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 reduce testosterone in men 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 reduce testosterone in men 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 reduce testosterone in men 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 reduce testosterone in men 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 reduce testosterone in men 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 cephalexin low cost 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 reduce testosterone in men 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 reduce testosterone in men 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 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 reduce testosterone in men = 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 , reduce testosterone in men 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 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 reduce testosterone in men of amb to the target tissue, as well as better tissue penetration the ability of cochleate vehicles to deliver systemic amb after single or multiple oral dosing suggest the 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, reduce testosterone in men 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 reduce testosterone in men 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 reduce testosterone in men 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 , reduce testosterone in men 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 reduce testosterone in men 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 reduce testosterone in men 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 reduce testosterone in men � 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 = reduce testosterone in men 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 reduce testosterone in men 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 reduce testosterone in men 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 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 reduce testosterone in men 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 reduce testosterone in men 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 reduce testosterone in men 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 reduce testosterone in men 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 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 reduce testosterone in men 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 reduce testosterone in men 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 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 reduce testosterone in men 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 reduce testosterone in men 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 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 reduce testosterone in men 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 reduce testosterone in men 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 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 reduce testosterone in men 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 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, 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 drugcochleate in the market place represents a big challenge for instance, when oral amphotericin � cochleates are ultimately available for patients, thus will provide a new opening in the treatment of systemic fungal infections references chien yw novel reduce testosterone in men drug delivery systems drugs and the pharmaceutical sciences, vol marcel dekker new york, ny rathbone mj, hadgraft j and michael sr modifiedrelease drug delivery technology drugs and the pharmaceutical sciences, reduce testosterone in men vol marcel dekker new york, ny charman wn lipids, lipophilic drugs and oral deliverysome emerging concepts j pharm sci bowtle w lipid formulations for oral drug delivery pharm technol eur reduce testosterone in men attwood d microemulsions, in kreutrer j ed colloidal drug delivery systems marcel dekker new york, pp lawrence mj microemulsions as drug delivery vehicles curr opin colloid interface sci pouton cw and charman wn 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formation reduce testosterone in men by fusion of unilamellar lipid vesicles bioehim biophys acta papahadjopoulos d large unilamellar vesicles luv and method of preparing the same us patent papahadjopoulos d, nir s and duzgunes n molecular mechanisms of calcium induced membrane fusion j bioenerg biomembr wilschut j and papahadjopoulos d ca induced fusion of phospholipid vesicles monitored by mixing of aqueous contents nature mannino rj and gouldfogerite s antigen cochleate formulations for oral and systemic vaccination, in levine mm ed new generation vaccines marcel dekker new york, pp zarif l and perlin d amphotericin � reduce testosterone in men nanocochleates from formulation to oral efficacy drug del technol zarif l, graybill jr, perlin d, navjar l, bocanegra r and mannino rj antifungal activity of amphotericin � cochleates against candida albicans in a mouse model antimi crob agents chemother walsh tj, viviani ma, arathoon e, chiou c, ghannoum m, groll ah and odds fc new targets and delivery systems for antifungal therapy medmycol supp l biodelivery sciences wwwbiodeliverysciencescom unger e method for delivering bioactive agents using cochleates us b zarif l, jin t, segarra i and mannino rj new cochleate formulations, process of preparation and their use for the delivery of biologically relevant molecules pct application wool a zarif l and mannino rj cochleates lipidbased vehicles for gene delivery reduce testosterone in men concept, achievements and future development, in habib n ed cancer gene therapy past achievements and future challenges kluwer academicplenum publishers new york, pp graham i, gagne j and silvius jr kinetics and thermodynamics of calcium induced lateral phase separations in phosphatidic acid containing bilayers biochemistry archibald dd and mann s selfassembled microstructures from ,ethanediol suspensions of pure and binary mixtures of neutral and acidic biological galactosylce ramides chem phys lipids l holland jw, hui c, cullis pr and madden td polyethylene glycollipid conjugates regulate the calciuminduced fusion of liposomes composed of phos phatidylethanolamine and phosphatidylserine biochemistry villardita c, grioli s, salmeri g, nicoletti f and pennisi g multicenter clinical trial of brain phosphatidylserine in elderly patients with intellectual deterioration, clin trials ] crook th, tinklenberg j, yesavage j, petrie w, nunzi mg and massari dc effects of phosphatidylserine in ageassociated memory impairment neurology engle rr, satzger w and gunther w doubleblind crossover study of phosphatidylserine vs placebo in patients with early dementia of the alzheimer type eur neuropsychopharmacol amaducci l phosphatidylserine in the treatment of alzheimers disease results of a reduce testosterone in men multicenter study psychopharmacol bull cennachi t, bertoldin t, farina c, fiori mg and crepaldi g cognitive decline in the elderly a double blind, placebocontrolled multicenter study on efficacy of phosphatidylserine administration aging guidin j et al effect of soy lecithin phosphatidylserine ps complex on memory impairment and mood in the functioning elderly dept geriatrics, kaplan hospital, rehovot, israel maggioni m, reduce testosterone in men picotti gb, bondiolotti gp et al effects of phosphatidylserine therapy in geriatric patients with depressive disorders acta psychiatr scand nerozzi d, aceti f, melia e, magnani a, marino r, genovesi g, amalfitano m, cozza g, murgiano s, de giorgis g, et al phosphatidylserine and memory disorders in the aged clin per monteleone p, beinat l, tanzillo c, maj m and kemali d effects of phosphatidylserine on the neuroendocrine response to physical stress in humans neuroen docrinology monteleone p et al blunting by chronic phosphatidylserine administration of the stressinduced activation of reduce testosterone in men the hypothalamopituitaryadrenal axis in healthy men eur ] clin pharmacol funfgeld ew, baggen m, nedwidek p, richstein � and mistlberger g double blind study with phosphatidylserine ps in parkinsonian reduce testosterone in men patients with senile dementia of alzheimers type sdat prog clin res zarif l and tan f cochleates made with purified soy phosphatidylserine us al duzgunes n, nir s, wischut j, reduce testosterone in men bentz j, newton c, portis a and papahadjopoulos d calcium and magnesium induced fusion of mixed phosphatidylserine phosphatidylcholine vesicles effect of ionbinding j membr biol portis a, newton c, pangborn reduce testosterone in men w and papahadjopoulos d studies on the mechanism of membrane fusion evidence for an intermembrane caphospholipid complex, synergism with mg, and inhibition by spectrin biochemistry santangelo r, paderu p, delmas g, chen zw mannino r, zarif l and perlin d efficacy of oral cochleates amphotericin b in a mouse model of systemic candidiasis antimicrob agents chemother zarif l, segarra i, reduce testosterone in men 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 reduce testosterone in men 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 reduce testosterone in men 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 reduce testosterone in men 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, reduce testosterone in men 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 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 reduce testosterone in men 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?