no lysis of erythrocytes lysis of erythrocytes j sensibilized sheep erythrocytes �� sheep erythrocyte complement proteins � antibody amisheep erythrocyte fig ch method for the evaluation of complement system activation time mm j � � � i fig evolution of radioactivity blood repartition after the intravenous administration of lnc expressed as a percentage of the injected dose site delivery meanwhile, it appears that the length of the peg chain in this case, ethylene oxyde groups per molecule should be increased to extend the vascular residence time recently, it has drawbacks of oral famotidine tablets been shown that adding different dspepeg to the system enhances the t , values to several hours, depending on the concentration and the peg length t halflife, mrt mean residence time in blood and auc area under curve were evaluated by using [h]cholesteryl hexadecyl ether mixed with the lipid and the surfactant at the beginning of the formulation the main conclusion was that the lnc formulated in this study compared advantageously with other nanoparticulate systems, particularly for their residence time in blood nanocapsule uptake by the different organs of rat was evaluated drawbacks of oral famotidine tablets hrs after intravenous administration it was shown that lnc deposited mainly in the liver and the spleen, but also in the heart, and the results were comparable to a liposome reference drug encapsulation and release ibuprofene lnc were characterized for their suitability as an ibuprofene delivery device for pain treatments after in vitro investigations, ibuprofene loaded lnc were evaluated after intravenous and oral administration in rats for each system, the carrier was evaluated through its potential antinociceptive efficiency we present in fig , the release of ibuprofene in a phosphate buffer drawbacks of oral famotidine tablets after its incorporation in lnc during formulation for each case, lnc provide high ibuprofene loadings the main feature is an initial burst followed by a � co jb ?z q mgml mgml mgml time [h] phosphate buffer fig ibuprofene release from three batches of drugloaded lnc ph sustained release, where the time for drug released values are , and hrs for , and mgml loaded amounts respectively furthermore, after oral administration, these nanocarriers offered a better bioavailability as well as prolonged antinociceptive effects than other nanoparticulate systems amiodarone amiodarone is widely used because drawbacks of oral famotidine tablets of its antianginal and antiarrythmic properties unfortunately, this molecule can provoke severe adverse effects due to its accumulation in other tissues, after classical intravenous or intraperitoneal administration in that manner, the use of lnc was evaluated in in vitro conditions in order to incorporate and release amiodarone from their lipidic core it was found that sustained drug release was achieved over a range of significant period between hrs and hrs depending on the ph of the release medium conclusions a new kind of colloidal drug carrier, the lnc, was formulated drawbacks of oral famotidine tablets without organic solvent or toxic surfactants via a rapid and easy protocol these nanoparticulate systems were designed in order to have biomimetic properties and can be considered as pseudolipoproteins a lipidic core is surrounded by a surfactant shell, stabilized by phospholipids in the inner part of the shell and by stearate of peg in the external part of the shell the structural characteristics of these carriers allow for the incorporation in their core of different lipophilic drugs, initially dispersed in the oily phase at the beginning of the formulation the narrow drawbacks of oral famotidine tablets size distribution can be selected anywhere in a nm range one of their most important features is the presence of peg groups on the surface ideally presented, providing very low recognition these surface properties are crucial in order to hide the lnc from the mps system in addition, the presence of hydroxyl groups should allow the func tionalization of the lnc surface to attach ligands of interest and to improve the specificity of drug targeting these peg groups could participate to the inhibition of the efflux pumps involved in multidrug drawbacks of oral famotidine tablets resistance in this context, preliminary in vitro studies are very promising different strategies of incorporation or attachment of a specific ligand of the bbb and also of a glioblastoma tumor are studied the linkage of a grafted monoclonal antibody is currently evaluated it could provide an interesting way of accumulating lnc in the brain after intravenous administration the release of simple lipophilic drugs taken as models were analyzed and have shown sustained release over several days furthermore, since we are able to elaborate stable lipidic complexes hydrophilic molecules associated to a drawbacks of oral famotidine tablets cationic lipid for example, these vectors could provide an interesting alternative to liposomes for the delivery of hydrophilic compounds like dna or proteins references heurtault b, saulnier p, pech b, proust je and benoit jp physicochemical stability of colloidal lipid particles, biomaterials heurtault b, saulnier p, pech b, proust je, richard j and benoit jp lipidic nanocapsules, formulation process and use as a drug delivery system, patent no w heurtault b, saulnier p, pech b, proust je and benoit jp a novel phase inversion based process for the preparation of lipid nanocarriers, pharm res heurtault b, saulnier p, pech b, proust je and benoit jp properties of polyethylene glycol hydroxy stearate at a triglyceridewater interface, int j pharm heurtault b, saulnier p, pech b, venierjulienne mc, proust je, phantanluu r and benoit jp the influence of lipid nanocapsule composition on their size distribution, eur j pharm sci dulieu � and bazile d influence of lipid nanocapsules composition on their aptness to freezedrying, pharm res heurtault b, saulnier p, pech b, proust je and benoit jp interfacial stability of lipid nanocapsules, coll drawbacks of oral famotidine tablets surfb biointerf minkov i, ivanova tz, panaiotov i, proust je and saulnier p reorganization of lipid nanocapsules at airwater interface i kinetics of surface film formation, coll surf � minkov i, proust je, saulnier p, ivanova tz and panaiotov i reorganization of lipid nanocapsules at airwater interface part properties of the formed surface film, coll surf � vonarbourg a, saulnier p, passirani � and benoit jp electrokinetic properties of noncharged lipid nanocapsules influence of the dipolar distribution at the interface, electrophoresis vonarbourg a, passirani c, saulnier c, simard p, leroux drawbacks of oral famotidine tablets jc and benoit jp, evaluation of pegylated lipid nanocapsules versus complement system activation and macrophage uptake, biomed mater res a, in press passirani � and benoit jp biomaterials for delivery and targeting of proteins and nucleic acids, ed ram and mahato i, crc press boca raton london new york washington, dc cahouet a, denizot b, hindre f, passirani c, heurtault b, moreau m, le jeune jj and benoit jp biodistribution of dual radiolabeled lipidic nanocapsules in the rat using scintigraphy and � counting, int j pharm hoarau d, delmas p, david drawbacks of oral famotidine tablets s, roux e and leroux jc novel longcirculating lipid nanocapsules, pharm res lamprecht a, saumet jl, roux j and benoit jp lipid nanocarriers as drug delivery system for ibuprofen in pain treatment, int ] pharm lamprecht a, bouligand y and benoit jp new lipid nanocapsules exhibit sustained release properties for amiodarone, control rel lipidcoated submicronsized particles as drug carriers evan c unger reena zutshi, terry o matsunaga and rajan ramaswami lipidcoated submicronsized particles afford a new platform for drug delivery and therapy in this chapter, we will discuss the characteristics and drawbacks of oral famotidine tablets some of the potential clinical applications of submicronsized particles technology in general, bubbles present a hydrophilic exterior and hydrophobic interior stabilized by detergents detergents are characterized by their polar head group and a hydrophobic domain consisting of long chain fatty acids, alcohols, ethers, etc in bubbles, fig detergents aggregate by orienting the hydrophilic polar groups on the outside in contact with aqueous environment and stacking their hydrophobic sections of alkyl chains on the inside, away from the water this results in an energy minimized spherical structure that can incorporate gas drawbacks of oral famotidine tablets andor other hydrophobic materials inside phospholipids are specialized surfactants with characteristics similar to that of detergents and can stabilize micron and submicronsized gas bubbles, especially when perfluoropropane is used perfluorocarbon pfc gases have low solubility in aqueous media, relatively high molecular weight and can be used to prepare stable microbubbles or submicronsized bubbles smbs that are less than micron in diameter fully aqueous environment hydrophilic head aezss i hydrophobic tail fig the structure of bubbles halogenated pfcs are inert and generally not metabolized in the body the table below lists some drawbacks of oral famotidine tablets of the different pfcs and other gases useful in making lipidcoated microbubbles and pfc emulsions solubility in water compound molecular weight boiling point nitrogen sulfur hexafluoride sf perfluoropropane cf perfluorobutane cf perfluoropentane cf sparingly sparingly insoluble insoluble insoluble insoluble sublimes perfluorohexane cf lipidcoated submicronsized particles may be prepared by agitating an aqueous mixture of lipids with a selected gas as in the approved product definity� microbubbles ultrasound contrast agent, marketed by bristolmeyers squibb, by lyophilizing the material and storing with a head space of the preselected gas, spraydrying or by drawbacks of oral famotidine tablets creating an emulsion of the gas in the bubbles, eg when a pfc material is used to formulate the particles below the boiling point of the gas, while the pfc is in its liquid state the properties of the lipidcoated bubble will vary in part, depending upon the gas or material that is encapsulated in the bubble lipidcoated microbubbles of air or nitrogen will be relatively short lived following intravascular injection, bubbles composed of air or nitrogen may be stable enough to pass from the right heart through the pulmonary circulation drawbacks of oral famotidine tablets and into the left heart, but will likely be unstable to undergo multiple passes through the circulation when bubbles are prepared from air or nitrogen, the gas is relatively watersoluble and diffuses rapidly across the lipid membrane into the blood pfc gases have much lower solubility in the blood and therefore make more stable bubbles the solubility of the pfc in part reflects the molecular weight of the compound with the higher molecular weight materials generally having lower solubility, and the boiling point of the materials increases with increasing molecular drawbacks of oral famotidine tablets weight pfcs with or less carbon atoms will be gases at room temperature dodecafluoropentane has a boiling point of about �c liquid perfluoropentane filled phospholipidcoated submicron droplets smds may volatilize in vivo to form gas bubbles after intravenous injection perfluorohexane will be a liquid at physiological temperature, but because of its vapor pressure, a small fraction of the material may be in gaseous state at physiological temperature a wide variety of different lipids can potentially be employed to make the lipidcoated microbubbles experiments were performed using agitation to prepare the microbubbles drawbacks of oral famotidine tablets microbubbles were more stable when prepared when the lipids were at gel state and when the same chain length of lipids was used in the formulation the product definity was developed using a blend of lipids dipalmi toylphosphatidylcholine dppc, dipalmitoylphosphatidic acid dppa and dipalmitoylphosphatidylethanolaminepeg dppepeg, polyethylene glycol, mw = the product is primarily composed of the neutral lipid dppc the anionic lipid in the formulation may aid in the electrostatic repulsion of the bubbles and the peg may form a steric barrier to further prevent aggregation or fusion of the drawbacks of oral famotidine tablets bubbles the microbubbles have various potential medical applications a they can be used as the active drug product b they can be coadministered with other biologically active drug substances c biologically active drug materials can be incorporated into the hydrophobic domain of the microbubbles d biologically active gases can also be entrapped inside the bubbles and used for delivery in a, the bubbles themselves can be used as contrast agents with diagnostic ultrasound, or as therapeutic agents with therapeutic ultrasound an unusual feature of lipidcoated microbubbles compared with other delivery systems drawbacks of oral famotidine tablets is that these agents can be activated by energy, particularly using ultrasound for localized therapy the ultrasound energy can be targeted precisely to small regions in the body localized therapy and drug delivery can be accomplished using ultrasound to activate the bubbles to disperse a clot, increase local capillary permeability or to release drugs from the bubbles [as in c & d above] figure below shows some of the ways that bubbles may be used to deliver therapeutic agents the following sections will review some of the specific biomedical applications drawbacks of oral famotidine tablets fig microbubbles can be used to transport materials in a variety of methods in a, the drug is injected in conjunction with the bubbles and driven into the target tissue by the acoustic activation of the bubbles to create drug carrying bubbles, the agent may be b attached to the outside of the lipid, c embedded in the lipid layer, d associated to the membrane by electrostatic interactions, e encapsulated directly in the bubble, or f dissolved in an oil or other compatible liquids and then encapsulated within the bubble also, drawbacks of oral famotidine tablets smaller bubbles or spheres eg delivering gene products may encapsulate the agent and then associate with larger bubbles as in g ultrasound contrast agents in biological fluids and tissues, microbubbles are efficient reflectors of sound ultrasound is the most common biomedical imaging modality and ultrasound contrast agents are used to increase the reflectivity or backscatter of blood and tissues in ultrasound imaging the reflectivity of the bubbles is proportional to r where r = the radius of the microbubble this implies that the larger the bubble, the more efficient it drawbacks of oral famotidine tablets is as a reflector of sound for intravascular applications, however, the bubbles must be smaller than the diameter of a red blood cell to safely pass through the capillaries without causing vascular blockade the relationships between reflectivity and effectiveness as an ultrasound contrast agent are far more complex than the prediction based upon mere size or diameter of the microbubbles biomedical ultrasound is commonly performed over a range of ultrasound frequency from mhz to mhz the resolution of ultrasound increases as the frequency increases shorter wavelengths of ultrasound, but penetration in drawbacks of oral famotidine tablets tissues also decreases linearly with frequency the highest frequencies of ultrasound eg mhz are mainly used for imaging with catheterbased ultrasound eg for looking within vessels, or for imaging very superficial tissues such as the skin the lower frequencies eg to mhz will penetrate abdominal tissues and other structures for general purpose imaging bubbles have resonant properties and reflect sound most efficiently at their resonant frequencies for example, the resonant frequency of a micron bubble is approximately mhz and the resonant frequency of a micron bubble is approximately mhz when insonated drawbacks of oral famotidine tablets at their resonant frequencies, microbubbles will emit harmonic signals at higher frequencies for example, when microbubbles are insonated with a fundamental insonation frequency = b, the bubbles will reflect signals at the bd frequency as well as signaling powerfully at xb the images below fig show fundamental and harmonic images of the heart pre and postcontrast, using the lipidcoated microbubble contrast agent, definity� as shown in the images, the harmonic image, obtained from the signal twice the insonation frequency, has higher contrast and greater suppression of background signal harmonic imaging drawbacks of oral famotidine tablets sampling the x bg signal as well as other techniques enable ultrasound to suppress signal from the background and to enhance the signal from blood fundamentalnd harmonic fig comparison of fundamental and second harmonic imaging the second precontrast harmonic image is clearer the contrast was unclear postcontrast, when the sonographer switched back to fundamental imaging the infusion rate was then increased, resulting in excessive shadowing, thereby further obscuring the details courtesy of kevin wei, md, university of virginia another factor contributing to the effectiveness of the ultrasound contrast agent is the drawbacks of oral famotidine tablets elasticity of the shell surrounding the microbubbles the more elastic the shell, the more efficient the bubble may be as a reflector of sound a less elastic shell will not only decrease the efficiency with which sound is reflected, but will also raise the frequency at which the bubble resonates lipid coatings surrounding microbubbles are thin and are most likely monolayers or bilayers of lipid, and as such, are relatively elastic compared with other materials that may be used to coat bubbles such as crosslinked synthetic polymers the lipid materials drawbacks of oral famotidine tablets used in coating the microbubbles, enable production of highly elastic and efficient reflectors of ultrasound in preparing bubbles for drug delivery, as materials are added to the bubbles, the bubbles may become less elastic and require higher amounts of ultrasound energy for activation fig plot of the cavitation threshold in water as a function of initial nucleus radius for three frequencies of insonification and mhz nuclei consist of air bubbles initially at � that undergo growth in a single cycle of ultrasound and collapse adiabatically to a temperature of k surface drawbacks of oral famotidine tablets tension, viscosity, and inertia of the host fluid are included in this analytical model holland and apfel, for mhz, the optimal nucleus radius is �� with a corresponding cavitation threshold, ppt, of mpa peak negative pressure note that at a pressure p greater than ppt, a broader size range of nuclei cavitate reproduced by permission of apfel and holland, ultrasound med biol initial radius [im in certain imaging regimes, bubbles can be ruptured from the ultrasound energy as shown in fig below, microbubbles lower the threshold of ultrasound energy for drawbacks of oral famotidine tablets cavitation to occur cavitation creates an acoustic signal that can be detected cavitation can occur as a stable inertial cavitation of a bubble, where the bubble expands and collapses in concert with the phase of the waves of ultrasound at higher energy, cavitation can lead to localized energy deposition analogous to a local explosion on the microscopic scale cavitation can be used for therapeutic purposes as described below, or it can be used to create a strong ultrasonic signal for diagnosis and detection of diseases calculations indicate that with cavitation imaging, drawbacks of oral famotidine tablets it is possible to detect a single microbubble bubbles as ultrasound contrast agents open the field of diagnostic ultrasound to molecular imaging in terms of sensitivity to concentration of material, ultrasound imaging using bubbles rivals the most sensitive imaging techniques such as nuclear medicine in addition to cavitationbased imaging which may detect a single bubble, when bubbles are targeted to a certain structure and accumulate to present an interface of several or more bubbles, they may form a socalled specular reflector or highly efficient interface for the reflection of ultrasound drawbacks of oral famotidine tablets our group has created targeting ligands for incorporation into the microbubbles and performed imaging of models of disease with these contrast agents, the images below show a thrombus in the left atrial appendage in a dog, pre and postcontrast the thrombus is not visible on the ultrasound images precontrast, but is readily detected when it is postcontrast figure is a depiction of the bioconjugate that was synthesized to develop the thrombus targeted ultrasound contrast agent the lipid in the bioconjugate serves as a hydrophobic anchor to bind the bioconjugate to the drawbacks of oral famotidine tablets surface of the bubble a small number of bubbles bound to the surface of a target such as a thrombus, appear to be sufficient for contrast enhancement and detection on ultrasound a number of different molecular targets have been imaged with ultrasound using targeted bubbles some of the different diseases that have been imaged include vulnerable plaque, inflammation, angiogenesis and ischemia figure shows pselectin targeted imaging in a model of ischemia with myocardial contrast echocardiography mce fig ultrasound images of left atrial appendage laa clot enhancement in the canine model drawbacks of oral famotidine tablets using an intravenous infusion of targeted microbubbles at a dose of cm kg precontrast image left postcontrast infusion image right, highlighting clear enhancement of the clot in the left atrial appendage ao, aorta la, left atrium pa, pulmonary artery [reproduced with permission of unger et at, in ultrasound contrast agents, nd edition, goldberg, raichlen & forsberg eds] anchor tether ligand fig mierobubble with bioconjugates attached with enlarged view showing the anchor, tether and ligand reproduced by permission unger et ni, ejr fig the left panel shows an area of hypoperfusion imaging drawbacks of oral famotidine tablets with mce during myocardial ischemia of the left circumflex artery the right panel shows enhancement min after re flow from pselectintargeted imaging in the risk area courtesy of jonathan r, lindner, md, university of virginia risk areapselectin sonothrombolysis bubbleassisted sonothrombolysis is the term we use to describe the ultrasound mediated cavitation of bubbles to aid in the lysis of venous and arterial thrombi mrx is the designation for imarx therapeutic incs imarx manufactured phospholipidcoatcd submicronsized bubble product that will be used in clinical trials mrx is the next generation bubble, drawbacks of oral famotidine tablets developed based on the definity bubble the bubbles in mrx exhibit a size profile where of the particle ��� lils ?v �� f jjm atex beads seme eopitlatkm bsh wsib�ms�m i �� tocoe fig sizing studies of submicron bubbles distribution is less than one micron and the mean size is less than micron in diameter the images below depict a photomicrograph of mrx bubbles alongside a photomicrograph of onemicron size latex microbeads the bubbles are one micron in diameter and smaller we found in our lab that the smallest bubbles are drawbacks of oral famotidine tablets not well shown on the light microscopy due to limitations of the imaging technique the sizing profile shows that there are bubbles up to approximately two microns in diameter, but more than of the bubbles are smaller than one micron in size investigators have demonstrated that ultrasound can be used to generate cavitation in an aqueous medium cavitation research has led to studies involving ultrasoundmediated clot lysis at a variety of frequencies furthermore, microbubbles and submicronsized bubbles provide a nucleus at which cavitation can occur, thereby lowering the ultrasound energy requirements drawbacks of oral famotidine tablets while intravenous administration with local application of ultrasound appears to be effective for sonothrombolysis in both preclinical and clinical models, applications using an infusion catheter are also being investigated it is believed that submicronsized bubbles and ultrasoundmediated cavitation are able to affect the thrombus architecture by increasing permeability through the thrombus matrix, thereby improving accessibility and the penetration of thrombolytic enzymes to more efficiently lyse clots studies by francis et al, demonstrated that ultrasound alone increased the spacing between fibrin strands in clots, presumably improving the penetration of lytic enzymes, drawbacks of oral famotidine tablets such as tpa, into the clot by way of explanation, when bubbles are insonified, these bubbles can oscillate in response to the acoustic pressure wave if driven with a sufficient acoustic pressure, the rapid expansion and contraction of the bubble will result in local velocities at the bubble surface on the order of hundreds of meters per second if the expansion of the bubble is large enough, the bubble will become unstable, resulting in the destruction of the bubble into smaller fragments the rapid oscillation of the bubble in response to drawbacks of oral famotidine tablets an acoustic pulse is referred to as cavitation bubbles undergoing this violent expansion and contraction produce liquid jets, local shock waves, and free radicals although the exact mechanism is still being studied, the effect of cavitating bubbles has been demonstrated to have several effects on the surrounding tissues, including the poration of cell membranes resulting in enhanced membrane permeability sonoporation or the disruption of local thrombus thus, the combination of ultrasound with microbubbles has potential applications in blood clot dispersion and local drug delivery to treat cardiovascular disease, cancer, and drawbacks of oral famotidine tablets diseases of the central nervous system the figure below shows individual images from ultrahigh speed videomicroscopy of a single bubble the bubble is shown in the resting state on the far left hand side of the figure the bubble expands after the application of the ultrasound pulse, then collapses and fragments the daughter bubbles expand and collapse again, leaving behind small nanosized fragments localized activation of bubbles with ultrasound can be used for a number of different medical applications including sonolysis whereas in diagnostic ultrasound contrast imaging where there is an drawbacks of oral famotidine tablets r dependence between size and ultrasound reflection for therapy, it is advantageous to have much smaller bubbles as shown in fig , when bubbles are cavitated by ultrasound, they may undergo a relatively greater increase in the expansion ratio rr, where r, is the maximum size for the radius of the bubble after insonation, and r � the initial resting radius the relative expansion with insonation is greatest for the smallest diameter submicronsized bubbles this conceivably results in a more effective cavitational force, and hence more efficient lysis of thrombi another drawbacks of oral famotidine tablets effect of ultrasound on microbubbles which has the potential to be utilized therapeutically is the use of acoustic radiation force to selectively concentrate microbubbles at a target site, microbubbles driven with ultrasound, experience radiation force in the direction of ultrasound wave propagation pulses of jjjjjl fig in the images above, a single �� bubble is shown far left in the resting state insonation with a single pulse of ultrasound energy causes the bubble to expand, collapse, and fragment, yielding nanometersized fragments as the bubbles expand and collapse, they generate a local drawbacks of oral famotidine tablets shockwave that can be used therapeutically reproduced with permission from chomas et al, appl phys lett, ��� i oycit ���]�� impfl i i� � ai � � i lillli r&olsrlun} a fig the relationship between nanobubbles size at resting state and expansion ratio under insonation reproduced with permission of d patel et al, ieee ultrasonics, eerro electrics, and frequency control in press many cycles can deflect resonant microbubbles over distances in the order of millimeters thus, it may be possible to bring microbubbles circulating in the blood pool into contact drawbacks of oral famotidine tablets with targeting sites on a blood vessel wall, in a region selected by the positioning of the ultrasound beam this effect has been demonstrated to increase the retention of microbubbles at a target site over an order of magnitude in addition to favorable acoustic characteristics, submicronsized bubbles have other potential advantages for therapy, compared with largersized microbubbles the smaller bubbles may penetrate a clot more easily and may have better biodistribution characteristics for targeting the pictorial representation below fig is the hypothetical mechanism of action for mrx bubbles flowing through the drawbacks of oral famotidine tablets vasculature in association with fig it is hypothesized that when submicronsized bubbles are injected systemically, some will aggregate on the thrombus, and due to their small size, work into the clot when the bubbles cavitate, the kinetic energy disperses the clot, both from its periphery, and due to the fact that bubbles are able to penetrate the clot from within manobubble red blood cell �cavilaling i nanobubble a thrombus ultrasound could cause cavitation of the bubbles, transferring their dispersive energy to the clot and dispersing the clot safely and painlessly drawbacks of oral famotidine tablets particle sizing studies of the effluent from in vitro studies of smbassisted sonothrombolysis have shown that the particles are submicron in size the figures below show the experimental setup used in our lab for a flow through phantom for testing sonothrombolysis, and then treatment of a clot in the phantom the clot was exposed to mhz ultrasound and tissue plasminogen activator tpa, followed by an infusion of mrx microbubbles as shown in the figures, after min of treatment there is near complete resolution of the clot the graph below shows the drawbacks of oral famotidine tablets results from a series of clots exposed to tpa, tpa ultrasound and tpa ultrasound mrx bubbles in our lab note that the greatest reduction of thrombi was in the group exposed to bubbles � �� �������� fig above a schematic of the experimental setup a the clot pretreatment, b after min of treatment, c after min of treatment the clot was dissolved v � z � � ���� ss =f=l saline us tpa tpa, smb, smb, us us us tpa fig smb = bubbles clinical studies vascular thrombosis is a major drawbacks of oral famotidine tablets cause of death in industrialized countries, responsible for myocardial infarction, stroke and peripheral arterial occlusions in addition, deep vein thrombosis dvt, which afflicts one in twenty americans during their lifetime, may also be an application for sonothrombolysis imarx completed a phase iii clinical trial in thrombosed dialysis grafts for the purpose of preliminary feasibility and safety for sonothrombolysis treatment of clotted grafts initial studies in thrombosed dialysis grafts provided a venue to evaluate the principle of sonothrombolysis in vascular thrombosis as such, clinical trial efforts will move forward to address drawbacks of oral famotidine tablets the treatment of stroke, peripheral arterial occlusions ��� and deep vein thrombosis dvt below are examples shown from clinical trials for sonothrombolysis in dialysis grafts and dvt the examples are not an indication that all sonothrombolysis treatments will have similar outcomes images from a venogram in a patient with dvt showed that the patient was administered bubbles via infusion catheter into the popliteal vein over a period of hr, while ultrasound was applied across the skin no thrombolytic drug such as tpa was administered clinically, this particular patient had marked reduction drawbacks of oral famotidine tablets in pain posttreatment with sonothrombolysis stroke is the third most common cause of death, after heart disease and cancer in north america it incurs far more expenses than any other diseases due to its long term disability in the us, stroke accounts for over $ billion each year to the health care system the only approved pharmacologic therapy to help restore blood flow in stroke patients is tpa activase� less than of patients are treated with tpa due to concerns over bleeding and the risk relative to the benefit encouraging drawbacks of oral famotidine tablets results have been obtained, however, in human studies with ultrasound and tpa, and most recently, with ultrasound tpa microbubbles fig the angiogram on the left is of a clotted dialysis graft very little contrast enters the graft as it is filled with clot the image on the right, postbubble treatment, shows complete opacification of the graft due to successful dissolution of thrombosis by sonothrombolysis fig on the pretreatment image left, there is complete occlusion of the superficial femoral vein sfv collateral veins are seen carrying the blood flow that would normally be carried by the sfv posttreatment, there is good flow in the sfv and much less flow is seen in the collateral vessels due to the increased flow in the sfv dr andrei alexandrov from the university of texas in houston led a study of ultrasound tpa in acute ischemic stroke, in this study, patients were randomized prospectively to receive either a hr infusion of tpa at a dose of mgkg alone, or tpa plus hrs of continuous transcranial doppler tcd ultrasound applied through the temporal window where the skull drawbacks of oral famotidine tablets is thinnest and most easily penetrated by ultrasound of the patients treated with tpa alone, there was a recanalization rate of the intracranial circulation at hrs, in the same number of patients receiving tpa ultrasound, there was a highly significant increase in recanalization to at two hours, indicating that ultrasoundmediated therapy aided in thrombus dispersion dr carlos molina, from barcelona, spain, conducted a similar study but with microbubbles the addition of microbubbles enhances the cavitational nuclei with a decrease in power requirements dr molinas study demonstrated that the recanalization rate increased drawbacks of oral famotidine tablets impressively to in this study, dr molina administered three doses of levovist�, a microbubble agent comprised of airfilled galactose microparticles dr molinas pioneering work has demonstrated the utility of using bubbles in conjunction with ultrasound to improve the clinical outcome of acute stroke imarx is currently moving mrx into stroke treatment trials smbassisted sonothrombolysis therapy could move beyond the current clinical regimens by eliminating the thrombolytic agent preclinical trials in both canine and porcine models have been encouraging, human studies will be conducted to determine if lipidcoated bubbles will improve drawbacks of oral famotidine tablets recanalization rates in patients treated with this new ultrasoundmediated paradigm blood brain barrier poor transport into the cns is an obstacle to effectively treat diseases including brain tumors, alzheimers and other neurodegenerative diseases there are two principal barriers to drug transport into the cns a the blood brain barrier bbb and b the abc transporters, abcc and abcb unlike the rest of the body, the capillary foot processes of the cerebral endothelial cells are tight, preventing peptides and macromolecules from leaking through to the brain although the bbb may be permeable drawbacks of oral famotidine tablets to selected ions and small molecules, abcb, also known as the pglycoprotein, acts to remove the molecules by a drugefflux system before they enter the brain several different strategies have been developed to overcome these limitations one approach to drug delivery to the brain is by the transient opening of the bbb hypertonic solutions containing mannitol, which act by shrinking the endothelial cells when coadministered with drugs, have been shown to result in enhanced cerebral drug uptake, however, to cause minimum side effects, it is essential for the therapy to drawbacks of oral famotidine tablets be regional and localized recently, hynynen et al have shown that the bbb can be transiently opened using ultrasound and microbubbles illustrated in fig when bubbles were administered intravenously and focused ultrasound was applied across the intact skull, the bbb could be reversibly opened, permitting passage of hydrophilic low molecular weight molecules such as gadoliniumdtpa, and macromolecules such as fluorescently labeled albumin fig into the cns the permeability resolved over a period of hours without damage to the neurons similar studies have been performed in a porcine model showing that non drawbacks of oral famotidine tablets focused ultrasound with microbubbles can be used to open the bbb figure shows increased dye deposition in the cerebral tissue introduction of microbubbles as the cavitation nucleus prior to the application of ultrasound, lowered the energy needed to open the bbb, thereby lowering the bioeffects of ultrasound using this technique, large biomolecules such as horseradish peroxidase a kda protein have been shown to pass through the bbb with minimal damage to the brain tissues it can be envisaged that drugs small or macromolecules bound to the microbubbles would function as drawbacks of oral famotidine tablets a more efficient drug delivery vehicle, since these fig cartoon representation of hypothesized ultrasound mediated drag delivery to the brain a cerebral capillaries with tight endothelial junctions prevent passage of molecules including microbubbles and nanoparticles into the brain b ultrasound is applied to the skull through the temporal window where the skull is thinnest inset, cavitating the microbubbles and opening up the endothelial junctions c therapeutic agents may now pass through the opened junctions fig tweighted mr images of rabbit brain after treatment shows contrast enhancement at locations arrows, coronal image drawbacks of oral famotidine tablets across focal plane reproduced with permission from hynynen et al, radiology would provide the cavitation nuclei and the drug payload in one entity, circumventing the coadministration of drug and microbubble in such instances, the drug could be a bound to the lipid membrane hydrophobic drugs, b bound to the charged lipids on the surface gene delivery, or c buried in the interior in an oily layer of a droplet hydrophobic drugs fig furthermore, d these drug loaded bubbles or droplets may have the potential to be targeted to a specific site drawbacks of oral famotidine tablets in the brain by surface ligands igg tissue p= i i t p i i untreated ultrasound mb untreated ultrasound fig control pigs and pigs treated with ultrasound alone showed no difference in evans blue uptake there was a significant difference in uptake when microbubbles were used in conjunction with ultrasound adapted from porter et al,} am soc echocardiogr fig different ways that bubbles or droplets may be able to transport drugs drugs may be a bound or embedded in the lipid membrane, b bound to the surface charges drawbacks of oral famotidine tablets of the phospholipid membrance c buried in the oil in a droplet d targeting ligands can be incorporated onto the membrance this technology of activation with ultrasound and microbubbles has the potential to also be used in the drug discovery process by exposing cultured neurons to drugs, ultrasound and bubbles, high concentrations of the drug may be able to deliver to the cells without damaging them this can potentially be used to screen neurons for new therapeutic compounds drugs potential cns diseases amenable to treatment with submicron bubble delivery and classes drawbacks of oral famotidine tablets of drugs disease alzheimers disease and other neurodegenerative disease, seizures and psychiatric disorders primary and secondary metastases brain tumors stroke, brain ischemia infection, eg, aids low molecular weight therapeutics with poor delivery to cns, proteins, genebased therapeutics low molecular weight therapeutics with poor delivery to cns, proteins, genetic drugs radiation sensitizers cavitation nuclei to augment sonothrombolysis, either with or without use of thrombolytic agent delivery of oxygen with microbubbles improvement of cerebral perfusion with microbubbleenhanced sonication delivery of antioxidants and growth factors delivery of antiinfectives, antiretrovirals to cns drug delivery drawbacks of oral famotidine tablets in the foregoing sections, we discussed activating the bubbles or using them in conjunction with ultrasoundmediated processes eg microbubble mediated sonothrombolysis to enhance the theraputic dose of generic wellbutrin local activity of the drug such as tpa, or that the availability of a drug may be increased, eg by opening the blood brain barrier in this section, we will discuss evaluating drugcarrying microbubbles for drug delivery targeted bubbles fig intravital microscopy demonstrating adherence of targeted microbubble to thrombus picture on the right is a graphic representation outlining the location of bound microbubbles on thrombus reproduced with drawbacks of oral famotidine tablets permission from schumann et al, investi radiol a as preliminary studies to demonstrate feasibility of using targeted bubbles as potential drug delivery agents, two different targeted bubbles were prepared using a mixture of dppc, dppepeg and dppa, as well as different oils and perfluorocarbons using a mixture of ddfp and nperfluorohexane in one study, a bioconjugate ligand targeted to the ���� integrin was synthesized by solid phase peptide methodology briefly, the bioconjugate, lipids, biocompatible drug, perfluoropropane were combined into a mixture and bubbles prepared by shaking the vials at approximately drawbacks of oral famotidine tablets rpm the size of the targeted bubbles was approximately im, as measured by light obscuration measurements on a particle sizing systems model sizer particle sizing systems, santa barbara, calif bubbles were injected into a mouse model where thrombi were previously formed in the cremasteric arterioles and venules fluorescent imaging revealed binding of the targeted bubbles to the thrombi in both arterioles and venules figure demonstrates the utility of a targeted bubble rd expansion cycle similarly, targeted bubbles were used in a huvec cell culture model briefly, bubbles with a targeting ligand drawbacks of oral famotidine tablets directed to avfo receptors on huvec cells were a � fig optical images of an a al with d frames occurring at times indicated on the streak image aal was insonated with a fivecycle pulse with peak negative pressure of mpa, at mhz a before insonation, radius is �� b d image acquired during the third cycle c d image acquired during the fourth expansion cycle d d image acquired after insonation and subsequent fragmentation e streak image, in which the horizontal axis is time with the entire image representing drawbacks of oral famotidine tablets fis, and the vertical axis indicates radial distance taken through the center of an aal reproduced with permission of may et al, ieee trans ultrason, ferroelect freq control incubated followed by washing of the cells with buffer imaging of the cells revealed that the targeted bubbles bound avidly to the cells, whereas the untargeted bubbles control did not once targeted, bubbles were demonstrated to bind to the receptor determinants acoustic studies were performed in vitro to test the ability of the drugcarrying bubbles or acoustically active lipospheres aals to cavitate in drawbacks of oral famotidine tablets response to insonation shown above is a streak image of an individual bubble in response to high mechanical index ultrasound as can be seen, the bubble expands and contracts in response to the ultrasound the aforementioned studies have indicated that we have the ability to combine targeting bubbles with ultrasoundmediated delivery techniques targeted submicronsized droplets another paradigm being studied is liquid perfluorocarbon and oilfilled droplets for targeting and drug delivery droplets offer a smaller size regime nm nm and a liquid core for drug loading just as with targeted bubbles, drawbacks of oral famotidine tablets droplets are sensitive to radiation force motility by ultrasound beams, although less compressible liquidfilled droplets require higher ultrasound intensities an experiment was performed in cell culture using pc human prostate cancer cells the cells were grown on # coverslips and incubated with droplets containing a targeting ligand directed to af receptors expressed on these tumor cells as a delivery system, droplets were loaded with a fluorescently labeled version of the chemotherapeutic paclitaxel cells were then exposed to mhz ultrasound at an intensity of mwcm for two min, followed by visualization on drawbacks of oral famotidine tablets fluorescence microscopy the figure below illustrates the results the center image shows a lowmagnification view of the cell monolayer, where the dotted line represents the region exposed to the circular focus of the ultrasound beam higher magnification images on the top and bottom show enlargements of regions with and without ultrasound exposure respectively the leftmost pair of images is an epifluorescence and transillumination image of the same region, illustrating that minimal paclitaxel was transferred to the monolayer outside of the region of insonation the transillumination image demonstrates that there are drawbacks of oral famotidine tablets cells present in this area the image pair on the right shows the monolayer in a region exposed to ultrasound, and one can clearly observe that the fluorescent paclitaxel has been transferred to the monolayer in this region the experiment described below demonstrates that ultrasoundmediated radiation force was able to siteselectively enhance the delivery of paclitaxel to a cell monolayer analysis showed that the fluorescence intensity of cells in the ultrasoundexposed region was approximately fold greater than the cells in fig fluorescent images of a pc cell monolayer administered fluorescent paclitaxel drawbacks of oral famotidine tablets containing droplets cells exposed to ultrasound denoted by the dotted circle received substantial delivery of the fluorescent chemotherapeutic, in contrast to cells not exposed to ultrasound images on the left show enlargements of the nonexposed top and exposed bottom areas respectively, in fluorescence and in white light reference dayton, pa, personal correspondence the nonexposed region since the only fluorescent component present was the fluorescentlylabeled paclitaxel, this intensity measurement correlates directly with the selectivity of ultrasoundmediated droplet delivery droplets are currently being tested in vivo in the scid severe combined immunodeficiency mouse drawbacks of oral famotidine tablets model with human tumor xenografts of prostate cancer experiments to determine if ultrasound will improve efficacy are currently in progress the agents have potential for a new, effective treatment of localized disease gene delivery cellular transfection of genes in the clinical setting has, to date, met with only anecdotal success lack of availability of safe, nonviral gene delivery vectors with high expression for localized delivery has impeded clinical development ultrasound enhanced delivery of lipidcoated microbubbles bearing genes or other genetic materials eg antisense oligonucleotides, sirna, etc holds promise to a drawbacks of oral famotidine tablets safe, effective delivery platform for localized gene delivery the figure below shows results from an experiment using ultrasound to stimulate local dna delivery to tumor in this study, lyophilized liposomes were prepared to entrap the gene for interleukin il the liposomal system was then injected intravenously, followed by insonation of tumors previously implanted in mice thighs studies were performed in sccvii squamous cell sc tumor bearing mice as shown in the figure below, ultrasound applied to the tumor resulted in significant tumor regression, compared with control or treatment with il gene drawbacks of oral famotidine tablets control excluding ultrasound fig effect of ultrasound treatment on the inhibition of tumor growth, following systemic administration of il transfection complexes sccvii tumorbearing mice were sono porated for min at wcm, followed by a single tailvein injection of dotmachol transfection complexes containing xg il plasmid or cat plasmid control animals received lactose tumor size was measured days after plasmid injection bars with different superscripts are statistically different f , mean � sd, n = , as determined by oneway anova and duncans multiple range test reproduced with permission from anwer et al, drawbacks of oral famotidine tablets gene ther a number of animal studies have been performed, showing that microbubbles with ultrasound can be used for efficient gene delivery to the cardiovascular system the figure below shows data from an experiment using cationic lipid coated perfluoropropane microbubbles, delivering the reporter gene for luciferase ant heart post heart liver brain pancreas muscle lung fig ultrasoundtargeted microbubble disruption led to the expression of plasmid derived luciferase the bars represent an average of samples negligible activity was detected in the control organs, with highly specific tissue expression in the heart study drawbacks of oral famotidine tablets performed in spraguedawley rats adapted from bekeredjian et al, j am coll cardiol the gene carrying bubbles were administered iv and focused ultrasound was applied to the left ventricle of rats high levels of luciferase expression in the anterior and posterior walls of the left ventricle coincided with the regions of ultrasound insonation, thus indicating that ultrasoundmediated delivery was effective oxygen delivery lipidcoated microbubbles may have potential applications as blood substitutes for oxygen delivery rapid oxygen delivery to tissues is critical for normal functioning, in patients suffering from trauma perfluorocarbons drawbacks of oral famotidine tablets are chemically inert hydrophobic molecules with the capacity to carry large amounts of oxygen liquid perfluorocarbons tested in clinical trials have been found to be safe, with side effects such as mild temperature increase and flulike symptoms compared with red blood cells or with liquid perfluorocarbon emulsions, perfluorocarbon gas microbubbles transport about times as much oxygen per unit volume since the longer chain length pfcs should give more stable microbubbles, and perfluoropentane dodecafluoropentane, ddfp is of as high a molecular weight as one can use being still a gas at physiological drawbacks of oral famotidine tablets temperature, ddfp is an excellent candidate for oxygen delivery ddfp boils at approximately �c and can be injected as a liquid emulsion to volatilize in the blood experimentally, the microbubbles have been visually observed with magnification light microscopy to increase and decrease in diameter as they imbibe oxygen when exposed to oxygen, and release oxygen under low oxygen tension conditions fig fig the action of perfluorocarbonfilled, lipidcoated microbubbles in different oxygen environments the potential utility of lipidcoated ddfp as an oxygen carrier was recently shown by lundgren et al at drawbacks of oral famotidine tablets a scientific presentation at the american heart association in this study, pigs breathing room air were subjected to blood volume loss of the pigs received an intravenous infusion of cckg, of wv ddfp emulsion, whereas control pigs received the vehicle without ddfp all of the treated pigs survived with normal weight gain and renal function out of control pigs died, and the only surviving pig had severe renal damage compared with other oxygen delivery technologies, lipidcoated ddfp emulsions may offer several advantages due to the high oxygen carrying capacity, only a drawbacks of oral famotidine tablets small volume might be required for administration to a human subject the studies described above, suggest that a volume of to cc should be sufficient to resuscitate a human subject from hemorrhagic shock, while breathing room air the ddfp is inert and eliminated by respiration over a period of several hours the gas gradually diffuses across the lipid membranes into the blood and is eliminated via the lungs this is contrasted to liquid pfcs, eg perfluorooctylbromide, which have been extensively studied as blood substitutes the liquid pfcs are retained long drawbacks of oral famotidine tablets term by the reticuloendothelial system res and require much larger volumes for the resuscitation of a hemorrhagic shock victim lipidcoated ddfp emulsions are not a blood substitute but a novel technology for oxygen delivery the small requisite volume eg cc for kg patient may enable rapid resuscitation without volume overload and allows for subsequent treatment with whole blood the small volume and characteristics of the lipidcoated ddfp emulsion may have advantages for resuscitation in critical environments like ischemia as the small volume can be administered without hemodynamically compromising the subject, the drawbacks of oral famotidine tablets technology might be exploited to minimize damage from ischemia, associated with conditions such as stroke, myocardial infarction and occlusive vascular disease the prolonged retention of the liquid pfcs by the res has proven problematic in the clinical development of these materials the rapid clearance of gaseous pfcs from the body in several hours may prove helpful in the development of lipidcoated microbubbles for oxygen delivery pulmonary delivery lipidcoated microbubbles have the potential for delivery of genes and drugs to the lungs since the internal volume of the microbubbles is mainly drawbacks of oral famotidine tablets gas, they have very low density as such, these low density carriers may have unique properties for pulmonary delivery a major problem with conventional aerosols is the precipitation onto the central airways, principally the oropharynx and trachea it is min fig inhaled insulin v inhaled microbubble encapsulated insulin advantageous, however, to deliver medicines into the terminal respiratory bronchioles to treat diseases such as asthma, and for the systemic delivery of medications via the lung it is also desirable to reach the alveoli for the most efficient absorption of the medication the drawbacks of oral famotidine tablets low hydrodynamic index of the lipidcoated microbubbles appears to enable the particles to reach beyond the bronchi and potentially reach the alveoli pulmonary delivery experiments were carried out in our laboratory to deliver both genes and drugs in mice a standard nebulizer was used to deliver lipidcoated perfluoropropane microbubbles into a holding chamber the mouse being treated was placed in this chamber for min the nebulizer reservoir contained enough materials for min of delivery and the animals were held in the chamber for an additional min mice were treated with streptozotocin to create a diabetic condition these mice were then treated with nebulized insulin either via the conventional formulation or via microbubbles conventional insulin showed no effect on blood sugar the blood sugar levels were greatly reduced by the microbubble insulin in min conclusion lipidcoated, submicronsized particles are used extensively in ultrasound imaging the ability to activate these agents with ultrasound energy affords unique potential applications to these agents acoustic activation of micro or submicron sized bubbles affords potential as a less invasive, safer way of treating vascular thrombosis, and the drawbacks of oral famotidine tablets ultimate utility of this technology will depend on results in the clinical development the technology has the potential to dramatically improve the therapeutic outcome in the treatment of stroke targeted ultrasound mediated delivery also affords potential in drug and gene delivery to treat cardiovascular disease, systemic disease and the central nervous system in addition to the unique applications of these agents in concert with ultrasound energy, bubbles may have therapeutic applications in their own right for delivering oxygen and other biologically active gases the low hydrodynamic radius of bubbles and the drawbacks of oral famotidine tablets fusogenic properties of the bubbles themselves also increase the potential for pulmonary delivery special thanks the authors would like to thank dr paul dayton for his help in preparing this manuscript references rawn jd biochemistry neil patterson publishers prosperetti a bubble phenomena in sound fields part one, ultrasonics plesset ms the dynamics of cavitation bubbles, j appl mech forsberg f and shi wt physics of contrast microbubbles, in ultrasound contrast agents basic principles and clinical applications goldberg bb, raichlen js and forsberg f martin dunitz eds pp personal communication de drawbacks of oral famotidine tablets jong n, hoff l, skotland t and bom n absorption and scatter of encapsulated gas filled microspheres theoretical considerations and some measurements ultrasonics apfel re and holland ck gauging the likelihood of cavitation from shortpulse, lowduty cycle diagnostic ultrasound, ultrasound med biol crum la, roy ra, dinno ma, church cc, apfel re and holland ck acoustic cavitation produced by microsecond pulses of ultrasound a discussion of some selected results j acoust soc am dayton pa, chomas je, lum af, allen js, lindner jr, simon si and ferrara kw optical and acoustical drawbacks of oral famotidine tablets dynamics of microbubble contrast agents inside neutrophils biophys ] takeuchi m, ogunyankin k, pandian ng, mccreery tp, sweitzer rh, caldwell ve, unger ec, avelar e, sheahan m and connolly r enhanced visualization of intravascular and left atrial appendage thrombus with the use of a thrombustargeting ultrasonographic contrast agent mrxa in vivo experimental echocardiographic studies am soc echocardiogr unger ec, wu q, mccreery tp and matsunaga to thrombusspecific contrast agents for imaging and thrombolysis, in ultrasound contrast agents basic principles and clinical applications goldberg bb, raichlen js and forsberg f martin drawbacks of oral famotidine tablets dunitz eds pp unger ec, matsunaga to, mccreery t, schumann p, sweitzer r and quigley r therapeutic applications of microbubbles eur } radiol personal communication chin ct and burns pn predicting the acoustic response of a microbubble population for contrast imaging in medical ultrasound ultrasound med biol tiemann k, lohmeier s, kuntz s, koster j, pohl c, burns p, nanda nc, luderitz � and becter h realtime contrast echo assessment of myocardial perfusion at low emission power first experimental and clinical result using power pulse inversion imaging echocardiography chin ct and burns pn predicting the acoustic response of a microbubble population for contrast imaging in medical ultrasound ultrasound med biol tiemann k, lohmeier s, kuntz s, koster j, pohl c, burns p, nanda nc, luderitz � and becter h realtime contrast echo assessment of myocardial perfusion at low emission power first experimental and clinical result using power pulse inversion imaging echocardiography crum la, roy ra, dinno ma, church cc, apfel re, holland ck and madanshetty si acoustic cavitation produced by microsecond pulses of ultrasound a discussion of some selected results j drawbacks of oral famotidine tablets accoust soc am ibid everbach ec and francis cw cavitational mechanisms in ultrasoundaccelerated thrombolysis at mhz ultrasound med biol siegel rj, atar s, fishbein mc, brasch av, peterson tm, nagai t, pal d, nishioka t, chae j, birnbaum y, zanelli � and luo h noninvasive transcutaneous low frequency ultrasound enhances thrombolysis in peripheral and coronary arteries echocardiography suchkova vn, baggs rb and francis cw effect of khz ultrasound on acute thrombotic ischemia in a rabbit femoral artery thrombosis model enhancement of thrombolysis and improvement in capillary muscle perfusion circulation rhodes jm, drawbacks of oral famotidine tablets cho js, gloviczki p, mozes g, rolle r and miller vm thrombolysis for experimental deep venous thrombosis maintains valvular competence and vasore activity} vase surg everbach ec and francis cw cavitational mechanisms in ultrasoundaccelerated thrombolysis at mhz ultrasound med biol culp wc, erdem e, roberson pk and husain mm microbubble potentiated ultrasound as a method of stroke therapy in a pig model preliminary findings,} vase interv radiol everbach ec and francis cw cavitational mechanisms in ultrasoundaccelerated thrombolysis at mhz, ultrasound med biol francis cw ultrasoundenhanced thrombolysis echocardiography allen js, drawbacks of oral famotidine tablets may dj and ferrara kw dynamics of therapeutic ultrasound contrast agents ultrasound med biol allen js, may dj and ferrara kw dynamics of therapeutic ultrasound contrast agents ultrasound med biol chomas je, dayton p, may d and ferrara kw threshold of fragmentation for ultrasonic contrast agents biomed optics d patel et al, ieee ultrasonics, ferroelectrics, and frequency control shortencarier mj, dayton pa, bloch sh, schumann pa, matsunaga to and ferrara kw a method for radiationforce localized drug delivery using gasfilled lipospheres, ieee trans ultrason, ferroelectrics freq control dayton pa, klibanov a, drawbacks of oral famotidine tablets brandenburger g and ferrara kw acoustic radiation force in vivo a mechanism to assist targeting of microbubbles, ultrasound med biol dayton pa, morgan ke, klibanov al, brandenburger g, nightengale kr and ferrara kw a preliminary evaluation of primary and secondary radiation forces on acoustic contrast agents, ieee trans ultrason, ferroelectrics freq control dayton pa, allen j and ferrara kw the magnitude of radiation force on ultrasound contrast agents} acoust soc am zhao s, borden m, bloch sh, kruse d, ferrara kw and dayton pa radiationforce assisted targeting facilitates ultrasonic molecular imaging mo!