Giardia lamblia enteritis is small-intestine gastroenteritis caused by the pathogenic protozoan Giardia lamblia, otherwise known as Giardia duodenalis or Giardia intestinalis (1), Giardia duodenalis assemblages A and B are the main human-infectious assemblages (2). There was a similar distribution of Giardia assemblages between children with and without diarrhea. Increasing age was a risk factor for Giardia infection [3].
It has a wide range of clinical manifestations, from asymptomatic carriage to acute or chronic diarrhoea with dehydration, abdominal pain, nausea, vomiting, excessive flatulence, and weight loss [4, 5], Furthermore, chronic infection can result in stunting and reduced psychomotor development [6, 7, 3].
Giardia infections estimated 280 million infections annually (8; 9; 10), The prevalence of giardiasis ranges from 3 to 7% in developed countries and 20 to 30% in developing countries (11; 12, 13). Despite being considered a predominant disease in low-income and developing countries, with low sanitation and socioeconomic conditions, current migratory flows have caused an increase in giardiasis cases in high-income countries (14, 15).
Giardia cysts are highly infectious; infection may occur after ingestion of just one to ten cysts from faecally contaminated food or water (16; 8).
Currently, there is a wide variety of chemotherapeutic treatments to combat this parasitosis, most of which have potentially serious side effects, such as genotoxic, carcinogenic, and teratogenic. The necessity to create novel treatments and discover new therapeutic targets to fight against this illness is evident (15, 10)
Cancer accounting for about 13% of all deaths in 2008, globally, with a predicted eleven million deaths in 2030. Viral, bacterial, and protozoan infections are the most substantial causes of death due to cancer which are preventable (17)
Results by (13) demonstrated that, the immunodeficiency status of cancer patients is a possible risk factor for acquiring Giardia infection, which requires strict preventive measures.
Chen et al., [18], investigate the Prevalence of Giardia lamblia infections among colorectal cancer patients, their study detected 8.1% prevalence of G. lamblia infections among the study subjects by PCR assay. Hurník et al [19] stated that, few cases of coincidental giardiasis and pancreatic tumors have been described. Among these cases, three described giardiasis cases coincided with confirmed pancreatic cancer. (13) claimed that, its results is the first systematic review and meta-analysis showing a general overview of G. duodenalis infection prevalence and associated risk factors among cancer patients globally and the estimated weighted prevalence of G. duodenalis infection in cancer patients was computed to be 6.9% globally, based on data from 32 studies.
The disease in people with a healthy immune status is self-limiting, without a clinical course, whereas immunocompromised patients may experience harsh clinical outcomes (20, 21). Application of chemotherapeutics in cancer patients may provide an immunosuppressive milieu, favourable for parasitic infections (13)
However, several promising drug candidates have been recently identified that can overcome antibiotic resistance in Giardia, including derivatives of 5-nitroimidazoles and benzimidazoles, as well as hybrid compounds created from combinations of different antigiardial drugs, a growing number of refractory cases were being reported (22; 23). Such infections are also overlooked in industrialized nations due to their low prevalence and the fact that they do not have pathognomonic signs (24). Thus they are a silent threat, particularly in immunocompromised individuals undergoing chemotherapy, leading to hyperinfection by parasitic as well as other infectious agents (25).
Drug resistance to common antigiardial agents and incidence of treatment failures have increased in recent years. Therefore, the search for new molecular targets for drugs against Giardia infection is essential (26, 12). Persistence of infection is linked to several causes including drug resistance, suboptimal drug concentrations, reinfection, immunocompromised state and immunoglobulin A deficiency (27; 8).
There are no randomized controlled trials determining the optimal treatment in nitroimidazole-refractory giardiasis. Refractory giardiasis has traditionally been treated with prolonged courses and/or higher doses of nitroimidazoles (28). However, these compounds present side effects associated with residual toxicity in the host. Dose-dependent side effects include leukopenia, headache, vertigo, nausea, insomnia, irritability, metallic taste, and CNS toxicity (29).
Combination therapy, based on the mechanisms of action of the antigiardial drugs, is another approach that may also be useful in patients with giardiasis refractory to first line drugs. Clinicians increasingly combine drugs with different mechanisms of action to treat refractory disease. Drug combinations may exert a synergistic or additive effect and avoid potential cross-resistance (30; 28).
MTZ is a synthetic antibiotic derivatized from azomycin, it has been effective against Giardia lamblia and a variety of infections due to its high efficacy compared with others drugs; however, their side effects must be considered such as nausea, abdominal pain, and diarrhea (31; 32). Nevertheless, serious neurotoxicity, optic neuropathy, peripheral neuropathy, and encephalopathy have been reported in rare cases, the neurotoxicity is not dose-dependent and is fully reversible with discontinuation of the drug (33).
Few studies have been done on human genotoxicity of MTZ, their genotoxic effects observed in animal models are controversial in humans. Genotoxicity of MTZ induces single and double DNA strand breaks, it can induce effects in human cells in vitro and in vivo; however, it has been established with a carcinogenic role in mice and rats. According to the IARC (International Agency for Research on Cancer), there is evidence to consider MTZ as an animal carcinogen, but insufficient evidence in humans (34; 32).
Paclitaxel (Pacl) (trade name Taxol) is a tricyclic diterpenoid compound naturally produced in the bark and needles of Taxus brevifolia. Its molecular formula is C47H51NO14 [35]. Pacl is a well-known anticancer agent with a unique mechanism of action. It is considered to be one of the most successful natural anticancer drugs available [36]. It is also used in coronary heart disease, skin disorders, renal and hepatic fibrosis, inflammation, and axon regeneration, and clinical trials are being conducted for degenerative brain diseases [37].
Pacl can affect the outcome of immunotherapy by various mechanisms of action on immune cells, and it also plays a role as an immunomodulator [36].
Many studies have shown that Pacl directly kills tumor cells and regulates various immune cells, such as effector T cells, dendritic cells, natural killer cells, regulatory T cells, and macrophages [38].
Recently, Pacl inhibits the growth of Toxoplasma gondii [39], trypanosomatid protozoa, such as Leishmania and Trypanosoma [40, 41], moreover Plasmodium spp [42].
The present work aimed to study the efficacy of Anti-tubulin drug (Pacl) as a single treatment and its combination with the commercially used drug metronidazole (MTZ) in the treatment of Giardiasis in the experimentally infected mice.