issues reported, focusing the treatment of infection using diethylcarbamazine. So far, because of the lack of ideal drug with micro and macrofilaricidal properties, together with the new understand about the disease and the new parameters for monitoring the efficacy of the drug, diethylcarbamazine has back its importance conquered at the begin of its discovery, almost fifth years ago.

Effect of acetylcholine, L-glutamine and diethyl carbamazine citrate on the release of microfilariae from Setaria digitata.

Release of microfilariae from adult filarial parasite S. digitata was reversibly arrested in presence of 2 mM L-glutamine. Diethylcarbamazine also showed a similar effect, but at a lower concentration (0.26 mM). Both compounds inhibited activities of protease and leucine amino peptidase enzymes. The only difference being, different concentrations of the two materials were required for comparable effects. Levels of histamine and acetylcholine in parasite were lowered during incubation under in vitro conditions. Direct effect of L-glutamine on the release of mf was also confirmed.

Effect of diethylcarbamazine on acetylcholine and gamma amino butyric acid in Setaria digitata.

In vitro studies on the effect of neurotransmitter amino acids and amines on the motility of S. digitata showed that acetylcholine (Ach) had a stimulatory and gama amino butyric acid (GABA) an inhibitory effect on the parasite. When the worms were incubated in different concentrations of diethylcarbamazine there was a significant dose related increase in the level of Ach, and the level of GABA remained unchanged. Inhibition of acetylcholine esterase activity by diethylcarbamazine caused the accumulation of Ach in the synapses resulting in receptor desensitization and after a momentary stimulation causes paralysis of the parasite.

Changes in the level of biogenic amines in experimentally infected and DEC treated proxy host mice.

The levels of biogenic amines, viz., epinephrine, histamine and dopamine were significantly altered in the blood and brain of the proxy host mice which were infected with the mf of Setaria digitata, a filarial parasite. When DEC, the drug of choice was administered to the infected mice, serotonine level was enhanced while the histamine level was decreased. The results were similar in normal mice which were given DEC.

Effect of diethyl carbamazine on neurotransmitter amino acids, biogenic amines and certain related enzymes in Setaria digitata.

Effect of diethyl carbamazine (DEC) on the levels of neurotransmitter amino acids and on the activities of related enzymes of S. digitata have been studied. When the worms were incubated in DEC, substances known to have neurotransmitter effect were found increased except glycine. Among the amines the level of serotonin, dihydroxy phenyl alanine and epinephrine were increased and that of histamine remained the same. DEC inhibited activities of monoamine oxidase, aspartate amino transferase and alanine amino transferase and enhanced those of cathepsin and glutamate dehydrogenase. The effect of DEC on the activities of the enzymes appear to account for the increased level of amino acids and amines. Results indicate that the reversible paralysis caused by DEC is due to the accumulation of neurostimulants and associated decrease in the concentration of inhibitors.

Características de la citoprotección con dietilcarbamacina: estudio comparativo con otras drogas / Characteristics of cytoprotecction with diethylcarbamazine: compative study with other drugs

Se estudiaron los efectos de la administración prolongada de citrato de dietilcarbamacina (DECC) en la citoprotección gástrica inducida por esta droga en el modelo de lesiones provocadas por etanol 96 % (1 mL intragástrico). Se realizó un estudio comparativo del efecto citoprotector del DECC (10 mg/kg) con otras drogas citoprotectoras: cromoglicato disódico (10 mg/kg), cimetidina (2,5 mg/kg) y sus combinaciones. Se comparó el DECC con el citrato de sodio a dosis equimolares en este modelo de inducción de lesiones

Glycosaminoglycan (GAG) level and activities of certain enzymes of GAG metabolism in Culex quinquefasciatus and Setaria digitata.

Significant differences were observed in GAG metabolism of S. digitata and one of its intermediate vectors, C. quinquefasciatus. Distribution of different components such as hyaluronic acid, heparin-sulphate, chondroitin-4-sulphate, chondroitin-6-sulphate, dermatan sulphate and heparin was comparable in both. However, there were quantitative differences; the difference was marked in the activity of enzymes of GAG metabolism in presence and absence of diethylcarbamazine (DEC) a known antifilarial drug. While the activities of beta-galactosidase and beta-N-acetyl glucosaminidase of S. digitata systems showed an inhibition of 96.5 and 92.6% respectively, in the Culex systems they showed an inhibition of 93.3% and an activation of 18% respectively. The differences clearly indicate the existence of basic differences in GAG metabolism of vector and parasite.

Diethylcarbamazine: inhibitory effect on acetylcholinesterase of Dirofilaria immitis and Brugia pahangi.

Anti-acetylcholinesterase activity of diethylcarbamazine (DEC) was studied. Acethylcholinesterase (AchE) of adult worms of Dirofilaria immitis, those of the 4th-stage larvae, early 5th-stage larvae and adults worms of Brugia pahangi, and that of hamster brain tissue were all inhibited by DEC. Michaelis constant (Km) of D. immitis and B. pahangi adult worm AchE were 1.47 x 10(-4) and 1.81 x 10(-4) M respectively. DEC was a competitive inhibitor of the filarial AchE. Inhibition constant (Ki) for AchE of D. immitis and B. pahangi adult worms were 2.56 x 10(-4) and 6.39 x 10(-4) M, respectively. DEC is a less potent anticholinesterase inhibitor, because Ki of DEC is 10(4) times higher than that of eserine, a potent anti-cholinesterase agent.

Citoprotección gástrica con citrato de dietilcarbamacina / Gastric cytoprotection with diethylcarbamazine citrate

El citrato de dietilcarbamacina (DECC) es una droga filaricida que posee acciones antiinflamatorias. Se estudia el efecto citroprotector gástrico de esta droga en ratas, según el concepto enunciado por Robert y colaboradores, en 1979. Inicialmente se demostró que las dosis utilizadas del DECC: 5, 10 y 15 mg/kg no disminuyeron significativamente la secreción ácida gástrica, con la técnica de ligadura del píloro durante una hora. Se estudió el efecto de la droga en las lesiones inducidas por la administración intragástrica de 1 ml del agente necrotizante: etanol 96%, HCl 0,6 M, NaOH 0,2 M ó NaOH 25%. Se demostró el efecto citoprotector del DECC con la dosis de 10 mg/kg en los modelos de etanol al 96% y HCl 0,6 M pero no en los modelos de NaOH 0,2 M ni NaCl 25%

Effect of diethylcarbamazine on Setaria cervi in vitro.

Diethylcarbamazine (DEC) produced an initial stimulation followed by depression of the movements of the intact worm and nerve-muscle preparation of Setaria cervi. The effective concentration of DEC was reduced to one hundredth in the nerve-muscle preparation as compared to the whole worm, suggesting that the cuticular barrier is highly effective in preventing the penetration of the drugs. The depressant effect of DEC was concentration dependent and was not reversed even after repeated changes of the bath fluid. The worms consumed 7.7 mg +/- 0.2 glucose/g wet weight/hr. The consumption of glucose was directly proportional to its motor activity; it increased during the stimulant phase with low doses of DEC and decreased during the depressant phase.