Leishmaniasis is a neglected tropical disease that introduces serious health and commercial burden on weak people and growing and undeveloped regions of the world (1). Leishmaniasis is native to 98 regions, where over 350 million humans are at risk of this illness(2) 50-70% of cases are kids(3). There are two types of experimental leishmaniasis in individuals, cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL). The former causes skin sores that heal automatically, although the sores may remain and cause scarring. The second (kala-azar) affects the vital organs of the body, such as the liver, bone marrow, and spleen, and causes death if not treated. Cutaneous leishmaniasis is engaged with Th1 reply and kala-azar with Th2 reaction(4) And it has a direct association with deprivation and has forced financial damage to needy families, which is related to the absence of effective and affordable treatment at the lower level of health maintenance(5). Households in which leishmaniasis affects one person are encumbered with deficits or sell their property to pay for treatment and fall into poverty(6). If we bring into account the point that reporting is hard in many areas, like refugee camps or in countries with very inadequate health care substructure, the real numbers are higher. For the sample, in Syria, where millions of individuals exist internally and externally displaced, multiple cases of CL occur among individuals living in refugee camps. Recent outbreaks have been described in several polities, including Burkina Faso, Iran, Spain, Argentina, and Brazil(7) In human places, sickness transmission, patient pursuit, and therapy of VL and Post Kala-azar dermal leishmaniasis (PKDL) are approaches to disease control(8). Among the epidemic elements of leishmaniasis infection, we can note starvation, malnutrition, abundance migration, civil disorders, adverse financial conditions, and host immune defect (HIV) (9) This illness too has signs such as bleeding nose, gums, and uterus(10) Visceral leishmaniasis is a deadly illness, and patients need crucial treatment(11). Transmission of visceral leishmaniasis during or after the rainy season increases clinical cases during the dry season (November to January). Another leishmaniasis is mucocutaneous leishmaniasis in the New World and is mainly caused by L. braziliensis and L. panamensis. They cause damage to the mucous tissue of the mouth and upper respiratory tract by releasing lymph and forming blood. The disease is characterized by destructive lesions of the nose, lips, and palate, which are caused by a strong immunopathological response. Lesions usually start from the nose or lips and are accompanied by discharge as nasal congestion worsens. 90% of all reports occur in Bolivia, Brazil, and Peru. The disease appears several months to years after the creation of a skin lesion, and the host's genetic factors are important in the disease's development. Mucosal leishmaniasis is more common in immunocompromised individuals and never resolves spontaneously and is potentially fatal and should be diagnosed and treated promptly(12). In L. donovani, several treated visceral leishmaniasis patients develop post-kala-azar leishmaniasis (PKDL), a condition not seen in visceral leishmaniasis caused by Leishmania infantum(13). PKDL usually develops after treatment of visceral leishmaniasis and clinically appears as maculopapular, granular, or nodule-like lesions and occurs in 1-40% of VL cases, depending on geographic region(14). Patients with HIV -VL concurrent condition are at grander risk for loss of therapy, recurrence and mortality rate. Secondary anti -leishmania anti -retroviral prevention and treatment should start with these people as shortly as probable(15). PKDL appearance is usually between 6 months and 1 year behind therapy but may occur before or simultaneously with the illness (Sudan) (16) Elements involving concurrent transmission in exposed peoples, such as camps and refugees, have high malnutrition and absence of access to diagnostic, therapeutic, and obstacles to vectors(17). Failure to cure the disease will lead to a 100 percent death rate in two years(18) But after a year without therapy, the CL improves itself and the Oscar is replaced. Sometimes the course of the infection becomes elongated and has been immune for many years(19) A reason for the lack of control and therapy for leishmaniasis around the globe is the different answers to drugs in different regions. For example, therapeutic efficacy in East Africa and South America needs increased doses of AmBisomes and Paromomycin(20) Expanding awareness of the effectiveness of fast diagnostic tests and therapies for visceral leishmaniasis is critical(21) Therefore, the first solution for rapid treatment is the immediate diagnosis of the parasite with two classic methods (direct observation of the parasite by preparing thin and thick smears of tissue and blood) and advanced molecular methods(22).
Another method of parasite detection, when the number of parasites is low and cannot be detected, is promastigote culture of the parasite (common methods serology such as DAT, ELISA, IFA) (23) A new method of detecting the leishmaniasis parasite is the use of biosensors to identify antibodies produced against the parasite in the host's body or specific sequences of nucleic acids of the Leishmania species. A biosensor is a device that converts a biological element into a signal with a biological detector and consists of a biological receiver and a biological molecule such as tissue, microorganism, enzyme, antibody, and nucleic acids that recognize the target molecule. Today, the usage of nanoparticles as biological Nano sensors in the therapy and detection of genetical sequences typical of different biological molecules such as nucleic acids and enzymes has attracted a concentration of researchers(24) PCR molecular methods, which are used according to the selected gene and the type of specific primers for the amplification of different genes of the Leishmania parasite(25) In the disease diagnosis and the type of parasite, the places where the disease is common and endemic, the history of illness and travel, the area of residence, and the clinical manifestations of the patient must be reviewed before using laboratory methods(26) Rapid diagnosis and therapy are necessary to pause the cycle of human-origin transmission(27) a reason an asymptomatic carrier enters the drug therapy step is to suppress the person's immune system for organ transplantation(28). For infection control, indoor spraying (IRS), case tracking (rK39), medical treatment with Miltefosine, surveillance, social mobilization, and operational research can be mentioned, and the distribution of mosquito nets has little effect(29) Regarding the efficiency of quick diagnostic tests and therapies for visceral leishmaniasis, there are significant geographic components(30). In East Africa, in contrast to South Asia, there is no elimination program. Kenya's national strategy for leishmaniasis management, detection (DAR or rk39), and therapy (SSG and PM) of cases and actions depends on NGO or WHO support(31) The infection is reoccurring in South Sudan, but the numeral of patients in Ethiopia is stable(7) In South America, transmission is by the animal reservoir and is the primary basis of control (culling of infected dogs and service of vaccines and insecticide-treated collars) with favorable results, and therapy of humans with Glucantime or Liposomal amphotericin B(32) Therapies for cutaneous leishmaniasis (topical and systemic regimens) are few endorsed and have less than optimal efficacy. Offers vary according to Leishmania species, geographic area, and clinical presentation(33) Preparedness and quick reaction can actually reduce the effect of epidemics, an outbreak in South Sudan between 2009-2011 with 25,000 VL patients treated and a CFR of less than 5%, much lower than the CFR of 35% during the early epidemic period. It was the 1990s; it was proven(34) No vaccine or drug prophylaxis is available to protect against cutaneous leishmaniasis, so most control programs concentrate on case finding and therapy and this issue in CL of human source (person-to-person transmission) can be lowered by early identification and therapy of active patients(35).
Treatment methods and recent developments in the therapy of visceral leishmaniasis
National therapy protocols usually do not reflect the latest developments, and few drugs for leishmaniasis are included in the national essential drug list, which takes time. Drugs that have negotiated preferential prices in low-income countries are often not registered by companies, require a special license to import them, and in countries with very low disease prevalence, there is no drug registration that has a direct impact on treatment practices(36) The existing drugs for leishmaniasis are far from optimal in terms of pharmacology and treatment and mainly rely on painful intravenous or intramuscular injections (Miltefosine is oral). Today oral chemicals have been selected to improve the treatment of visceral leishmaniasis and have therapeutic potential for the cutaneous form, and have been obtained from phenotypic drug discovery methods and offer great promise for the development of novel therapies and their mechanisms of action are not well known(37). Few medicines are now available to minister visceral and cutaneous forms of leishmaniasis and individuals with HIV co-infection(38). Recently, monotherapy with antimonial for 20-30 days has been the main basis for visceral leishmaniasis treatment. In the past 15 years, liposomal amphotericin B, puromycin, and Miltefosine have been developed and are available for use and are not long-lasting, toxic, or expensive. The disadvantages of these treatments are that they are long, toxic, or expensive, and many works have been done on neglected diseases to optimize drug regimens(39). A pharmacovigilance study enrolled 3,000 patients from four countries and indicated an efficacy rate of 92%(40)
In 2010, a study was conducted in India on three combinations (Miltefosine and Puromycin, Ambisome and Miltefosine, Ambisome and Puromycin) and a single dose of Ambisome, and all of them indicated efficacy of over 95%, and in another study (retrospective), patients with Multiple doses of Ambisam were treated. Miltefosine is the first-line drug in the elimination program in Nepal, and after seven years of use, the initial treatment indicated an effectiveness rate of 95.8%, and in Bangladesh a cure rate of 97.7%.(41, 42) In connection with the treatment of visceral leishmaniasis (WHO Expert Committee, 2010), the most effective is related to Ambisome IV drug for more than four doses and MF both for 10 days, Ambisome IV single dose, Amphotericin 1 for more than 30 days, with 98-95% effect. And oral Miltefosine (MF) for 28 days, Paromomycin (PM) IM for 21 days, SSG for 30 days, Glucantime for 30 days, Ambisome for 7 days, Ambisome for 7 days, SSG both IM for 17 days with 90-95% effectiveness(43) According to group studies, the optimal drug for the therapy of VL in East Africa was obtained. The outcomes of group studies of visceral leishmaniasis in East Africa displayed that the mixture of oral drugs is more effective, safe, and affordable, and all therapeutic combinations should be assessed for toxicity before clinical investigations. Ambisome changes the distribution of Amphotericin B, and because the amount of Amphotericin B released into the plasma is minimal, it has far fewer side effects than amphotericin deoxycholate therapy. Also, in macrophages infected with L. donovani, it is likely to cause resistance to all drugs used in therapeutic combinations, although induction of resistance by MF-PM is more comfortable than other drug combinations(44). The therapy choices for PKDL and HIV-VL are narrow and unfavorable and need a lengthy and usually repeated period of therapy with antimonials(17). Better diagnostic tools, including antigen-based tests, are needed to assess the type of diagnosis, outcome, and treatment in a non-invasive manner. Standardized markers of pharmacodynamics are required to evaluate drug response to treatment quantitatively(45). Cutaneous leishmaniasis has limited drug therapy choices, pentavalent antimonials (SbV) are the most widely used medicines worldwide, despite their high cardio, hepatic, and renal toxicity, as Meglumine antimoniate and Sodium stibogluconate(46). According to the spectrum of the illness, the suitable treatment for CL should be based on clinical manifestations: For patients with few and small lesions that can be treated superficially (local treatment) and for large and multiple lesions that have the potential to destroy the appearance and cause disability or are located places that make local treatment impossible (general oral drugs) (47) Qualified options with less systemic toxicity are local therapies (thermotherapy), cold therapy, paromomycin ointment, and local infiltration with antimonials, and are recommended for patients with L.mexicana, L.major infections with small and few lesions, but systemic treatments (Miltefosine, Antimonials, Pentamidine or Amphotericin B) is recommended for more complex cases, those who do not respond to topical treatments or patients with compromised immune systems(48). Amphotericin B formulations (deoxycholate and liposomal) are used in a limited patients number, mainly for the therapy of complicated cases (mucosal, diffuse, and disseminated cutaneous leishmaniasis) unresponsive to Miltefosine and Antimonials(49). Despite the efforts of WHO and non-governmental organizations and manufacturers, access to drugs for the treatment of visceral, cutaneous, and mucocutaneous leishmaniasis is difficult in poor countries with high disease incidence(50). Amphotericin B is a natural complex that was first known as an antifungal rep and was successfully targeted for the therapy of leishmaniasis. Its high molecular weight and polar nature prevent its absorption(51). Puromycin (an Aminoglycoside antibiotic) is used to treat leishmaniasis. Its polar nature prevents its oral use and demands the administration of painful intramuscular injections, and this therapy can lead to side effects (reversible kidney and liver toxicity and irreversible deafness) (52) It has restricted use for the therapy of cutaneous leishmaniasis in the New World and provides secondary prophylaxis for visceral leishmaniasis-HIV co-infection to reduce the risk of relapse after therapy(53). To overcome the limitations of a numeral of anti-leishmania drugs, researchers have discovered combination therapies (Sodium stibogluconate and Paromomycin for the therapy of VL in East Africa) to increase efficacy, reduce toxicity, increase tolerance, and shorten treatment courses, with the possible additional benefit of reducing the risk of resistance. Have been successful in improving patients, but creating effective, safe, tolerable, and easy-to-use treatments that truly meet the requirements of patients will require a new generation of drugs(54). For the successful design and development of new drugs for the therapy of leishmaniasis, pharmaceutical researchers must have information about Leishmania parasites and the environments in which they are present. This makes it possible to design pseudo-drugs with suitable effects to reach the infected tissues of patients and destroy the parasites. Different compounds can be tested for their ability to kill Leishmania parasites of animal origin at different stages of their life cycle, but in the treatment of human disease, intracellular amastigote is important. They accumulate in acidic phagolysosome (local pH 5) of macrophages and, as a result, drugs pass through additional membranes, pH concentration gradient, and an environment rich in proteases and hydrolases. They must stay healthy and survive before reaching their goal(55). Functional clinical therapy has the desirable feature of seeking sterile therapy and complete clearance of infection, such therapy being highly desirable in immunocompromised patients (HIV–VL co-infection) and reducing the risk in patients with progressing PKDL(56). Recently, the potential of retargeting amphotericin B, Miltefosine, and paromomycin in the treatment of leishmaniasis has been presented. The antiparasitic drug Fexinidazole (described in 1978), however, was not developed in the initial stage of discovery. This compound was rediscovered by DNDi and then further developed to treat sleeping sickness. Reports of the anti-leishmanial effect of Fexinidazole, along with encouraging progress in the clinical development of sleeping sickness therapy, suggest that it may be re-targeted for the therapy of leishmaniasis(57-61) Nitroheterocylic medicines are operated to treat parasitic and bacterial diseases, including tuberculosis. Despite multiple efforts and investments in the domain of leishmaniasis drug discovery in the past years, the treatment of VL is still pendant on a few drugs that have limitations, such as injection administration, low tolerance and toxicity, long treatment period, and high cost. Due to the scarcity of new compounds in the clinical pathway in the last decade and the content of VL in different regions, efforts have been focused on optimizing the currently available treatments, and the development and optimization of clinical treatments for VL are essential. In Southeast Asia, a single-dose regimen of Miltefosine-paromomycin for ten days has been shown to be highly effective and safe and is now used as routine treatment. In East Africa, SSG with paromomycin for 17 days is recommended as the main treatment. While in Brazil, where nearly 90% of VL cases in the Americas are reported, meglumine antimony is still prescribed as the main treatment for 20 to 30 days, followed by liposomal amphotericin B treatment for more than it takes 7 days(50). Despite improvement in the development of securer formulations or compounds, new oral therapies that are safe and of a short period of therapy for VL are still sorely required(62) Multiple protocols are operated by different groups in rather different situations to gauge the viability of Leishmania parasites after a course of remedy with drugs.
The application of PK-PD tools in clinical trials using common drugs to better characterize exposure-response relationships in different patient populations allows the use of the most advanced modeling and simulation to further optimize treatments. In the pharmaceutical and clinical development of Miltefosine for VL, priority was given to its use in the treatment of cancer, especially solid tumors. The activity against VL was proven more or less simultaneously with the oral study of Miltefosine in BALB/c mice and indicated superiority over the standard drug sodium Acebo gluconate(63-65).
The existence of an oral medicinal VL drug of human source, along with the capacity to recognize it with an easy and reliable diagnostic algorithm founded on clinical results and an easy-to-use interface, a regionally compatible quick diagnostic test (rK39), the launch of an initiative to clean up the drug in India, It provoked Nepal and Bangladesh in 2005(66).
In a study in India, Bangladesh, and Nepal, stage IV (India 2007) was performed to investigate the feasibility of Miltefosine therapy in real-life stages and was enforced in 13 medical centers in Bihar and the treatment was evaluated as weekly clinic visits and compliance rate. Patients were counseled and instructed clearly about the nature of expected side effects, especially Gastrointestinal reactions. The observed effectiveness during the six-month follow-up period was 81.9%. Among patients who completed the study, the final cure rate was 95.5%, with a higher recurrence rate in children compared to adults(67).
In the investigation of the evolutionary trend of the effectiveness of Miltefosine in India after a decade of its use, 567 VL patients were treated in a hospital, and at the end of the six-month follow-up, the effectiveness rate was 90.3%. In this investigation, the patient was directly observed, and it seems unlikely that the reasons for the failure are related to the level of compliance. However, since Miltefosine was available in the demand at a reasonable cost for the poor regional people, as well as incomplete therapy practices, the availability of the drug without a proper prescription and inconsistent with the full period of therapy, altogether with the long half-life of Miltefosine, concerns They made an important point about the risk of creating resistance. With the use of antimonials, the region was already at risk of developing resistance, and now Miltefosine, after less than a decade of use, is at risk if strict access control criteria and an appropriate application are not implemented through a public distribution system. There was resistance. In Nepal, the Miltefosine remedy has been introduced as part of an eradication initiative, replacing antimonials to which resistance was clearly documented (2009 to 2011, a prospective cohort of 120 VL patients), after the end of treatment, they were observed for 12 months. After 6 and 12 months of follow-up, at the end of the treatment, the effectiveness was evaluated with treatment rates of 95.8%, 82.5%, and 73.3%, respectively. Lack of success was attributed to disease recurrences at the rate of 10.8% at the 6-month follow-up and 20% at the 12-month follow-up; These relapses were related to the same parasite (not re-infection), and there was no significant change in parasite susceptibility before treatment compared to after treatment. Recurrence was very common in children under 12 years of age(41, 68, 69).
Miltefosine treatment in East Africa was first described by MSF, with routine use in a population with a high prevalence of co-infection. Adult male VL patients were randomized to receive Miltefosine or standard care treatment with SSG. The cure rate at six-month follow-up among patients without HIV co-infection was 75.6% for Miltefosine and 77.4% for SSG treatment(70). Disparities in therapy ratios in Asia and East Africa could be correlated to differences in the parasite, host, and/or medicine exposure.
A study on the evaluation of scattered pharmacokinetics in Nepal indicated a difference in the final concentrations of therapy between children and adults by approximately 30%. Comparable findings were observed in East Africa, where patients weighing less than 30 kg (children aged 7–12 years) were exposed to lower amounts of Miltefosine than patients weighing 30 kg or more, in both groups after 28 On the day of Miltefosine monotherapy and after ten days of combined Miltefosine medicine, the average differences in the final concentrations of the medicine were 36% and 32%, respectively(71, 72).
Therapy failure of Miltefosine, in terms of infection recurrence during a 12-month follow-up duration, has been indicated associated with lower drug exposure(73). Treatment with Miltefosine is well tolerated. The most typical adverse events are gastrointestinal outcomes, with vomiting occurring in at least 20-30% of treated patients. These side effects are mild, often occurring within the first week of therapy, and less than 1% of patients are predicted to cease medicine due to intolerance(67). Use of Miltefosine is prohibited in pregnant women, and due to the very long clearance half-life of Miltefosine, it can be detected in the blood plasma of patients up to 6 months after medicine, which is a suitable period. Withdrawal duration to prevent teratogenic effects. It should still be unclear. To assess this, a translatable animal-to-human PK model and simulation framework were designed that created a more rational teratogenic risk management strategy and extended contraceptive periods up to four months after the end of therapy with a standard 28-day Miltefosine regimen. recommends, while two months appears sufficient for all shorter diets(74). Of the 850 new drug-therapeutic products registered in 2000-2011, only 5 were considered for neglected tropical diseases, none of which were of a new chemical nature(75). A new drug for any disease is desirable to be used to improve efficacy and prevent drug resistance(76) . The main characteristics of any antimicrobial compound in early drug discovery are efficacy, selectivity, and traceability(77). Alternatively, Novartis combinations are undergoing genetic and chemical validation of promising therapeutic targets for the therapy of kinetoplastid infections(78, 79). AMICS-based technologies have emerged as valuable tools for the discovery and development of innovative chemotherapeutic approaches to parasitic diseases(80). In Leishmania, the expansion of drug resistance and/or side effects of some medicines due to off-target effects harshly limits the effectiveness of treatments. Thus, the development of new selective and tolerable drugs is required(77).
Nitroaromatic compounds, despite the toxicity associated with compounds carrying a nitro group, are currently experiencing a renaissance in these types of compounds for the treatment of trypanosomatid diseases(81). Many of the nitroaromatics in development result from drug retargeting programs (nifurtimox for the therapy of human African trypanosomiasis or the development of fexinidazole for visceral leishmaniasis)(57). Leishmaniasis is a public health problem affecting many countries. Current treatments are suboptimal for some reasons (limitations such as drug toxicity or the emergence of resistant strains), so new drug discovery and development are still needed(82). Delamanid is a clinically approved treatment for visceral leishmaniasis(83). Oral sitamaquine was prescribed for the medicine of visceral leishmaniasis in India and Africa(84, 85). Tafenoquine also has the ability to be taken orally in the therapy of leishmaniasis. Azole antifungals have been successfully used to treat cutaneous leishmaniasis by inhibiting ergosterol synthesis, and there is a chance for retargeting to treat visceral leishmaniasis(86, 87). Selective arginase inhibitors of L. amazonensis have indicated high anti-leishmanial activity(88, 89). The Discovery of Leishmania metabolic ways is a method to treat leishmaniasis that is different or absent in mammals(90).
Leishmania control is a challenge for public health strategies in developing countries. Although some new drug-therapeutic approaches have been suggested, including the first oral drug Miltefosine, new drug combinations, and different drug regimens, the available clinical choices still paint a worrying picture(91).
The historical outlook of leishmaniasis drugs has strong connections with the chemistry of natural products, Amphotericin B (produced by Streptomyces nodosus) and Paromomycin (produced by Streptomyces rimosus) (92, 93)
Organometallic compounds have not been widely considered for pharmaco-therapeutic applications, due to the presence of a carbon-metal bond that may lead to subsequent toxic properties and chemical instability, thus, widely incompatible in biological systems. considered(94, 95). The use of Antimony in modern medicine began with the use of sodium and Potassium antimony(III) tartrate in 1905 by Polymer and Thompson against trypanosomes, which was subsequently used in Africa for several decades to treat trypanosomiasis(96). Gaspar Vianna was the first to report the successful use of tartar emetic in the treatment of cutaneous leishmaniasis (CL) in 1912(96, 97). The efficacy of tartar emetic in the treatment of visceral leishmaniasis (VL) was later by Rogers in India (98) and Di Cristina and Caronia in Sicily were confirmed(42).
Administration of TARTAR was prohibited due to side effects and recurrence of the disease(99, 100). The discovery of the organo-antimony drug Ureastibamine (pentavalent antimonials, the year 1922), an effective agent against sleeping sickness, which was also proven as a useful agent in the treatment of VL(101-103). Pentavalent antimonials glucantime and pentostam were prescribed to treat all types of leishmaniasis(104, 105). And still, in most developing countries, they are the frontline drugs and they are the most important and cost-effective drugs available up to this date. They are effective in treating both VL and CL(101) .
For the treatment of leishmaniasis, Amphotericin B Miltefosine is a substitute for glucantime and pentostam in many countries and showed excellent effectiveness(85, 106, 107).
Both Organoantimony (V) and Organoantimony (III) complexes are promising pharmaceutical candidates for the therapy of leishmaniasis resistant to ordinary inorganic antimonial pharmaceuticals(108). In the past, Organotellurium compounds have been investigated as medicinal-therapeutic mechanisms. It has been confirmed that they are involved in inhibiting proteases, specifically Cysteine protease (Papain and Cathepsin B), and are anti-leishmanial agents with lower cytotoxicity(109-111). Iniguez et al. synthesized Organoruthenium (II) complexes with Ketoconazole and tested them for anti-leishmanial action(112).
Currently, there is no vaccine to protect against infection. The only way to control the condition is to target the vector or any host reservoir, with practical modes to prevent individuals from becoming infected (mosquito nets or insect repellants). Medicines for the therapy of leishmaniasis are narrow and the emergence of medicine resistance in the parasite population has limited their use in some geographic zones(113, 114). Efforts to prolong the clinical life of existing drugs and pharmaceutical resistance have led to the development of combination drug therapies. A recent study in Sudan showed that combined treatment with SSG and Paromomycin for 17 days is equivalent to the protection and effectiveness of standard therapy with SSG for 30 days(40).
Improving the therapy with existing medicines is reformulating them into a drug delivery system and targeting the Amastigote and increasing the In vivo half-life of the drug and modifying its side effects(115).
Miltefosine is the only oral drug for the therapy of visceral leishmaniasis, which was originally developed for the therapy of cancer, but in studies on mice, it was discovered to be effectual against L. donovani(116). One of its disadvantages is the emergence of MIL-resistant L. donovani strains in India(117). Various types of drug delivery systems (emulsions, vesicle systems, and lipid particles) are under study, and the chosen system depends on the condition being treated and the most useful method of drug administration. The properties of the drug (ability to dissolve in water and compatibility with the parts of the drug distribution system) are an effective selection of the drug distribution system(118, 119). The parasite's ability to survive in certain environments is pendant on the developmental regulation of multiple genes, the knowledge of which can lead to drug-therapeutic goals(120).
Although there is no human vaccine for leishmaniasis due to resistance, safety and price, there are specific treatments for each species, and leishmaniasis affects the poorest sections of low-income societies(121-123). Advances in omics technologies (genomics, transcriptomics, and proteomics) provide essential tools to improve our current understanding of the molecular biology of Leishmania for the development of new alternatives to anti-leishmania therapies(124). The findings show that the parasite genome plays a small role in determining the clinical manifestations of the disease; This problem makes it almost impossible to use species-specific genes to develop pharmacotherapeutic agents to help treat specific clinical manifestations caused by Leishmania species(125). Leishmania parasites exhibit unique biological features that range from gene organization through transcription and mRNA processing to post-translational modifications(120, 126). This major difference between Leishmania species and higher eukaryotes has been widely studied and has potential pharmaco-therapeutic evidence for drug discovery(127-129). Among the forgotten tropical diseases, leishmaniasis is more important for human health. Apart from the treatments based on physical methods (laser wound surgery or heat and cold therapy) which are limited to cutaneous leishmaniasis, nowadays chemotherapy is the only effective treatment for this disease(130, 131).
A relative heterodoxy approach in chemotherapy to treat leishmaniasis is the interaction of antimicrobial peptides and peptide-like agents with the plasma membrane of Leishmania. Resistance to proteolytic degradation. A reasonable lifetime under physiological conditions is essential for AMP-based therapies(132). In addition, AMPs averted visceral leishmaniasis(133).
A concern with the therapeutic use of AMPs is the induction of cross-resistance, because of phospholipid interactions as a common target(134). Basal amounts of AMPs are required to treat or ease leishmaniasis in animal models(135, 136). even when administered topically(133, 137). The high production costs associated with AMP therapy have led to high-volume applications in poor and low-income patient populations. Gene therapy by expressing exogenous AMPs was predicted to eliminate intracellular pathogens, but so far it has not been tested on Leishmania. Pentavalent antimonial drugs are the main standard treatment of leishmaniasis, although there is increasing resistance in endemic areas. Pentamidine diamidine is an alternative to SbV in the treatment of leishmaniasis(138, 139). Sugar consumption and FBPase activity are required for the proliferation and pathogenicity of intracellular amastigote, and the formation of G6P by sugar uptake and phosphorylation by HK and/or GlcK, and gluconeogenesis are targets of therapy(140). phosphoglycerate mutase has been proposed as an attractive drug-therapeutic target in trypanosomatids, as these parasites possess a version of the enzyme, cofactor-independent PGAM (iPGAM), which is completely identical to its human counterpart, cofactor-dependent PGAM (dPGAM). It is different(141). The metabolism of T(SH)2 is related to the mode of action of some drugs that are used to treat leishmaniasis, and in pentavalent antimonials, T(SH)2 can act with different mechanisms(142, 143). among enzymes. Spermidine biosynthesis pathway, probably ODC and AdoMetDC, as drug-therapeutic targets, there is more hope for them because they can be inhibited without harming the host due to the different turnover rates of ODCs and AdoMetDCs in parasites and mammals(144-146).
Several anti-leishmania drugs inhibiting ODC and AdoMetDC, pentamidine, which was initially considered as an anti-trypanosome drug and now for the second-line treatment of leishmaniasis, its mode of action includes inhibition of AdoMetDC(147-153) and in relation to D, L-α Difluoromethylornithine, a drug that inhibits ODC and has been on the market for over two decades to treat sleeping sickness caused by T. brucei gambiense. DFMO is also an active leishmanial ODC inhibitor (154) that exhibits cytotoxic effects against promastigote (154-157) and improves but does not clear Leishmania infection in mice (158, 159) and hamsters (156) Leishmania may overcome DFMO toxicity by inducing ODC expression (160) or a more complex mechanism involving other proteins (161).
A powerful Spermidine targeting strategy to treat leishmaniasis should probably target both endogenous synthesis and transporter-mediated uptake. The hydrophobicity of transmembrane proteins is a clear limitation for drug discovery and should focus on POT1, the molecule responsible for spermidine internalization in Leishmania species whose primary shows a little divergence from polyamine permeases found in other organisms(162). Similar to other NTDs, the first drugs of choice (glucantime and pentostam) against leishmaniasis were developed in the early 20th century and alone or in combination with other antifungal drugs and antibiotics form the basis of current VL treatment in endemic countries(163-165). Excessive use and discontinuation of treatment because of the occurrence of adverse side effects are the source of relapses and resistances(77). The lipid ether Miltefosine-combined drug (initially anti-tumor) but with a potential anti-leishmanial effect, drastically changed the medical-therapeutic landscape of these diseases(67, 166) . Miltefosine is an oral drug that allows the patient to self-medicate according to WHO recommendations(167) The proven teratogenicity of this drug prevents its therapeutic prescription for pregnant women and children(168) For several decades, pentavalent antimonials have been the treatment of choice for visceral leishmaniasis (VL) (169). As treatment began in the 1970s, treatment errors increased in highly endemic areas of the Indian subcontinent, with clinical strains resulting from post-treatment showing reduced drug susceptibility in vitro(170). The spread of antimony resistance led to the creation of alternative treatments in endemic areas using drugs such as amphotericin B, Miltefosine and Paromycin. One of the major concerns of strains resistant to these drugs have been reported(171, 172). Drug resistance of Leishmania is studied in several ways. Comparative evaluation of strains derived from infected patients (those treated, those with treatment relapse or treatment failure). Identical pairs of strains are not available, because of which the proper interpretation of drug sensitivity change is hindered(173, 174). In vitro treatment of Leishmania with Sb (III) also leads to leakage of TSH and GSH, which are important antioxidants to protect the parasites against oxidative stress, and in macrophages, Sb (III) has similar activity on antioxidant leakage, intracellular free GSH levels. Which leads to higher relative levels of GSH-disulfide(175, 176).
In VL infections, it has been found that treatment with Sb highly depends on the host’s functional immune system, T and Th1 cell responsiveness, and a pro-inflammatory cytokine profile to control the liver parasite load, before and after treatment (177-180) and 2- IL has important roles and in its absence, Sb is less effective against Leishmania donovani and the mice with drug treatment have lowered the levels of IFN-γ, demonstrates the important role of 4-IL in regulating the production of IFN-γ as a determining factor for the treatment(181) and Leishmania 1 double-stranded RNA in L. braziliensis is related to the increased risk of Sb(V) treatment failure (182) and is not related to the decrease in drug sensitivity of the parasite. A similar role of LRV1 virus was also described in L. guyanensis (181-183), here it affected the treatment outcome of pentamidine and confirmed the hypothesis that the virus affects the host-parasite interaction and the immune status of the host is a confirmatory factor in the treatment outcome as shown in animal models. HIV infection and a range of other medical conditions have resulted in an immunodeficiency state that coexists with impaired immunological control and a high risk of reactivation after treatment (184). The consequences of Miltefosine treatment that have been reported are the absence of ROS, losing mitochondrial membrane potential, the release of cytochrome c into the cytosol, and the activation of cellular proteases(185, 186). In endemic areas with extensive Sb resistance, AmB has gradually replaced Sb(V) as the preferred first-line treatment, and now the current widespread use of AmB may be at risk of the emergence of acquired resistance to AmB(171).