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Treatment of experimental alveolar echinococcosis: comparative study of mebendazole, isoprinosine and a mebendazole isoprinosine association.

A comparative biochemical study of the effects of mebendazole and Isoprinosine used separately or associated was conducted in six-month old gerbils infected three months ago by Echinococcus multilocularis metacestodes. Mebendazole treatment induced a decrease of glucose (81%) whereas Isoprinosine increased the glucose uptake in the parasite. The combination of the two drugs led to a decrease of about 40% of the glucose concentration. The specific activities of alkaline and acid phosphatases were also modified. Isoprinosine seemed more effective when used alone than associated with mebendazole with the chosen procedure of treatment.

Acid Phosphatase

The lethal effect of mebendazole on secondary Echinococcus granulosus, cysticerci of Taenia pisiformis and tetrathyridia of Mesocestoides corti.

Oral administration of mebendazole at a rate of 1 g/kg feed (approximately 50 mg/kg body weight/day) for 14 days killed mature and immature cysticerci of Taenia pisiformis in rabbits, and multiplying tetrathyridia of Mesocestoides corti in mice. Progressive degrees of parasite damage caused by mebendazole treatment could be assessed by histological examination of calcereous corpuscles. A single subcutaneous injection of 10 percent mebendazole in carrier, at a rate of 100 mg/kg body weight, resulted in the death of all M. corti tetrathyridia in mice within 4 weeks, but the drug in saline was slowly mobilized and was relatively ineffective. Neither subcutaneous injections of mebendazole in saline or in carrier could kill cysticerci of T. pisiformis within 5 weeks, but the drug in carrier was effective after several months. Mebendazole in saline was effective when injected intraperitoneally, but adhesions often resulted from this route of administration. Echinococcus granulosus protoscoleces administered to mice by intraperitoneal injection were rapidly encapsulated by host lymphoid cells. The vesiculating protoscoleces were all contained within a fibrous capsule for more than 2 months after infection, but by 4 months almost all had grown free of the host reaction. Treatment of the encapsulated protoscoleces with mebendazole in feed for 14-21 days caused collapse of the outer cysts and death of the germinal membrane of all but the innermost protoscoleces. Six weeks later, however, cysts had regrown from surviving germinal tissue and a further treatment with mebendazole in feed for 14-21 days again did not destroy all germinal cells. Treatment of the 4-month-old scoleces with mebendazole in feed for 14 days caused all cysts to collapse and destroyed practically all E. granulosus germinal tissue. Three subcutaneous injections of mebendazole at fortnightly intervals, of drug in saline at 500 mg/kg body weight, or in carrier at 100 mg/dg body weight, were required in order apparently to kill all secondary cysts of E. granulosus. Host lymphoid cells were not able to traverse the laminated membrane of either untreated or collapsed cysts, and it has been shown that only a small amount of living germinative tissue is required to produce a new E. granulosus cyst. These factors could contribute to the relative ability of E. granulosus cysts to recover from mebendazole treatment, compared with cysticerci or tetrathyridia. The effectiveness of mebendazole thus seemed to depend on the formulation of the drug and its route of administration. Mebendazole is probably the first anthelmintic to have a lethal effect on larval cestodes. When applied orally there do not appear to be any adverse effects due to treatment.

Administration, Oral

A clinical trial of mebendazole in the treatment of alveolar hydatid disease.

In July 1974, mebendazole was reported to be effective against the larval stage of Echinococcus granulosus in experimentally infected mice. A clinical trial of mebendazole was initiated in December 1974 in 4 patients with far advanced, nonresectable lesions caused by Echinococcus multilocularis. A daily dose of 40 mg of the drug per kg of body weight was administered to the 4 patients for more than 3 years. No evidence of toxicity or adverse reactions has been observed. Detectable plasma mebendazole concentrations were achieved with high-dose mebendazole therapy. Serum concentrations of IgE increased and decreased early in therapy. There was no evidence that the larval cestode was killed. The metastatic lesions appeared to be stabilized or diminished, and over-all clinical results were encouraging. Progressively enlarging thoracic metastases in 2 patients regressed during therapy, and symptomatic improvement was observed in all 4 patients. Mebendazole, a highly effective antihelmintic in enteric infections, is poorly absorbed by the gastrointestinal tract. Resulting low serum concentrations limit treatment of the massive, scirrhous lesions characteristic of E. multilocularis infections. Nevertheless, encouraging clinical responses observed with mebendazole therapy suggest that a more soluble form of this or a related drug might prove highly effective in the medical management of hydatid disease in humans.

Administration, Oral

Mebendazole.

The broad-spectrum of activity and safety of mebendazole remain, after 5 years of clinical experience, unique features of this anthelmintic. Through microtubular destruction, mebendazole kills helminths by inhibiting glucose uptake into susceptible parasites. The drug's poor absorption does not appear to affect clinical efficacy except, perhaps, in the treatment of systemic helminth infections. Mebendazole is generally considered the drug of choice for trichuriasis and has therapeutic advantages over other anthelmintics in the treatment of enterobiasis and hookworm infections. Although mebendazole is an effective agent against ascariasis, there are preferable alternatives. Among its nonapproved uses, mebendazole shows great promise in the treatment of capillariasis and hydatid disease. Further investigation is needed to establish its role in the treatment of taeniasis, Hymenolepsis nana, strongyloidiasis, trichinosis, and Dipetalonema perstans. Undoubtedly, mebendazole will find its greatest value in the treatment of patients with multiple helminth infections.

Ascariasis

[Long-term therapy of cystic liver echinococcosis with mebendazole].

Surgery is the therapy of choice in the treatment of infestations with Echinococcus (E.) granulosus and E. multilocularis. Chemotherapy with mebendazole, a benzimidazole derivative, introduced 1976 in the therapy of human echinococcosis, showed good results only in cases of infestation with E. multilocularis. In the cases of liver cysts, caused by E. granulosus, the treatment with mebendazole did not succeed as well. Between 1977 and 1986, 44 patients, suffering from infestations with E. granulosus, were referred to the Clinical Department of the Bernhard-Nocht-Institut. In a retrospective study, the data of seven patients had been evaluated: They had not undergone surgery because of the size of the lesions or because they refused the operative treatment. Receiving mebendazole as the only therapy, they had been treated and followed up for more than four years. Mebendazole was given in a dosage of 50 mg/kg body weight in repeated cycles of one month's duration followed by a treatment-free interval of two months. After a median of 55 months (median 13 effective treatment months) six of the seven patients presented a therapeutical success as demonstrated by ultrasound and computed tomography. The cystic lesions had dissolved or decreased in size considerably. One case showed unaltered findings of the liver lesion. Mebendazole treatment was well tolerated by all patients. If the size of the cystic liver-lesions excludes a curative operative treatment or if the patient refuses surgery, the indication for chemotherapy with mebendazole is given.

Adult

Brugia malayi in Mastomys natalensis: efficacy of mebendazole in combination with Freund's complete adjuvant.

The chemotherapeutic efficacy of mebendazole given in combination with Freund's complete adjuvant (FCA) against Brugia malayi in multimammate rat was evaluated. Animals treated with mebendazole, orally at 200 mg/kg x 5 consecutive days along with FCA given subcutaneously (s.c.) on day -10, day 0 and day +15 of the drug treatment killed 48.51% of the adult worms. This drug given alone at the same regimen and by the same route showed only 18.7% mortality rate on adults. Mebendazole given intraperitoneally along with FCA given s.c., however, was four times more efficacious as filaricide than mebendazole alone. Nevertheless, the animals receiving FCA alone also revealed 23.5% mortality rate of adult worms. The animals receiving a combination therapy or FCA alone showed significant increase in antibody titre to the filariae which however decreased in the later stages. No enhancement of antibody level could be detected in animals treated with mebendazole alone. The non-specific immunopotentiation induced by FCA appeared to play a major role in enhancing the activity of mebendazole.

Administration, Oral

[On the effect of mebendazole on metacestodes of Mesocestoides corti and Echinococcus multilocularis (author's transl)].

Mebendazole (5-benzoyl-2-methoxycarbonylaminobenzimidazole) was highly effective against tetrathydridia of Mesocestoides corti in the peritoneal cavity, liver and in the subcutis of mice when administered orally in the food (450 or 465 ppm) from days 7 or 40/50 post infectionem (p.i.) for 10 or 20 days in total doses of approximately 660-1660 mg/kg body weight (b.w.). All tetrathyridia were killed when treatment began at day 7 p.i., and only some survived when medication was started on days 40/50 p.i. A treatment of 5 days was only partially effective. In experiments with Echinococcus multilocularis laboratory animals were intraperitoneally infected with metacestode tissue transplants. Beginning on days 4-7 p.i. or on day 40 p.i. the animals were treated for 5, 10 or 20/21 days with mebendazole medicated food. In mice a treatment for 10 or 20/21 days with total mebendazole doses of approximately 660-2180 mg/kg b.w. caused an average reduction on metacestode weight of 61-89%. An average reduction between 58 and 84% was achieved in Meriones after a treatment for 20/21 days with total doses of approximately 650/530 mg/kg b.w. However, histological examinations and transplantation experiments revealed that in most of the treated animals metacestode tissue survived and retained its capability for budding. On the other hand, indications for a partial destruction of the parasite tissue were found in some of the treated animals. The oral mebendazole treatment was well tolerated. After intraperitoneal injection of 3 X 150 mg/kg b.w. mebendazole - as applied by Campbell et al. (1975) - all of 36 mice or Meriones died.

Animals

A comparative study of the effect of oxantel-pyrantel suspension and mebendazole in mixed infections with Ascaris and Trichuris.

A comparative trial was carried out in 4 orphanges in Seoul, to compare the anthelminthic efficacy of oxantel-pyrantel suspension and mebendazole tablets against mixed infections of Ascaris lumbricoides and Trichuris trichiura. 40 patients were divided into 4 groups and received oxantel-pyrantel suspension at 15 or 20mg/kg once only or on 2 consecutive days. Another group of 20 patients was treated with 100mg of mebendazole twice a day for 3 days. Both drugs achieved a 100% cure rate for Ascaris infections. Against Trichuris infections, the average cure rate and egg reduction rate of oxantel-pyrantel treated groups was 87.5% and 92.3% respectively, and that for mebendazole was 65% and 89.1%. There were no side-effects. The results of the present study suggest that oxantel-pyrantel is more effective in the treatment of mixed infections of Ascaris and Trichuris, and was more acceptable to the patients, than mebendazole.

Ascariasis

Investigations on the biotransformation of mebendazole using an isolated perfused rat gut system.

1. The intestinal metabolism of the benzimidazole, mebendazole (MEB), has been investigated using isolated perfused jejunal segments of rats. Significant absorption and intestinal metabolism of the substance was observed. 2. The metabolites, the reduced alpha-hydroxy-analogue, its glucuronide, and the decarbamoylated 2-amino-analogue, were transported into the resorbate collected at the serosal side or were resecreted into the gut lumen. 3. The intestinal decarbamoylation of mebendazole increased up to 20-fold after pretreatment with 3-methylcholanthrene (MC), and complete re-secretion of this metabolite into the gut lumen led to a total loss of the absorption of mebendazole and metabolites across the gut wall. 4. The results indicate the ability of the gut to metabolize mebendazole by phase I and II reactions. 5. An almost complete loss of bioavailability after induction of the gut enzyme system by MC was observed.

Animals

Chemotherapy of hydatid disease (Echinococcus granulosus) in mice with mebendazole and bithionol.

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.

Animals

The effects of mebendazole and fenbendazole on Trichinella spiralis in mice.

Oral administration of either Mebendazole or Fenbendazole at 50 mg/kg body weight was effective in killing a 7-hr Trichinella spiralis infection in mice. Adult worms, 72 hr postingection, were unaffected by the same dose of Fenbendazole, while Mebendazole showed partial activity. Both Mebendazole and Fenbendazole were active against developing muscle larvae. Mebendazole was effective against encysted muscle larvae while 50 mg of Fenbendazole per kg per day for 7 days from 28 days postinfection failed to have any effect on this stage of the life-cycle.

Animals

Mebendazole and pyrantel pamoate as broad-spectrum anthelmintics.

The efficacy of mebendazole and pyrantel pamoate was studied in two groups of 59 and 58 cases, respectively, of patients with polyparasitosis. Mebendazole had a cure rate of 96%, 82.2%, 71.4% and 66.6% in A. lumbricoides, hookworm, T. trichiura and S. stercoralis, respectively, while the corresponding figures for pyrantel pamoate were 92.6%, 85.7%, 19.4% and 0%. Pyrantel pamoate is considered to have no significant effect on T. trichiura and S. stercoralis. None of the drugs had any effect on T. saginata. Both drugs have been found to be equally effective against enterobiasis by various authors. It is recommended that pyrantel pamoate be the drug of choice in cases of multiple parasitic infections excluding T. trichiura and S. stercoralis whereas those with one or both of these in addition to others should be treated with mebendazole. Mebendazole can be prescribed for patients with clinical evidence of helminthic infections even where stool examination is not possible as it covers almost the whole range of common helminthic infections. The only limitation for poorer patients however is its cost. Pyrantel pamoate has a wider applicability for the poorer patients in spite of the fact that it is ineffective against trichurids and S. stercoralis.

Adolescent

[Double blind study of the efficacy of mebendazole in minor forms of human toxocariasis].

The authors discuss the results of a double-blind, placebo-controlled, randomised study on the efficacy of mebendazole versus placebo in the treatment of human toxocariasis in 45 and 43 patients respectively, who exhibited evocative clinical and biological symptoms and a seropositivity. Scores were used to quantify clinical (20 parameters) and biological (blood count, sedimentation rate, determination of total and anti-Toxocara IgE, serodiagnosis by immunoelectrophoresis) abnormalities. The reassessment were done 1 month after the end of treatment. Analyzing the results showed a similar efficacy of mebendazole and placebo on the score of clinical signs; the score of biological abnormalities was significantly reduced in mebendazole group, but the serodiagnosis by immunoelectrophoresis was the only parameter that was significantly normalized. These results corroborate previous prospective studies and allow to make a conclusion in favour of a moderate efficacy of mebendazole.

Adult

[Mebendazole in the therapy of hydatidosis].

The effectiveness of mebendazole as adjuvant treatment in hydatidosis was evaluated in 19 patients; 12 were treated both before and after surgery, 6 were not treated, one had primary treatment only, owing to the refuse of surgery. Mebendazole was administrated at the dosage of 30-50 mg/kg/day po for 30 days followed by a washout of 15 days, for a mean of 4 cycles (range 1-7) and 12 cycles (range 1-24) before and after surgery, respectively. Patients were monitored by total IgE, specific anti-echinococcus IgE and IgG, at diagnosis, just before surgery and thereafter every six months. Antibody titer decrease was observed soon after the first cycles of medical treatment before surgery, as well as a clear-cut drop after surgery, followed by a continuing decrease after the following cycles of mebendazole. Relapse of disease was observed in two patients only at one and two years after surgery respectively. These preliminary results seem to point out that mebendazole might play a role in the treatment of hydatidosis as adjuvant of surgical therapy.

Adolescent

[The efficacy of mebendazole and praziquantel on larval taeniids from mouse, rabbit and pig (author's transl)].

The efficacy of Mebendazole (Janssen) and Praziquantel (Bayer) on Cysticercus fasciolaris, C. tenuicollis resp. C. pisiformis was studied in 125 mice, 63 pigs and 30 rabbits. All mice were infected naturally with C. fasciolaris. The pigs were infected experimentally with 2000 resp. 5000 eggs of Taenia hydatigena and the rabbits with 1500 eggs of Taenia pisiformis. 8 weeks p.i. animals were divided into groups and received 25 mg/kg Mebendazole or 50 mg/kg Praziquantel on 5 consecutive days as well as 5 mg/kg Mebandazole resp. 10 mg/kg praziquantel for 14 days. The applied doses of 62.5 and 12.5 mg/kg Mebendazole to mice for 10 days or 14 days showed almost no efficacy against C. fasciolaris whereas 250 and 125 mg/kg Praziquantel given for 10 days gave 100% good results. We found that Mebendazole is highly efficient only against C. tenuicollis at a concentration of 25 mg/kg in the pig, whereas in the rabbit the 5 mg dose over 14 days still revealed good results. Praziquantel showed a virtually 100% success using 50 mg/kg for 5 days and 10 mg/kg for 14 days, whereas the efficacy of Praziquantel against C. pisiformis in rabbits administering the same dose was not satisfying.

Animals