from ref with permission concentration of drug fig tissue burden for mice infected in a model of invasive aspergillosis after oral administration of camb from ref with permission the tissue fungal burden for target organs, kidneys, liver and lungs, demonstrated the benefic effect of camb fig camb showed a pronounced dose dependent reduction in the fungal burden in al organs the near eradication of aspergillus was observed above a concentration of mgkgday camb at mgkg po was as effective as camb at mgkg po in reducing fungal tissue amitriptyine mix mirtazapine burden in cryptococcal meningitis animal model oral amphotericin � cochleates were effective in a murine cryptococcal meningitis model with an survival after days, obtained after oral treatment with camb lomgkg amitriptyine mix mirtazapine to mice having intracerebral infection with cryptococcus neoformans toxicity of amphotericin � cochleates in vitro, amphotericin � cochleates camb showed a low toxicity on red blood cells when compared with amitriptyine mix mirtazapine fungizone damb camb showed no hemoglobin release and therefore no hemolysis of red blood cells when incubated at igml in contrast, damb was hemolytic at xgml due to the presence of the detergent, sodium desoxycholate in vivo, camb was non toxic to mice when administered orally at mgkgday for days no nephrotoxicity was observed as demonstrated by the normal bun level, and the histopathology of kidneys, lungs, liver, spleen and gi tract showed that animals dosed with camb were comparable to controls pharmacokinetics of amphotericin � cochleates oral pharmacokineticspt pharmacokinetic studies have shown that after oral administration of camb, amb is distributed into the target tissues eg brain, liver, lung, spleen and kidneys in healthy mice and amb tissue level suggests a zeroorder uptake process for all tissues when camb was administered po to cbl mice at lomgkg � = , and blood and tissues collected and amb level measured by amitriptyine mix mirtazapine hplc, blood shows a plateaushaped profile with tmax = h and cmax = mgml non compartmental nca analysis showed blood aucoo = xghml, ti = h, mrto�� = h, clf amitriptyine mix mirtazapine = mlminkg, vzf = lkg amb tissue exposure auco��, mghg evaluated using nca was greater for lungs , followed by liver , spleen kidneys and heart tissue elu tion tih kidneys , lungs , heart , liver and spleen for all tissues, tmax = h and cmax ranged between xgml for heart and igml for lungs the delivery of amb by cochleates after multiple oral amitriptyine mix mirtazapine doses was assessed in the same mouse model and was compared with ambisome it was found that cochleate provides therapeutic levels in tissue and presents better delivery and transfer efficiency amitriptyine mix mirtazapine of amb to the target tissue, as well as better tissue penetration the ability of cochleate prednisone forte eyedrop aggravated hypertension vehicles to deliver systemic amb after single or multiple oral dosing suggest the amitriptyine mix mirtazapine potential of camb formulations to treat and prevent systemic fungal infections pharmacokinetics amb given intraveneously iv to mice showed a twophase pharmacokinetic profile, pharmacokinetic analysis in target tissues liver, spleen, kidney and lungs shows a multipeak profile, large auc and mrt after iv administration of mgkg, amb presented a twophase blood concentration time course [fig a] this profile is characterized amitriptyine mix mirtazapine by a very fast distribution phase and an elimination phase with t = hrs the auco�� was a,ghml, ci = mlminkg, mrtoo = hrs and vss = lkg this amitriptyine mix mirtazapine pharmacokinetic profile indicates that camb is removed fast from blood in addition, the large vss also indicates a large distribution into the tissues the results obtained in target tissues showed this extensive distribution and penetration [fig b] calculation of pharmacokinetic parameters showed that the main target tissues have a large amb exposure reflected in the auc and cmax values table , amitriptyine mix mirtazapine as well as the tissue to blood auc ratio the large amb exposure in liver and spleen suggests involvement of the mononuclear phagocyte system mps in the removal of camb amitriptyine mix mirtazapine cochleates are particulates that can be quickly cleared from the circulation by the macrophages of the reticular endothelial system res related to the liver and the spleen in addition, physical retention seems to play a role in the kinetic profile of the lungs due to its capillary nature time hours fig a amb profile in blood after a single dose amitriptyine mix mirtazapine � iv pk profile of amb in target tissues, from ref , with permission table pharmacokinetics parameters for camb in different target organs after iv administration to cbl mice n = per time point from ref , with permission tissue auc t ma � max zv mgh min mgg hrs liver spleen lung kidney heart intestine stomach this phenomenon and the mobility amitriptyine mix mirtazapine of the macrophages seem to cause certain redistribution of cochleates that gives a multipeak and plateau shape profiles in liver and spleen finally, amb was also detected in bile and intestine contents, suggesting that bile excretion may be an additional elimination route , other potential applications for cochleates cochleate for the delivery of antibiotics as cochleate has shown a high affinity to be engulfed by macrophages [fig a] probably due to a dual mechanism, the cochleate essential particulate feature and possibly a ps receptor mediated internalization of the cochleate into macrophage putfl� fig uptake of amphotericin � cochleates by j macrophages as seen by a fluorescence microscopy, b confocal microscopy from ref , with permission this particulate system would have potential amitriptyine mix mirtazapine for the delivery of antibacterial agents such as aminoglycosides and vancomycin illustration is given by the encapsulation of clofazimine, an antitb drug, and tobramycin, an aminoglycoside antibiotic used in treating bacterial infections, both given intraveneously thus far the cochleate system may possibly offer a new oral way of delivery delivery of clofazimine clofazimine cochleates were prepared by the trapping method amitriptyine mix mirtazapine clofazimine is a known hydrophobic antitb drug, the efficacy of clofazimine cochleate was assessed by measuring the ic in vero cells and in bone marrow derived macrophage bmm clofazimine cochleates exhibit a greater decrease in toxicity versus free clofazimine and had a higher efficacy in killing intracellular m tuberculosis than free clofazimine log reduction ce was achieved at igml for amitriptyine mix mirtazapine cochleates, while free clofazimine was toxic at this concentration this shows that encapsulation of clofazimine in cochleates potentiates the antimicrobial efficacy of the drug, ie when higher concentration of drug can be used because of less toxicity, bactericidal levels of the drug could be attained delivery of tobramycin a recent research work has been published on the possible use of nanocochleates as an oral delivery system for tobramycin tobramycin is a well known aminoglycoside antibiotic used in treating bacterial infections, and is usually administered by intravenous iv infusion, intramuscular im amitriptyine mix mirtazapine injection, or inhalation this amin ogycoside drug is known for its side effects such as mineral depletion ie calcium, magnesium, potassium after iv administration in this work, the author described that tobramycin which is positively charged at low ph, will be encapsulated in the interbilayer space of cochleates the fusion of unilamellar liposomes is no longer induced by a metal cation such as ca, but by the organic molecule to be encapsulated the cochleate cylinders formation has been described by papahadjoupolos as resulting partly from the intrinsic properties of the amitriptyine mix mirtazapine calcium cation indeed, phosphatidylserine shows considerable selectivity for calcium due to the propensity of calcium to lose part of its hydration shell, and to displace water upon complex formation in amitriptyine mix mirtazapine the cochleate solid crystalline structures formation, calcium plays a crucial role in bringing bilayers together closely through partial dehydration of the membrane surface and the cross linking of opposing molecules amitriptyine mix mirtazapine of phosphatidylserine in our opinion, in this recent work where formation of cochleate is claimed with no calcium present, additional relevant physicochemical evidence on cochleate formation and the localization of amitriptyine mix mirtazapine the drug in the interbilayer space will be needed cochleate for the delivery of antiinflammatory drugs as a result of the deep embedding of the molecules in the cochleates structures, drug molecules are hidden from the outside environment this should have two beneficial effects one is to hide and protect the molecule from the degradation due to environment the amitriptyine mix mirtazapine other is to protect, the environment when needed, from the active molecule when such molecule presents side effects this is the case of antiinflammatory drugs, which associates cure to the disturbance of gi tract stomach for instance cochleates were described to act beneficially in this area, reducing the stomach irritation when antiinflammatory drugs such as aspirin is hidden in the amitriptyine mix mirtazapine cochleate structure, and administered to a car rageenan rat model for acute inflammation other uses of cochlea tes cochleates were also described as vehicles for nutrients as an improved drug amitriptyine mix mirtazapine and contrast agent delivery system, as well as intermediate in the preparation of special liposomes such as large unilamellar vesicles luv and proteoliposomes in fact, the discovery of the cochleate structures was a result of the desire to prepare luv by pr papahadjoupoulos which were developed for the delivery of hydrophilic drugs proteoliposomes prepared from cochleates intermediates were described for vaccine applications in general, and more recently, when containing lipopolysaccharide as a novel adjuvant conclusion cochleates lipidbased nanocarrier appears to have potential for the oral delivery of bioactive molecules future amitriptyine mix mirtazapine work should be directed towards more fundamental science, as many research aspects of the cochleate drug carrier system are still hardly known eg localization of the drug in lipid bilayers, amitriptyine mix mirtazapine impact of multivalent cations on the cochleate formation, mechanism of action of cochleate after oral uptake in addition, the development of friendly analytical assays to monitor the drug localization and loading percentage in cochleates will be desired this nano drug carrier is currently under development by biodelivery sciences international having the first 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amphotericin b in a mouse model of systemic candidiasis antimicrob agents chemother zarif l, segarra i, amitriptyine mix mirtazapine jin t, scolpino a, hyra d, daublin p, krause s, perlin ds, lambros c, graybill jr and mannino rj lipidbased cochleate system for oral and systemic delivery of drugs aaps eastern regional meeting and exposition segarra i, hyramovshin da, chen zw, santangelo r, perlin d, paderu p, mannino rj and zarif l amb cochleates, a new lipidbased formulation for amphotericin b from iv pharmacokinetics to oral efficacy millenial world congress of pharmaceutical sciences, san franscisco, ca, april, pp segarra i, jin t, hyra d, mannino rj and zarif l oral administration of amphotericin � with a new ambcochleate formulation tissue distribution after single and multiple oral dose icaac abs segarra i, movshin d, mannino rj and zarif l pharmacokinetics and tissue distribution of amphotericin � in mice after oral administration of amb cochleates, a new effective lipidbased formulation for the oral treatment of systemic fungal infections icaac abs segarra i, amitriptyine mix mirtazapine chen zw, movshin da, tan f, mannino rj and zarif l tissue distribution of oral amphotericin � lipidbased cochleate formulation comparison with ambisome th international symposium on controlled release of bioactive materials, paris france, pp zarif l, segarra i, jin t, hyra d and mannino rj amphotericin � cochleates as a novel oral delivery system for the treatment of fungal infections th international symposium on controlled release of bioactive materials boston, ma, june perlin d, santangelo r, mannino r and zarif l oral delivery of cochleates containing amphotericin � camb amitriptyine mix mirtazapine is highly effective in a candidiasis murine model, focus fungal infect zarif l, segarra i, jin t, hyra d, perlin d, graybill jr and mannino jr oral and systemic delivery of amphotericin � mediated by cochleates aaps annual meeting and exposition, november zarif l, jin t, scolpino a and mannino rj are cochleates the new lipidbased carrier for oral drug delivery?