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Life Cycle: Infective larvae are transmitted by infected biting mosquitoes during a blood meal. The larvae migrate to lymphatic vessels and lymph nodes, where they develop into microfilariae-producing adults. The adults dwell in lymphatic vessels and lymph nodes where they can live for several years. The female worms produce microfilariae which circulate in the blood. The microfilariae infect biting mosquitoes. Inside the mosquito, the microfilariae develop in 1 to 2 weeks into infective filariform (third-stage) larvae. During a subsequent blood meal by the mosquito, the larvae infect the vertebrate host. They migrate to the lymphatic vessels and lymph nodes of the human host, where they develop into adults.

Most infected people have no symptoms and will never develop clinical symptoms. These people do not know they have lymphatic filariasis unless tested. A small percentage of persons will develop lymphedema. This is


caused by fluid collection because of improper functioning of the lymph system resulting in swelling. This mostly affects the legs, but can also occur in the arms, breasts, and genitalia. Most people develop these symptoms years after being infected. The swelling and the decreased function of the lymph system make it difficult for the body to fight germs and infections. These people will have more bacterial infections in the skin and lymph system. This causes hardening and thickening of the skin, which is called elephantiasis. Many of these bacterial infections can be prevented with appropriate skin hygiene and exercise. Men can develop hydrocele or swelling of the scrotum due to infection with one of the parasites that causes LF specifically W. bancrofti. Filarial infection can also cause pulmonary tropical eosinophilia syndrome, although this syndrome is typically found in persons living with the disease in Asia. Symptoms of pulmonary tropical eosinophilia syndrome include cough, shortness of breath, and wheezing. The eosinophilia is often accompanied by high levels of IgE (Immunoglobulin E) and antifilarial antibodies. Albendazole

Methyl [5-(propylthio)-1H-benzoimidazol-2-yl]carbamate A benzimidazole broad-spectrum anthelmintic structurally related to mebendazole that is effective against many diseases MOA: Albendazole causes degenerative alterations in the tegument and intestinal cells of the worm by binding to the colchicine-sensitive site of tubulin, thus inhibiting its polymerization or assembly into microtubules. The loss of the cytoplasmic microtubules leads to impaired uptake of glucose by the larval and adult stages of the susceptible parasites, and depletes their glycogen stores. Degenerative changes in the endoplasmic reticulum, the mitochondria of the germinal layer, and the subsequent release of lysosomes result in decreased production of adenosine triphosphate (ATP), which is the energy required for the survival of the helminth. Due to diminished energy production, the parasite is immobilized and eventually dies. P’cokinetics: Poorly absorbed from the gastrointestinal tract due to its low aqueous solubility. Oral bioavailability appears to be enhanced when coadministered with a fatty meal. Albendazole is rapidly converted in the liver to the primary metabolite, albendazole sulfoxide, which is further metabolized to albendazole sulfone and other primary oxidative metabolites that have been identified in human urine. Halflife ranges from 8 to 12 hours

By CYP3A4+CYP1A2+ Flavin containing Mono oxygenase active

active


Synthesis: 3-Chloro-6-nitroacetanilide (I) is condensed with propylmercaptane (A) in the presence of aqueous refluxing NaOH to produce 2-nitro-5-propylthioaniline (II), which was reduced with H 2 over Pd/C in ethanol HCl to afford 4-propylthio-o-phenylenediamine (III). The cyclization of (III) with cyanogen bromide affords 2-amino-5-propylthiobenzimidazole (IV), which is finally condensed with methyl chloroformate. It can be condensed directly with a mixture of cyanamide and methyl chloroformate or with carbomethoxycyanamide (B). All these condensations are performed in basic medium.

Mebendazole

methyl (5-benzoyl-1H-benzimidazol-2-yl)carbamate P’cokinetics: Poorly absorbed (approximately 5 to 10%) from gastrointestinal tract. Fatty food increases absorption. Metabolism takes place in liver. Primary metabolite is 2-amino-5-benzoylbenzimidazole, but also metabolized to inactive hydroxy and hydroxyamino metabolites. All metabolites are devoid of anthelmintic activity.


both inactive Toxicity : Symptoms of overdose include elevated liver enzymes, headaches, hair loss, low levels of white blood cells (neutropenia), fever, and itching. Diethylcarbamazine An anthelmintic used primarily as the citrate in the treatment of filariasis, particularly infestations with Wucheria bancrofti or Loa loa.

N,N-diethyl-4-methylpiperazine-1-carboxamide MOA: DEC is inactive in vitro but in vivo has rapid onset of axn that means cellular comp has is essential for filaricidal axn. Involvement of platlets triggere by the axn of filarial excretory Ag 3 mech. Have been suggested: 1. Morphological damage to microfilaria--- loss of cellular sheath----- xposing antigenic eterminants to the immune system components---- damage to cell organelle--- death. 2. Inhibition of microtubule polymerization—disruption of microtubule function. 3. Disruption of arachidonic acid metabolim. It has leukotriene synthetase and COX-1 inhibiting activity. P’cokinetics: Readily absorbed following oral administration. Partially metabolized to diethylcarbamazine-Noxide. t1/2 is approx. 8 h. 10-20% drug is excreted unchanged in urine.


Ivermectin

Ivermectin is a semisynthetic, anthelminitic agent. It is an avermectin which a group of pentacyclic sixteenmembered lactone (i.e. a macrocyclic lactone disaccharide) derived from the soil bacterium Streptomyces avermitilis. Avermectins are potent anti-parasitic agents. Ivermectin is the most common avermectin. It is a broad spectrum antiparasitic drug for oral administration. It is sometimes used to treat human onchocerciasis (river blindness). It is the mixture of 22,23-dihydro-avermectin B1a (at least 90%) and 22,23dihydro-avermectin B1b (less than 10%). MOA: Ivermectin binds selectively and with high affinity to glutamate-gated chloride ion channels in invertebrate muscle and nerve cells of the microfilaria-----causes an increase in the permeability of the cell membrane to chloride ions -----hyperpolarization of the cell, ------- paralysis and death of the parasite. Ivermectin ------- agonist of the GABA------ disrupts GABA-mediated CNS neurosynaptic transmission. Ivermectin may also impair normal intrauterine development of O. volvulus microfilariae and may inhibit their release from the uteri of gravid female worms. P’cokinetics: Moderately well absorbed. Improved absorption with high fat meal. Ivermectin and/or its metabolites are excreted almost exclusively in the feces over an estimated 12 days, with less than 1 % of the administered dose excreted in the urine. Ivermectin is metabolized in the liver, and ivermectin and/or its metabolites are excreted almost exclusively in the feces over an estimated 12 days, with less than 1% of the administered dose excreted in the urine.


Leishmaniasis Leishmania are protozoan parasites belonging to the family Trypanosomatidae that causes high morbidity and mortality levels with a wide spectrum of clinical syndromes. The World Health Organization has identified leishmaniasis as a major public health problem. As a zoonotic infection, transmission is difficult to interrupt, although some attempts to reduce vector and mammalian reservoir populations have been successful. There are currently no vaccines for leishmaniasis. The drugs available for leishmaniasis treatment are toxic, expensive and frequently ineffective. The transmission of Leishmania occurs through

vectors Phlebotomus and Lutzomyia. Parasites

multiply in the vector digestive tract, and they are transmitted to the mammalian host during vector blood feeding. Inside the vectors, Leishmania are in promastigotes form, which are long, elongated and extracellular. In the vertebrate host, the parasite multiplies inside the macrophages as amastigotes, which are spherical, with an internalized flagellum. Leishmania parasite is able to survive to stress conditions, lyses the macrophage and are phagocyted by new host cell.


Drugs Derivatives of pentavalent antimonial Pentavalent antimonials (SbV) become the drug of choice for the treatment of all types of leishmaniasis. Pentostam, sodium stibogluconate, manufactured by Wellcome Foundation was first used; following the Glucantime, meglumine antimoniate, is manufactured by Rhone Poulenc in France can be used. Pentostam (sodium stibogluconate)

2,4:2',4'-O-(oxydistibylidyne)bis[D-gluconic acid MOA: The precise mechanism of action of antimonials remains an enigma and their antileishmanial action probably depend on the following: 1. in vivo reduction of SbV form to a more toxic Sb III form, due to that only amastigotes are susceptible to the Sb V. 2. SbV acts upon several targets that include influencing the bioenergetics of Leishmania parasite by inhibiting parasite glucolysis, fatty acid beta-oxidation and inhibition of ADP phosphorylation . 3. It has also been reported to cause non specific blocking of SH groups of amastigote proteins and cause inhibition of DNA topoisomerase I. 4. Antimony can alter the thiol-redox potential in both forms of parasite by actively promoting efflux of thiols, glutathione and trypanotione, thus rendering the parasite more susceptible to oxidative stress.


P’cokinetics: The drug can be administered intramuscularly or intravenously, which is distributed in high concentration in the plasma, liver and spleen. Its half life is 2 hours. In liver, it biotransforms to its trivalent state (SbIII) and about 50% of antimony is excreted from 24 hours to 76 hours through urine. Side effects: The long course treatment allows antileishmanial levels vof the drug to accumulate in tissues, particularly in liver and vspleen. The treatment with antimonials has been caused several side effects, such as: nausea, abdominal pain, myalgia, pancreatic inflammation, cardiac arrhythmia and hepatitis, leading to the reduction or cessation of treatment. There has been a development of resistance. Second, new generic of Pentostam have been produces with the aim to decrease the high cost of the treatment. bad batches because of caused fatal cardiotoxicity. Amphotericin B Amphotericin B3 is a macrolide polyene antifungal antibiotic agent, discovered in 1956, from a bacterium: Streptomyces nodusus, actinomycetes obtained from the soil. In early 1960s it was demonstrated its antileishmanial activity.

MOA: The antileishmanial activity of amphotericin B is attributable to its selectivity for 24 substituted sterols, namely ergosterol, the primary sterol counterpart in mammalian cells eventually helping to increase drug selectivity towards the microorganism. In higher concentrations (>0.1 M), it triggers cationic and anionic influx via formation of aqueous pores resulting in cell lyses. Kinetics: The drug is poorly absorbed by gastrointestinal tract. Amphotericin B exhibits multicompartmental distribution and is found to be present in low concentrations in aqueous humour, pleural, pericardial, peritoneal and synovial fluids. The elimination in adult is approximately 24 hours and can be found in blood for upto 4 weeks and in urine for 4-8 weeks in case of discontinuation of therapy Uses: Amphotericin B has excellent leishmanicidal activity and constitutes an option in patients that showed resistance to treatment with antimonials. The major limiting factor about the use of this drug is due to their toxicity. Currently, toxic effects of amphotericin B have been largely ameliorated with the advent of lipid formulations. In these formulations, deoxycholate has been replaced by other lipids that mask amphotericin B from susceptible tissues, thus reducing toxicity, and facilitating its preferential uptake by reticuloendothelial cells. Thus, this drug delivery result in increasing efficacy and reduced toxicity. S/Effects: Fever with rigor and chills, thrombophlebitis and occasional serious toxicities like myocarditis, severe hypokalaemia, renal dysfunction and even death. Pentamidines Aromatic diamidines were first synthesized as hypoglycemis drugs and their chemotherapeutic profile against antiprotozoal therapy was early discovered.


4-[5-(4-carbamimidoylphenoxy) pentoxyl benzenecarboximidamide MOA: Pentamidine acts on the genome of parasite by hampering replication and transcription at the mitochondrial level. Kinetics: This drug can be administered parenterally, by intramuscular or intravenous route. It has a half-life is 5 to 15 minutes and 54 minutes, respectively. Drug distribution shows their concentration to be considerable higher in the liver, kidneys, adrenal glands and spleen, while only a small amount is found in lungs. S/E: Commonly, the treatment with pentamidine causes myalgias, pain at the injection site, nausea, headache and less frequently result in a metallic taste, a burning sensation, numbness and hypotension. Reversible hypoglycemia occurs in about 2% of cases. It causes irreversible insulin dependent diabetes mellitus and death. Miltefosine Miltefosine has been hailed as a novel oral drug for treatment of VL, with successful in immunocompetent and immunocompromised patients and perhaps the most significant recent advances

2-(hexadecoxy-oxido-phosphoryl)oxyethyl-trimethyl-azanium

MOA: The antileishmanial mechanism of action of this compound can be extrapolated from its effect on mammalian cells, 1. where it causes modulation of cell surface receptors, 2. inositol metabolism, phospholipase activation, protein kinase C and other mitogenic pathways, eventually culminating in apoptosis. S/E: Adverse effects of miltefosine include gastrointestinal disturbances and renal toxicity. Fortunately, these symptoms are reversible and they are not a major cause for concern. As miltefosine is teratogenic, it is contraindicated in pregnancy and women of child bearing age group, not observing contraception. Paromomycin Paromomycin 6 (aminosidine) is an aminoglycosidic aminocyclitol produced by Streptomyces riomosus var. Paromomycinus, which was isolated in 1956. It is effective against a wide range of bacteria and protozoa.


MOA: The mechanism of action of paromomycin in Leishmania requires further elucidation and it inhibits protozoan protein synthesis. It binds to the 30S ribosomal subunit, interfering with initiation of protein synthesis by fixing the 30S-50S ribosomal complex at the start codon of mRNA, leading of accumulation of abnormal initiation complex. Kinetics: The drug is poorly absorbed into systemic circulation after oral administration, but rapidly absorbed from intramuscular sites of injection. Peak concentration in plasma occurs in 30-90 min and its apparent volume of distribution is 25 % of body weight. The half-life varies between 2 and 3 hours in patients with normal renal function. Their clearance is almost entirely by glomerular filtration. S/E: The most common side effect associated with the paromomycin is the ototoxicity, as well as problems in liver function. In patients treated with the ointment formulation skin rashes, local pruritus and burs have been the side effects encountered. Sitamaquine Sitamaquine is an orally active 8-aminoquinoline analogue (8-aminoquinoline (8-[6(diethylamino)hexyl] amino)-6-methoxy-4-methylquinoline) known as WR 6026. This new primaquine was originally developed by Walter Reed Army Institute of Research (Unite States) for malaria. Animal studies showed very encouraging results against VL; although in clinical trials it did not shows high efficacy after treatment during 28 days


antifilarial and antiliesnmanial drugs