Evaluation of the cytotoxicity of the Bithionol-paclitaxel combination in a panel of human ovarian cancer cell lines.

Previously, Bithionol (BT) was shown to enhance the chemosensitivity of ovarian cancer cell lines to cisplatin treatment. In the present study, we focused on the anti-tumor potential of the BT-paclitaxel combination when added to a panel of ovarian cancer cell lines. This in vitro study aimed to 1) determine the optimum schedule for combination of BT and paclitaxel and 2) assess the nature and mechanism(s) underlying BT-paclitaxel interactions. The cytotoxic effects of both drugs either alone or in combination were assessed by presto-blue cell viability assay using six human ovarian cancer cell lines. Inhibitory concentrations to achieve 50% cell death (IC50) were determined for BT and paclitaxel in each cell line. Changes in levels of cleaved PARP, XIAP, bcl-2, bcl-xL, p21 and p27 were determined via immunoblot. Luminescent and colorimetric assays were used to determine caspases 3/7 and autotaxin (ATX) activity. Cellular reactive oxygen species (ROS) were measured by flow cytometry. Our results show that the efficacy of the BT-paclitaxel combination depends upon the concentrations and sequence of addition of paclitaxel and BT. Pretreatment with BT followed by paclitaxel resulted in antagonistic interactions whereas synergistic interactions were observed when both drugs were added simultaneously or when cells were pretreated with paclitaxel followed by BT. Synergistic interactions between BT and paclitaxel were attributed to increased ROS generation and enhanced apoptosis. Decreased expression of pro-survival factors (XIAP, bcl-2, bcl-xL) and increased expression of pro-apoptotic factors (caspases 3/7, PARP cleavage) was observed. Additionally, increased expression of key cell cycle regulators p21 and p27 was observed. These results show that BT and paclitaxel interacted synergistically at most drug ratios which, however, was highly dependent on the sequence of the addition of drugs. Our results suggest that BT-paclitaxel combination therapy may be effective in sensitizing ovarian cancer cells to paclitaxel treatment, thus mitigating some of the toxic effects associated with high doses of paclitaxel.

Evaluation of marked rise in fecal egg output after bithionol administration to horse and its application as a diagnostic marker for equine Anoplocephala perfoliata infection.

To establish a reliable diagnostic measure for equine Anoplocephala perfoliata infection, the impact of deworming was examined in 12 Thoroughbreds to which bithionol (5-10 mg/kg body weight) was administered and feces were examined by the modified Wisconsin method using sucrose solution. One day after the administration, cestode eggs were detected in previously fecal egg-negative 3 horses and increased in the other 9 horses. The optimum time for post-deworming egg detection was examined in following horses: 17 mares were administered bithionol and 10 mares were used as controls. The fecal egg count was significantly (P<0.01) higher one day after the administration than that on other pre- and post-administration days, while no significant changes occurred in fecal egg count in the controls, demonstrating that one day after bithionol administration is the optimum time for detecting fecal cestode eggs. The diagnostic deworming involving bithionol and fecal examination on the day following administration provides a reliable diagnosis for equine Anoplocephala perfoliata infection.

Further development of bithionol therapy as a treatment for amoebic gill disease in Atlantic salmon, Salmo salar L.

This study examined the efficacy of bithionol as a prophylactic or therapeutic oral treatment for Atlantic salmon (AS), Salmo salar, affected by amoebic gill disease (AGD). Furthermore, it explored the interaction of bithionol oral therapy with the current standard treatment (a freshwater bath for at least 3 h). The efficacy of three medicated feeds was determined in the trial by feeding AGD-affected AS at 1% body weight (BW) day(-1) either oil coated commercial feed (control) or prophylactic and therapeutic bithionol at 25 mg kg(-1) feed. Feeding commenced 2 weeks prior to exposure to Neoparamoeba spp. at 300 cells L(-1) and continued for 49 days post-exposure (PE). Bithionol when fed as a 2-week prophylactic or therapeutic treatment at 25 mg kg(-1) feed delayed the onset of AGD pathology and reduced the percentage of gill filaments with lesions. Administration of a 3-h freshwater bath at 28 days PE significantly reduced amoeba numbers to a similar level across all treatments; in contrast, gross gill score and percent lesioned filaments were reduced to different extents, the control having a significantly higher score than both bithionol treatments. Following the freshwater bath, clinical signs of AGD increased at a similar level across all treatments, albeit controls were significantly higher than the bithionol treatments immediately following freshwater treatment. This study demonstrated that bithionol at 25 mg kg(-1) feed, when fed as a 2-week prophylactic or a therapeutic treatment, delayed and reduced the intensity of AGD pathology and warrants further investigation as a treatment for AGD-affected AS.

Evaluation of bithionol as a bath treatment for amoebic gill disease caused by Neoparamoeba spp.

This study examined the toxicity of bithionol to Atlantic salmon Salmo salar and rainbow trout Oncorhynchus mykiss in fresh- and seawater and the efficacy of bithionol as a 1h seawater bath treatment for amoebic gill disease (AGD). To examine toxicity, fish were bathed for 1, 3 and 6h in bithionol, an anti-protozoal at 0, 1, 5, 10, 25 and 35mgL(-1) with toxicity determined by time to morbidity. Efficacy was examined by bathing AGD-affected Atlantic salmon and rainbow trout for 1h at bithionol concentrations of 1-25mgL(-1). Efficacy was determined by examining gill amoeba counts and identifying percent lesioned gill filaments at 1 and 24h after bath exposure to bithionol. For both species, bithionol was determined to be toxic at 25 and 35mgL(-1) exhibiting median lethal times (LT50s) ranging from 21 to 84min. Morbidity occurred in the 5 and 10mgL(-1) treatments, however, due to sampling regime there were not enough fish available to calculate LT50s. Only bithionol at 1mgL(-1) was considered non-toxic with no signs of morbidity. Bithionol was more toxic in seawater than freshwater and had no acute effects on gill Na+/K+ ATPase and succinic dehydrogenase, or plasma osmolality and chloride concentration. Bithionol at 1mgL(-1) reduced percent lesioned gill filaments in Atlantic salmon and rainbow trout by 33 and 27 per cent, respectively, compared to the seawater control. Similarly, numbers of amoeba were reduced by 33 and 43 per cent for Atlantic salmon and rainbow trout, respectively, when compared to the seawater control. Furthermore, bithionol reduced percent lesioned gill filaments as much as did the current industry standard of freshwater. This study demonstrated that a 1h seawater bath containing 1mgL(-1) bithionol could be an improvement to the current method of treatment for AGD-affected Atlantic salmon and rainbow trout.

[Fascioliasis: diagnosis, epidemiology and treatment]. / Fascioliasis. Diagnóstico, epidemiología y tratamientos.

Fascioliasis is a trematode, disease of liver and bile ducts of sheep, cattle, and other ruminants throughout the world that is caused by the fluke, Fasciola hepatica. Human infection has been reported in Mexico, Cuba, Puerto Rico, Chile, Peru, Uruguay, Brazil, Argentina, the US, Europe, eastern Africa, Japan and Australia. The parasite's miracidium invades one of the various Lymnaea water snail hosts. Infection results from ingestion of encysted metacercariae attached to raw watercress (Nasturtium officinale). Symptoms recorded from human cases included irregular fever, epigastric pain and abdominal tenderness, obstructive jaundice and leucocytosis with eosinophilea up to 60%. Specific diagnosis is based on recovery of the eggs in the patient's stool or from biliary tract drainage. Treatment is with emetine hydrochloride given intramusculary. Bithionol is given orally at a dosage of 30-50 mg/kg but on alternate days from 10 to 15 doses. Praziquantel is probably effective. Preventive measures include education of the public on mode of transmission of life cycle of the parasite, and dipping fresh watercress into boiling water for a few sec, or drying suspected watercress.

[Human fascioliasis: comparison of a fasciolicidal effect of bithionol and praziquantel].

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.

[Hepatic fascioliasis: the usefulness of CT and US]. / Fasciolasis hepática: utilidad de la TC y US.

We present a case report of invasive hepatic fascioliasis. Ramified hypodense lesions with peripheral distribution were found in the CT-scan. These lesions disappeared after treatment with Bithionol. CT-scan plays an important role in the diagnosis of invasive fascioliasis whereas ultrasound is useful in the chronic phase. Both are helpful to evaluate response to treatment.

Synthetic polymers as drugs.

Biologically active compounds have been incorporated into synthetic polymers. Bithionol, a well-known and potent antibacterial agent, has been used as bisphenol monomers for polyesters, polyphosphates, and phosphonates; the bischloroformate of bithionol has been converted into copolycarbonates and polyurethanes. The copolycarbonates of bithionol, optimally designed polymer structures with poly(ethylene oxide) glycols as the other comonomer, have been hydrolyzed under physiological conditions at a degradation rate of about 1% per day. Primaquine, an antimalarial, and amantadine, an antiviral agent, when reacted with isocyanates gave polymeric biurets as do other primary aliphatic amines. Primaquine also underwent nucleophilic substitution reactions on polyepichlorohydrin. 3-Vinyl-, 4-vinyl-, and 5-vinylsalicylic acids have been synthesized, polymerized, and copolymerized to polymeric antibacterials. Copolymers of vinylsalicylic acid can be selective in their activity, depending on the comonomer. Selectivity can also be achieved by derivation of the poly(vinylsalicylic acid).