j control rel cui z, patel j, tuzova m, ray p, phillips r, woodward jg, nath a and mumper rj strong t cell type immune responses to hiv tat proteincoated nanoparticles vaccine fifis t, gamvrellis a, crimeenirwin b, pietersz ga, li j, mottram pl, mckenzie if warning paxil and plebanski m sizedependent immunogenicity therapeutic and protective properties of nanovaccines against tumors } immunol singh m, briones m, ott g and ohagan d cationic microparticles a potent delivery system for dna vaccines proc natl acad sci usa roy �, mao hq, huang sk and leong kw warning paxil oral gene delivery with chitosan � dna nanoparticles generates immunologic protection in a murine model of peanut allergy nat med bivasbenita m, van meijgaarden ke, franken klmc, junginger he, borchard g, otten hoff thm and geluk a pulmonary delivery of chitosandna nanoparticles enhances the immunogenicity of a warning paxil dna vaccine encoding hlaarestricted t cell epitopes of mycobacterium tuberculosis vaccine locher cp, putnam d, langer r, witt sa, ashlock bm and levy ja enhancement of a human immunodeficiency virus env dna vaccine using a novel polycationic nanoparticle formulation immunol lett pharmaceutical nanocarriers in treatment and imaging of warning paxil infection raymond m schiffelers, cert storm and irma a j m bakkerwoudenberg nanoscaled carrier systems can be used in the treatment and imaging of infectious diseases to optimize accumulation of the carrier at the site of infection, the characteristics of the nanocarriers should complement the pathophysiological processes warning paxil that play a role during infection as carriers are recognized as foreign materials, they can be employed for targeting the mononuclear phagocyte system mps the mps consists of cells that are specialized in the clearance of the body of foreign particles as such, these cells are involved warning paxil in the clearance of microorganisms and they form an important replication site for infectious organisms to survive intracellularly if carriers can avoid recognition by the mps, it allows them to take advantage of the enhanced capillary permeability that is one of the hallmarks of the inflammatory reaction warning paxil coinciding with infection together with the local efflux of plasma, nanoscaled carriers can enter the inflamed area through convective forces finally, the carrier can be locally administered to interact specifically with tissues, cells or microorganisms that are present at the site of infection introduction pharmaceutical nanocarrier systems include warning paxil liposomes, nanoparticles, micelles and emulsions, and they can be used hormone replacement bioidentical testosterone dfw southlake in the treatment and imaging of infectious diseases these systems are used to improve the degree of localization or the persistence of encapsulated antimicrobial drugs or imaging molecules at the site of infection by altering the molecules warning paxil pharmacokinetics and tissue distribution profiles to optimize accumulation of the carrier at the site of infection, factors on the side of the carrier, as well as on the side of the infected host should be taken into account ideally, the characteristics of the nanocarriers should be tailored warning paxil to complement the pathophysiological processes that play a role during infection three strategies to target sites of infection have been employed the use of carriers that are recognized as foreign materials the use of carriers that avoid recognition as foreign materials, and local delivery of carriers these warning paxil targeting strategies are discussed in the light of recent developments in delivery strategies and the introduction of new antimicrobial agents such as the nubiotics for bacterial infections and sirna for viral infections carriers that are easily recognized as foreign materials most carriers that are administered in vivo are warning paxil almost always rapidly recognized as foreign materials proteins in biological fluids such as activated complement components, opsonize the carriers to facilitate recognition and uptake by cells that constitute the mps these cells are continuously surveiling the body to detect and phagocytose these opsonized foreign particles this avid warning paxil recognition and uptake mechanism can be employed for targeting purposes these cells are of interest since many infectious agents are also recognized as foreign materials and end up in the same type of cells microorganisms that are able to survive intracellularly may be difficult to reach for warning paxil conventional antimicrobial treatment, due to the barriers posed by the cellular membranes one of the first demonstrations of the value of nanoscale carriers for the delivery of drugs to the mps was delivered by new and colleagues as early as liposomeencapsulated antimony was used in this study to warning paxil treat experimental leishmaniasis, showing several orders of magnitude increase in the therapeutic index leishmaniasis is still an endemic disease in several parts of the world and also occurs as an opportunistic infection in immunocompromised patients nowadays, treatment of leishmaniasis is complicated by widespread resistance to antimony compounds warning paxil leading to treatment failure and relapse lipid formulations of amphotericin � are currently employed in the clinic as possible option for the treatment of visceral and cutaneous leishmaniasis the lipid formulation is used to facilitate drug accumulation in the macrophages as such, it is preferred over free warning paxil amphotericin � deoxycholate fungizone� the nanoparticulate structures in this formulation are unstable in the blood stream, leading to higher toxicity especially in the kidneys oilin wateremulsions of submicron sizes, also known as lipid nanospheres that have been loaded with piperine, have been described as a new formulation warning paxil for the treatment of visceral leishmaniasis all nanosphere formulations applied were more effective than the free drug in reducing parasite counts in all organs investigated in a model of leishmania donovani infection in balb� mice at a dose of mgkg the most effective formulation also contained the cationic warning paxil lipid steary lamine inclusion of charged lipids usually promotes phagocyte uptake of lipidic carrier systems, which probably explains the increased therapeutic effect alternatively, stearylamine has been described as leishmanicidal agent furthermore, it was shown that enzyme levels in blood as a measure for liver toxicity and creatinine, warning paxil and urea levels in the blood as a measure for renal toxicity were not altered after administration of the drug in the nanosphere formulations, indicating that toxicity of these formulations in these organs is limited recently, a liposomal pentavalent antimony formulation was described, targeted at the macrophage warning paxil via the scavenger receptors a and � for the treatment of leishmania chagasi amastigotes the natural affinity of these receptors for polyanions was used by the inclusion of the negatively charged phospholipid phosphatidylserine in the liposomal membrane the negative charge mediates receptor mediated endocytosis furthermore, the authors warning paxil demonstrated that the scavenger receptor was upregulated upon infection, possibly through secretion of transforming growth factorpi, which could preferentially increase uptake by infected macrophages nevertheless, infected macrophages ingested less liposomes than normal macrophages, possibly because of the high parasite burden per macrophage that could affect normal cell metabolism warning paxil overall, the targeted drug showed a fold higher efficacy, compared with free compound in vitro the same strategy with phosphatidylserine was used to target liposomes to macrophages infected with cryptococcus neoformans incorporation of chloroquine in liposomes resulted in increased delivery to macrophages in vitro and in vivo warning paxil this promoted infected mouse survival and reduced parasite counts in liver and brain mannose was used as a recognition signal for macrophage uptake by the man nose receptor by medda et al phospholipid microspheres consisting of polylactic coglycolic acid and phosphatidyl ethanol amine were grafted with mannose warning paxil and subcutaneously injected in this system, dihydroindolo [,a] indolizine, an antileishmanial agent, was incorporated the drug was administered at a dose of mgkg in leishmania donovani infected hamsters, mannosegrafted microspheres suppressed parasite numbers in the spleen over , whereas free drug only reduced numbers by furthermore, it was warning paxil shown that infection induced changes in the blood levels of hepatic enzymes, creatinine and urea these changes could largely be prevented by the formulated drug mannosecoated liposomes were also employed to deliver cpgcontaining oligodeoxynucleotides to macrophages infected with leishmania donovani these cpgoligonucleotides activate macrophages through the presence warning paxil of cytidine phosphorothioate guanosine islands that are strong activators of macrophages via tolllike receptors, leading to interleukin and interferon� production in mice, suffering from visceral leishmaniasis, mannosecoated liposomes containing cpgoligonucleotides, were more effective in inhibiting amastigote growth than liposomeencapsulated cpgoligonucleotides or free cpgoligonucleotides in the spleen, the warning paxil mannosecoated liposomal formulation of the cpgoligonucleotides completely eliminated the parasites, whereas both controls failed to achieve complete eradication a dual targeting approach combining tuftsin and nystatin in liposomes was reported by khan et al, in their studies, the effects of the liposomal antifungal agents on candida albicans warning paxil infection in mice was studied the tuftsinbearing liposomes were taken up by macrophages by binding to the tuftsin receptor which activated these cells as these cells were loaded with liposomal nystatin, this may improve their killing of phagocytosed c albicans organisms through the added action of the drug warning paxil alternatively, the macrophages may function as a depot for subsequent prolonged release of the drug in this study, combination of tuftsin and nystatin in the liposome formulation increased c albicans clearance in liver, spleen, kidneys and lungs, and reduced the numbers of organisms in the blood stream, warning paxil thereby promoting mice survival, compared with free agents or liposomal formulation of either tuftsin or nystatin alone in another study, delivery of immunomodulatory compounds to macrophages was demonstrated the important role of macrophages in generating proinflammatory reactions had been the basis for targeting antisense molecules to these warning paxil cells antisense oligomers against tumor necrosis factoralpha were incorporated into albumin microspheres endotoxin was administered iv or escherichia coli was administered ip to rats animals received fig antisense tnf and tnf inhibition and rat survival was measured microencapsulated antisense improved survival in these endotoxin and e coli warning paxil peritonitis models, compared with free anti sense importantly, delivery by albumin encapsulation prolonged the action of the antisense to hrs in a similar approach, sioud and sorensen employed the process of rna interference to silence tnfproduction the process was based on cellular delivery of small interfering rna sirna, warning paxil small doublestranded rna molecules that mediate degradation of complementary mrna sequences sirna was administered at a dose of to ig and was complexed to liposomes that were based on the cationic lipid dioleoyl trimethylammonium propane the complexes were injected ip and shown to prevent the induction of warning paxil tnf production upon challenge by endotoxin the specificity of the inhibition was demonstrated by the fact that the induction of il expression remained unchanged carriers that avoid recognition as foreign materials the specific accumulation of carriers that are easily recognized as foreign materials by macrophage can offer warning paxil great benefits when the infectious organism is exclusively localized in these cells for microorganisms that are primarily present in other tissues, this fast recognition can become a major obstacle to reach distant sites therefore, carriers have been developed to avoid recognition by the mps, allowing these carrier warning paxil systems to take advantage of the increased capillary permeability at the site of infection the increased capillary permeability as well as vascular leakage are accompanying inflammatory reactions together with infection with the local efflux of plasma, plasma proteins and immune cells, nanoscaled carriers can enter the inflamed area warning paxil through convective forces this approach has been used in the treatment and imaging of infections in magnetic resonance based imaging, the natural tropism of nm iron oxide particles to be rapidly taken up by liver and spleen macrophages prevented imaging of peripheral infections in the studies by warning paxil kaim et al, the usage of ultra small nanoparticles was explored, the nanoparticles consisted of a core of iron oxide crystals that is coated with dextran the mean particle size was nm as a result of this small particle size, the blood halflife in rats increased to warning paxil approximately hrs the authors demonstrated successful imaging of soft tissue infections in rats using this system they postulate that the mechanism responsible is the uptake by peripheral macrophages in the blood stream, followed by extravasation at the site of infection based on the absence of nonphagocytosed particles in warning paxil the inflammatory milieu however, the presence of noningested particles may be underestimated due to the cellular accumulation, making it difficult to quantify individual extracellular particles longcirculating liposomes, which have a substantially prolonged circulation time compared with the iron oxide particles that were described above a halflife of approximately hrs in rats, have also been successfully employed to image a variety of infectious diseases the use of longcirculating liposomes for imaging purposes has been reviewed recently recent advances include the detection of invasive pulmonary aspergillosis at an early stage of infection the causative fungus aspergillus warning paxil fumigatus is difficult to detect using conventional imaging agents, and in most cases, only at an advanced stage of the disease furthermore, interpretation of ctscan images is difficult as the supposedly characteristic halo or air crescentsign of the infection is not always clear imaging of intravenously injected warning paxil mtcpeg liposomes in a rat model of leftsided invasive pulmonary aspergillosis, demonstrated that of the scintigraphic images revealed the presence of the fungus already at hr inoculation active infection was needed for the accumulation of labeled liposomes to occur, as inoculation with saline or killed aspergillusspores did not warning paxil cause increased liposome accumulation in the inoculated lung the long circulatory halflife of pegliposomes results in a gradual increase in accumulation at the site of infection, which is in general considered an advantage as the scintigraphic image improves nevertheless, in specific situations when the infection is localized warning paxil in the vicinity of the heart or large blood vessels, the background activity of the blood remains high for prolonged periods of time, thus hampering visualization laverman et al demonstrated that biotincoated mtc pegliposomes kept their longcirculating halflife however, upon injection of avidin, complexes were formed intravenously, warning paxil resulting in a rapid clearance from the blood stream by mpsorgans this clearance coincided with a loss of activity in the blood pool, allowing visualization of an experimental abscess in the neck region of the rabbits, previously undetected due to the activity in the heart region these warning paxil longcirculating pegliposomes can also be loaded with antimicrobial agents to achieve sitespecific drug delivery, as has been recently reviewed, in our own laboratory, we have evaluated the factors on the side of the host, as well as on the side of the liposome that determine target localization it warning paxil appeared that the area under the blood concentration timecurve determined the degree of localization at the site of infection whereas the level of vascular leakage was the most important determinant on the side of the host optimized pegliposomes were loaded with gentamicin and therapeutic effects were studied warning paxil in a rat klebsiella pneumoniae model rat survival was strongly dependent on the gentamicin formulation in immunocompetent rats, liposomal gentamicin was superior over the free drug, even though complete therapeutic efficacy could be achieved with multiple administrations of the free drug in leukopenic rats, a combination of warning paxil free and liposomal gentamicin showed best therapeutic effects, compared with either treatment alone it is postulated that liposomal gentamicin produces low therapeutically active drug concentrations in the blood stream, which are insufficient to control the rapidly occurring bacteremia in the case of impaired host defense however, liposomal gentamicin warning paxil does localize in the infected lung and leads to local bacterial killing therefore, the combination of free drug producing active antimicrobial levels in the circulation and liposomal drug leading to high drug levels in the lung showed optimal results pegliposomes were also loaded with a combination of warning paxil antimicrobial agents that was predicted to interact synergistically based on in vitro data whether synergistic drug action in vivo also occurs when the agents are administered in the free form is questionable, as their differing pharmacokinetic profile and tissue distribution do not correlate with the static drug warning paxil concentrations present in the in vitro assays however, the use of a targeted drug carrier such as long circulating pegliposomes, could enforce a parallel tissue distribution resulting in increased concentrations at the site of infection gentamicin and ceftazidime were coencapsulated in longcirculating liposomes, as these agents were warning paxil demonstrated in vitro to act synergistically on k pneumoniae these liposomes were tested for their ability to prolong the survival of rats infected in the left lung with a high gentamicinceftazidimesusceptible or a gentamicinceftazidimeresistant k pneumoniae the high susceptible k pneumoniae could be effectively treated with single doses warning paxil of lipsomalgentamicin or liposomalceftazidime liposomal co encapsulation of both agents allowed reductions in doses due to a synergistic therapeutic effect of these antibiotics in the resistant k pneumoniae model, the coencapsulated agents again resulted in the synergistic activity of both antibiotics, allowing effective treatment of the otherwise warning paxil lethal pneumonia interestingly, in both models, combinations of the two free drugs were merely additive ostearylamylopectin was used as a recognition signal for the uptake of peg liposomes by lung macrophages the macrophages in this organ are an important replication site for mycobacterium tuberculosis replication in a warning paxil murine model of m tuberculosis infection, administration of liposomeencapsulated isoniazid and rifampicin reduced the number of bacteria in lungs, liver and spleen more efficiently than the free drugs there was no significant reduction in bacterial numbers in mice treated with free drugs once weekly for weeks, compared warning paxil with untreated control mice liposomal treatment resulted in approximately decrease in bacterial numbers the enhanced efficacy of the liposomeencapsulated drugs is likely to enhance delivery to macrophages in liver, spleen, and lungs in another study focused on osteomyelitis, vancomycin and ciprofloxacin were encapsulated in liposomes as compared with neutral or anionic liposomes, cationic liposomes entrapped the highest percentage of drugs and showed highest antibacterial activity in vitro, probably due to the charge based cell interactions that can occur in vitro the cationic liposomes were tested for therapeutic efficacy in a rabbit model of chronic staphylococcal warning paxil osteomyelitis both free ciprofloxacin or vancomycin over a period of two weeks failed to achieve bone sterilization after iv injection combination of free ciprofloxacin and vancomycin was more effective only at the expense of renal dysfunction and severe diarrhea complete sterilization of the bone was seen in the group treated for two weeks with the combination of drugs in liposomal form, while nephrotoxicity and diarrhea were less frequent although the cationic liposomes showed preferable characteristics in vitro regarding drug encapsulation and antibacterial effect, it is likely that the use of neutral or pegcoated liposomes would warning paxil have improved results as the localization at the site of infection for cationic liposomes is expected to be limited due to the rapid clearance of charged liposome species another application of longcirculating liposomes is that they can be employed as a sustained drug delivery system in the blood stream when ciprofloxacin is encapsulated in the pegliposomes, there is a gradual release of antibiotic from the liposomes, as such, the liposomal formulation displayed a prolonged presence in the blood and tissues of ciprofloxacin as the encapsulated ciprofloxacin is shielded from the tissues by the liposomal warning paxil membrane, the antibiotic could also be administered at relatively high doses interestingly, in the rat pneumonia model with high ciprofloxacin susceptible k pneumoniae, animal survival could not be achieved with the free drug at a once daily dosing schedule where the highest doses could be administered in warning paxil contrast, liposomeencapsulated ciprofloxacin injected once daily was still effective at this low frequency dose schedule to promote localization of amphotericin � at infectious foci, a number of formulations have been devised trying to achieve prolonged presence of amphotericin � in the blood stream and to shield the toxicity warning paxil of the drug espuelas and colleagues used polyepsiloncaprolactone nanospheres coated with poloxamer or mixed micelles with of this surfactant to deliver amphotericin b both formulations had an approximately fold lower activity in vitro against c albicans however, the activity towards infected macrophages was similar to that of warning paxil fungizone� that is fold reduced however, the reduced toxicity was paralleled by a fold reduced efficacy similar observations have been noted in most studies concerning alternative formulations of amphotericin b, achievement of the reduction of the toxicity of the drug parallels a reduction in therapeutic efficacy a warning paxil study by fukui et al, however, shows that these two phenomena can be uncoupled lipid nanospheres were used to deliver amphotericin b, and this new formulation was compared with the commercially available lipid formulations of amphotericin b plasma amphotericin blevels of amphocil� or abelcet� were low, reaching warning paxil levels below xgml within minutes after intravenous injection in rats at a dose of mgkg amphotericin � levels in the lipid nanosphere formulation were nearly two orders of magnitude higher and similar to those yielded by ambisome� interestingly, in dogs, plasma amphotericin � concentrations after administration in the warning paxil nanosphere formulation were approximately fold higher than that of ambisome� in a rat model of local candidiasis, amphotericin bcontaining nanospheres significantly inhibited the growth of c albicans, whereas ambisome� did not, even though local amphotericin � concentrations were similar these results were similar as obtained in vitro warning paxil where nanopshereincorporated amphotericin � was as effective as fungizone�, while ambisome� activity was reduced similarly, amphotericin bcontaining nanoparticles were designed coated with heparin to achieve localization at the infected site, at the site of lesions the heparincoated formulation did achieve fold higher concentrations in the lungs of warning paxil mice with pulmonary blastomycosis than fungizone� however, this could reflect a difference in pharmacokinetics rather than the specific binding at the target site in this mouse model, fungizone� dosed at the maximum tolerated dose mgkg failed to cure mice, whereas the nanoparticles dosed at mgkg achieved a warning paxil cure rate local application of carriers nanoparticulate drug delivery systems may also be applied locally at the site of infection to increase drug delivery or to act as a local depot from which the drug is gradually released a new class of dna or rnabased antimicrobial agents known warning paxil as nubi otics was investigated by dale et al the compounds are thought to act antimi crobially by virtue of their proton donor capacity the hydrogen ions would then be responsible for the killing of the bacteria due to membrane depolarization however, the exact mechanism of action warning paxil remains yet to be confirmed in a burnwound infection caused by pseudomonas aeruginosamodel, the therapeutic effects of neutral liposomeencapsulated nubiotics were investigated it appeared that intravenously and subcutaneously injected liposomeencapsulated drug at a dose of mgkg was able to promote the survival of mice, whereas free nubiotics warning paxil or pbs failed nucleic acid based therapeutics were also employed to treat respiratory syncytial virus the nucleic acid was an sirna that was intracellularly produced in the host by an encoding dnavector the sirna was directed towards the viral ns gene cell entry of this sirna will prevent the protein from being synthesized, hence inhibiting viral replication the dnavector was complexed to oligomeric nanometersize chitosan particles and administered intranasally sirna against ns were shown to be produced in the lung tissues and protected against respiratory syncytial virus multiplication for at least days these studies show warning paxil that this formulation may have prophylactic potential to prevent viral buy pseudoephedrine hydrocloride infection the results obtained, however, should be interpreted critically, as polylclc and cpg oligonucleotides are able to mount antiviral responses that are not specific and the phenomena of the resulting interferon production is also noted in the warning paxil study using sirna described above prophylactic administration of liposome encapsulated polylclc completely protected mice against a lethal respiratory challenge of influenza a virus in mice, whereas all animals died in the control group the antiviral effect was shown to last up to weeks after administration the strong warning paxil aspecific activity of liposomeloaded nucleic acids cautions against the straightforward attribution of therapeutic effects to specific mechanisms a series of studies used local application of nanoparticles to address helicobacter pylori infection one study employed mucoadhesive gliadin nanoparticles, containing amoxicillin for increased retention in the stomach, for the eradication warning paxil of h pylori rhodamine labeled particles were administered to rats by gavage to test their gastric mucoadhesive properties it was found that the mucoadhesive characteristics of nanoparticles increased with increasing gliadin content in mongolian gerbils, the eradication of h pylori was evaluated after oral administration of amoxicillinloaded warning paxil nanoparticles amoxicillin alone was also able to kill h pylori, but the dose needed was higher than that of the nanoparticles, likely owing to the prolonged presence of the particles in the stomach improvement of drug residence time was also the objective of a study using floating warning paxil microspheres polycarbonate based particles were tested for their floating capacity and they were loaded with acetaminohydroxamic acid in vivo studies on h pyloriinfected mongolian gerbils showed that both free drug and drugloaded particles displayed antibacterial activity in vivo, but particle encapsulation lowered the drug dose required for warning paxil h pylori eradication, by one order of magnitude, likely as a result of the prolongation of the gastric residence time of the particles in another study, lipobeads were used these beads consist of a polymeric particle core that is coated with a lipid bilayer consisting of phosphatidylethanolamine the warning paxil concept aims at binding the lipobeads to h pylori phosphatidylethanolamine receptors in addition, the particle is loaded with acetohydroxamic acid for gradual drug release in the bacterias vicinity in in vitro studies, the drug loaded particles were shown to be most efficacious in inhibiting bacterial growth and warning paxil stomach cell adherence, compared with free drug and empty lipobeads wong et al studied the effects of aerosolized nonpegylated liposomes encapsulating ciprofloxacin levels of drug in the lungs were higher after aerosoliza tion than that of free drug the therapeutic efficacy of liposomeencapsulated ciprofloxacin was compared with warning paxil free drug in a mouse model of pulmonary infection by francisella tularensis at hrs after the mice were infected intranasally with ten times the ld, they were treated with aerosolized liposomeencapsulated ciprofloxacin or ciprofloxacin in the free form, resulting in survival and survival respectively at the doses chosen warning paxil tobramycin was encapsulated in fluid liposomes that were administered intratracheally for the treatment of pseudomonas aeruginosa in rats similarly, as described above, drug exposure in the lungs was improved upon administration of tobramycin in the liposomal form single doses of free drug or liposomal drug were hardly effective, as lung counts of bacteria remained in of the animals for both formulations only after repeated administrations, bacterial numbers were noted in of the animals treated with free drug and of the animals treated with the liposomeencapsulated drug concluding remarks for mpstargeted carriers, the new developments warning paxil in this category indicate an increasing focus on specific targeting of macrophages using receptormediated endocytosis, possibly to increase the celltype specificity of targeting it may be expected that future studies will try to address different subpopulations of macrophages infected vs noninfected, activated vs quiescent to increase specificity warning paxil even more in addition, increased understanding of the immunologically important role of macrophages has generated interest in modulating their function during inflammation especially, the potent and highly specific new technique of rna interference may offer powerful ways to modulate macrophage function nevertheless, other mechanisms such as the activation warning paxil of macrophages through cpgoligonucleotides may be less specific, but they can still raise a strong response that may have important clinical benefits for longcirculating carrier systems, the gradual accumulation at the sites of infection due to locally increased capillary permeability is an important asset for the imaging warning paxil studies the use of biotin labeled liposomes to obliterate this long circulating characteristic at chosen timepoints by the injection of avidin is to remove activity from the blood pool in certain cases, this may improve the contrast long circulating characteristics may also be used for drug delivery warning paxil at peripheral sites this may also be of value for several of the microorganisms surviving inside phagocytes although liver and spleen are the prime target organs for phagocyte drug delivery, tissue macrophages may also be of interest where these infections are concerned as longcirculating carriers are ultimately warning paxil taken up by deep seated tissue macrophages in addition to mps, these carriers can also be used to reach intracellular infections outside the liver and spleen local application of drug delivery systems can have important therapeutic benefits for localized infections the confinement of h pylori to the stomach offers an ideal opportunity for local delivery the approaches discussed in this chapter are aimed at increasing stomach residence time, so as to increase drug exposure of the pathogen the same objective is true for the local delivery in the lung however, pathogens causing pneumonia may be warning paxil expected to spread from the primary site of infection to the distant tissues more easily, requiring additional treatment the local delivery approach may also be of value for nucleic acidbased drugs that are otherwise, due to their inherent instability and charged character, difficult to deliver references allen warning paxil tm and cullis pr drug delivery systems entering the mainstream science kubik t, boguniakubik � and sugisaka m nanotechnology on duty in medical applications curr pharm biotechnol l emerich df nanomedicine � prospective therapeutic and diagnostic applications exp opin biol ther ll smith al inhaled antibiotic therapy what drug?