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Wright staining of Leishmania infantum intracellular amastigotes in mouse peritoneal macrophages (B) (Adapted from J generic losartan 50 mg on line diabetes symptoms nausea dizziness. Indeed purchase 25 mg losartan amex diabetes diet help, the promastigotes’ metacyclogenesis can be mimicked in vitro losartan 50mg fast delivery diabetes type 2 zonder insuline, since procyclic forms correspond to promastigotes in the exponential phase of their growth, and metacyclic forms are found in stationary phase cultures (Sacks and Perkins, 1985). The morphological, biochemical, biological and immunogical properties of the axenic amastigotes resemble the amastigotes isolated from host infected cells, thus representing an in vitro model to Leishmania differentiation, immunogical and drug research studies (Hodgkinson and Soong, 1997). Moreover, the compartmentalisation of energy metabolism with the glycolytic pathway and other enzymes sequestered in glycosomes, a redox metabolism based on a unique thiol called trypanothione, and a polycistronic transcription with post- translational regulation of gene expression are among the unusual characteristics of trypanosomatids. Indeed, the Old World Leishmania species have 36 chromosomes, compared with 35 from New World species and 34 from the L. Even the precise mechanism is still unknown; their occurrence can be spontaneous or as a consequence of parasite exposure to adverse conditions such as drug selection (Beverley, 1991; Segovia, 1994). Their unusual chromosome organization in directional gene clusters previously reported to L. Moreover, the regulation of gene expression is not presumably done at the level of transcription initiation as the rate of polycistronic transcription seems to be stable (Clayton, 2002). Even though the mechanisms of how kinetoplastid parasites regulate gene expression are not fully understood, this appears to involve: the 8 Chapter I Leishmania spp. Moreover, the lower pK values of trypanothione compared to glutathione are coincident with the intracellular pH of the parasites (Moutiez et al. The trypanothione reductase play an important role in the parasites redox state as it is the responsible of maintaining the trypanothione pool reduced. The transmission of leishmaniasis is attributed to about 70 of around 1000 known sandfly species (Murray et al. Those belonging to the genus Lutzomya are prevalent in the New World (ie, the Americas), and those belonging to the genus Phlebotomus are prevalent in the Old World (ie, Africa, Europe and Asia). Phlebotomine sandflies are not active during the day and seek out cool and relatively humid dark niches which allow them to survive in hot and dry climates. Leishmania infections typically occur through the bite of sandflies belonging to either Phlebotomus spp. The classification of the mammal-infective Leishmania into subgenera, Leishmania and Viannia, was originally based on the vector gut parts colonized by the parasites (Lainson et al. Leishmania (Leishmania) parasites are transmitted to either female Phlebotomus (Old World) or Lutzomya (New World) species while Leishmania (Viannia) species are only found in the New World and therefore all the vectors are Lutzomya species (Bates, 2007). The ingestion of a blood meal containing Leishmania amastigotes by the female sandfly induces the amastigotes’ transformation into procyclic promastigotes, a weakly motile and replicative form that multiplies in the blood meal confined by the periotrophic matrix, a mesh of proteins and chitin secreted by the insect midgut. Few days later, the parasites slow their replication and differentiate into strongly motile promastigotes that break the blood meal’s periotrophic matrix and migrate. The species belonging to the subgenus Leishmania move towards the anterior midgut and some attach to the microvilli of the midgut’s epithelium, while the species belonging to the Viania subgenus can be found in the pyloric region of the hindgut (Walters et al. Differences in the ability to inhibit or to resist killing by proteolitic enzymes released into the vector midgut after blood feeding, and/or to remain in the gut during excretion of the digested blood meal define vector competence in most species. The natural transmission of leishmaniasis is mediated by the bite of an infected female sandfly when she has a blood feeding. The sandfly saliva is required for the blood feeding due to its potent vasodilator and anti-haemostatic properties (Ribeiro, 1987). Furthermore, it is a disease exacerbation factor, at least for cutaneous leishmaniasis (Titus and Ribeiro, 1988). Co-inoculation of sandfly saliva and parasites led to disease exacerbation in several studies, which seems to be related with the modulation of the immune system to favor parasite survival and replication (Kamhawi, 2000; Rohousova and Volf, 2006). By contrast, the bites of uninfected sand flies or the vaccination with salivary gland extracts induce T cell mediated protection against an experimental challenge and disclose its potential for vaccination (Belkaid et al. Furthermore, in infected humans, anti-saliva antibodies are detected (Gomes et al. Visceral leishmaniasis can be induced through blood containing amastigotes (shared needles, transfusion, transplacental spread) or organ transplantation (Morillas- Marquez et al. The several Leishmania species that cause disease in humans have a zoonotic transmission, with the exception of L. However, even for these species, some animal reservoirs in endemic areas have recently been identified (Dereure et al. Furthermore, the different Leishmania species do not seem to exhibit reservoir strain or specie specificity, unlike what happens with the sandfly. Indeed, certain Leishmania species are maintained by several hosts, and several Leishmania species may be found in the same host (Saliba et al. This disease is prevalent in the Central and South America, Mediterranean basin and Asia. Dogs are the main domestic reservoirs while jackals, foxes and wolves are the sylvatic ones (for review see Gramiccia and Gradoni, 2005). However, unusual Leishmania animal hosts such as cats and equines have recently been identified in those endemic areas (for review see Mancianti, 2004). The role of cats is still under debate, but they seem to be secondary reservoirs, while equines are incidental hosts (Gramiccia and Gradoni, 2005). The large spectrum of clinical manifestations reflects leishmaniasis’ complexity, mainly associated with the number of Leishmania species that cause disease, as well as many sandfly and mammalian species indicated as vectors and reservoirs, respectively. This could indeed be due, in part, to improved diagnostic and case notification, but inadequate vector and reservoir control, increased detection of cutaneous leishmaniasis associated with opportunistic infections (e. Cutaneous leishmaniasis in endemic areas affects mainly children of up to 15 years of age, and the main risk factors besides age are household design and construction materials, and the presence of domestic animals (Reithinger et al. Indeed, several authors refer to them as synonyms, despite the disagreement of others (Shaw, 1994; Lukes et al. Furthermore, they present high parasite loads in organs, low sensitivity to the serological-based diagnostic tests and treatment failure (Murray et al. Therefore, specific and sensitive tests are very important, not only for a prompt and accurate diagnosis but also for a successful treatment and subsequent disease control. Occasionally, the culture of biopsy triturates or aspirates is 15 Chapter I Leishmania spp. Even though it is very specific, the sensitivity of this method is highly variable and depends largely on the number and dispersion of parasites in the biopsy, the technical skills of the personnel, the sampling procedure and the sample origin (Herwalt, 1999). However, spleen aspirates require considerable technical expertise, since life threatening haemorrhages can occur (Kager et al. Furthermore, the possibility of identifying the Leishmania specie and predicting the disease severity and treatment outcome is becoming important in the patients’ clinical management (Murray et al. One is related to the persistence of the anti-Leishmania antibodies for long periods of time after the cure (Hailu, 1990;De Almeida Silva et al. These tests should therefore be used in combination with clinical symptoms for an 16 Chapter I Leishmania spp. The several limitations of the poor Leishmania endemic areas have boosted the development of diagnostic tests that could be used in the field: easy to perform, cheap, reproducible and rapid.
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The effect has been demonstrated in 12–34% of didanosine- treated patients buy generic losartan 50mg diabetes diet low carb, and is reversible upon withdrawal of the drug (Rozencweig et al purchase on line losartan diabetes test leeds. Among 7806 zidovudine-resistant patients participating in the Didanosine Expanded Access Program purchase losartan master card managing diabetes exercise, 5% reported pancreatitis (Pike & Nicaise, 1993). In all of the studies, the symptoms correlated with cumulative treatment and typically subsided after disconti- nuation of therapy. Like zidovudine and zalcitabine, didanosine occasionally caused a rare (1 in 105 to 1 in 106 patients) idiosyncratic syndrome consisting of increased liver enzyme acti- vity, hepatic steatosis, fulminant hepatitis and severe lactic acidosis after long-term (more than three months) treatment; this syndrome can be fatal (Lai et al. Other miscellaneous and rare human toxic effects include acute, reversible thrombocytopenia (Lor & Liu, 1993), retinal toxicity (Cobo et al. Cell-mediated (T cell) immunity was moderately suppressed at 250 mg/kg bw for > 14 days, and suppression of humoral (B cell) immune response was observed at 100 mg/kg bw given for > 28 days. In order to investigate the mechanism of didanosine-induced neuropathy, rats were dosed orally twice daily with 41. Myelin splitting and intramyelin oedema were observed in the sciatic nerves of treated animals in a dose-related fashion (Schmued et al. In rabbits given 750 or 1500 mg/kg bw didanosine per day for 6 or 16 weeks, no evidence of peripheral neuropathy was found (Warner et al. Attempts to model the effects of didanosine in the human pancreas have been unsuccessful. No changes in the numbers of resorptions or pups per litter or in external embryo morphology were reported in animals examined on gestational day 11. The pups of treated dams were born live, developed at a normal rate and had a normal lifespan (Sieh et al. No selective cytotoxicity was seen in neuronal, cardiac or skeletal muscle or cartilage cells (Sieh et al. References such as The Physician’s Desk Reference (Medical Economics Data Production, 1999) provide results but few or no details of the experimental conditions used in the assays. The manufacturer of the drug has yet to publish a detailed report equivalent to those available in the literature on aciclovir and zidovudine. Mutagenicity was seen in vitro and in vivo only with high doses of didanosine (Table 1). Didanosine did not induce reverse mutation in Salmonella typhimurium with or without exogenous metabolic activation [no information on doses or strains] and did not induce differential toxicity in Escherichia coli or Bacillus subtilis. Didanosine caused clastogenic effects in Chinese hamster ovary cells and human lymphocytes. Studies of the mutagenicity of didanosine in animals in vivo are limited to assays for micronucleus formation in rodents. As didanosine can be inacti- vated by the low pH of the stomach, it was subsequently administered by intra- peritoneal injection for three consecutive days. A significant clastogenic response was found in peripheral blood at the low and high doses. Over a range of concentrations, the induced mutant frequencies at the two loci were three to four times greater than the values obtained after exposure to didanosine or zidovudine alone. The few available studies on the mutagenicity of didanosine show that it produces primarily clastogenic effects at high doses. It is in widespread use in combination regimens with other antiretroviral agents, and potentiation of the anti- viral effect of didanosine by hydroxyurea is being investigated. About half of the human urinary metabolites are represented by hypoxanthine, and 40% is unchanged drug. Phosphorylation is a minor pathway but is essential for the antiviral activity of the drug. The toxic effects of didanosine in humans include peripheral neuropathy, pancrea- titis, hepatitis and leukopenia. No relevant studies of the reproductive and prenatal effects of didanosine in humans were available. Didanosine crosses the placenta of women and monkeys by bidirectional, passive diffusion. Didanosine but not didanosine triphosphate was observed in placental and fetal tissues. Little information was available on the genetic and related effects of didanosine. Treatment of human cells in culture significantly increased the mutant frequencies after short-term expo- sure to concentrations 10–20-fold greater than the peak plasma concentrations found in some patients. In the same studies, didanosine was more cytotoxic and less muta- genic than zidovudine. There is inadequate evidence in experimental animals for the carcinogenicity of didanosine. Overall evaluation Didanosine is not classifiable as to its carcinogenicity to humans (Group 3). A review of its antiviral activity, pharmaco- kinetic properties and therapeutic potential in human immunodeficiency virus infection. The gelatin capsules may also contain citric acid, gelatin, glycerol, iron oxide, parabens (ethyl and propyl), polyethylene glycol 400, sorbitol and titanium dioxide. Etoposide concentrate for injection is a sterile, non-aqueous solution of the drug in a vehicle, which may be benzyl alcohol, citric acid, ethanol, polyethylene glycol 300 or polysorbate 80. Etoposide phosphate for injection is a sterile, non-pyrogenic, lyophilized powder containing sodium citrate and dextran 40; after reconstitution of the drug with water for injection to a concentration of 1 mg/mL, the solution has a pH of 2. The following impurities are limited by the requirements of The British Pharma- copoeia: 4′-carbenzoxy ethylidene lignan P, picroethylidene lignan P, α-ethylidene lignan P, lignan P and 4′-demethylepipodophyllotoxin (British Pharmacopoeia Commission, 1994). Trade names for etoposide phosphate include Etopofos and Etopophos (Swiss Pharmaceutical Society, 1999). Methods for the analysis of etoposide and its metabolites in plasma, serum and urine have included reversed-phase high-performance liquid chromatography with oxidative electrochemical detection, fluorescence detection and ultraviolet detection. Podophyllotoxin is isolated from the dried roots and rhizomes of species of the genus Podophyllin, such as the may apple or American mandrake (Podophyllin peltatum L. Etoposide can be synthesized from naturally occurring podophyllotoxin by first treating the podophyllotoxin with hydrogen bromide to produce 1-bromo-1-deoxyepi- podophyllotoxin, which is demethylated to 1-bromo-4′-demethylepipodophyllotoxin. The bromine is replaced by a hydroxy group, resulting in 4′-demethylepipodo- phyllotoxin. After protection of the phenolic hydroxyl, the 4-hydroxy group is coupled with 2,3,4,6-tetra-O-acetyl-β-D-glucopyranose. The protecting group at the 4′- hydroxy is removed by hydrogenolysis and the acyl groups by hydrolysis, and the cyclic O-4,6 acetal is formed by reaction with acetaldehyde dimethyl acetal (Holthuis et al. During early clinical trials for cancer chemotherapeutic use, podophyllotoxin proved to be too toxic and, in the 1960s, two epipodophyllotoxins were described, teniposide (see monograph, this volume) and etoposide (Keller-Juslén et al. The first clinical trial of etoposide was reported in 1971, and etoposide entered routine use after 1981 (Oliver et al. Etoposide is one of the most widely used cytotoxic drugs and has strong anti- tumour activity in cases of small-cell lung cancer, testicular cancer, lymphomas and a variety of childhood malignancies.