In vitro efficacy of nitro- and halogeno-thiazolide/thiadiazolide derivatives against Sarcocystis neurona.

Sarcocystis neurona is an obligate intracellular parasite that causes equine protozoal myeloencephalitis (EPM). The aim of this work was to document inhibitory activities of nitazoxanide (NTZ, [2-acetolyloxy-N-(5-nitro 2-thiazolyl) benzamide]) and new thiazolides/thiadiazolides on S. neurona in vitro development, and investigate their structure-activity relationships. S. neurona was grown in bovine turbinate cell cultures. At concentrations varying from 1.0 to 5.0mg/L, nitazoxanide and 21 of 32 second generation thiazolide/thiadiazolide agents exerted a > or =95% maximum inhibition on S. neurona development. Most active agents were either NO(2) or halogen substituted in position 5 of their thiazole moiety. In contrast, other 5-substitutions such as hydrogen, methyl, SO(2)CH(3), and CH(3) negatively impacted activity. Compared with derivatives with an acetylated benzene moiety, deacetylated compounds which most probably represent primary metabolites exhibited similar inhibitory activities. Present data provide the first evidence of in vitro inhibitory activities of nitazoxanide and new thiazolides/thiadiazolides on S. neurona development. Active halogeno-thiazolide/thiadiazolides may provide a valuable nitro-free alternative to nitazoxanide for EPM treatment depending on further evaluation of their in vivo activities.

Nitazoxanide in the treatment of acquired immune deficiency syndrome-related cryptosporidiosis: results of the United States compassionate use program in 365 patients.

BACKGROUND: Cryptosporidiosis in patients with acquired immune deficiency syndrome is a serious, life-threatening disease. AIM: A large compassionate use clinical trial was conducted in the USA to make nitazoxanide available to patients with acquired immune deficiency syndrome-related cryptosporidiosis and to collect data related to safety and effectiveness of the drug in this population. METHODS: Patients at least 3 years of age with acquired immune deficiency syndrome, diarrhoea (> or =4 stools/day for >2 weeks) and Cryptosporidium-positive stools received 500-1500 mg of nitazoxanide twice daily. Patients were evaluated at weeks 1, 2, 4 and monthly thereafter for drug safety and effectiveness including the stool examinations, review of symptoms and patient diaries. Data analysis for clinical and parasitological response was intention-to-treat. RESULTS: Three hundred and sixty-five patients were enrolled at 165 study centres throughout the USA. The duration of treatment ranged from 1 to 1,528 days (median 62 days). Among the 357 patients included in the intent-to-treat analysis, 209 (59%) achieved a sustained clinical response while on treatment. Clinical responses were closely associated with Cryptosporidium-negative stools (P < 0.0001). No safety issues were identified at doses up to 3000 mg/day or for long durations of treatment. CONCLUSIONS: Nitazoxanide can be considered useful therapy for treatment of with acquired immune deficiency syndrome-related cryptosporidiosis.

Nitazoxanide in the treatment of viral gastroenteritis: a randomized double-blind placebo-controlled clinical trial.

BACKGROUND: Enteric viruses including noroviruses and rotavirus are leading causes of diarrhoeal disease and gastroenteritis worldwide, and there is no effective treatment. AIM: To evaluate nitazoxanide, a thiazolide anti-infective agent, in treating viral gastroenteritis in adults and adolescents. METHODS: 50 out-patients at least 12 years of age (mean 33.5 years) presenting with diarrhoea and stool-positive by enzyme-linked immunosorbent assay for norovirus, rotavirus or adenovirus were enrolled in a double-blind, placebo-controlled clinical trial. Patients were randomly assigned either nitazoxanide 500 mg or placebo twice daily for 3 days. The primary end point was time from first dose to resolution of symptoms. Analysis was modified intent-to-treat for 45 patients, excluding five patients with other identified enteropathogens at baseline. RESULTS: The median time from first dose to resolution of symptoms was 1.5 days (IQR: 0.5-2.5) for nitazoxanide-treated patients and 2.5 days (IQR: 1.5-4.5) for the placebo group. Significant reductions in time to resolution of symptoms were observed for all patients analysed (P < 0.0001) and for subsets of patients with rotavirus (P = 0.0052) and norovirus (P = 0.0295). The number of patients with adenovirus (n = 5) was too small to draw any conclusion. No significant adverse events were reported. CONCLUSIONS: Nitazoxanide may play an important role in managing viral gastroenteritis in adults.

Double-blind, randomized, placebo-controlled study of nitazoxanide in the treatment of fascioliasis in adults and children from northern Peru.

BACKGROUND: Human fascioliasis is a significant world-wide health problem, and massive or repeated infections by Fasciola hepatica can lead to considerable morbidity. AIM: : To evaluate the safety and efficacy of nitazoxanide, when compared with placebo, in the treatment of fascioliasis in adults and children from northern Peru. METHODS: A double-blind, placebo-controlled study was carried out in 50 adults and 50 children infected with F. hepatica. The diagnosis of infection was based on the presence of F. hepatica eggs in one stool sample obtained before inclusion in the study. Patients were randomized to receive treatment with either a 7-day course of nitazoxanide (100 mg b.d., age range 2-3 years; 200 mg b.d., age range 4-11 years; 500 mg b.d., age > 12 years) or matching placebo. Three post-treatment stool examinations were carried out between 30 and 90 days after initiation of treatment. RESULTS: The parasite was eliminated in 18 of 30 (60%) adults completing the study who received nitazoxanide vs. one of eight adults in the placebo group (P = 0.042), and similarly in 14 of 35 (40%) children completing the treatment vs. none of eight in the placebo group (P = 0.038). Only mild, transient adverse events were reported. CONCLUSIONS: A 7-day course of nitazoxanide was effective in adults and children in the treatment of F. hepatica, when compared with placebo.

Nitazoxanide in the treatment of Taenia saginata and Hymenolepis nana infections.

Nitazoxanide , a nitrothiazole derivative, was tested in 22 patients infected with Taenia saginata and 18 infected with Hymenolepis nana. A single 25 mg/kg body weight dose was effective against T. saginata, while twice this dose level (50 mg/kg), also as a single dose, was required for treating H. nana infection. Tolerance of the drug was good at both dose levels used.

Albendazole: a new broad spectrum anthelmintic. Double-blind multicenter clinical trial.

A new anthelmintic drug, albendazole, has been tested in a multicenter double-blind placebo controlled study in 392 patients from France and West Africa in children and adults with single or mixed infections caused by roundworms, hookworms, whipworms, threadworms and tapeworms. All patients were closely observed before and after treatment for clinical side effects, hematological or clinical blood chemical changes. Fecal samples obtained before, and 7 days and 21 days after treatment were examined using a concentration technic (Ritchie), a coproculture (Harada-Mori) and an egg count (Kato). Following a single dose of 400 mg in adults, cure rates of 96% in ascaridiasis, 96% in ancylostomiasis caused by dose of 400 mg in adults, cure rates of 96% in ascaridiasis, 96% in ancylostomiasis caused by Ancylostoma duodenale, 90% in ancylostomiasis caused by Necator americanus and 76% in trichuriasis were recorded. About 48% of the patients infected by Strongyloides stercoralis were cured following administration of 400 mg per day for 3 consecutive days. The efficacy of half of the adult dose (200 mg) was much lower in children. None of the patients who received placebo were cured. The drug did not produce any significant side effects and approximately the same numbers were reported in the albendazole and the placebo groups. No variations of the hematology and clinical blood chemistry values were recorded.

Nitazoxanide in the treatment of cryptosporidial diarrhea and other intestinal parasitic infections associated with acquired immunodeficiency syndrome in tropical Africa.

Eighteen patients hospitalized with intestinal parasitic infections associated with diarrhea and dehydration completed a study of nitazoxanide in the treatment of Cryptosporidium parvum and other intestinal parasitic infections. Seventeen of the 18 patients were positive for human immunodeficiency virus. Twelve patients were diagnosed with clinical Stage 4 acquired immunodeficiency syndrome (AIDS) according to the 1990 World Health Organization proposed clinical classification system and cryptosporidiosis. Nitazoxanide (500 mg tablets) were administered orally, one tablet twice a day for seven consecutive days. Cryptosporidium parvum oocysts were eradicated or reduced by more than 95% in seven of the 12 Stage 4 AIDS patients who completed the study based upon two post-treatment fecal examinations conducted on days 7 and 14 following the initiation of treatment. The elimination or reduction of C. parvum oocysts was associated with a complete resolution of diarrhea in four of the seven patients. The test drug was also effective against cases of Isospora belli, Entamoeba histolytica, Giardia lamblia, Ascaris lumbricoides, Enterobius vermicularis, Hymenolepis nana, and Dicrocoelium dentriticum. Treatment with nitazoxanide was well tolerated by the patients. There were no abnormalities in blood chemistry or hematology data that were considered to be attributable to nitazoxanide therapy. Transient episodes of vomiting were observed in four patients, all with Stage 4 AIDS and cryptosporidiosis, which resolved spontaneously without discontinuation of treatment and were not considered to be related to administration of nitazoxanide.

PIP: The effectiveness of nitazoxanide in the treatment of Cryptosporidium parvum and other intestinal parasitic diseases was assessed in 18 patients hospitalized at Point G. National Hospital in Bamako, Mali, with parasite-related diarrhea, dehydration, and weight loss. 17 of the 18 patients were infected with HIV, and 12 of these had progressed to clinical stage 4 AIDS. 500 mg tablets of nitazoxanide were administered twice a day for 7 days. After completion of treatment, Cryptosporidium parvum oocysts were eradicated or reduced by more than 95% in 7 of the stage 4 AIDS patients; diarrhea was completely resolved in 4 of these patients. Nitazoxanide was also effective against other parasites common in AIDS patients, including Entamoeba histolytica, Giardia lamblia, and Isospora belli. The test drug was well tolerated by all recipients, with no blood chemistry abnormalities.

Albendazole: placebo-controlled study in 870 patients with intestinal helminthiasis.

A total of 870 patients, both males and females, from 3 to 79 years old, received either albendazole or a placebo for the treatment of nematode and cestode infections. Each patient was interviewed and underwent a complete physical examination on the initial visit. In addition, complete blood count, clinical blood chemistry values and routine urinalysis were performed before and at least 24 hours after the last treatment. Stool examinations were performed before, 7 and 21 days after treatment. Direct examination, an egg count using the Kato technique and faecal concentration were carried out for each patient. In ancylostomiasis and strongyloidiasis, faeces were cultured by the Harada-Mori technique. Albendazole, as a single 400 mg oral dose, was highly effective against Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale and Trichuris trichiura; efficacy against Strongyloides stercoralis was observed after three consecutive days of treatment at the same daily dose level. Efficacy against Hymenolepis nana was fair. Based on both clinical signs and biological values, albendazole did not produce any significant side effects.

Treatment of imported cases of falciparum malaria in France with halofantrine.

Halofantrine is a 9-phenanthrenemethanol which is effective against multi-drug resistant strains of Plasmodium falciparum. It has been shown to be highly effective and extremely well tolerated in the treatment of imported cases of falciparum malaria in France. A total of 1,500 mg administered in three 500 mg doses at six-hour intervals results in a 100% cure rate in semi-immune subjects. This dosage should be repeated after 14 days to obtain the same cure rate in non-immune patients. Minor clinical side effects included epigastric pains, nausea and, in one case, a skin rash.

A double-'blind' placebo-controlled study of nitazoxanide in the treatment of cryptosporidial diarrhoea in AIDS patients in Mexico.

Sixty-six patients with human immunodeficiency virus infection and diarrhoea caused by Cryptosporidium parvum were enrolled in a double-'blind' placebo-controlled study to evaluate the safety and efficacy of nitazoxanide in the treatment of cryptosporidiosis related to the acquired immune deficiency syndrome. Patients were randomly assigned to one of 3 treatment groups and received either 500 mg twice daily of nitazoxanide, 1000 mg twice daily of nitazoxanide, or placebo orally for 14 d; the patients on nitazoxanide then crossed over to placebo while the placebo patients crossed over to nitazoxanide therapy at either the high or low dose depending on their randomization. Three post-treatment faecal examinations were conducted on days 15, 22 and 29 following initiation of treatment: patients were considered 'cured' if none revealed any C. parvum oocysts. Both doses of nitazoxanide produced parasitological cure rates superior to the placebo responses (12/19 [63%, P = 0.016] for patients receiving 1 g/d and 10/15 [67%, P = 0.013] for those receiving 2 g/d). Parasitological cure was correlated with the complete resolution of the diarrhoeal syndrome in 19 of the 22 treated patients who were considered parasitologically cured (86%). Both doses of nitazoxanide were well tolerated by the patients.

Albendazole: a new single dose anthelmintic. Study in 1455 patients.

Albendazole has been tested in an open trial conducted in France, seven countries of West-Africa, Martinique and the People's Republic of China in a total of 1455 patients harboring single or mixed infections caused by round-worms, pinworms, hookworms and whipworms. All patients were closely observed before and after treatment for clinical side effects and hematology and clinical chemistry values were done in about 5% of the cases. Fecal samples obtained before and approximately 15, 16 and 17 days after treatment were examined using the Kato test, and when negative, a concentration technic. In case of ancylostomiasis, a coproculture was carried out for species identification. Following a single oral dose, albendazole was highly effective in enterobiasis (100%), ascariasis (89%), ancylostomiasis caused by Necator americanus (88%) and trichuriasis (70%). The drug did not procedure any significant adverse reactions or modifications of the hematological and clinical blood chemistry values and only 6% of the 1455 patients reported minor side effects.

Nitazoxanide: pharmacokinetics and metabolism in man.

OBJECTIVES: Nitazoxanide (N), a new broad-spectrum parasiticidal agent, is rapidly deacetylated to tizoxanide (T). The objective of the study was to determine if metabolites other than T are present in the plasma and excreted after single dose oral administration of radiocarbon-labelled N in healthy subjects. METHODS: Six healthy volunteers received a single 500 mg oral dose of N labelled with 2.92 MBq radiocarbon. The radioactivity in blood, plasma, urine, feces and expired air was monitored at scheduled intervals for up to 10 days. Selected samples were assayed by HPLC for T and submitted to metabolite identification by mass spectrometry. In vitro experiments were also conducted (incubation with animal and human microsomes, deacetylation kinetics). Plasma and bile samples obtained in a patient treated with N for sporozoal infection were also assayed for T. RESULTS: Elimination of radiocarbon occurred both in the urine (31.5% of the dose on average) and in the feces (66.2% on average). T and T-glucuronide contributed 15% of total urine radioactivity. N was found to deacetylate extremely rapidly to T in plasma (half-life of about 6 minutes at 37 degrees C) as well as in presence of liver microsomes. T was the only species obtained by incubation with human microsomes while rat microsomes yielded hydroxylated T in addition. The main species identified in human plasma, urine and bile was T-glucuronide, the identification of which was confirmed by comparison with an authentic sample. No species other than T was detected in feces, indicating intensive intestinal deconjugation, while radioactivity and absorbance detectors showed largely unresolved clusters.

Pharmacokinetics of nitazoxanide after single oral dose administration in 6 healthy volunteers.

The objective of this study was to gather first information on the time course of plasma concentrations and urinary excretion of the antiprotozoal nitazoxanide (N) and to identify potential metabolites in healthy subjects after a single oral dose of 500 mg of nitazoxanide. The clinical trial was conducted as an open single oral dose study in 6 healthy male subjects. After a standardized continental breakfast the subjects took a single oral dose of 500 mg nitazoxanide (coated tablet) with 100 ml tap water. The plasma concentration and the urinary excretion of nitazoxanide (N), desacetyl-nitazoxanide (DN), aminonitrothiazole (ANT), acetylsalicylate (AS), salicylate (S), gentisate (G) and salicylurate (SU) were monitored up to 72 h after administration. The only measurable species in plasma was DN, which reached a Cmax of 1.9 mg/l (range 1.1-2.5) 2-6 h after dosing, and an AUC of 3.9-11.3 mg x h/l. Its terminal half-life ranged from 1.03 to 1.6 h. DN was extensively bound to plasma proteins (> 97.5%). Only 8% of the dose was recovered in the urine, in the form of DN (5%), SU (3%), and traces of ANT (0.1%). In vitro N was very rapidly hydrolyzed to DN by plasma esterases.

[Efficacy of halofantrine in Plasmodium falciparum or Plasmodium vivax malaria in a resistance area (French Guiana)]. / Efficacité de l'halofantrine dans le paludisme à Plasmodium falciparum ou à Plasmodium vivax. Dans une zone de résistance (Guyane française).

Halofantrine (WR 171.669) is a phenanthrene methanol derivative effective against the multidrug resistant strains of Plasmodium falciparum. One hundred and one patients, 48 men and 53 women, 53 adults and 48 children (less than or equal to 12 years old) aged from 1.5 to 57 years were treated. Fifty-one patients received a single 16 mg/kg dose and 50 patients received 24 mg/kg/day in 3 doses at 6-hour intervals. Parasite counts with examination of both thin and thick smears were performed twice daily for 5 to 6 days following treatment, or until smears were negative for parasites for 24 hours, and then weekly for 4 weeks. Thirteen patients reported clinical side effects. Six treated patients had no parasites. One patient had mixed parasitemia. Eighty three patients had P. falciparum malaria, with mean parasitemias between 26,850 +/- 36,679 and 35,412 +/- 50,527 per cubic millimeter. Halofantrine was very effective in the two doses tested from 87.5 to 100 p. 100. Eleven patients had in vivo resistant strains; ten in vitro tests were successful and nine were resistant to chloroquine. Thirteen patients with P. vivax and a mean parasitemia of 13,858 +/- 10,835 per cubic millimeter were cured but 3 had a relapse 3 to 4 weeks after treatment. At the 2 dosage levels tested halofantrine proved highly effective in the treatment of malaria caused by resistant and sensitive strains to P. falciparum.