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A liquid chromatographic method is described for determining bithionol sulfoxide and its metabolites, bithionol and bithionol sulfone, in milk. Samples are treated with HCl to precipitate proteins and to permit extraction of bithionol sulfoxide in nonionized form. Tetrahydrofuran is added to the organic phase to facilitate extraction in diethyl ether; the dried residue is dissolved in chloroform, hexane, and sodium hydroxide and subjected to LC analysis. Residues of bithionol sulfoxide and its 2 metabolites were determined in milk of lactating cows. Holstein-Friesian dairy cows were administered a single oral dose of bithionol sulfoxide (50 mg/kg). Milk samples were analyzed with a reliable detection level of 0.025 microgram/mL for each compound. Residues of bithionol sulfoxide and bithionol were detected during 30 and 16 milkings, respectively; bithionol sulfone was never present at detectable levels.
The photochemical reactions of the bacteriocide bithionol (a known photoallergen in man) with soluble proteins and peptides, were investigated. Solutions of human serum albumin (HSA), human gamma-globulin, bovine insulin and poly-L-lysine were irradiated with ultraviolet light of wavelength 313 nm in the presence of [35S]-bithionol and the extent of photochemical (covalent) binding determined. HSA bound at least four molecules of bithionol per molecule of HSA. Bithionol was also found to bind to gamma-globulin to a similar extent; lower levels of binding were achieved with bovine insulin and poly-L-lysine. A bithionol-HSA photoadduct was treated with cyanogen bromide to determine the selectivity of binding. Fractionation after cyanogen bromide treatment showed that bithionol was bound to both major fragments of HSA, with a preference for the N-terminal region of the protein.
Fascioliasis is the parasitic infestation of the liver and biliary tract related to Fasciola hepatica. Bithionol is proposed as the treatment of choice for human fascioliasis without major side effects. However, the efficacy of bithionol has been evaluated in chronic but not in acute fascioliasis. In this study we report on the success of treatment with bithionol in 10 patients with fascioliasis, 8 having acute fascioliasis. The criteria for the diagnosis of fascioliasis were hypereosinophilia, positive immunoelectrophoresis and indirect hemagglutination. Bithionol was given orally to hospitalized patients at the daily dose of 25 mg/kg body wt for 10 days. Three patients with acute fascioliasis received a second course of bithionol 2 or 3 mo after the first because of the recurrence of diarrhea and fatigue in one patient and persistent hypereosinophilia in two patients. All patients were cured. The follow-up period after the first course of treatment was between 16 and 47 mo. No major side effects were observed. We conclude that bithionol is the drug of choice for both acute and chronic fascioliasis. Moreover, its oral administration may allow treatment of fascioliasis in outpatients who do not have serious symptoms.
Endogenous and 2-propanol-supported respiration of intact trophozoites of of Entamoeba histolytica (stain HM-1:IMSS) were inhibited by bithionol, an effective chemotherapeutic agent for some trematode and cestode infections in humans. Dichlorophene and hexachlorophene also inhibited 2-propanol-supported respiration of the parasite. In contrast, ethanol formation by E. histolytica extract in the presence of N2 was scarcely inhibited by bithionol. The compound also inhibited in vitro growth of axenic (HM-1 strain) and polyxenic (strain HJ-1:KEIO) amoebae in culture. It took less than 24 hr to kill and disrupt virtually all amoebae of either strain with 0.28 mM bithionol. Omission of bovine serum from BI-S-33 medium resulted in considerably less disruption of HM-1 strain amoebae by the compound. However, organisms that looked undisrupted were strained with trypan blue. Moreover, the number of amoebae incubated for 10 min in the serum-free BI-S-33 medium containing 0.14 mM bithionol did not increase, even after incubation for 24 hr following replacement of the experimental culture fluid with fresh complete BI-S-33 medium free of the compound. These findings suggest that, although serum appears to diminish the antiamoebic action, some halogenated bisphenols (in particular bithionol) may be useful for treatment of amoebiasis.
Clinical trials of bithionol in treating Paragonimus westermani lung infection have been conducted in areas of endemic infection. Bithionol has been reported to cure over 90% of infected patients. We report a case of a 32-year-old Laotian man residing in Connecticut who relapsed with P. westermani pneumonitis 4 months after apparent eradication of infection with bithionol (40 mg/kg by mouth every other day for 10 doses). He was successfully treated with a second course of bithionol (40 mg/kg by mouth every other day for 15 doses). The mechanism of relapse of P. westermani infection following bithionol therapy should be evaluated.
The mutagenic effects of bithionol sulfoxide and its two major metabolites, bithionol and bithionol sulfone, on 4 Salmonella typhimurium strains (TA97, TA98, TA100 and TA102) were investigated. Bithionol sulfoxide was found to be mutagenic to TA98 and TA100. However, mutagenicity was abolished in the presence of rat-liver S9 fractions.
There is no consensus about the optimal treatment for fascioliasis. Here we report 5 cases of fascioliasis and 12 cases of fascioliasis reviewed from the literature, and discuss the clinical characteristics and treatment of this parasitic disease. The diagnosis was made in 88% of all patients by the serological test and eggs in the feces were negative in all patients. The characteristic CT findings of all patients in our series were cluster of multiple abscess-like lesions in the liver. Eosinophilia was present in all patients. Bithionol was effective in all of the 13 patients and praziquantel was effective in 4 of 8 patients. Three of 4 patients, in whom praziquantel was not effective, were treated with bithionol successfully. No severe side effects were noticed in all patients. Bithionol seems to be more effective against fasciola sp. than praziquantel. Bithionol is proposed as the drug of choice for the treatment of human fascioliasis.
To elucidate the mechanism of anthelmintic action of bithionol, the inhibitory effect of the drug on NADH-fumarate reductase (NADH-FR) of Ascaris lumbricoides suum was examined. NADH-FR, an enzyme of anaerobic carbohydrate metabolic pathway was solubilized from the mitochondria of the worm's muscle with deoxycholate, and then partially purified with the monoethanolamine-Sepharose 4B column chromatography. Rhodoquinone (RQ), which is required for the electron transfer from NADH to fumarate, was separated from the enzyme protein and phospholipids. Although the enzyme protein fraction eluted from the above column did not show NADH-FR activity, this enzyme was reactivated by the addition of purified RQ and phosphatidylcholine. The IC50 value of bithionol for reconstituted NADH-FR was 18 +/- 2 microM. The inhibition type was competitive to RQ. Bithionol inhibited at most 30% NADH-ferricyanide reductase, which did not require RQ, even at high concentration of 150 microM. These results suggest that the pharmacological action of bithionol, a phenolic anthelmintic, depends on the inhibition of the electron transport system by the competition with RQ.
Liver biopsies from 5 patients with established fascioliasis, before and after bithionol treatment were studied by immunoalkaline phosphatase technique for relative distribution of T cells and their subpopulations. T cell and its subsets are defined for OKT3+ (pan T), OKT4+ (helper/inducer) and OKT8+ (suppressor/cytotoxic) cells by using mouse monoclonal antibodies. Before bithionol treatment, lymphocytic infiltration in all hepatic lesions were predominantly of OKT3+ (pan T) lymphocytes. The distribution of OKT8+ cells was moderate to severe in comparison to the few OKT4+ cells presentation. After bithionol a noticeable regression of the OKT3 lymphocytic in all liver sections. The majority of the lymphocytic infiltration was of the OKT8+ cells, in comparison to the absence of the OKT4+ ones. This may indicate that suppressor/cytotoxic lymphocytes may have a role in the immune regulation of the disease and the mode of action of bithionol is by the accentuation of this immunoregulatory effect.
The anthelmintic effects of anti-tapeworm drugs, bithionol, paromomycin sulphate, flubendazole and mebendazole on immature and mature Hymenolepis nana in mice were compared. Immature worms were not affected by paromomycin sulphate or flubendazole administered for 12 consecutive days (days one to 12 after infection) at 100 mg/kg/day but 48% and 100% of H. nana were eliminated from mice by bithionol and mebendazole respectively, at the same dosage regimen. Bithionol, paromomycin sulphate, flubendazole and mebendazole given at 100 mg/kg/day for five consecutive days (days 12 to 16 after infection) eliminated 32%, 29%, 36% and 100% of mature worms respectively. 10 and 20 mg of mebendazole/kg/day for five consecutive days (days 12 to 16 after infection) had little effect on mature worms whereas 50 and 100 mg/kg/day for the same period eliminated 99% and 100% of mature worms, respectively. ED50 of mebendazole in the elimination of mature H. nana was 14 or 15 mg/kg/day for five days from the reduction in dry weight or in number of worms recovered respectively. The effects of mebendazole given 2 to 4 days, 8 to 10 days or 13 to 15 days after infection at 100 mg/kg/day were compared. Very low, if any, activity of the drug given 2 to 4 days after infection was seen, whereas the drug given 8 to 10 days or 13 to 15 days after infection eliminated 84% and 86% of H. nana respectively.
Bithionol, dichlorophene, and hexachlorophene, which are used in treating some helminthic infections, killed trophozoites of Giardia lamblia and Trichomonas vaginalis in modified BI-S-33 and Asami media, respectively. Virtually all G. lamblia and T. vaginalis cells were killed within 24 h with a 0.42 mM concentration of these compounds, except that 0.93 mM dichlorophene was required for sterilizing T. vaginalis in the same period. In modified BI-S-33 and Asami media from which bovine and human sera were omitted, respectively, the inhibitory actions of the compounds against in vitro growth of these protozoa were significantly enhanced. Trophozoites of G. lamblia and T. vaginalis could be killed in shorter than 10 min with 0.074 mM dichlorophene and 0.0025 mM hexachlorophene, respectively, in serum-free media. G. lamblia, which was incubated in the complete medium containing dichlorophene, showed a characteristic swelling of the ventral side which led to disruption of the parasite, whereas bithionol caused a thin crack in the cytoplasm of T. vaginalis incubated in Asami medium. The crack appeared to enlarge and result in vacuolization of T. vaginalis. These observations suggest that bithionol, dichlorophene, and hexachlorophene merit further evaluation to ascertain whether they are useful for treatment of giardiasis and trichomoniasis.
We treated female Swiss Webster mice with heavy, long standing infections of Echinococcus granulosus with mebendazole, 50 mg/kg body weight daily for 10 days and bithionol, 70 mg/kg every other day for four doses. Necropsy performed 6 weeks after completion of therapy showed no gross or histologic differences between untreated controls and bithionol-treated mice or their cysts. Mebendazole-treated mice had a significant decrease in the total number of cysts (15 vs. 100), with many of those present being ruptured. Electron microscopy of intact, mebendazole-treated cysts revealed a marked increase in vacuolization and disarray of the distal cytoplasm, dilated and degenerating microtubules, increase in the size and number of lysosomes, a decrease in the number of normal appearing golgi, and increased density of mitochondria. Several mice died shortly after the termination of mebendazole therapy, all with ruptured cysts. Due to the large volume of the cysts, the presumed cause of death was acute volume overload, but toxic or anaphylactic reactions could not be excluded. We suggest that any proposed chemotherapy of humans with hydatid disease be done cautiously, with careful monitoring.
The present study was conducted on 14 patients with established fascioliasis. The effect of infection on the haematological and biochemical parameters was determined and the liver and gall bladder were studied by ultrasonography. Bithionol was given in the dose of 30 mg kg-1 body weight every other day for 5 doses. The therapeutic efficacy was assessed by egg and eosinophilic counts and quantitative estimation of antibody titres by indirect haemagglutination test. Results revealed that fascioliasis caused normocytic hypochromic anaemia and eosinophilia. Serum bilirubin, ALT and AST were within normal range. Ultrasonography showed a normal echogenic pattern of the liver and gall bladder. One case showed thickness of the gall bladder wall which was tender under the transiducer. Fasciola eggs disappeared completely after the 5th dose giving a cure rate of 100%. Antibody titres reached a normal level at the end of the 3rd month post treatment. Bithionol proved to be a potent fasciolicidal drug with minimal side-effects.
The present work is an update evaluation of the glutathione status in patients with established fascioliasis before and after treatment with bithionol. Blood glutathione (GSH), erythrocyte glutathione S-transferase (GST) and serum gamma-glutamyl transferase (GGT) activities were studied. After treatment, the variations observed in these parameters were restored to the corresponding normal control values confirming the toxic features resulting from fascioliasis and suggesting no adverse effect of bithionol on the parameters studied. We recommend the use of serum GGT, blood GSH and erythrocyte GST for the early detection of therapeutic response in fascioliasis.
The pathology of human fascioliasis was studied before and after bithionol treatment using light and transmission electron microscopy. Fine needle biopsies were taken from five patients, with established fascioliasis, before and after drug administration. By light microscope the pathology of human fascioliasis was similar to that reported in experimental fascioliasis. The ultrastructural picture revealed bile ductular hyperplasia, fibrosis of portal tracts, widening of the interhepatic spaces by many microvilli and dilated Disse space with collagen fibres. Bile ductular hyperplasia may be the initial factor to fibrinogenesis, which subsequently enhance the development of the microvilli on the surface of the hepatocytes. Both light and electron microscopic studies revealed regression of the picture of fascioliasis to normal after bithionol treatment with no sign of toxicity on the liver.