Nitazoxanide - Educational material

Nitazoxanide, known chemically as 2-(acetyloxy)-N-(5-nitro-2-thiazolyl)benzamide, was developed in the early 1970s as a new antiparasitic agent. It is synthesized by changing one benzene ring in niclosamide to nitrothiazole [1]. It was initially tested for its potential against a variety of protozoal and helminth infections in a number of animal species, and soon showed efficacy against intestinal cestodes (worms) in human studies. This early success led to FDA approval by Romark Laboratories, becoming the first and only drug approved for Cryptosporidium infections in the US [1].

Moreover, nitazoxanide has also shown efficacy against various bacterial infections, including Clostridium difficile and Mycobacterium tuberculosis, which is attributed to interfering with essential enzymes of anaerobic energy metabolism [1]. Its safety and efficacy in the treatment of intestinal parasitic infections are well documented, with more than 75 million people treated worldwide [1], underscoring its valuable role in modern medicine against intestinal worms, including Ascaris lumbricoides (human roundworm) and Gardia lamblia (Giardia intestinalis).

Nitazoxanide against Ascaris lumbricoides and others

Intestinal worms such as hookworm, human roundworm (Ascaris lumbricoides), pinworm, trichomoniasis, pinworm and various types of flatworms and tapeworms can significantly disrupt our digestive health, leading to discomfort and other serious health problems. Nitazoxanide, known to treat certain protozoal infections, has also shown promising results against these parasites. Studies have shown that nitazoxanide successfully cured 91% cases of Ascaris lumbricoides infection [2]. In a comparative study involving 70 children with human roundworm (Ascaris) infections, those treated with nitazoxanide had an 89% cure rate and almost complete elimination of all eggs from their system. This drug was also effective against various tapeworm species, with success rates between 75% and 85% [2]. The efficacy of nitazoxanide is likely due to its ability to block a specific enzymatic reaction important for the survival of these parasites without oxygen. This makes nitazoxanide a valuable alternative in the fight against these common but troublesome infections.

In addition, in Colima, Mexico, a study involving 280 participants, including children, adolescents and adults, dealing with Ascaris lumbricoides infection was found in 38% communities [3]. Through detailed fecal analyses and socioeconomic and hygienic assessments, 81% individuals with parasites had A. lumbricoides. Remarkably, nitazoxanide treatment cured 88% cases of ascariasis and significantly reduced the incidence by 97.5% [3]. These results underscore the potential of nitazoxanide as an effective solution for intestinal parasite infections, especially in areas with poor hygienic conditions.

Nitazoxanide, a Giardia lamblia

Nitazoxanide has shown potential antiparasitic activity against Giardia lamblia and a broad spectrum of other parasitic infections. The study, which involved 272 children between the ages of 2 and 14, examined the efficacy of nitazoxanide as a single treatment for mixtures of protozoal and helminthic intestinal infections [4]. Using household questionnaires, the researchers collected socioeconomic and hygiene-related data. Fecal examinations confirmed infections with protozoa, such as Giardia lamblia and Entamoeba histolytica/E. dispar, and helminths, including Hymenolepis nana and Ascaris lumbricoides. After treating 121 infected children with nitazoxanide, 84% of protozoal infections and 95% of helminth infections were successfully eradicated [4], indicating nitazoxanide's high efficacy and excellent safety profile, with no significant side effects. These results indicate the potential of nitazoxanide as an effective, broad-spectrum antiparasitic agent for children with mixed parasitic infections. In addition, a study conducted in Cajamarca, Peru, consisted of administering nitazoxanide to children according to their age - 100 mg for children aged 1-3 years and 200 mg for children aged 4-11 years, twice daily for three days [5]. The treatment successfully cured 89% cases of ascariasis and trichuriasis and 82% cases of hymenolepiasis, highlighting the broad efficacy of nitazoxanide [5]. Moreover, this was achieved with minimal side effects, confirming the drug's safety and efficacy as a treatment option for children with parasitic infections.

In the case of Entamoeba histolytica/E. dispar, Giardia duodenalis and others, a study conducted in San Pedro Tolimán, Querétaro, Mexico demonstrated the effectiveness of nitazoxanide [6]. The results revealed that nitazoxanide successfully eliminated infections caused by parasites such as Entamoeba histolytica/E. dispar, Giardia duodenalis and others, with efficiencies ranging from 71 to 100% [6]. Importantly, the treatment (administered at doses of 500 mg for adults and 200 mg for children under 12, twice a day for three days) did not affect hematology or clinical chemistry values, indicating its safety. In addition, the drug was well taken by most, with only a small proportion experiencing mild abdominal discomfort. Moreover, in a clinical trial involving 100 children aged about 3.3 years, nitazoxanide significantly reduced the duration of infectious diarrhea [7]. In this double-blind study, children experiencing diarrhea for 3 to 29 days received nitazoxanide or placebo for three days. Those on nitazoxanide recovered in about 23 hours, much faster than the placebo group, which recovered in 103.5 hours [7]. The drug was particularly effective against Giardia lamblia and undiagnosed cases, with no significant side effects. These results underscore the potential of nitazoxanide as a safe treatment option for childhood diarrhea, including when the cause of the infection is unclear.

Interestingly, in another study at Point G. National Hospital in Bamako, Mali, 18 hospitalized patients suffering from diarrhea due to parasitic infections, including 17 with HIV and 12 with stage 4 AIDS, were treated with nitazoxanide [8]. Administration of 500 mg of nitazoxanide twice daily for seven days resulted in a significant reduction or complete eradication of Cryptosporidium parvum oocysts in seven of 12 patients with stage 4 AIDS [8]. In addition, four patients experienced complete resolution of their diarrhea. This study also reported the efficacy of nitazoxanide against other parasites such as Isospora belli, Entamoeba histolytica and Giardia lamblia. These results underscore the potential of nitazoxanide as a well-tolerated and effective treatment for intestinal parasitic infections, especially in patients with advanced HIV/AIDS.

Moreover, in a comparative study of the treatment of giardiasis, caused by the parasite Giardia intestinalis, 110 children were treated with nitazoxanide for three days or metronidazole for five days [9]. Remarkably, by the seventh day, 85% of those treated with nitazoxanide experienced complete resolution of diarrhea, matching the 80% success rate observed in the metronidazole group, with faster resolution in most cases [9]. These results highlight nitazoxanide as a powerful, fast-acting and well-tolerated treatment option for giardiasis in children, offering a shorter course of treatment compared to the traditional metronidazole regimen. In addition, another study compared nitazoxanide and tinidazole in the treatment of giardiasis in 166 children infected with Giardia lamblia [10]. Participants were divided into two groups; one received nitazoxanide (7.5 mg/kg twice a day for three days) and the other a single dose of tinidazole (50 mg/kg). Of the 137 who completed the study, the tinidazole group had a higher cure rate of 90.5%, compared to 78.4% for the nitazoxanide group [10]. Despite the lower efficacy, nitazoxanide was well tolerated, with only minor temporary side effects. This study points to nitazoxanide as a promising alternative to tinidazole in the treatment of giardiasis in children, particularly valuable in the face of concerns about drug resistance.

Nitazoxanide, and viral infections

Nitazoxanide, traditionally known to combat parasitic infections, has recently been studied for its potential against viral diseases, including COVID-19 (caused by SARS-CoV-2 virus). Various studies have evaluated the efficacy of nitazoxanide in reducing the viral load and preventing the progression of viral diseases [18, 19, 20]. In a clinical trial to evaluate the efficacy of nitazoxanide against COVID-19, adult patients presenting early symptoms were treated with nitazoxanide or placebo [18]. Despite similar rates of symptom resolution between the two groups, patients treated with nitazoxanide showed a significant reduction in viral load. Specifically, 29.9% of those on nitazoxanide showed no detectable virus compared to 18.2% in the placebo group [18], indicating its potential to reduce the spread of virus early in COVID-19 cases. This finding highlights nitazoxanide as a promising option for early treatment to suppress SARS-CoV-2 transmission. In addition, a multicenter study highlighted nitazoxanide's ability to enhance viral elimination when added to standard care for patients with non-severe COVID-19 [19]. The nitazoxanide group showed a higher percentage of virus-free patients compared to standard care alone.

For viral gastroenteritis, the study tested 500 mg of nitazoxanide in 50 outpatients aged 12 years and older with diarrhea caused by norovirus, rotavirus or adenovirus [20]. The results showed that those who were treated with nitazoxanide experienced resolution of symptoms significantly faster, at a median of 1.5 days, compared to 2.5 days for those who received placebo. Moreover, this improvement was particularly notable in patients with rotavirus and norovirus infections [20]. This study, which reported no significant adverse events, suggests that nitazoxanide could be a safe and effective treatment option for reducing the duration of viral gastroenteritis in adults and adolescents. In addition, another study reported that Nitazoxanide has significant activity against measles and canine distemper viruses [21]. Despite vaccines, measles and canine distemper virus (CDV) infections have resurged, causing more than 100,000 deaths annually. Notably, Nitazoxanide interferes with the virus' fusion protein, responsible for the virus' ability to spread [21]. This finding suggests that Nitazoxanide could be considered as a promising candidate for developing treatments against measles and canine distemper, offering new hope for human and animal health.

Nitazoxanide, and liver health

A study evaluating nitazoxanide as an alternative to metronidazole for uncomplicated liver abscess caused by amoebae found it to be equally effective. Administered at a dose of 500 mg twice daily for 10 days, nitazoxanide led to a 73.3% total abscess resolution rate after 6 months, offering better tolerability and fewer side effects [22]. Another study compared Nitazoxanide to Rifaximin in the treatment of hepatic encephalopathy in 60 patients. The results showed that Nitazoxanide significantly improved mental status, prolonged remission and improved quality of life with few side effects, suggesting a safer, more effective alternative [23]. In addition, a study on 120 cirrhotic patients with overt hepatic encephalopathy (HE) showed beneficial effects of nitazoxanide in combination with lactulose. The combined administration significantly improved mental status compared to lactulose alone, indicating the potential of nitazoxanide to improve HE treatment [24]. Moreover, for the treatment of fasciolosis, a study in Atlixco, Puebla State, Mexico, involving school children, revealed a 5.78% average prevalence of Fasciola hepatica infection, mainly due to the consumption of raw vegetables. In terms of treatment, nitazoxanide administration showed 94% to 100% efficacy against fasciolosis, marking the first identification of an endemic area of human fasciolosis in North America and suggesting nitazoxanide as an effective alternative to traditional treatments [25].

In addition, a study in the Nile Delta in Egypt showed that nitazoxanide is highly effective in the treatment of intestinal and hepatic amebiasis, with 94% resolution of intestinal amebiasis symptoms and positive responses in all patients with hepatic amebiasis. This points to nitazoxanide as a powerful treatment for amebiasis [26]. In addition, another study conducted in Egypt showed that 30.4% patients with chronic hepatitis C genotype 4 treated with nitazoxanide achieved undetectable levels of HCV RNA during therapy. Importantly, this response persisted 24 weeks after therapy in 17.4% treated patients, indicating sustained benefit. This suggests nitazoxanide as a potential monotherapy for chronic hepatitis C, particularly effective in patients with lower initial HCV RNA levels [27]. Finally, in northern Peru, a study compared the efficacy of nitazoxanide to placebo in the treatment of fasciolosis, a serious health problem caused by Fasciola hepatica infections. Of the 100 participants-50 adults and 50 children-a post-treatment evaluation showed a clear advantage of nitazoxanide over placebo, with 60% adults and 40% children treated with nitazoxanide eliminating the infection, compared to much lower success rates in the placebo groups. The treatment was not only effective, but also well tolerated, with only mild and temporary side effects [8]. These findings underscore the potential role of nitazoxanide as a safe and effective treatment for a variety of liver conditions, including liver abscess, infection and fasciolosis [28].

Nitazoxanide, and the health of the digestive system

The study tested the efficacy of nitazoxanide against Helicobacter pylori, comparing it with standard antibiotics in 100 patients. The nitazoxanide group recorded a 92% recovery rate, significantly reducing the risk of developing resistance to treatment by 54%. This suggests nitazoxanide as a viable alternative to treating H. pylori, especially in resistant cases [29]. Another study in Egypt involving 224 patients with H. pylori was treated with either a nitazoxanide-based regimen or traditional therapy. The nitazoxanide group had an eradication rate of almost 95%, significantly higher than 61% with standard treatment, indicating its effectiveness as a first-line treatment for H. pylori [30]. In addition, another study at Tanta University Hospital tested a nitazoxanide-based regimen on 100 patients who had not responded to standard therapy for H. pylori. The new treatment achieved an 83% eradication rate, offering a promising secondary treatment option for resistant H. pylori infections [31].

In the case of Cryptosporidiosis, a study on children with Cryptosporidium showed that nitazoxanide treatment cleared the parasite in 80% patients with a competent immune system as early as the first week. Similarly, after four weeks, clearance rates improved to 93.3% in the NTZ group compared to 43.3% in the placebo group. Diarrhea resolved in most cases within three to five days, underscoring the efficacy of nitazoxanide against cryptosporidiosis [32]. For ulcerative colitis (UC), a study in Uzbekistan on 100 patients with UC evaluated the effect of treatment with intestinal parasites with nitazoxanide. The combination of nitazoxanide and mesalazine significantly improved mucosal healing compared to each treatment used alone, suggesting a potential benefit for the management of UC [33].

Nitazoxanide, and diarrhea

A study involving young children with rotavirus diarrhea tested the effectiveness of nitazoxanide and probiotics. Given to 75 children, nitazoxanide significantly reduced the length of hospital stay and duration of diarrhea compared to standard treatments, with slight advantages over probiotics. This shows nitazoxanide as a key option for the treatment of acute rotavirus diarrhea in children [34]. Against Cryptosporidium, a study in Egypt tested the effect of nitazoxanide on adults with Cryptosporidium-induced diarrhea. In a double-blind study involving 90 outpatients, those treated with nitazoxanide saw a 96% clinical response and 93% clearance of Cryptosporidium, significantly outperforming placebo. This demonstrates the efficacy of nitazoxanide in treating Cryptosporidium infection in non-immunodeficient patients aged 12 years and older [35].

In addition, nitazoxanide was evaluated for the treatment of diarrhea and intestinal inflammation associated with Blastocystis hominis. Among participants, 86% treated with nitazoxanide showed resolution of symptoms and clearance of B. hominis, significantly outperforming the placebo group. The study confirms B. hominis as a pathogen and nitazoxanide as a powerful treatment [36]. Another study, involving patients with AIDS and cryptosporidiosis, observed symptom improvement in 59% of the 357 patients treated with nitazoxanide. The treatment was well tolerated, even at high doses, highlighting the potential of nitazoxanide as a safe and effective option for cryptosporidiosis in AIDS patients [37]. In addition, a study at Cairo University Children's Hospital of severe rotavirus diarrhea in children under the age of 7 showed that nitazoxanide significantly shortened the duration of illness. Children receiving a dose of nitazoxanide 7.5 mg/kg reported an average time to resolution of illness in 31 hours compared to 75 hours for the placebo group, indicating the effectiveness of nitazoxanide for rotavirus infections treated in the hospital [38].

Another study, involving 66 HIV patients with Cryptosporidium parvum diarrhea, showed significant improvement after treatment with nitazoxanide. Patients received doses of nitazoxanide 500 mg or 1000 mg or placebo for two weeks. Both doses of nitazoxanide significantly outperformed placebo in eradicating the parasite, with about two-thirds of patients in each nitazoxanide group achieving parasite cure and resolution of diarrhea. The treatment was also well received, indicating the potential of nitazoxanide as a safe and effective option for this vulnerable population [39]. Finally, a study in the Nile Delta in Egypt tested nitazoxanide in 100 adults and children with diarrhea caused by the

Cryptosporidium parvum. Doses varied by age, leading to resolution in 80% treated patients after seven days, compared to 41% with placebo. This demonstrates the potential of nitazoxanide to effectively and rapidly treat Cryptosporidium-induced diarrhea [40].

Nitazoxanide, and E. coli bacteria

Nitazoxanide has shown potential efficacy against colistin-resistant strains of Escherichia coli (E. coli), offering a new strategy for eliminating these resistant microbes. In combination with colistin, NTZ may enhance the antibacterial effect of colistin, providing an alternative option for dealing with such bacterial resistance challenges [41]. In addition, Nitazoxanide has shown potential activity against Escherichia coli (E. coli) strains, particularly against aggregative E. coli (EAEC). EAEC is known to cause chronic diarrhea and malnutrition among children and HIV-infected individuals. In vitro studies have revealed that although E. coli strains show resistance to Nitazoxanide in rich nutrient environments, its efficacy improves in minimal media, indicating its potential under certain conditions [42]. Nitazoxanide interfered with biofilm formation - a key virulence factor for EAEC - by inhibiting the assembly of fimbrial adhesins, essential for bacterial adhesion to the intestinal mucosa. Moreover, in the context of reducing childhood infections and related growth disorders, a study using nitazoxanide in combination with azithromycin showed transient reductions in infection by aggregating E. coli. Although the antimicrobial intervention did not have a significant effect on long-term infection rates or growth outcomes, this indicates a significant role for Nitazoxanide in the management of intestinal infections, including those caused by EAEC [43]. These findings underscore the role of nitazoxanide against E. coli strains, particularly its ability to enhance the efficacy of colistin against resistant strains and interfere with EAEC adherence and biofilm formation.

Nitazoxanide, and staphylococcus aureus

Nitazoxanide shows powerful activity against resistant strains of Staphylococcus aureus, including those resistant to conventional treatment. Based on scientific studies, Nitazoxanide is effective against S. aureus strains that are resistant to other drugs, making it a potential option for difficult infections [44]. Importantly, Nitazoxanide enhances the efficacy of linezolid, a key antibiotic, creating a powerful combination against both susceptible and resistant S. aureus infections. This synergy offers a promising approach to treating resistant infections [44]. In addition, Nitazoxanide prevents S. aureus from forming biofilms, which is a major challenge in treating infections because biofilms protect bacteria from antibiotics. Although Nitazoxanide does not break down existing biofilms, it inhibits the accumulation of new biofilms by disrupting the bacterial defense mechanism [45]. Interestingly, a major problem with antibiotics today is that bacteria can become resistant to them. However, S. aureus does not appear to develop resistance to Nitazoxanide, which means it can remain effective for a longer period of time [44]. Nitazoxanide's antibiofilm effect is thought to interfere with the zinc-dependent processes responsible for biofilm formation, targeting biofilm assembly at the molecular level without direct chelation of zinc. This mechanism indicates Nitazoxanide's potential to combat biofilm-associated infections through a novel pathway, highlighting its value in addressing complex bacterial infections [45].

Nitazoxanide substance dosage

According to FDA recommendations, the dosage of nitazoxanide is 500 mg orally with food every 12 hours for a period of 3 days for patients aged 12 years and older. For children 11 years of age or younger, nitazoxanide tablets should not be administered, as the dose contained in a single tablet exceeds the recommended amount for this age group.

Based on the above discussion, for the treatment of gastrointestinal infections caused by protozoa, dosages are optimized specifically for the patient's age group:

- For adults with Giardia lamblia infections: Nitazoxanide 500 mg orally every 12 hours with food for three days of treatment is recommended.

- For the treatment of Giardia lamblia infection in children: nitazoxanide is administered at a dose of 7.5 mg/kg twice a day for three days.

- For the treatment of infections caused by Ascaris lumbricoides: the typical dose of nitazoxanide for adults and children 12 years of age and older is 500 mg orally every 12 hours with food. This dose is usually recommended for a period of three days.

- For children under 12: The recommended dose for the treatment of Cryptosporidium-induced diarrhea among children was segmented based on age categories. Children ages 1-3 received 100 mg of nitazoxanide, those ages 4-11 received 200 mg, and adolescents ages 12 and older received 500 mg. These doses were administered twice daily for a three-day course.

- For adults and adolescents aged 12 years and older: In the context of treating intestinal and hepatic amebiasis, as well as Cryptosporidium-induced diarrhea, the recommended dose is 500 mg of nitazoxanide administered twice daily. The duration of treatment varied depending on the condition; a ten-day course was specified for amebiasis, while a three-day course was sufficient for Cryptosporidium-induced diarrhea.

- For the treatment of rotavirus diarrhea in children: In a study focused on children with severe rotavirus diarrhea, a specific dose of 7.5 mg/kg of nitazoxanide oral suspension was administered twice daily for three days. It targeted hospitalized children younger than 7 years old.

- For AIDS-related cryptosporidiosis: Treatment of patients with AIDS-related cryptosporidiosis included doses of nitazoxanide ranging from 500 to 1,500 mg twice a day, with the length of treatment and dosage adjusted according to the patient's response and tolerance.

**Nitazoxanide Adverse Reactions and Considerations**.

The most commonly reported adverse reactions were abdominal pain, headache, chromaturia (changes in urine color) and nausea. Above-market surveillance has identified additional side effects such as diarrhea, gastroesophageal reflux disease, dizziness, shortness of breath, rash and urticaria, although their exact frequency remains uncertain due to the spontaneous nature of the reports [46].

Drug interactions, especially with other drugs that bind strongly to plasma proteins with narrow therapeutic indices, such as warfarin, require monitoring due to potential competition for binding sites. The extensive binding of nitazoxanide to plasma proteins (>99.9%) warrants caution [46].

Pregnancy and lactation considerations underscore the lack of data on the presence of nitazoxanide in human milk and its effects on breastfed infants or milk production. Animal studies in pregnant rats and rabbits have shown no teratogenicity or fetotoxicity at doses much higher than recommended for humans, suggesting no drug-related risks in human pregnancies.

The use of nitazoxanide in specific populations, including pediatric and geriatric patients, underscores safety and efficacy in those aged 12 to 17 years, with caution recommended for those aged 11 years and younger due to dosing considerations [46].

Nitazoxanide, tolerance and overdose

Tolerable Dose Range: Nitazoxanide was well tolerated up to a maximum single dose of 4 grams (g) in studies, with or without food [47]. An acceptable daily dose in repeated administration studies showed that 0.5 grams taken twice daily (b.i.d.) was well tolerated with only mild side effects at a similar level to placebo [48].

Overdose Concerns: Higher doses, such as 1 g b.i.d., have been associated with increased gastrointestinal side effects, including diarrhea and abdominal discomfort, indicating a threshold above which drug tolerance declines [48]. Although no significant changes in electrocardiograms (ECGs), vital signs or laboratory results were observed even at higher doses, the increased frequency of side effects suggests caution.

Safety Profile: Despite the increased incidence of side effects at higher doses, the safety profile of nitazoxanide remains favorable, with no significant adverse events or clinically meaningful changes in ECG, vital signs or laboratory results reported up to the maximum tested dose of 4 g [47].

Nitazoxanide - what else should one know?

Summary of nitazoxanide's effect as an anti-parasitic agent

Nitazoxanide, developed in the early 1970s as 2-(acetyloxy)-N-(5-nitro-2-thiazolyl)benzamide, is recognized for its broad-spectrum activity against a variety of parasitic and bacterial pathogens. Its initial success against intestinal cestodes led to FDA approval of the drug for the treatment of Cryptosporidium infections; however, it has also demonstrated efficacy against protozoal and microbial infections such as Clostridium difficile and Mycobacterium tuberculosis. Nitazoxanide's role against intestinal worms such as Ascaris lumbricoides and Giardia lamblia underscores its importance in addressing parasitic infections that significantly affect global health. In addition, nitazoxanide's potential against viral diseases, including its ability to reduce viral load and prevent the progression of viral diseases, is noteworthy. Interestingly, the drug's antiviral properties, combined with its anti-inflammatory benefits, are being investigated for a variety of applications, including the treatment of Crohn's disease and viral hepatitis, demonstrating its broad applicability in the management of infectious diseases. Nitazoxanide's ability to fight various infections, its safety and the potential for new medical applications underscore its importance in helping people maintain their health in the future against parasites and microbes, including bacteria and viruses.

Disclaimer

This article was written for educational purposes and is intended to raise awareness of the substance being discussed. It is important to note that the substance discussed is a substance, not a specific product. The information contained in the text is based on available scientific research and is not intended to serve as medical advice or promote self-medication. The reader should consult any health and treatment decisions with a qualified health professional.

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