Oral Fenbendazole for Cancer Therapy in Humans and Animals.

Fenbendazole is a benzimidazole anthelmintic agent commonly used to treat animal parasitic infections. In humans, other benzimidazoles, such as mebendazole and albendazole, are used as antiparasitic agents. Since fenbendazole is not currently approved by the FDA or EMA, its pharmacokinetics and safety in humans have yet to be well-documented in medical literature. Despite this, insights can be drawn from existing in vitro and in vivo animal studies on its pharmacokinetics. Given the low cost of fenbendazole, its high safety profile, accessibility, and unique anti-proliferative activities, fenbendazole would be the preferred benzimidazole compound to treat cancer. To ensure patient safety in the repurposing use of fenbendazole, it is crucial to perform clinical trials to assess its potential anticancer effects, optimal doses, therapeutic regimen, and tolerance profiles. This review focuses on the pharmacokinetics of orally administered fenbendazole and its promising anticancer biological activities, such as inhibiting glycolysis, down-regulating glucose uptake, inducing oxidative stress, and enhancing apoptosis in published experimental studies. Additionally, we evaluated the toxicity profile of fenbendazole and discussed possibilities for improving the bioavailability of the drug, enhancing its efficacy, and reducing potential toxicity.

Development and analytical characterization of a new antiparasitic fenbendazole compound tablet and pharmacokinetic investigations after its oral administration to dogs.

The objective of this study was to prepare a new compound fenbendazole tablet containing 29.7 % fenbendazole, 1.50 % praziquantel and 0.059 % ivermectin for oral administration. The tablets were successfully prepared using mannitol as filler agent, polyvinyl polypyrrolidone as disintegrant, 5 % povidone (PVAK30) as a binder agent and magnesium stearate as lubricant. The appearance, hardness, fragility, time limit of disintegration and fenbendazole dissolution at 45 min all met the technical standards of the Ministry of Agriculture for the People's Republic of China. We used high performance liquid chromatography and electrospray-mass spectrometry for drug detection. Oral administration of 100 mg/kg fenbendazole, 5 mg/kg praziquantel and 0.2 mg/kg ivermectin using a non-compartmental model defined peak plasma concentrations (Cmax) of 495, 826, 73 ng/mL, and 218 ng/mL for the metabolite oxfendazole, respectively. The area under the curve (AUClast) values for these drugs were 4653, 1045, 1971 and 5525 h×ng/mL, respectively. This study enriches the pharmacokinetic data of compound fenbendazole tablets using dogs as a model system. The new tablet formulation was assimilated quickly and systemically and this study will be beneficial for the clinical application of parasite treatments in dogs.

Development and evaluation of a protocol for control of Giardia duodenalis in a colony of group-housed dogs at a veterinary medical college.

OBJECTIVE To develop and evaluate a protocol for control of Giardia duodenalis in naturally infected group-housed dogs at a veterinary medical college. DESIGN Prospective evaluation study. ANIMALS 34 dogs. PROCEDURES All dogs were tested for evidence of G duodenalis infection. Dogs were treated with fenbendazole on study days 1 through 10. On day 5, dogs were bathed and moved into clean, disinfected kennels in a different room to allow for disinfection and drying of their assigned kennels at 26.7°C (80°F) for 24 hours on day 6. After treatment, dogs were returned to their original housing; fecal samples were collected weekly from days 8 through 41 and then every 3 weeks until day 209. Samples were fixed in formalin and examined by direct immunofluorescence assay. Additionally, 1 pretreatment sample underwent PCR assay and DNA sequencing to determine the assemblage (genotype) of the organism. Normal handling routines for the dogs and their use in teaching activities were not changed. RESULTS Initially, all dogs in the colony shed G duodenalis cysts. During and immediately after treatment (days 8 and 13), no cysts were detected in any dogs. On day 20, 1 cyst was observed in the fecal sample from 1 dog; results for all subsequent fecal analyses were negative. The G duodenalis cysts collected from the pretreatment sample had an assemblage C genotype. CONCLUSIONS AND CLINICAL RELEVANCE The integrated protocol was successful in controlling G duodenalis infection in this dog colony, despite exposure of dogs to a variety of environments and frequent handling by multiple individuals. Sequence analysis identified an assemblage typically found in dogs but not in people, indicating that zoonotic transmission would be unlikely.

Diagnosis and therapy of Capillaria plica infection: report and literature review.

Worldwide, data on Capillaria (Pearsonema) plica infections of the urinary tract in domestic carnivores are limited. Nevertheless, cystitis with hematuria, dysuria or pollakiuria may suggest a C. plica infection. A three-year old dog from Poland showing pollakiuria and hematuria was presented. At urine analysis, C. plica eggs were found in the urine sediment. The dog was unsuccessfully treated with a daily oral dose of fenbendazole 50 mg/kg BW for 5 days, while a single subcutaneous administration of ivermectin 0.2 mg/kg BW once effectively eliminated C. plica infection.

Efficacy of bath and orally administered praziquantel and fenbendazole against Lepidotrema bidyana Murray, a monogenean parasite of silver perch, Bidyanus bidyanus (Mitchell).

We investigated the efficacy of praziquantel (PZQ) and fenbendazole (FBZ), each administered by bath and orally, against the monogenean Lepidotrema bidyana Murray, a gill parasite of the freshwater fish silver perch, Bidyanus bidyanus (Mitchell). PZQ and FBZ were each administered by bath at 10 mg L⁻¹ for 48 h and on surface-coated feed pellets at 75 mg kg⁻¹ per body weight (BW) per day for 6 days. Bath treatments of PZQ and FBZ had an efficacy of 99% and 91%, respectively, against adult L. bidyana. Oral treatments of PZQ and FBZ had an efficacy of 79% and 95%, respectively, against adult L. bidyana. Fish rejected feed pellets surface-coated with PZQ, suggesting that palatability of surface-coated PZQ-medicated feed is poor, which undermined efficacy. In all trials, some juvenile parasites were present on fish after treatment during efficacy assessment, indicating that efficacy may be lower against juvenile parasites or that recruitment occurred post-treatment, demonstrating that repeat treatments are necessary to effectively control L. bidyana in aquaculture.

Use of fenbendazole-containing therapeutic diets for mice in experimental cancer therapy studies.

Pinworm infection (oxyuriasis) is a common problem in rodent colonies. Facility-wide prophylactic treatment of all mice with a diet containing therapeutic levels of fenbendazole for several weeks is often used to control pinworm outbreaks. We examined the effect of feeding a therapeutic diet containing 150 ppm fenbendazole on the growth of EMT6 mouse mammary tumors implanted into BALB/c Rw mice. Mice were randomized to receive either a fenbendazole-containing or control diet for 1 wk before tumor cells were injected intradermally in the flanks and throughout tumor growth. Tumor growth was monitored by serial measurements of tumor diameters from the time tumors became palpable until they reached 1000 mm3. The medicated diet did not alter tumor growth, invasion, or metastasis. When tumors reached volumes of approximately 100 mm3, some were irradiated locally with 10 Gy of X-rays. Irradiation significantly delayed tumor growth; fenbendazole did not alter the radiation-induced growth delay. However, cell culture studies showed that fenbendazole concentrations not far above those expected in the tissues of mice on this diet altered the growth of the tumor cells in culture. Recent data from other laboratories also have demonstrated effects of fenbendazole that could complicate experiments. Care should therefore be exercised in deciding whether chow containing fenbendazole should be administered to mouse colonies being used in cancer research.

Clinical features and outcome of Heterobilharzia americana infection in dogs.

BACKGROUND: Heterobilharzia americana (HA), the causative agent of canine schistosomiasis, is a flatworm with a freshwater snail as an intermediate host. Only case reports or small case series evaluating naturally infected dogs have been published. OBJECTIVE: Describe clinical signs in dogs naturally infected with HA. ANIMALS: Twenty-two dogs naturally infected with HA from 1985 to 2009. METHODS: Retrospective study. All medical records were searched for HA and schistosomiasis. Only dogs with a diagnosis based on identification of ova on histopathology or fecal saline sedimentation were included. RESULTS: The median age was 3.1 years (1-12). The median duration of clinical signs before diagnosis was 0.63 months (0.03-12). The most common clinical signs were lethargy (91%), weight loss (77%), hyporexia (68%), vomiting (59%), and diarrhea (55%). Eleven of the 22 dogs were hypercalcemic. Hypercalcemia did not resolve without definitive treatment with praziquantel. HA infection was an incidental diagnosis in 7/22 dogs. Diagnosis was obtained via necropsy (4), histopathology (9), and fecal examination (9). Definitive treatment included praziquantel and fenbendazole. Eighteen dogs were diagnosed antemortem and 17 were treated. Twelve dogs were alive for 6 months to 3 years after diagnosis. CONCLUSIONS AND CLINICAL IMPORTANCE: HA infection occurs in younger, larger breed, indoor dogs. Hypercalcemia does not resolve without praziquantel treatment. Prognosis is good and neither hypercalcemic-induced renal failure nor ascites appears to worsen prognosis. Dogs in affected areas or that have traveled to affected areas that present for weight loss, gastrointestinal or liver disease, and hypercalcemia, should be tested.

Efficacy and safety of emodepside 2.1%/praziquantel 8.6% spot-on formulation in the treatment of feline aelurostrongylosis.

The objective of the present study was to evaluate the efficacy and safety of the antiparasitic spot-on formulation containing emodepside 2.1%/praziquantel 8.6% (Profender, Bayer) in the treatment of natural feline infection with the lungworm Aelurostrongylus abstrusus (Nematoda, Strongylida). Efficacy of Profender given once at the licensed dose was tested in comparison to a control oral formulation containing fenbendazole 18.75% (Panacur, Intervet) given over three consecutive days at the licensed dose. Efficacy assessment was based on larvae per gramme of faeces (LPG) counts, measured on days 28 +/- 2 following treatment and compared to counts on days -6 to -2. In total 24 cats treated either with Profender (n = 12) or with Panacur (n = 12) were included in the assessment of efficacy and safety. Mean LPG post-baseline counts (days 28 +/- 2) were 1.3 LPG for both Profender and Panacur, demonstrating similar efficacy of 99.38% for Profender and 99.29% for the control product. No treated animals showed adverse events. This trial demonstrated that both Profender spot-on formulation and oral paste Panacur are safe and effective in the treatment of aelurotrongylosis in cats. Future practical perspectives in feline medicine and the major advantages of the spot-on product compared to the oral paste are discussed.

Unexpected antitumorigenic effect of fenbendazole when combined with supplementary vitamins.

Diet containing the anthelminthic fenbendazole is used often to treat rodent pinworm infections because it is easy to use and has few reported adverse effects on research. However, during fenbendazole treatment at our institution, an established human lymphoma xenograft model in C.B-17/Icr-prkdcscid/Crl (SCID) mice failed to grow. Further investigation revealed that the fenbendazole had been incorporated into a sterilizable diet supplemented with additional vitamins to compensate for loss during autoclaving, but the diet had not been autoclaved. To assess the role of fenbendazole and supplementary vitamins on tumor suppression, 20 vendor-supplied 4-wk-old SCID mice were assigned to 4 treatment groups: standard diet, diet plus fenbendazole, diet plus vitamins, and diet plus both vitamins and fenbendazole. Diet treatment was initiated 2 wk before subcutaneous flank implantation with 3 x 107 lymphoma cells. Tumor size was measured by caliper at 4-d intervals until the largest tumors reached a calculated volume of 1500 mm3. Neither diet supplemented with vitamins alone nor fenbendazole alone caused altered tumor growth as compared with that of controls. However, the group supplemented with both vitamins and fenbendazole exhibited significant inhibition of tumor growth. The mechanism for this synergy is unknown and deserves further investigation. Fenbendazole should be used with caution during tumor studies because it may interact with other treatments and confound research results.

Field testing of a fenbendazole treatment combined with hygienic and management measures against a natural Giardia infection in calves.

The need of a combination of animal treatment and environmental measures against a natural Giardia infection in calves between the age of 1 and 6 months was emphasized and evaluated. Ten commercial farms with a total of 94 calves suffering from chronic diarrhea, ill thriving and impaired growth, were included in two subsequent studies. The first study indicated that treatment of all animals with fenbendazole at 15 mg/kg during 3 consecutive days combined with environmental measures on the final day of treatment, which were either removal of bedding, thorough cleaning and ammonia 10% disinfection or relocation of the treated animals to a Giardia free environment, resulted in a total reduction in cyst excretion for at least 2 weeks. In the second study, the immunofluorescence assay (Merifluor Cryptosporidium/Giardia; Meridian Diagnostics Inc., Cincinnati, Ohio) was used quantitatively and confirmed that the combination of treatment and environmental measures resulted in a total reduction of cyst excretion during 2 weeks and in a significant (P<0.05; >or=98.0%) reduction of the cyst excretion until at least 4 weeks after treatment. Furthermore, there was a noticeable improvement of the clinical symptoms in all animals towards day 28 after treatment and 4 months after treatment health in all calves was normal.

Individual intake and antiparasitic efficacy of free choice mineral containing fenbendazole for grazing steers.

A 95-day study (June 25-September 27, 2001) was conducted using 120 steers (311.9+/-2.4 kg) randomly allocated to two treatments: (1) mineral containing 0.55% fenbendazole (FBZ) and (2) control, no FBZ in the mineral. Animals in the FBZ group were individually identified by an electronic tag that was read each time an animal attended the mineral feeder. The feeder was equipped with load cells that enabled individual mineral intakes to be estimated. The FBZ group was provided with non-medicated mineral during a 14-day adaptation period (July 23-August 5) and an 8-day post-medication period (September 17-24). The intake of FBZ was monitored for 14 days during each of the two treatment periods; August 6-19 and September 3-16, separated by a 14-day non-medicated period, August 20-September 2. Control animals had access to non-medicated mineral for the entire 95-day study period. All steers were grazed on alfalfa-grass pasture for the duration of the study and had free access to flocculated, filtered and chlorinated water via an automatic waterer. Fecal samples were collected from steers three times during the experiment July 23, August 27 and September 27, and analyzed for nematode eggs and Giardia sp. cysts. Seventy-five and 83% of the steers in the FBZ group visited the mineral feeder during the first and second treatment periods, respectively. Individual daily mineral and FBZ intake for the first and second treatment periods was 52.9+/-6.6g per day and 10.1+/-1.2mg/kg BW; 72.3+/-8.4 g per day and 11.8+/-1.4 mg/kg BW, respectively. FBZ animals were separated into three groups during each treatment period based on the recommended dose (RD) of FBZ (5 mg/kg/BW), those that received > the RD, those that received < RD but > 50% RD and those that received < 50% of RD. Nematode egg counts and the number of animals infected with nematodes was reduced (p < 0.05) in all cattle that consumed FBZ as compared to control animals. In contrast to nematode eggs, numbers of Giardia cysts was not reduced (p > 0.05) by FBZ as compared to controls in either treatment period. These results may be a reflection of Giardia re-infection occurring following treatment and highlight the need for variation in treatment regimes specifically targeted at the parasite of interest.

Bone marrow hypoplasia and intestinal crypt cell necrosis associated with fenbendazole administration in five painted storks.

Five painted storks were treated with fenbendazole for 5 days for internal parasitism. Four birds died following treatment. Profound heteropenia was a consistent finding in all samples evaluated; additionally, the 1 surviving bird had progressive anemia. Consistent necropsy findings in the 4 birds that died were small intestinal crypt cell necrosis and severe bone marrow depletion and necrosis. Fenbendazole has been associated with bone marrow hypoplasia and enteric damage in mammals and other species of birds. The dosages of fenbendazole used in birds are often substantially higher than those recommended for mammals, which may contribute to bone marrow hypoplasia and intestinal crypt cell necrosis associated with fenbendazole administration in birds.

Giardiasis in dairy calves: effects of fenbendazole treatment on intestinal structure and function.

Twelve Giardia duodenalis-infected Holstein dairy calves were allocated into a treatment (n=6) and placebo group (n=6) according to pre-study faecal cyst counts. Calves in the treatment group received an oral dose of 5 mg/kg fenbendazole once daily for 3 days, while placebo calves received a sterile saline solution. Calves were euthanised 7 days following the initiation of treatment and intestinal were collected and prepared for trophozoite quantitation, histology, electron microscopy, and disaccharidase assays. In all calves treated with fenbendazole, intestinal trophozoites were below detection limits, while in saline-treated calves, trophozoites were observed in all intestinal segments. Histologically, no significant difference was observed between treatment groups with respect to intestinal villus height or crypt depth. However, a significant decline in the number of intraepithelial lymphocytes (IEL) was observed in fenbendazole-treated calves when compared with placebo-treated calves in the duodenum (13.9+/-1.2 vs. 17.0+/-1.1 IEL/100 enterocytes) and jejunum (21.6+/-0.8 vs. 30.7+/-1.0 IEL/100 enterocytes). In addition, measurements from TEM micrographs demonstrated a significant increase in microvillus surface area in the jejunum of fenbendazole-treated calves compared with saline-treated calves (31.2+/-10.2 vs. 22.8+/-7.6 microm(2)). This increase in microvillus surface area was also associated with an increase in jejunal maltase activity in fenbendazole-treated calves compared with calves treated with saline. These results demonstrate that fenbendazole is an effective treatment for giardiasis in calves. fenbendazole treatment eliminated Giardia trophozoites from the small intestine of calves resulting in increased microvillus surface area and greater intestinal enzyme activity. This study also demonstrates that the pathogenesis of giardiasis in calves is similar to that observed in humans and laboratory animals, and provides further evidence that Giardia is a pathogen of cattle with potential economic importance.

Individual intake and antiparasitic efficacy of free choice mineral and fenbendazole in range calves.

The current study was conducted to assess the feasibility of fenbendazole (FB) administration to steers in a free choice mineral supplement. Provision of free choice FB reduces the need for handling of animals as well as decreases the level of animal parasitism. Two separate trials were conducted using 400 +/- 19 kg Holstein steers (n=14 and 17) during the months of July and August. Each steer was tagged with a unique electronic identification (EID) ear tag and randomly allocated into one of two groups. The tags worked in conjunction with a mineral feeder equipped with a load cell by registering the steer's EID number every time the animal entered the electromagnetic field. Individual daily mineral intake and feeding times were determined over two 8-day periods of non-medicated mineral (no FB), separated by a 14-day period of medicated mineral (0.55% FB). Fecal samples were collected at the beginning and end of each trial period and were analyzed for gastrointestinal nematode eggs and Giardia cyst. There was a consistently high level of attendance for the entire experimental period, with the exception of the first six days of the adaptation period. There were three preferential times for visiting the mineral feeder, approximately 07:00, 12:00 and 18:00 h. Individual daily mineral and FB intake was 229 +/- 27.21 g/day and 2 +/- 0.14 mg/kg BW/day, respectively, for the 14-day drug delivery period. The levels of fecal nematode eggs and Giardia cysts decreased significantly (<0.01) between pre- and post-sampling, with reductions of 92% for nematode eggs and 85% for Giardia cysts. Free choice medication for the control of gastrointestinal parasites is potentially effective, provided that the appropriate drug concentration, adaptation period, intake level and duration of treatment is utilized.

[Intensity of liver tumor promotion effects in rats given repeated oral administrations of benzimidazole compounds].

Liver tumor-promoting effects of anthelminthic agents, febantel (Feb), fenbendazole (Fen) or oxfendazole (Oxf), were investigated in a rodent 2-stage carcinogenesis model. Five-week-old male F344 rats were initiated with or without diethylnitrosamine (DEN) and one week later given diet containing Fen (3600, 1800, 600, 200 or 70 ppm), Feb (2000, 1000, 500 or 100 ppm) or Oxf (500, 250, 100 or 10 ppm) for 8 weeks. Induction of CYP1A1/2 was observed in treated groups of DEN + Feb and DEN + Oxf groups, and its induction was most marked in DEN + Oxf groups. CYP2B1 and CYP4AI were also induced in these treated groups. The number or area of Cx32 positive spots per hepatocyte was significantly decreased in treated groups except for DEN + Oxf 100 ppm group, as compared to DEN alone group. GST-P positive foci was significantly increased in DEN + Fen groups treated with 1800 ppm or more, DEN + Feb groups treated with 1000 ppm Feb or more and DEN + Oxf groups treated with 250 ppm Oxf or more. These results suggest that these three compounds have liver tumor promotion effects and the promoting action in Oxf is most strong among them.

Efficacy of fenbendazole against giardiasis in dogs.

Efficacy of fenbendazole at 2 dosages for treating naturally acquired giardiasis in dogs was assessed. Giardia cysts were not detected in the feces of 6 of 6 group-1 dogs (as determined by use of the zinc sulfate concentration technique) after fenbendazole treatment (50 mg/kg of body weight, PO, q 24 h, for 3 doses). Cysts were not detected in the feces of 6 of 6 group-2 dogs after fenbendazole treatment (50 mg/kg of body weight, PO, q 8 h, for 3 days). However, cysts were not detected in the feces of only 1 of 6 group-3 (nontreated control) dogs. Signs of toxicosis were not observed in any dog. These results indicate that the current label dosage (for the treatment of Toxocara canis, Toxascaris leonina, Ancylostoma caninum, Uncinaria stenocephala, Trichuris vulpis, and Taenia pisiformis, but not Giardia spp) of fenbendazole (50 mg/kg, PO, q 24 h, for 3 doses) is also effective for treating giardiasis in dogs.

[Fenbendazole therapy of experimental larval echinococcosis. I. The effect of fenbendazole on worm burden and protoscolex development of Echinococcus multilocularis (author's transl)]. / Zur Chemotherapie der experimentellen larvalen Echinococcose mit Fenbendazol. 1. Der Einfluss von Fenbendazol auf Befallsstärske und Protoscolex-Bildung bei Echinococcus multilocularis.

Application of fenbendazole (methyl-5-(phenyl-thio)-benzimidazole-2-carbamate) in Echinococcus multilocularis infected mice showed a significant efficiency on the development of the cysts; the worm burden and the number of protoscolices were significantly reduced in the treated animals in comparison with the non-treated control mice. The degree of efficiency was subject to the way of application, the duration of medication, and the parasite strain: 1. On application of f. as medicated feed (500 ppm) worm burden and protoscolex number were reduced the most an average parasite weight of 105 mg and 2 protoscolices against 1942 mg and 99 protoscolices. Treatment by oral application with emulsion of 2.5% (1 ml/mouse/day, 5 x per week over a period of 2--5.5 months) the efficiency was less expressed (845 mg, 53 protoscolices). 2. By extending the treatment from 60 to 102 and 165 days resp. the reduction of worm burden can be increased from 81 to 95%. 3. From 2 parasite strains one which was recently isolated from a fox, reacted more on the treatment than the other one: 85 mg parasite weight against 1218 mg in the nontreated controls. On the other strain continued since about 25 years by intraperitoneal inoculation, the efficiency was more reduced: The worm burden was 866 against 2666 mg in the control mice.

Nippostronglylus brasiliensis infection in the rat: effect of iron and protein deficiency and dexamethasone on the efficacy of benzimidazole anthelmintics.

Malnutrition, anaemia, and gut parasites are commonly interrelated. Using the Nippostrongylus brasiliensis-rat model, the effect of iron and protein deficiency on the efficacy of benzimidazole anthelmintics was studied. It was demonstrated that the anthelmintics mebendazole and fenbendazole were significantly less effective in eradicating parasites when animals were deficient in iron and protein. This decreased efficacy of anthelmintics in iron and protein deficiency could not be overcome by intraperitoneal administration of the drug. Since nutritional deficiencies may act via impairment of the immune response, anthelmintic efficacy was determined in adequately nourished rats treated with the immunosuppressive drug dexamethasone. A similar decrease in efficacy of mebendazole was shown when these animals were treated with dexamethasone. Thus it is possible that lowered anthelmintic efficacy in iron and protein deficient animals is mediated by immune deficiency. These findings may be relevant to anthelmintic programmes in malnourished communities.