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PubMed1996

Purification, kinetics and inhibition by antimonials of recombinant phosphofructokinase from Schistosoma mansoni.

We reported before on the cloning of a cDNA encoding S. mansoni PFK. In the present investigation we established optimal conditions for expression of the enzyme in insect cells with high yield. The recombinant PFK was purified to homogeneity. Kinetic properties of the pure enzyme were studied with respect to its two substrates, Fru-6-P and ATP, and were compared with properties of mammalian PFK. ATP inhibited the parasite enzyme only at concentrations higher than those which inhibited mammalian muscle PFK. Saturation curves for Fru-6-P showed typical cooperative kinetics. AMP, cAMP and Fru-2,6-bisP activated the enzyme causing reduced apparent Km for Fru-6-P and an increase in maximal activity. Both ATP inhibition and cooperative kinetics for Fru-6-P occur at both pH 6.9 and 8.2. This is a distinct difference from the mammalian enzyme which shows these kinetic properties only at neutral or slightly acidic pH, but not at an alkaline pH. Recombinant PFK is more sensitive to inhibition by the trivalent antimonials, antimony potassium tartrate and Stibophen, than is the mammalian heart muscle enzyme. The inhibition is at least partially antagonized by the sulfhydryl protective reagent, dithiothreitol.

Animals↗
PubMed1981

Histopathological cochlear changes induced by antimonial antibilharzial drugs.

Sixteen normal guinea-pigs were injected by two different antimonial antibilharzial drugs (Stibophen NF and Bilharcid EP). Therapeutic doses of either drug produced hydropic degeneration in the hair and supporting cells of the organ of Corti. The pillar cells and the neurones of the spiral ganglion were not affected. Doubling the dosage produced atrophy of the organ of corti and its replacement by granular epithelioid cells. These antibilharzials carry a definite risk to the cochlear auditory elements aggravated by exceeding the therapeutic dosage.

Animals↗
PubMed1957

The relationship between inhibition of phosphofructokinase activity and the mode of action of trivalent organic antimonials on Schistosoma mansoni.

The addition of purified mammalian phosphofructokinase to homogenates of schistosoma mansoni increased the rate of lactic acid production from glucose and reversed the inhibition of glycolysis produced by low concentrations of trivalent organic antimonials. Neither mammalian phosphofructokinase nor trivalent antimonials affected the rate of lactic acid production from fructose-1:6-diphosphate (HDP) by schistosome homogenates. Accordingly, in the schistosome, the rate of glycolysis of glucose is determined by the activity of phosphofructokinase.The aldolase of S. mansoni has a high requirement for HDP; relatively slight reductions in the concentration of this substrate below the optimum resulted in a sharp decline of aldolase activity. Therefore, decreased formation of HDP, due to inhibition of schistosome phosphofructokinase activity by antimonials, reduced the activity of aldolase and resulted in an inhibition of glycolysis of schistosome homogenates.Kinetic data revealed differences in the nature of the phosphofructokinase of S. mansoni and that of the enzyme catalysing the same reaction in the host. Exposure of schistosomes to low concentrations of potassium antimonyl tartrate or administration of subcurative doses of stibophen to the host resulted in an accumulation of the substrate (fructose-6-phosphate), and a reduction of the product (HDP) of the phosphofructokinase reaction, indicating that the activity of this enzyme was inhibited by antimonials in the intact parasite. It is concluded that inhibition of phosphofructokinase activity can account for the mechanism of the chemotherapeutic action of trivalent organic antimonials in schistosomiasis.

Animals↗
PubMed1980

Antitrypanosomal activity of trivalent antimonials in vitro and its significance.

The SbIII preparations available for clinical use were compared in vitro for their concentration/time/effect curves on Trypanosoma venezuelense (T. evansi), measuring decrease of motility and of parasite numbers. With these two criteria leading to similar relative results, the drugs are classified into a rapidly acting group, led by sodium emetic (AST), followed by its dimethylcysteine chelate (NAP) and Anthiomaline, and a less and more slowly acting one: Triostam, Astiban and Stibophen. The relative activity of these drugs in vitro is parallel to that encountered against Schistosoma mansoni, attributed to a similar pattern of intracellular absorption. In vivo effectiveness may depend on bioavailability of Sb in the host and the direct action on the parasite, reflected by its in vitro activity. The interplay of these two factors leads to a different in vitro/in vivo activity relationship of the antimonials even in the same host (mouse) and to its variation in other host species.

Antimony↗
PubMed1977

Anthelmintics.

This article describes the drugs used in helminthic infections and their therapeutic indications, mode of action, toxicity and other details of each of the recommended drugs, and discusses the nature and treatment of infection by helminths important in human medicine. Infestation due to the roundworms Enterobius vermicularis, Ascaris lumbricoides and the hookworms, Ancylostoma duodenale and Necator americanus can all be treated effectively with pyrantel pamoate. For Enterobius vermicularis, however, a newer drug, mebendazole, is equally as effective. The advantage of these drugs in the indicated circumstances is that they can be administered in a single dose. Unfortunately, pyrantel pamoate is not a panacea and in the case of Necator it is not as effective as in the other roundworms. In that situation the use of tetrachlorethylene is preferable. For treatment of Strongyloides stercoralis, and important human parasite, because it can become disseminated and lead to fatal infections in immunoincompetent hosts, the only effective drug is thiabendazole. In treatment of Trichuris trichiura infection, mebendazole, administered over a period of 3 days, is the most effective available drug. For the roundworms inhabiting tissues--either as aberrant infections of man or as the normal part of their life cycle in man--therapy tends to be largely non-specific. For example, in visceral larva migrans, caused by the dog roundworm Toxocara canis, only palliative therapy with systemic anti-inflammatory agents and corticosteroids may be helpful. Cutaneous larva migrans, caused by the dog hookworms Ancylostoma brasiliensis and Ancylostoma caninum, is also treated primarily with symptomatic measures, but there is a suggestion that thiabendazole may kill the larvae and thus be effective. Trichinella spiralis may cause severe, even fatal infections in man, but only symptomatic therapy can be offered. Therapy for filarial infections is regrettably complicated and not completely effective. Diethylcarbamazine remains the best available drug, but in some of these infections local surgical excision may also be used. It is important to bear in mind that release of antigens from dying or dead worms may cause systemic inflammatory and allergic reactions that may require therapy with corticosteroids. Therapy for Cestodes is achieved most effectively with niclosamide, but the antimicrobial agent paromomycin has also been effective. For the aberrant cestode infections of man, such as echinococcal cysts or Taenia solium cycticerci, treatment is surgical if the affected areas are accessible. Treatment of schistosomal infections is quite toxic and, therefore, it is mandatory to determine viability of the worms before recommending therapy. If therapy is required, then Schistosoma mansoni infections are treated with stibophen and S. japonicum with antimony potassium tartrate, taking care in both of these instances to watch for the early signs of antimony toxicity; therapy of S. haematobium infections is based on administration of niridazole...

Anthelmintics↗
PubMed1975

Evaluation of a technique of circumoval precipitin test using blood taken on filter paper and a microtiter technique of complement fixation test of Schistosoma japonicum.

For the circumoval precipitin test (COPT) blood was taken on quantitative blood sampling filter paper by finger prick from outpatients at the Schistosomiasis Control Pilot Project, Palo, Leyte, Philippines. The volume of serum available per strip of filter paper was 0.04 ml and this was extracted at 1:3, 1:5 and 1:8 dilutions. Lyophilized eggs of Schistosoma japonicum were mixed with the diluted serum on a microscope glass slide and incubated at 37 degrees C for 2 days. The reaction was read following the criterion made by Yokogawa et al. [11]. The serum at 1:8 was too dilute to make correct diagnosis; serum at 1:3 dilution contained too much hemoglobin which made microscopic observation difficult and the extract at 1:5 was found to be appropriate. There was no remarkable difference in antigenicity among 3 preparations of lyophilized eggs from Kofu strain, Japan, and those of new and old preparations from Philippine strain. Under the best condition, false negative results appeared in 15.3% of 152 outpatients in Leyte and false positives in 2% of 50 human sera collected in Tokyo. This method of COPT is not satisfactory for the diagnosis of individual cases but is useful in the epidemiological assessment of Schistosoma infections because of the simplicity of blood sampling from dwellers of infested areas and also because it shows nearly the same sensitivity as that of a single fecal examination by the MIFC method. A microtiter technique of complement fixation test (CFT) was also studied. This method, however, was less sensitive than the COPT or a single fecal examination as to give 23.7% false negatives. Frequency distributions of CF and COP titers were analysed among egg positive, egg negative and treated groups. The results showed that treatment with stibophen had little influence in lowering the serum response, especially in COPT.

Blood Specimen Collection↗
PubMed1992

[Hemolytic anemia caused by excessive use of analgesics].

A 40-year-old female patient is reported who gave a history of analgesics abuse (phenacetin) and had haemolytic anaemia. The probable mechanism of the toxic effect of phenacetin on the haemopoietic system through induction of intravascular haemolysis (so called stibophen-type haemolysis) is discussed. One-year follow-up demonstrated the reversibility of these haematological changes.

Adult↗
PubMed1976

Current chemotherapy of schistosomiasis japonica in the Philippines.

For the past several decades, the drug being used for the treatment of schistosomiasis in the Philippines has been Stibophen. It is administered intramuscularly at a dose of 1 ml per 10 kg body weight with a maximum of 5 ml every other day after 2 initial daily smaller sensitivity doses at a total dose of 45 to 70 ml fof adult patients. In recent years, a number of drugs for the treatment of schistosomiasis have been developed. These were evaluated clinically either in the hospital or in field trials in Leyte. Unfortunately, none of these were found to be suitable for mass treatment on account of toxicity to prolonged course of treatment. In view of the pressing need for a safe and effective schistosomicidal agent, the search for a better drug is imperative.

Adult↗
PubMed1976

Drug trial of Schistosoma japonicum enfection in Indonesia.

A limited drug trial was carried out on 42 cases with schistosomiasis japonica from an endemic area of Central Sulawesi. The drugs used were niridazole and stibophen. The effects of treatment were reported and discussed. The results of this study offer promise for treating S. japonicum infection in Central Sulawesi on a larger scale.

Adolescent↗
PubMed1977

Liver monoamine oxidase (MAO) in liver homogenate of mice infected with Schistosoma mansoni and effect of certain therapeutic agents.

MAO activity in liver homogenate of mice infected with Schistosoma mansoni was determined from the second till the 14th week following infection. Significant diminution of MAO activity was noticed starting from the sixth week following infection, reaching its lowest value at the eighth week, obviously denoting progress of hepatic fibrosis. Treatment of the infected, animals with four different antischistosomal agents, tarter emetic, stibophen, niridazole and hycanthone, resulted in an improvement of the enzyme level to an almost normal value. This may indicate the ease with which the lesions in the liver including fibrosis recover when the infection is successfully treated.

Animals↗
PubMed1968

The effects of drugs on Onchocerca volvulus. 2. The antimonial preparations TWSb and MSbE.

Antimonial preparations (Pentostam, Neostibosan, stibophen, and tartar emetic) have occasionally been used in the treatment of onchocerciasis without very promising results. The advent of the preparations TWSb (stibocaptate) and MSbE (Friedheim) of allegedly reduced toxicity made it desirable to test them against Onchocerca volvulus.The action of both preparations on the parasites was found to vary from one patient to another, ranging from complete elimination of all parasites in a few cases to no detectable action in others. A microfilaricidal action was detectable in many patients, particularly after treatment with TWSb, which was used at higher doses than MSbE. A lethal or sterilizing action on some or all adult female worms was observed in some patients. However, toxic reactions to the drugs were common and distressing, and often it was necessary to stop treatment on this account. Anorexia, nausea, vomiting and prostration were the most common manifestations, and there was one fatality from coincident yellow fever, which may well have been aggravated by antimony treatment.The uncertain action of these preparations on O. volvulus and the toxic manifestations that accompany their use render them unsuitable for the treatment of onchocerciasis, and it is probable that the effects of antimony on O. volvulus are produced only at or above the normal level of human tolerance.

Animals↗
PubMed1971

Chemotherapeutic studies on experimental Schistosoma mansoni infection of Mastomys natalensis.

Comparative chemotherapeutic studies on various well known or newly developed schistosomicidal agents have been carried out in Mastomys natalensis experimentally infected with Schistosoma mansoni. Hycanthone, lucanthone, niridazole, Mirasan, the experimental compounds HOE S616, HOE S683, HOE S688, and HOE S201, tartar emetic, stibophen, and stibocaptate acid have shown marked activity when administered in standard daily dosages for 5 consecutive days. Dehydroemetine and bis (p-rosaniline pamoate) proved to be ineffective. The mode of action and the dose-activity relationship of hycanthone methanesulfonate are discussed and compared with the results found for other antimonial and non-antimonial substances.

Animals↗
PubMed1971

Chemotherapeutic studies on Litomosoides carinii infection of Mastomys natalensis. 3. The activity of drugs against adult parasites.

Comparative studies of the chemotherapeutic activity of various filaricides were carried out and the results in Litomosoides carinii infections of Mastomys natalensis were analysed with special reference to macrofilaricidal activity. The administration of suramin in daily subcutaneous doses of 40 mg per kg of body weight for 5 consecutive days showed marked activity against macrofilariae and killed the adult worms within 6 weeks after the beginning of treatment. The microfilarial count of the circulating blood declined steadily to nearly 0 in more than 2 months after microfilarial production by female worms in the pleural cavities had ceased. Amodiaquine proved to be markedly effective against adult parasites, whereas stibophen, tartar emetic, and the free acid of stibocaptate gave inadequate results.

Animals↗
PubMed1978

Evaluation of the intrathoracic injection method for screening of filaricides.

Intrathoracic injection technique was utilized to examine its value in screening of antifilaria drugs in Litomosoides carinii in the cotton rat, Sigmodon hispidus, using existing filaricides such as diethylcarbamazine, Mel W. metrifonate, suramin, arsenics and antimonials. Diethylcarbamazine at a dose of 100 mg/kg for 5 days given intrathoracically caused marked decrease of more than 95% of the microfilaria count in the blood 1 week after the initial injection which is the same effect as was observed by intraperitoneal injection. Whereas adult worms in the pleural cavity were not affected. Mel W at a dose of 10 mg/kg for 5 days killed all adults but had no effect on microfilaria density in the blood. When it was given intraperitoneally, even a larger dose of 50 mg/kg did not affect adults in the pleural cavity. In cotton rats tolerating suramin at 80 and 40 mg/kg for 5 days, adult worms were intact. However, a reduced dose of 20 mg/kg and 10 mg/kg given weekly for 6 weeks showed remarkable macrofilaricidal activity. Thus the slow action of suramin was reproduced by this method. There was no significant change in the microfilaria density in the blood. Aresenics such as Mapharsemin and Neo Neo Arsemin, and antimonials such as stibophen and tartar emetic were shown to have macrofilaricidal activity by intrathoracic injection with no effect on microfilaria density in the blood within a week. Effect of existing filaricides by this method showed remarkable coincidence with their action Wuchereria bancrofti.

Animals↗