Abstract: Gas or air filled microbubble and microballoon suspensions in aqueous phases usable as imaging contrast agents in ultrasonic echography. The microbubble suspensions contain laminarized surfactants and, optionally, hydrophilic stabilizers. The laminarized surfactants can be in the form of liposomes. The microbubble suspensions are obtained by exposing the laminarized surfactants to air or a gas before or after admixing with an aqueous phase. The microballoons have a mean size in the range of 0.5 to 1000 microns bounded by a 50 to 500 nm thick polymer membrane. One can impart outstanding resistance against collapse under pressure to these gas-filled microbubbles and gas-filled microballoons used as contrast agents in ultrasonic echography by using as fillers gases whose solubility in water, expressed in liter of gas by liter of water under standard conditions, divided by the square root of the molecular weight does not exceed 0.003.

Abstract: The present invention relates to methods and drugs for ameliorating insulin resistance in skeletal muscle, a major contributing abnormality to impaired glucose handling in such diseases as type 1 and type 2 diabetes, hypertension, obesity and critical care patients. This invention provides drugs, methods for screening those drugs and methods specifically targeted to ameliorating insulin resistance by increasing capillary blood flow in muscle.

Abstract: The invention relates to injectable media for ultrasonic echography in the form of microbubbles or microballoons comprising at least two biocompatible substances A and B (gaseous at the body temperature) forming a mixture which when in suspension with usual surfactants, additives and stabilisers provides useful ultrasound contrast agents. At least one of the components (B) in the mixture is a gas whose molecular weight is greater than 80 daltons and whose solubility in water is below 0.0283 ml per ml of water at standard conditions. The presence of the first component (B) in the contrast medium may vary between 0.5 and 41 volume percent. The other component (A) of the ultrasound contrast media is a gas or a mixture of gases whose molecular weight is below 80 daltons. The second component is present in a proportion of between 59-99.5% by vol., and is preferably chosen from oxygen, air, nitrogen, carbon dioxide or mixtures thereof.

Abstract: The present invention relates to a composition that includes gadolinium particles encapsulated in microsphere shells. The composition is suitable for use as a contrast agent with a plurality of imaging modalities, including, for example, ultrasound, magnetic resonance imaging, and computed temography. The compositions also are useful for therapeutic applications, including neutron capture therapy.

Abstract: Ultrasonic visualisation of a subject, particularly of perfusion in the myocardium and other tissues, is performed using novel gas-containing contrast agent preparations which provide controllable and temporary growth of the gas phase in vitro following administration and can therefore act as deposited perfusion tracers. The preparations comprise an injectable aqueous gas dispersion and an administrable substance or substances capable of destabilising the dispersed gas to provide temporary growth thereof. In cardiac perfusion imaging the preparations may advantageously be coadministered with vasodilator drugs such as adenosine in order to enhance the differences between return signal intensity from normal and hypoperfused myocardial tissue respectively.

Abstract: New ultrasound contrast agents that comprise microbubbles encapsulating a gas within a shell made from a blend of bipolar compounds having mixed carbon chain length. The compounds have hydrophobic groups selected from the group consisting of straight-chained alkyls, alkylethers, alkylthiolethers, alkyldisulfides, polyfluoroalkyls, and polyfluoroalkylethers having a carbon chain length greater than or equal to 16 and less than or equal to 32. The polar groups are connected to the hydrophobic groups by means of a linker. The polar head groups are selected from the group consisting of CO2-M+, SO3−M+, SO4−M+, PO3−M+, PO4−M+2, N(R)4+, a pyridinium or substituted pyridinium group, and a zwitterionic group; R is selected from the group consisting of —H, —CH3, alkyl, cycloalkyl, substituted cycloalkyls containing one or more heteroatoms, and benzyl and can be the same or different; and Z′ is a nonionic and M is a cation.

Abstract: Ultrasonic visualisation of a suject, particularly of perfusion in the myocardium and other tissues, is performed using novel gas-containing contrast agent preparations which promote controllable and temporary growth of the gas phase in vivo following administration and can therefore act as deposited perfusion tracers. The preparations include a coadministerable composition comprising a diffusible component capable of inward diffusion into the dispersed gas phase to promote temporary growth thereof. In cardiac perfusion imaging the preparations may advantageously be coadministered with vasodilator drugs such as adenosine in order to enhance the differences in return signal intensity from normal and hypoperfused myocardial tissue respectively.

Abstract: A composition for ultrasonic imaging is described having a microbubble population of controlled fragility. The microbubbles comprise an outer shell and a hollow core. The ratio of shell thickness to microbubble diameter is substantially similar across the population of microbubbles. A method of using such composition for imaging a fluid filled cavity, vessel or tissue is described.

Abstract: Low density microspheres, methods for preparing same, and use of same as contrast agents are described. The microspheres have a void having a volume that comprises at least about 75% of the total volume of the microspheres, and which contains a gas or the vapor of a volatile liquid selected from the group consisting of aliphatic hydrocarbons, chlorofluorocarbons, tetraalkyl silanes and perfluorocarbons.

Abstract: Ultrasonic visualisation of a subject, particularly of perfusion in the myocardium and other tissues, is performed using novel gas-containing contrast agent preparations which promote controllable and temporary growth of the gas phase in vivo following administration and can therefore act as deposited perfusion tracers. The preparations comprise an injectable aqueous medium comprising dispersed gas and an injectable oil-in-water emulsion in which the oil phase comprises a diffusible component capable of diffusion in vivo into the dispersed gas to promote temporary growth thereof, such that material present at the surfaces of the dispersed gas phase and material present at the surfaces of the dispersed oil phase have affinity for each other, e.g. as a result of having opposite charges.

Abstract: Targetable diagnostic and/or therapeutically active agents, e.g. ultrasound contrast agents, having reporters comprising gas-filled microbubbles stabilised by monolayers of film-forming surfactants, the reporter being coupled or linked to at least one vector.

Abstract: Ultrasonic visualisation of a suject, particularly of perfusion in the myocardium and other tissues, is performed using novel gas-containing contrast agent preparations which promote controllable and temporary growth of the gas phase in vivo following administration and can therefore act as deposited perfusion tracers. The preparations include a coadministerable composition comprising a diffusible component capable of inward diffusion into the dispersed gas phase to promote temporary growth thereof. In cardiac perfusion imaging the preparations may advantageously be coadministered with vasodilator drugs such as adenosine in order to enhance the differences in return signal intensity from normal and hypoperfused myocardial tissue respectively.

Abstract: The present invention provides contrast agents for use in diagnostic ultrasound studies comprising microbubbles of gas or a gas precursor encapsulated by non-proteinaceous crosslinked or polymerised amphiphilic moieties.

Abstract: Ultrasound contrast agents of the phase shift colloid type, comprising emulsions of volatile oils in water, are provided with gas-containing nucleation sites associated with (e.g. within) droplets of the dispersed oil phase, in order to enhance efficacy and control of the liquid-to-gas phase transition.

Abstract: The invention relates to ultrasound contrast agents comprising vesicles comprising a protein capable of formation of gas-containing vesicles, wherein the vesicles contain gas which comprises sulphur hexafluoride or a low molecular weight fluorinated hydrocarbon. These contrast agents exhibit stability in vivo upon administration so as to permit ultrasound visualization while allowing rapid subsequent elimination from the system.

Abstract: Air or gas filled microballoons bounded by an interfacially deposited polymer membrane which can be dispersed in aqueous carrier liquids to be injected into living organisms or administered orally, rectally and urethrally for therapeutic or diagnostic purposes (echography). The properties of the polymeric membrane of the microballoons (elasticity, permeability, biodegradability) can be controlled at will depending on the selected polymer, the interfacial deposition conditions, and the polymer additives.

Abstract: Disclosed herein are agents for enhancing the contrast in an ultrasound image. These agents are extremely small bubbles, or “microbubbles,” comprised of specially selected gases. The microbubbles described herein exhibit long life spans in solution and may be produced at a size small enough to traverse the lungs, thus enabling improved ultrasound imaging of the cardiovascular system and other vital organs. Also disclosed herein is a method for selecting gases from which contrast agents may be produced. The method is based on calculations using inherent physical properties of gases and describes a means to associate the properties of a gas with the time for dissolution of microbubbles comprised of the gas.

Abstract: Improved therapeutic sclerosing microfoams are provided that have advantage in producing a consistent profile injectable foam with minimal input by the physician yet using high volume percentages of blood dispersible gases, thus avoiding use of potentially hazardous amounts of nitrogen.

Abstract: An apparatus and method for determining the viscosity of the circulating blood of a living being over plural shear rates caused by a decreasing pressure differential by monitoring the changing weight of the blood, or the changing level of a column of blood over time. The apparatus and method utilize a riser, a capillary tube, a collector and a mass detector, such as a precision balance or a load cell, for monitoring the changing weight of a sample of fluid that flows through these components under the influence of the decreasing pressure differential; alternatively, the apparatus and method use a column level detector to monitor the changing level of the column of blood over time.

Abstract: Microparticles are provided comprising a shell of an outer layer of a biologically compatible material and an inner layer of biodegradable polymer. The core of the microparticles contain a gas, liquid or solid for use in drug delivery or as a contrast agent for ultrasonic contrast imaging. The microparticles are capable of passing through the capillary systems of a subject.

Abstract: This invention relates to ultrasound imaging, more specifically to a method of ultrasound investigation involving the use of an ultrasound contrast agent and administration of at least two gases or gas mixtures having different partial pressure of inert gas. The method may be used in assessing blood perfusion in tissue. A timed change of administered gases gives a subsequent change in contrast echogenicity. The gases are preferably administered by inhalation. The invention further relates to gas-microbubble containing ultrasound contrast agents used according to the method, and to kits to be used in assessments of tissue perfusion.

Abstract: Agents for use in ultrasound contrast include protein microspheres in which a gas such as perfluoropropane, perfluorobutane or perfluoropentane is contained.

Abstract: The present invention describes, among other things, the surprising discovery that gaseous precursor filled compositions are profoundly more effective as acoustically active contrast agents when they are thermally preactivated to temperatures at or above the boiling point of the instilled gaseous precursor prior to their in vivo administration to a patient. Further optimization of contrast enhancement is achieved by administering the gaseous precursor filled compositions to a patient as an infusion. Enhanced effectiveness is also achieved for ultrasound mediated targeting and drug delivery.

Abstract: Fluoroalkanes such as fluoromethane labeled with 17F are produced by contacting 17F labeled F2 with alkanes, preferably methane, substituted or unsubstituted alkenes, or substituted or unsubstituted alkynes in the presence of a metal oxide catalyst, preferably a silver oxide catalyst, to produce the 17F labeled fluoroalkane. The 17F may be produced by irradiating 20Ne with protons, preferably having an energy of about 11 MeV and produced by a cyclotron. The 17F labeled fluoromethane or fluoroalkanes may be produced continuously. A method for determining the location of an 17F labeled tracer includes generating an 17F labeled fluoroalkane, administering the 17F labeled fluoroalkane to a test subject, and scanning the test subject with a radiosensitive detector such as a positron emission tomography scanner.

Abstract: A kit and method for causing tissue death within a tissue site is disclosed. The kit includes a media with a light activated drug activatable upon exposure to a particular level of ultrasound energy. The kit also includes a catheter with a lumen coupled with a media delivery port through which the light activated drug can be locally delivered to the tissue site. The ultrasound transducer is configured to transmit the level of ultrasound energy which activates the light activated drug with sufficient power that the ultrasound energy can penetrate the tissue site.

Abstract: A method of contrast agent-enhanced imaging involving induction of vasomodification, e.g. by physical or pharmacological means, in which pre- and post-vasomodification images in respect of free-flowing contrast or tracer agent in a substantially steady state distribution are recorded as part of a single imaging sequence and are compared to identify any local variations resulting from changes in vascular volume caused by the vasomodification. Imaging techniques which may be employed include ultrasound imaging, magnetic resonance imaging, X-ray imaging and nuclear tracer techniques such as scintigraphy.

Abstract: A microbubble preparation formed of a plurality of microbubbles comprising a first gas and a second gas surrounded by a membrane such as a surfactant, wherein the first gas and the second gas are present in a molar ratio of from about 1:100 to about 1000:1, and wherein the first gas has a vapor pressure of at least about (760-x) mm Hg at 37° C., where x is the vapor pressure of the second gas at 37° C., and wherein the vapor pressure of each of the first and second gases is greater than about 75 mm Hg at 37° C.; also disclosed are methods for preparing microbubble compositions, including compositions that rapidly shrink from a first average diameter to a second average diameter less than about 75% of the first average diameter and are stabilized at the second average diameter; kits for preparing microbubbles; and methods for using such microbubbles as ultrasound contrast agents.

Abstract: A microbubble preparation formed of a plurality of microbubbles comprising a first gas and second gas surrounded by a membrane such as a surfactant, wherein the first gas and the second gas are present in a molar ration of from about 1:100 to abut 1000:1, and wherein the first gas has a vapor pressure of at least about (760-X) mm Hg at 37° C., where x is the vapor pressure of the second gas at 37° C., and wherein the vapor pressure of each of the first and second gases is greater than about 75 mm Hg at 37° C.; also disclosed are methods for preparing microbubble compositions, including compositions that rapidly shrink from a first average diameter to a second average diameter less than about 75% of the first average diameter and are stabilized at the second average diameter; methods and kits for preparing microbubbles; and methods for using such microbubbles as contrast agents.

Abstract: Targetable diagnostic and/or therapeutically active agents, e.g. ultrasound contrast agents, comprising a suspension in an aqueous carrier liquid of a reporter comprising gas-containing or gas-generating material, said agent being capable of forming at least two types of binding pairs with a target.

Abstract: The invention relates to a method of generating an image of an animate human or non-human animal body or part thereof. The method comprises administering to said body a physiologically tolerable contrast agent comprising a radiation absorbing component and/or a pressure inducing component, exposing said body to radiation, detecting pressure waves generated in said body by said radiation and generating an optoacoustic image therefrom of at least a part of said body containing the administered contrast agent.

Abstract: A microparticle composition is provided for delivery of a pharmaceutical agent by ultrasound triggering. The microparticles have a porous, gas-containing interior polymer matrix and a plurality of cavities in the matrix which contain a gas and the agent. Methods for forming the microparticles and their use in ultrasonic diagnostic imaging and drug delivery are also provided.

Abstract: A method is provided to prepare gas-filled, porous microparticles having a polymer matrix interior which are useful as ultrasound echogenic contrast agents. An oil-in-water suspension is formed, both phases are frozen, then the aqueous and nonaqueous frozen phases are removed by sublimation. The resulting porous microparticles can receive a gas and be used as an ultrasound contrast agent.

Abstract: The invention provides embolic particles, agents and compositions, suitable for effectuating embolization or occlusion of a vessel or a duct, which particles, agents and compositions are visible under ultrasound. Particularly, the embolic particles, agents and compositions comprise gas or microbubbles of gas such that the embolic particles, agents and compositions are visible under ultrasound. The invention further provides for methods of treatment of diseases such as cancer. The invention further provides for methods of embolization and detection of embolic occlusion using the embolic particle, agents, and compositions of the invention.

Abstract: Disclosed herein are agents for enhancing the contrast in an ultrasound image. These agents are extremely small bubbles, or “microbubbles,” comprised of specially selected gases. The microbubbles described herein exhibit long life spans in solution and may be produced at a size small enough to traverse the lungs, thus enabling improved ultrasound imaging of the cardiovascular system and other vital organs. Also disclosed herein is a method for selecting gases from which contrast agents may be produced. The method is based on calculations using inherent physical properties of gases and describes a means to associate the properties of a gas with the time for dissolution of microbubbles comprised of the gas.

Abstract: Microbubble dispersions stabilised by phospholipids predominantly comprising molecules which individually have an overall net charge exhibit advantageous stability, rendering them useful as efficacious contrast agents. An improved process for preparing microbubble-containing contrast agents is also disclosed, this comprising lyophilising an aqueous dispersion of gas microbubbles stabilised by one or more membrane-forming lipids to yield a dried product which may be reconstituted in an injectable carrier liquid to generate a microbubble-containing contrast agent.

Abstract: Gas or air filled microbubble suspensions in aqueous phases usable as imaging contrast agents in ultrasonic echography. They contain surfactants and, optionally, hydrophilic stabilizers. The surfactants can be in the form of liposomes. The suspensions are obtained by exposing the surfactants to air or a gas before or after admixing with an aqueous phase. One can impart outstanding resistance against collapse under pressure to these gas-filled microbubbles used as contrast agents in ultrasonic echography by using as fillers gases whose solubility in water, expressed in liter of gas by liter of water under standard conditions, divided by the square root of the molecular weight does not exceed 0.003. Contrast agents with particular mixtures of gases are also disclosed that have advantageous properties.

Abstract: A booster comprising a plurality of microbubbles of a gas in a liquid, e.g. about 4×107 cells/ml of microbubbles of a gas having a diameter of 0.1 to 100 &mgr;m in a 3 to 5% human serum albumin solution, and a pharmaceutical liquid composition comprising the booster as set forth above and a medicament, which are useful for the therapy of various diseases together with exposure of ultrasonic, where the therapeutic effects of the medicament is enhanced by the application of ultrasound in the presence of the booster.

Abstract: A process for forming microcapsules comprising (i) providing a solution of a protein in an aqueous solvent and (ii) spraying the said solution into a gas such that the aqueous solvent evaporates, thereby forming hollow microcapsules, characterised in that the aqueous solution contains a liquid of greater volatility than water. The protein is preferably albumin and the volatile liquid is preferably ethanol. The microcapsules may be used as ultrasound echogenic contrast agents.

Abstract: Gas or air filled microbubble suspensions in aqueous phases usable as imaging contrast agents in ultrasonic echography. They contain surfactants and, optionally, hydrophilic stabilizers. The surfactants can be in the form of liposomes. The suspensions are obtained by exposing the surfactants to air or a gas before or after admixing with an aqueous phase. One can impart outstanding resistance against collapse under pressure to these gas-filled microbubbles used as contrast agents in ultrasonic echography by using as fillers gases whose solubility in water, expressed in liter of gas by liter of water under standard conditions, divided by the square root of the molecular weight does not exceed 0.003. Contrast agents with particular mixtures of gases are also disclosed that have advantageous properties.

Abstract: Disclosed herein are agents for enhancing the contrast in an ultrasound image. These agents are extremely small bubbles, or “microbubbles,” comprised of specially selected gases. The microbubbles described herein exhibit long life spans in solution and may be produced at a size small enough to traverse the lungs, thus enabling improved ultrasound imaging of the cardiovascular system and other vital organs. Also disclosed herein is a method for selecting gases from which contrast agents may be produced. The method is based on calculations using inherent physical properties of gases and describes a means to associate the properties of a gas with the time for dissolution of microbubbles comprised of the gas.

Abstract: Gas or air filled microbubble suspensions in aqueous phases usable as imaging contrast agents in ultrasonic echography. They contain surfactants and, optionally, hydrophilic stabilizers. The surfactants can be in the form of liposomes. The suspensions are obtained by exposing the surfactants to air or a gas before or after admixing with an aqueous phase. One can impart outstanding resistance against collapse under pressure to these gas-filled microbubbles used as contrast agents in ultrasonic echography by using as fillers gases whose solubility in water, expressed in liter of gas by liter of water under standard conditions, divided by the square root of the molecular weight does not exceed 0.003. Contrast agents with particular mixtures of gases are also disclosed that have advantageous properties.

Abstract: The invention provides a method of contrast agent drug candidate selection which involves: (i) obtaining a combinatorial library comprising an admixture of potential contrast agent drug candidates each incorporating a reporter moiety which is detectable in the animate human or non-human animal body (e.g. mammalian, avian or reptilian body), said library comprising a plurality of said reporter moieties which are interdistinguishably detectable in said body; (ii) administering said library to an animate human or non-human animal body; (iii) identifying in vivo one or more of said reporter moieties which has a desired distribution and/or elimination pattern in said body and thereby identifying a member of said library which has said pattern site or a sub-set of said library which contains a member of said library which has said pattern.

Abstract: A kit and method for causing tissue death within a tissue site is disclosed. The kit includes a media with a light activated drug activatable upon exposure to a particular level of ultrasound energy. The kit also includes a catheter with a lumen coupled with a media delivery port through which the light activated drug can be locally delivered to the tissue site. The ultrasound transducer is configured to transmit the level of ultrasound energy which activates the light activated drug with sufficient power that the ultrasound energy can penetrate the tissue site.

Abstract: Novel ultrasound methods comprising administering to a patient a targeted vesicle composition which comprises vesicles comprising a lipid, protein or polymer, encapsulating a gas, in combination with a targeting ligand, and scanning the patient using ultrasound. The scanning may comprise exposing the patient to a first type of ultrasound energy and then interrogating the patient using a second type of ultrasound energy. The targeting ligand preferably targets tissues, cells or receptors, including myocardial cells, endothelial cells, epithelial cells, tumor cells and the glycoprotein GPIIbIIIa receptor. The methods may be used to detect a thrombus, enhancement of an old or echogenic thrombus, low concentrations of vesicles and vesicles targeted to tissues, cells or receptors.

Abstract: The invention relates to gas-filled microcapsules that consist of functionalized polyalkylcyanoacrylates that are produced by copolymerization of one or more alkylcyanoacrylates with a functional monomer and/or by partial side-chain hydrolysis of a polyalkylcyanoacrylate, as well as a process for the production of gas-filled microcapsules and their use for ultrasound diagnosis.

Abstract: The present invention is directed to methods and apparatus for the targeted initiation or deactivation of chemical reactions by an acoustic energy source in a host. Methods and apparatus for the targeted delivery of drugs, diagnostic agents and other compounds using an acoustic energy source are also provided.

Abstract: A medicinal preparation capable of lowering the threshold of cavitation and generating active oxygen species via acoustic cavitation caused by an ultrasound is provided. The preparation, which is to be used in combination with ultrasonic irradiation, comprises a shell within the internal space of which a gas is enclosed and which contains or retains a substance capable of generating active oxygen species upon ultrasonic irradiation of the shell.

Abstract: A gas emulsion for ultrasound contrast enhancement comprising a plurality of gas bubbles in a liquid medium, the gas bubbles comprising at least one fluoroether selected from the group consisting of CF3OCF2OCF3, CF3(OCF2)2OCF3, CF3(OCF2)3OCF3, and CF3(OCF2)4OCF3.

Abstract: Ultrasound imaging using gas microbubble-containing contrast agents may be performed in the recirculating phase following admixture of the contrast agent with the blood pool, thereby prolonging the useful imaging time window compared to that conventionally obtained during the backscatter signal peak resulting from first pass of a contrast agent bolus. The length of the time window may further be increased by imaging at ultrasound frequencies of 2 MHz or less, particularly by harmonic imaging at transmit frequencies less than the resonance frequencies of the gas microbubbles.

Abstract: One can impart outstanding resistance against collapse under pressure to gas-filled microvesicle used as contrast agents in ultrasonic echography by using as fillers gases whose solubility in water, expressed in liter of gas by liter of water under standard conditions, divided by the square root of the molecular weight does not exceed 0.003.