phosphorylcholine

The primary anti-phosphorylcholine (PC) response in BALB/c, C57BL/6, and congenic and recombinant inbred strains of these parental types has been examined in the splenic focus system. The frequencies of PC-specific precursors were shown to vary among these strains from 2 to 20 precursors per 10(6) splenic B cells. The distribution of these frequencies suggests that elements closely linked to or within the major histocompatibility complex may play a role in the determination of this parameter, although additional experiments are necessary to adequately assess this possibility. Moreover, all strains tested, regardless of immunoglobulin allotype, expressed monoclonal antibodies indistinguishable from the TEPC 15 myeloma protein (T15) clonotype. Further, the frequency of this clonotype in a given strain did not appear related to allotype, since both high and low T15 frequencies were found among strains of either the BALB/c (a(1)) or C57BL/6 (a(2)) allotype. The examination of normal ser...

Miltefosine, the only oral drug for visceral leishmaniasis (VL), is being used as the first-line drug under the VL elimination program in the Indian subcontinent. Miltefosine is an oral drug which was used as a topical application for skin metastasis of breast cancer. It was found to be effective against Leishmania donovani The main adverse events (AE) reported previously with miltefosine use includes diarrhea, vomiting, and dehydration. Other AEs include, raised serum alanine transaminase/aspartate aminotransferase and renal parameters such as creatinine. In this study, we report AEs in a large patient cohort of VL treated with miltefosine. The purpose of this pharmacovigilance study was to assess adverse drug reactions (ADRs)/AE of miltefosine treatment under unrestricted condition in the field setup. Patients were followed up to 6 months for therapeutic effectiveness. Outcomes of a larger data set of patients treated with this regimen from April 2012 to March 2015 were recorded. ...

Specific genetic alterations during malignant transformation may induce the synthesis and breakdown of choline phospholipids, mediating transduction of mitogenic signals. The high level of water-soluble choline metabolites in cancerous breast tumors, relative to benign lesions and normal breast tissue, has been used as a diagnostic marker of malignancy. To unravel the biochemical pathways underlying this phenomenon, we used tracer kinetics and 13C and 31P magnetic resonance spectroscopy to compare choline transport, routing, and metabolism to phospholipids in primary cultures of human mammary epithelial cells and in MCF7 human breast cancer cells. The rate of choline transport under physiological choline concentrations was 2-fold higher in the cancer cells. The phosphorylation of choline to phosphocholine and oxidation of choline to betaine yielded 10-fold higher levels of these metabolites in the cancer cells. However, additional incorporation of choline to phosphatidylcholine was ...

In Colombia, pentavalent antimonials and miltefosine are the drugs of choice for the treatment of cutaneous leishmaniasis; however, their toxicity, treatment duration, (treatment adherence problems), cost, and decreased parasite sensitivity make the search for alternative treatments of American cutaneous leishmaniasis necessary. Based on the results found in a controlled, open, randomized, phase III clinical trial, the efficacy and safety of miltefosine was compared to that of thermotherapy for the treatment of cutaneous leishmaniasis in Colombia. Adult patients from the Colombian army participated in the study; they received either 50 mg of miltefosine three times per day for 28 days by the oral route (n = 145) or a thermotherapy (Thermomed®) application of 50 °C for 30 seconds over the lesion and surrounding area (n = 149). Both groups were comparable with respect to their sociodemographic, clinical, and parasitological characteristics. The efficacy of miltefosine by protocol and ...

Existing standard treatment options for visceral leishmaniasis are less than optimal. We report here the use of oral miltefosine in the treatment of two paediatric cases of visceral leishmaniasis at a tertiary care hospital in Karachi, Pakistan. One patient came from Balochistan while the second patient was from Northern Pakistan. Both presented with a prolonged history of fever, massive hepatosplenomegaly, anaemia and thrombocytopenia. Visceral leishmaniasis was diagnosed with bone marrow studies. Amphotericin B was first started in the first patient; however severe hypokalaemia and allergic reaction occurred. Oral miltefosine was then administered. The child showed clinical improvement with regards to signs of leishmania infection but succumbed to a nosocomial infection during the hospital stay. In the second patient, miltefosine was started in the first instance. He showed remarkable clinical improvement. At 2 months follow-up, the child showed adequate weight gain along with suc...

We have measured the 31P nuclear magnetic resonance spectra of EMT6/Ro multicellular tumor spheroids over a wide range of sizes under constant nutrient conditions which matched those used for culturing the spheroids. The amount of nucleotide triphosphate per cell decreased with spheroid growth, roughly in proportion to the decrease in cell volume. There was no correlation between the intracellular pH, the nucleotide triphosphate:Pi ratio, or the phosphocreatine:Pi ratio and either the spheroid cellularity, the mean cell volume, the S-phase fraction, the clonogenic capacity, or the amount of central necrosis. The phosphoryethanolamine:phosphorylcholine ratio also increased with increasing spheroid size. There was a negative correlation between the phosphoryethanolamine:phosphorylcholine ratio and the S-phase cell fraction or the mean cell volume; this ratio was positively correlated with the extent of central necrosis. The membrane degradation components glycerophosphorylcholine and ...

The pharmacokinetics of miltefosine in leishmaniasis patients are, to a great extent, unknown. We examined and characterized the pharmacokinetics of miltefosine in a group of patients with Old World (Leishmania major) cutaneous leishmaniasis. Miltefosine plasma concentrations were determined in samples taken during and up to 5 months after the end of treatment from 31 Dutch military personnel who contracted cutaneous leishmaniasis in Afghanistan and were treated with 150 mg miltefosine/day for 28 days. Samples were analyzed with a validated liquid chromatography-tandem mass spectrometry assay with a lower limit of quantification (LLOQ) of 4 ng/ml. Population pharmacokinetic modeling was performed with nonlinear mixed-effect modeling, using NONMEM. The pharmacokinetics of miltefosine could best be described by an open two-compartment disposition model, with a first elimination half-life of 7.05 days and a terminal elimination half-life of 30.9 days. The median concentration in the la...

This article reviews essential topics of canine visceral leishmaniasis (CVL) due to Leishmania infantum infection. It focuses on the current serological and molecular diagnostic methods used in epidemiological research and veterinary clinics to diagnose CVL and includes new point-of-care (POC) tests under development. The efficacy of different treatment regimens on the clinical improvement and infectiousness of dogs is also addressed. In the last section, the review provides a critical appraisal of the effectiveness of different control measures that have been implemented to curb disease transmission.

A dodecylphosphocholine micelle of 86 monomers with 5776 water molecules has been simulated under NPT conditions for 3.2 ns using GROMACS2.0. The micelle was found to be very dynamic. Some of the C-C bonds, independent of their position in the DPC monomer, adopt gauche conformation and the trans <--> gauche transitions are quite frequent. An average of about 11% of the C-C bonds in the micelle are observed to be in the gauche conformation (i.e., |dihedral angle|< 120 degrees). The terminal methyl groups are randomly distributed all over the micelle whereas the nitrogen atom of phosphocholine headgroup atoms is restricted to the interface region. Some of the monomers were found to lie on the surface. The shape of micelle, influenced by the packing considerations, shows deviations from spherical shape. The phosphocholine headgroup is well solvated and there is no water penetration into the micelle core. The overall features of the micelle of 86 DPC monomers conforms to the la...

Trypanosomes are blood protozoan parasites that are capable of producing illness in the vertebrate host. Within Australia, several native Trypanosoma species have been described infecting wildlife. However, only Trypanosoma copemani has been associated with pathological lesions in wildlife hosts and more recently has been associated with the drastic decline of the critically endangered woylie (Bettongia penicillata). The impact that some trypanosomes have on the health of the vertebrate host has led to the development of numerous drug compounds that could inhibit the growth or kill the parasite. This study investigated and compared the in vitro susceptibility of two strains of T. copemani (G1 and G2) and one strain of Trypanosoma cruzi (10R26) against drugs that are known to show trypanocidal activity (benznidazole, posaconazole, miltefosine and melarsoprol) and against four lead compounds, two fenarimols and two pyridine derivatives (EPL-BS1937, EPL-BS2391, EPL-BS0967, and EPL-BS12...

AmBisome therapy for VL has an excellent efficacy and safety profile and has been adopted as a first-line regimen in Bangladesh. Second-line treatment options are limited and should preferably be given in short course combinations in order to prevent the development of resistant strains. Combination regimens including AmBisome, paromomycin and miltefosine have proved to be safe and effective in the treatment of VL in India. In the present study, the safety and efficacy of these same combinations were assessed in field conditions in Bangladesh. The safety and efficacy of three combination regimens: a 5 mg/kg single dose of AmBisome + 7 subsequent days of miltefosine (2.5 mg/kg/day), a 5 mg/kg single dose of AmBisome + 10 subsequent days of paromomycin (15 mg/kg/day) and 10 days of paromomycin (15 mg/kg/day) + miltefosine (2.5 mg/kg/day), were compared with a standard regimen of AmBisome 15 mg/kg given in 5 mg/kg doses on days 1, 3 and 5. This was a phase III open label, individually ...