trends biotechnol harada a and kataoka � pronounced activity of enzymes through the incorporation into the core of polyion complex micelles made from charged block copolymers control rel godbey wt, wu kk and mikos ag polyethylenimine and its role in gene delivery } control rel kopecek j, kopeckova p, atarax 10mg pet medicine side effects minko t, lu zr and peterson cm water soluble polymers in tumor targeted delivery ] control rel hoste k, de winne � and schacht e polymeric prodrugs int j pharm ulbrich � and subr v polymeric anticancer drugs with phcontrolled activation adv drug del rev shuvaev w, dziubla t, wiewrodt atarax 10mg pet medicine side effects r and muzykantov vr streptavidinbiotin crosslinking of therapeutic enzymes with carrier antibodies nanoconjugates for protection against endothelial oxidative stress meth mol biol dziubla td and lowman am gels, in schwartz m ed encyclopedia of smart materials wiley and sons new york lowman am, dziubla td, bures p and peppas na atarax 10mg pet medicine side effects structural and dynamic response of neutral and intelligent networks in biomedical environments, in peppas na and sefton mv eds advances in chemical engineering molecular and atarax 10mg pet medicine side effects cellular foundations of biomaterials academic press new york wiewrodt r, thomas ap, cipelletti l, christofidousolomidou m, weitz da, feinstein si, schaffer d, albelda sm, koval atarax 10mg pet medicine side effects m and muzykantov vr size dependent intracellular immunotargeting of therapeutic cargoes into endothelial cells blood torchilin vp immunoliposomes and pegylated immunoliposomes possible use for targeted atarax 10mg pet medicine side effects delivery of imaging agents immunomethods hermanson gt bioconjugate techniques acedemic press san diego, ca olivier jc, huertas r, lee hj, calon f and pardridge wm atarax 10mg pet medicine side effects synthesis of pegylated immunonanoparticles pharm res tessmar j, mikos a and gopferich a the use of polyethylene glycolblock polylactic acid derived copolymers for the rapid atarax 10mg pet medicine side effects creation of biomimetic surfaces biomaterials nanoparticulate carriers for delivery to the brain jorg kreuter introduction drug the following chapter deals with a subject that according to the journals science or nature, is of no general interest, namely the brain or to be more specific, drug delivery to the brain personal communication atarax 10mg pet medicine side effects the brain is one of the best protected organs of the body, to the outside by the skull and towards the blood circulation by the atarax 10mg pet medicine side effects bloodbrain barrier bbb the purpose of the bbb is to maintain the homeostasis of the brain, and to allow the creation of a unique extracellular atarax 10mg pet medicine side effects fluid environment within the central nervous system cns, whose composition can as a consequence be precisely controlled the extracellular fluid compartments of the cns comprise atarax 10mg pet medicine side effects of the brain, the spinal cord parenchymal interstitial fluid and the cerebrospinal fluid contained within the ventricles of the brain, as well as the cerebral and spinal subarachnoid spaces the structural bbb is created by the endothelial cells forming the capillaries of the brain and the spinal cord these endothelial atarax 10mg pet medicine side effects cells are characterized by having tight continuous circumferential junctions between them, thus abolishing any aqueous paracellular pathways between these cells the presence of the tight junctions and the lack of aqueous pathways between cells greatly restricts the movement of polar solutes across the cerebral endothelium certain substances may diffuse passively atarax 10mg pet medicine side effects across the brain endothelial cells this diffusion is dependent on lipophilicity and molecular weight drugs with a molecular weight above da are normally excluded from atarax 10mg pet medicine side effects a passive diffusional transport across the bbb however, a large number of drugs that would possess a favorable lipophilic ity and molecular weight, which should normally enable an easy transport across the bbb, are rapidly pumped back into the blood stream by extremely effective efflux pumps these pump systems include atarax 10mg pet medicine side effects among others, pglycoprotein pgp, also referred to as multidrug resistance protein mdr, as well as moat multiple organic anion transporter since the brain is dependent atarax 10mg pet medicine side effects on the blood to deliver substrates as well as to remove metabolic waste, the endothelial cells are also required to maintain a high level of carriermediated transport systems that enable the entry or the elimination of a variety of endogenous compounds including hydrophilic substances such as hexoses, amino acids, purine compounds, atarax 10mg pet medicine side effects and monocarbonic substances, as well as lipoproteins including ldl low density lipoprotein, some of these transporters are unidirectional and some bidirectional in their transport of solutes across the cell membrane this polarization means that some solutes can be preferentially transported into or out of the brain as a consequence, the atarax 10mg pet medicine side effects bbb presents a huge challenge for the effective delivery of a large number of therapeutics to the brain, and, therefore, many attempts have been made to overcome this barrier for instance, these attempts include the osmotic opening of the tight junctions use of prodrugs or carrier systems such as antibodies liposomes, and nanoparticles opening of the tight junctions by osmotic pressure, however, is a very invasive procedure that also enables the entry of unwanted substances into the brain the employment of prodrugs may yield a higher lipophilicity, enabling a better permeation and transport into and across the lipophilic endothelial barrier, andor these prodrugs may use the membrane associated carrier systems in many cases, however, a suitable prodrug cannot be synthesized, or the resulting molecular weight atarax 10mg pet medicine side effects is too large colloidal carriers also can take advantage of these carrier systems present in the bbb these systems, for instance, include the lipoprotein receptors and the transferrin transcytosis systems, and may be employed in the delivery of drugs by the above particulate colloidal drug delivery systems nanoparticles nanoparticles for atarax 10mg pet medicine side effects pharmaceutical purposes as defined by the encyclopedia of pharmaceutical technology are solid colloidal particles ranging in size from to nm fim, consisting of macromolecular materials atarax 10mg pet medicine side effects in which the active principle drug or biologically active material is dissolved, entrapped, or encapsulated, or to which the active principle is adsorbed or attached atarax 10mg pet medicine side effects the use of nanoparticles for the transport of drugs across the bbb was already suggested in the early s by prof speiser at the eth swiss atarax 10mg pet medicine side effects federal institute of technology in zurich personal communication, who was also the first to systematically develop nanoparticles for drug delivery purposes in the late s and early s � dal ps mgkg dalnp mgkg dalnp ps mgkg dalnp ps mgkg dalnp ps mgkg fig antinociceptive effects after intravenous injection of atarax 10mg pet medicine side effects different dalargin dal formulations into mice mpe = maximal possible effect np = nanoparticles ps = polysorbate dal saline mgkg the possibility to use nanoparticles for the transport of drugs into the brain across the bbb was first shown with the hexapeptide dalargin tyrdalaglyphe leuarg, a leuenkephalin analogue with opioid atarax 10mg pet medicine side effects activity, this drug was bound to nanoparticles of a size of about nm, made of the very rapidly biodegradable polymer poly butyl cyanoacrylate this material is one of the most rapidly biodegradable nanoparticle materials the nanoparticles were incubated with this drug for hrs, yielding the sorptive binding of of the initial amount of dalargin overcoating of these particles with the surfactant polysorbate tween� was then achieved by further incubation for another min with this surfactant, atarax 10mg pet medicine side effects resulting in an equilibrium between surfacebound polysorbate and polysorbate in solution a dosedependent antinociceptive analgesic effect was observed using the tailflick test, after intravenous injection to mice fig which was later repeated by other research groups with the hot plate test, the antinociceptive effect was accompanied by a pronounced straub effect and could be totally inhibited by injection of the �opiate receptor antagonist naloxone min before the injection of the nanoparticle preparation both results indicate a central action of dalargin on the cns, demonstrating that it was indeed transported across the bbb and that the observed antinociceptive effects were not due to peripheral activity in contrast to the polysorbate coated nanoparticles, none of the controls including a solution of dalargin, a solution of polysorbate , a suspension of poly butyl cyanoacrylate nanoparticles, a mixture of dalargin with polysorbate , dalargin with nanoparticles or a mixture of all three components, dalargin, polysorbate , and nanoparticles, atarax 10mg pet medicine side effects mixed immediately before injection, as well as dalargin bound to nanoparticles without polysorbate coating, were able to exhibit any antinociceptive action fig the antinociceptive effects also showed circadian phaseday timedependency, as well as a shift of the minima and maxima of the nociceptive reactions of the mice of almost hrs compared with the controls and the dalargin solution biodistribution influence of surfactants on the biodistribution of nanoparticles fundamental biodistribution studies of troster et al with atarax 10mg pet medicine side effects clabelled polymethyl methacrylate nanoparticles demonstrated that the coating of these nanoparticles with certain surfactants increased the whole brain concentrations of the nanoparticles in rats after atarax 10mg pet medicine side effects intravenous injection however, at that time, the authors were convinced that the nanoparticles were not taken up by any brain associated cells, including the brain atarax 10mg pet medicine side effects capillary endothelial cells, nor were transported across the bbb, but rather remained in the blood lumen adhering to the luminal surface of the endothelial cells in addition, it has to be noted that some surfactants in trosters experiments led to high [c] brain concentrations, which were unable to achieve any atarax 10mg pet medicine side effects antinociceptive effects with dalargin bound to the nanoparticles these important antinociceptive effects in the cns with the polysorbate coated dalargin nanoparticles reported above sec led atarax 10mg pet medicine side effects to the investigation of the biodistribution of this drug after intravenous injection to mice, using h labelled dalargin in the form of [leucyl,h]dalargin as well as of [htyr] dalargin up to fold higher concentrations in brain homogenates were found with the polysorbate coated nanoparticles than with dalargin solution these atarax 10mg pet medicine side effects concentration differences were statistically different at most time points, although smaller than expected from the huge difference in the pharmacological responses however, it has to atarax 10mg pet medicine side effects be considered that the determination of the hradioactivity in brain homogenates cannot discriminate between drug that has and drug that has not actually crossed the bbb atarax 10mg pet medicine side effects in addition, the observed concentration differences between different brain homogenate fractions may be the reason for the lack of efficient bbb crossing of dalargin in atarax 10mg pet medicine side effects solution form much larger and important brain concentration differences were obtained after intravenous injection of polybutyl cyanoacrylate nanoparticles loaded with doxorubicin in this case, the drug was added during polymerization four doxorubicin formulations, doxorubicin solution in saline, doxorubicin solution plus polysorbate in saline, doxorubicin bound to nanoparticles, or doxorubicin bound atarax 10mg pet medicine side effects to nanoparticles coated with polysorbate , were injected into the tail vein of rats at a doxorubicin dosage of mgkg in the brain, the polysorbate coated atarax 10mg pet medicine side effects nanoparticles yielded high doxorubicin concentrations of xgg tissue between and hrs after injection the brain concentrations were still at a level of about xgg after atarax 10mg pet medicine side effects hrs, while the three other preparations remained below the detection limit of xgg at all times in contrast, very low concentration differences appeared between all atarax 10mg pet medicine side effects four preparations in the blood only interestingly, the heart concentrations of both nanoparticle formulations remained very low, confirming earlier results of couvreur et al,h atarax 10mg pet medicine side effects whereas the heart concentrations with the two solutions were about times higher than with the nanoparticles since the use of doxorubicin is limited by its atarax 10mg pet medicine side effects cumulative high heart toxicity, this observation is of major significance solid lipid nanoparticles sln were also able to achieve significant brain concentrations after intravenous, and atarax 10mg pet medicine side effects even after duodenal administration slns consisting of stearic acid, the surfactant epicuron� , and taurocholate sodium loaded with doxorubicin, tobramycin, or idarubicin were prepared by dispersing atarax 10mg pet medicine side effects a microemulsion containing the above components in water at a dose of mgkg doxorubicin, brain concentrations of about �gg were obtained after min only with the slns, and no doxorubin was detectable in the brain of rats after iv administration of the solution through the jugular vein with tobramycin mgkg, the atarax 10mg pet medicine side effects intravenous route was compared with duodenal administration through a surgically implanted cannula no tobramycin was detectable in the brain after administration of tobramycin solution to the rats however, with the solid lipid nanoparticles, the amount of tobramycin in the brain hrs after duodenal administration xgg was comparable to that after iv administration xgg the tobramycin brain concentration was decreased hrs after duodenal dosing, while the levels after iv administration remained fairly high mgg in all atarax 10mg pet medicine side effects other tissues except the brain, the tobramycin levels were higher after iv administration of the solution than those obtained with the solid lipid nanoparticles duodenal atarax 10mg pet medicine side effects administration of idarubicin, at a dose of lmgkg bound to solid lipid nanoparticles, yielded brain concentrations of about ngg after hrs this concentration was similar atarax 10mg pet medicine side effects to that in the heart ng g and about half of that in the liver no detectable idarubicin nor the metabolit idarubicinol was found in atarax 10mg pet medicine side effects the brain after administration of the solution solid lipid nanoparticles consisting of stearic acid, soybean lecithin, and the surfactant poloxamer pluronic� f loaded with the atarax 10mg pet medicine side effects anticancer drug camp tothecin were produced by high pressure homogenization the in vitro release of the drug lasted for one week after intravenous injections of mgkg camp tothecin to mice, the drug residence time in the body was significantly prolonged by the nanoparticles compared with the solution, and the plasma auc was increased by a factor of , the brain auc even by a factor of , and the auc in other organs by a factor of between lungs and heart an increase of the dose to mgkg camptothecin factor in the nanoparticle formulation further increased the plasma auc by , the brain auc by , and the auc in the other organs by times on the average incorporation of ,dioctanoylfluorodeoxyuridine into solid lipid nanoparticles also increased its brain atarax 10mg pet medicine side effects uptake after iv injection of the slns, its brain auc was increased twofold over the solution of this compound different types of solid lipid nanoparticles with atarax 10mg pet medicine side effects a size of about nm, consisting of emulsifying waxbrij� and out of brij� polysorbate , were made by lockman et al and koziara et al and atarax 10mg pet medicine side effects investigated in rat brain perfusion experiments for both nanoparticle types, a statistically significant uptake was observed compared with [c]sucrose in rat brain perfusion experiments, suggesting central nervous system uptake of the nanoparticles perfusion of the nanoparticles did not induce any statistically significant changes in barrier integrity, membrane permeability, or facilitated choline transport [h]thiamine was then bound to the emulsifying waxbrij� nanoparticles via a pegspacer distearoylphosphatidylethanolamine dspepegnhs to target the particles to the thiamine transporters in atarax 10mg pet medicine side effects the brain although an association with the thiamine transporter occurred, no difference in the brain uptake was observed in balbc mice after iv injection between emulsifying waxbrij� nanoparticles with protruding peg chains on the outside and nanoparticles with thiamine bound to the peg chains the emulsifying waxbrij� solid lipid nanoparticles atarax 10mg pet medicine side effects were then loaded with paclitaxel and tested in the u and hct cell lines and by rat brain perfusion entrapment of paclitaxel in the solid lipid nanoparticles significantly increased its brain uptake and its toxicity towards the pglycoprotein expressing tumor cells influence of pegylation on the biodistribution of nanoparticles besides, atarax 10mg pet medicine side effects by coating with surfactants, the body distribution may also be altered by covalent attachment of polyethylene glycol trazodone review peg chains to the nanoparticle surface pegylation like atarax 10mg pet medicine side effects a number of surfactants such as poloxamine and , the nanoparticlesurfacebound peg chains can prevent the opsonization and rapid capture and removal of the nanoparticulate carriers by the cells of the reticuloendothelial system res, and consequently, can significantly prolong the blood circulation times of the particles calvo et al showed in mice and rats that the cconcentration in different brain tissues was also significantly enhanced after intravenous injection of pegylated [c]poly[methoxy poly ethylene glycol cyanoacrylatecohexadecyl cyanoacrylate] nanoparticles [c]pegp!