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Treatment of hydatid disease with high oral doses of mebendazole. Long-term follow-up of plasma mebendazole levels and drug interactions.

Plasma mebendazole levels were analysed retrospectively in patients treated for inoperable infections with Echinococcus multilocularis or granulosus. In 10 patients receiving mebendazole at 4 dose levels there was no relation between dose and plasma concentration. In 17 patients followed on the same dose for more than 18 months, the plasma levels varied with individual coefficients of variation ranging from 27 to 72%. The data reveal the limitations of single measurements of plasma mebendazole and emphasize the need for repeated monitoring. Coadministration of phenytoin and carbamazepine seemed to lower plasma levels, presumably as a result of enzyme induction. It was not possible appreciably to raise the mebendazole concentrations by inhibition of drug metabolizing enzymes with cimetidine.

Adult

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

Studies on paragonimiasis: treatment with mebendazole, emetine with mebendazole and praziquantel.

One hundred cases of paragonimiasis from Saraburi province, Thailand were studied with respect to epidemiology, clinical manifestations, radiography and treatment. Highly endemic areas were Cha-om and Sum-pugpaew villages in Kang-koy district. The ratio of male to female was 48:52. Uncooked crabs and shrimps are the second intermediate hosts of Paragonimus. Hemoptysis and chronic cough were the main symptoms; with crepitations and rhonchi in both lungs. There was no specific changes in chest X-rays of the lungs, except in cases of hemoptysis where changes in pulmonary vessels were observed. Tomograms of the lungs provided 100% accuracy and confirmation of diagnosis of pulmonary paragonimiasis. Praziquantel 25 my/kg body weight three times a day for 2 days gave a cure rate of 90%, mebendazole plus emetine hydrochloride gave a cure rate of 70% and mebendazole alone was not effective.

Adolescent

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

[Treatment of strongyloidiasis with mebendazole and its combination with thiabendazole].

Although Strongyloides stercoralis (S. stercoralis) infection rate in Okinawa Prefecture was less than 2% by the traditional method, it has been proven to be 6.2% by the new technique--agar plate method. Thiabendazole has strong activity to eradicate the organism, but it is well known that the rate of severe side effects is extremely high. Therefore, we attempted to evaluate the new treatment for the infection by mebendazole and its combination with thiabendazole. The reason for use of the drug is based on the reports of successful treatment of S. stercoralis infection in humans with the mild and infrequent side effects produced by the drug. Thirty three patients were orally given mebendazole 100 mg twice daily for 28 days. Twenty six patients were given thiabendazole 500 mg thrice daily for 5 days and after that, mebendazole 100 mg twice daily for 9 days. This combination therapy was repeated twice. The following results were obtained: 1) Out of a total of 59 patients, the cure rate was 83.3% (20/24) in single use of mebendazole and 100.0% (22/22) in the combination therapy. 2) Constipation (9.1%) and headache (9.1%) were of relatively high incidence in the mebendazole group, but they were mild. Nausea (19.2%) and headache (15.4%) were observed in the combination therapy group and the drug was discontinued in 2 patients. 3) The incidence of the elevation of S-GOT, S-GPT was noted in 71.4% (20/28) for the mebendazole group and 52.2% (12/23) for combination therapy group. All 13 patients of the mebendazole group were negative in lymphocyte stimulation test for mebendazole.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

Treatment of cystic echinococcosis (Echinococcus granulosus) with mebendazole: assessment of bound and free drug levels in cyst fluid and of parasite vitality in operative specimens.

Chemotherapy of the larval stage of Echinococcus granulosus in man with high oral doses of mebendazole has only been partly successful. In order to improve effective pharmacotherapy of this disease with mebendazole, the optimal time for blood sampling has been assessed and the mebendazole concentrations acting on the parasite have been compared with their viability. The optimal time for blood sampling was analysed in 14 patients during longterm treatment with mebendazole. The plasma level 4 h after the morning dose exhibited the best correlation with the average 24-h concentration, suggesting that the plasma level should be monitored 4 h after the morning dose. In 22 patients undergoing surgery for hydatid disease, the mebendazole concentration in cyst fluid was significantly correlated with its plasma level 4 h after the morning dose. In 13 of them the free drug concentration was determined by equilibrium dialysis and it was almost identical with the free mebendazole concentration in plasma. Results of viability tests in 12 cases revealed viable cysts in 6 cases and possibly viable cysts in 6 other cases. Even patients treated for more than 12 months still had viable cysts.

Adult

Chemotherapy of onchocerciasis: a controlled comparison of mebendazole, levamisole, and diethylcarbamazine.

Four drug regimens for treating onchocerciasis were compared in a double-blind study in persons from an endemic area in southern Mexico. 40 men were randomly assigned to receive either diethylcarbamazine (DEC) (200 mg/day), mebendazole (2 g/day), levamisole (150 mg per week), or mebendazole plus levamisole. DEC produced the most rapid fall in skin microfilaria counts, but by 6 months the two groups receiving mebendazole showed similar or slightly greater reductions. Despite the administration of corticosteroids to persons receiving DEC, more systemic side-effects were seen in this group. Ocular complications were also commoner and more severe in those receiving DEC. The reduction in the number of intraocular microfilariae at 6 months was similar to those receiving DEC and mebendazole, alone or in combination with levamisole. Levamisole alone had no significant effect on microfilaria counts. Examination of adult worms in nodules excised at 2 months showed changes suggestive of an interruption of embryogenesis in those persons receiving the mebendazole-containing regimens only. The findings suggest that mebendazole may be a useful alternative to DEC in the treatment of onchocerciasis.

Adolescent

The effect of dose form on the bioavailability of mebendazole in man.

Four different dose forms of mebendazole were administered to human volunteers, and urine was collected and assayed for mebendazole and unconjugated metabolites of mebendazole. Oral administration of mebendazole as an oily suspension slightly enhances the bioavailability of the drug, however mebendazole is not absorbed following rectal administration. The major urinary metabolite of mebendazole in humans is 2-amino-5(6)[alpha-hydroxybenzyl]benzimidazole (IV), not 2-amino-5(6) benzoylbenzimidazole (II), as previously reported.

Administration, Oral

Cimetidine increases serum mebendazole concentrations. Implications for treatment of hepatic hydatid cysts.

In eight patients (five with peptic ulcer disease and three with hydatid cysts), the [14C]-aminopyrine breath test (ABT) and maximum serum concentration of mebendazole following a dose of 1.5 g of mebendazole three times daily were determined before and after treatment with cimetidine (400 mg three times daily for 30 days). Serum mebendazole concentrations were measured in blood samples taken 2 h after each drug intake. Cimetidine lowered the 14CO2 specific activity (SA) at 1 h (P less than 0.01) and increased the maximum serum concentration of mebendazole (P less than 0.01). A significant correlation was found between SA at 1 h and the highest concentration of mebendazole before (r = -0.71, P less than 0.05) and after (r = -0.82, P less than 0.05) cimetidine ingestion. Combined administration of cimetidine and mebendazole resulted in the complete resolution of previously unresponsive hydatid cysts.

Adult

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

Improvement of metabolic control in diabetic patients during mebendazole administration: preliminary studies.

After the observation of decreasing insulin resistance in a diabetic patient during treatment with mebendazole for nematosis, we investigated the effect of mebendazole on metabolic control in six Type 1 (insulin-dependent) and six Type 2 (non-insulin-dependent) diabetic patients, eight of whom were chronically resistant to conventional treatment. Before and after mebendazole treatment for 1 month, plasma glucose and serum C-peptide concentrations were determined both fasting and 4 h after a mixed breakfast. Improvements in fasting blood glucose concentrations occurred in Type 1 (12.83 +/- 1.11 versus 6.56 +/- 0.56 mmol/l; p less than 0.05) and Type 2 (10.22 +/- 0.56 versus 7.56 +/- 0.67 mmol/l; p less than 0.05) diabetic patients and were associated with increases in post-cibal C-peptide responses in Type 1 and Type 2 diabetic patients. Following discontinuation of mebendazole, metabolic control deteriorated in five out of the six Type 1 diabetic patients and in all the Type 2 diabetic patients. We conclude that mebendazole increases insulin secretion, and decreases plasma glucose concentration in Type 1 and Type 2 diabetic patients. However, these beneficial effects may be transient.

Adult

Anthelmintic effects of bithionol, paromomycin sulphate, flubendazole and mebendazole on mature and immature Hymenolepis nana in mice.

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.

Animals