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Biomedical subjects

J G Riess

Publications and source records attributed to J G Riess.

At least 37 records · Page 2Linked to original sources
PubMed1994

Improved control over particle sizes and stability of concentrated fluorocarbon emulsions by using mixed fluorocarbon/hydrocarbon molecular dowels.

The use of a surfactant system consisting in equimolar amounts of egg yolk phospholipids and of a mixed fluorocarbon/hydrocarbon amphiphile (C8H17CH = CHC8F17) allows the preparation of concentrated (90% w/v, i.e. 47% v/v) emulsions of perfluorooctyl bromide (perflubron), with average particle sizes ranging from 0.12 to 16 microns post-sterilization, depending on the surfactant/fluorocarbon ratio. Emulsion droplet diameters varied linearly as a function of the emulsifier's concentration, thus allowing easy pre-determination of the emulsion's average particle size. Excellent stability was observed for the dowel-containing emulsions for at least 6 months at 40 degrees C over the whole domain of particle sizes investigated.

Drug Stability↗
PubMed1994

Biodistribution and excretion of a mixed fluorocarbon-hydrocarbon "dowel" emulsion as determined by 19F NMR.

To investigate the biodistribution, possible metabolism and excretion of mixed fluorocarbon-hydrocarbon "dowel" molecules used as stabilizers of fluorocarbon emulsions, we have prepared a 25% w/v emulsion of such a molecule, and quantitatively evaluated, by means of 19F NMR, its behavior in the blood and reticuloendothelial system (RES) of rats. C6F13CH = CHC10H21 (F6H10E) was emulsified using egg yolk phospholipids (EYP). The emulsion (F6H10E/EYP: 25/6% w/v) was injected intravenously into 33 Sprague Dawley female rats at a 3.6 g/kg body weight dose of F6H10E. The animals were sacrificed at regular intervals of time. 24 hours after the injection, 70% of the injected dose was located in the liver, 17% in the spleen, 4% in the lungs, 2% in the kidneys and 2% in the blood. The half-time retention of the dowel molecule in the liver was estimated to be 25 +/- 5 days. None of the 33 treated animals died prior to the planned sacrifice date. The dowel molecule F6H10E proved to be well tolerated, and excreted reasonably fast, without metabolism. This appears to warrant the use of such molecules as stabilizers in injectable fluorocarbon emulsions destined to serve as oxygen carriers, contrast agents or drug delivery systems.

Animals↗
PubMed1994

Mixed fluorocarbon/hydrocarbon molecular dowels help protect concentrated fluorocarbon emulsions with large size droplets against coalescence.

Mixed fluorocarbon/hydrocarbon amphiphiles, the so-called molecular dowels, have previously been reported to strongly stabilize concentrated (90% w/v, i.e. 47% w/v) submicronic size perfluorooctyl bromide emulsions emulsified by egg yolk phospholipids. The dowel molecules, used in equimolar amounts with phospholipids, enable the preparation of emulsions with large-sized particles which are impossible to obtain with phospholipids alone. We report here that molecular dowels (C6F13C10H21, F6H10) also hinder droplet coalescence induced by mechanical stress in sterilized emulsions with average particle sizes ranging from ca 1 to 16 microns. In contrast, the addition of equimolar amounts of perfluorodecyl bromide was found to have little influence on these emulsions' resistance to mechanical stress. This is consistent with the view that mixed fluorocarbon/hydrocarbon dowels are held in the interfacial film and reinforce its cohesion with the fluorocarbon phase.

Drug Stability↗
PubMed1994

Amphiphilic sugar phosphates with single or double perfluoroalkylated hydrophobic chains for use in oxygen and drug delivery systems.

New anionic amphiphiles with a phosphate ester junction between the fluorophilic-lipophilic tail and the sugar-based hydrophilic head were synthesized and evaluated. The single hydrophobic chain surfactants 1 a, b and 2a allowed the preparation of stable and fine highly concentrated emulsions of perfluorodecalin or perfluoroocytl bromide, either when used alone or in conjunction with egg yolk phospholipids (EYP). Surfactants 3d, 5d, 6d and 6e, with two hydrophobic chains, one fluorinated the other not, gave liposomal structures, and displayed encapsulation properties for carboxyfluorescein. The phosphodiesters tested cause no significant inhibition of the growth and viability of Namalva cell cultures (0.1-1 g/L range). Single chain phosphodiesters manifest no detectable hemolytic activity (at 100 g/L for 1a) whereas double chain compounds do moderately (ca 20% hemolysis at 20 g/L). The maximum tolerated dose compatible with the survival of all of a series of 10 intravenously injected mice is in 130 mg/kg body weight range.

Alkylation↗
PubMed1994

Fluorinated phospholipid-based vesicles as potential drug carriers: encapsulation/sustaining of drugs and stability in human serum.

The release of entrapped 5(6)-carboxyfluorescein from fluorinated vesicles in a buffer or in human serum is considerably less than that from hydrogenated liposomes. The presence of a fluorinated core inside the liposomal membrane definitely reduces its permeability. In some cases, the stability of liposomes made from fluorinated phospholipids alone is better than that of egg phosphatidylcholine cholesterol 1/1 vesicles, which are among the least permeable and most stable hydrogenated liposomes.

Blood Physiological Phenomena↗
PubMed1994

Novel injectable fluorinated contrast agents with enhanced radiopacity.

Novel emulsions containing iodinated fluorinated radiopaque (IFR) molecules were prepared and evaluated as injectable contrast agents with prolonged intravascular persistence. Various stable IFR/egg yolk phospholipid emulsions were produced, heat-sterilized, and tested as to their radiopacity, shelf-stability and in vivo tolerance. No significant change in mean particle sizes was observed over a 3-month storage period at 40 degrees C. Intravenous injection of an emulsion of a 0.39 g/kg bw dose of a typical IFR, C6F13CH = CIC6H13 (F6H6IE) in rabbits led to high contrast in the liver and spleen. The same radiopacity of the liver was achieved with 7 times less IFR than perfluorooctyl bromide. Histological examination after 24 h, and blood analysis after 24, 48 h and 7 days, demonstrated normal functioning of the liver, even when high concentrations of IFR were present. The neat IFR was tolerated i.p. in mice at a 45 g/kg bw dose. Emulsified IFR was tolerated in rats and mice i.v. at a 8 g/kg bw dose. The iodinated fluorinated molecule tested appears promising for the formulation of new contrast agents for diagnosis.

Animals↗
PubMed1994

Normothermic preservation of "multiple organ blocks" with a new perfluorooctyl bromide emulsion.

To evaluate the efficiency of fluorocarbon emulsions as oxygenating media for the normothermic preservation of organs (multiple organ blocks, MOB), a new perfluorooctyl bromide (perflubron) emulsion was compared with a mixture of modified Krebs solution and blood. The fluorocarbon emulsion used (90% w/v of fluorocarbon) contained a low amount of egg yolk phospholipid (EYP, 2% w/v) and was stabilized by a mixed fluorocarbon-hydrocarbon amphiphile C6F13C10H21 (F6H10). Blood of 4 rat MOBs was replaced with a 36% w/v fluorocarbon emulsion which has been complemented with albumin and electrolytes (EMOBs). 5 MOBs were perfused with a mixture of blood and albumin-containing Krebs solution (KBMOBs). Lactate, amylase and creatine kinase were lower (p < 0.05) at 60 and 120 min in EMOBs than in KBMOBs,

Animals↗
PubMed1994

Double-tailed perfluoroalkylated glycolipids as components for drug delivery and targeting systems. Preliminary biocompatibility results.

Vesicles are being investigated as drug carriers, especially for enhancing the therapeutic effectiveness of the drug while minimizing its side effects. Drug targeting can be achieved if there is a specific recognition of the vesicle's outer wall by specific cells. With these objectives in mind new glycolipids fitted with fluorinated, hydrogenated or mixed, single and double-tails, containing either a gluco- or a galactopyranose residue in their hydrophilic head, were synthesized and their ability to achieve self-organized supramolecular systems was assessed. Replacement of hydrogen by fluorine in these glycolipids was found to enhance biological tolerance. Thus, a fluorinated single-tailed glycolipid displayed no action on red blood cells at concentrations as high as 50 g/l while its hydrogenated analog was hemolytic at 5 g/l. 100% of survival was obtained one month after intravenous or intraperitoneal injection into mice of isotonic dispersions of single and double-tailed glycolipids at a dose of 500 mg/kg. These glycolipids were innocuous on Namalva cell cultures at a concentration of 0.1 g/l.

Alkylation↗
PubMed1993

Extended in vivo blood circulation time of fluorinated liposomes.

The clearance from blood circulation of fluorinated liposomes made with perfluoroalkylated phosphatidylcholines was investigated in mice using liposome-entrapped 5(6)-carboxyfluorescein. The presence of a fluorinated core inside the membrane strongly retards their blood clearance. The fluorinated vesicles showed circulation half-lives of up to 8.6 h, which are 6-13 and 3-6 times larger than those of similarly sized conventional distearoylphosphatidylcholine and distearoylphosphatidylcholine/cholesterol liposomes, respectively. Their blood clearance was similar to that of some polyethylene glycol (PEG)-labelled 'stealth' liposomes and was dose-independent in a 3.3-330 mumol/kg body weight dose range.

Animals↗
PubMed1993

Biocompatibility of alkyl and perfluoroalkyl telomeric surfactants derived from THAM.

A preliminary, comparative biological evaluation of two new families of non-ionic telomeric surfactants derived from Tris(hydroxymethyl)acrylaminomethane (THAM) is reported. These trisacryl conjugates, or TAC, were designed with the purpose of improving the stability and biocompatibility of fluorocarbon emulsions to be used in injectable oxygen-delivering systems. Their amphiphilic character arises from the simultaneous presence in the same molecule of several hydrophilic THAM residues and of a hydrophobic tail consisting in either a hydrocarbon (H-TAC family) or a fluorocarbon (F-TAC family) chain. The acute toxicity in mice after intravenous injection is low (LD50 in the 625 to 1250 mg/kg body weight range for the H-TAC compared to 630 to 4500 mg/kg body weight range for F-TAC) and increases with the length of the hydrophobic chain. No hemolytic activity was detected for the F-TAC at concentrations up to 200 g/l, while hemolysis is found for the H-TAC at a concentration of 5 g/l or less and increases with the alkyl chain length. The impact of the new surfactants on the growth and viability of Namalva cell cultures also increases with the length of the hydrophobic chain, with again a better tolerance for the F-TAC. Altogether the fluorinated amphiphiles display better tolerance than their hydrocarbon analogs in spite of their significantly increased surface activity. Both families of compounds appear to have potential as strongly hydrophilic surfactants for biomedical applications.

Acrylates↗
PubMed1992

Synthesis of D-glucose 3- and 6-[2-(perfluoroalkyl)ethyl] phosphates: a new type of anionic surfactant for biomedical use.

D-Glucose 3- and 6-[sodium 2-(perfluoro-hexyl or -octyl)ethyl phosphates) have been synthesized by condensation of 1,2,3,4,-tetra-O-acetyl-beta-D-glucopyranose and 1,2:5,6-di-O-isopropylidene-alpha-D-glucofuranose with 2-(perfluoroalkyl)ethylphosphoroditriazolides followed by O-deacetylation or deacetalation. The structures of the compounds were established on the basis of 1H-, 19F-, 31P-, and 13C-NMR data. These salts display strong surface activities and appear to have good biocompatibility.

Biocompatible Materials↗
PubMed1992

[Fluorocarbon emulsions as injectable oxygen carriers. Recent progress and perspectives].

Fluorocarbon emulsions are presently being developed to serve as injectable oxygen carriers (so-called "blood substitutes"). In this approach oxygen is simply dissolved in the liquid carrier and the amount of gas dissolved is proportional to its partial pressure. Increasing the O2-delivering capacity is therefore achieved more easily by increasing the oxygen content of the air breathed by the patient than by increasing the dose of fluorocarbon administered. The absence of a chemical bond between the gas and its carriers allows over 90% of the transported oxygen to be delivered. The fluorocarbon droplets act as oxygen carriers , and also appear to facilitate its diffusion. Chemically and biologically highly inert, fluorocarbons are excreted by exhalation without being metabolized. The first generation of emulsions, exemplified by Fluosol has only limited efficacy due to its low fluorocarbon content, low intravascular persistence and insufficient stability. It has to be stored and distributed frozen, then reconstituted prior to use. Fluosol has nevertheless been licensed by the Food and Drug Administration for use during high risk PTCA. The second generation of injectable fluorocarbon emulsions, exemplified by Oxygent is 4-5 times more concentrated and consequently more efficacious than Fluosol. Considerably more stable, this emulsion can be stored for over one year at 5-8 degrees C and is ready for use. The fluorocarbon used has a significantly shorter organ-retention time. The applications of the present emulsions are still limited by their short intravascular persistence, and are those for which prolonged efficacy is not required, which includes perioperative hemodilution, ischemia, cardioplegia, reperfusion, sensitization of tumors to radio- and chemotherapy, organ preservation and diagnosis. The efficacy of the new emulsions has been established in various animal models. The mild side-effects observed in Phase I clinical trials appear to result from a transient activation of the monocyte/macrophage system and to be suppressed prophylactically by cyclooxygenase inhibitors or corticosteroids. Research is presently oriented towards controlling intravascular persistence better, increasing emulsion stability further, minimizing side-effects and optimizing emulsion characteristics for specific indications.

Animals↗
PubMed1992

Overview of progress in the fluorocarbon approach to in vivo oxygen delivery.

The development of fluorocarbon-based oxygen carriers has experienced rapid progress over the past few years. Fluosol has been approved for use during percutaneous transluminal coronary angioplasty (PTCA) for high-risk patients. Its clinical evaluation is being pursued as an adjunct to cancer therapy and for treatment of myocardial infarction in conjunction with thrombolytic therapy. O2-delivery efficacy has been achieved with the development of the new highly concentrated (4 to 5 times more concentrated than Fluosol), fluid, emulsions of perfluorooctyl bromide (perflubron), trade-named Oxygen. The stability of fluorocarbon emulsions has also improved considerably and the new emulsions can be stored unfrozen and are ready for use. The side-effect profile of these emulsions has been characterized as being the normal response of the body's phagocytes to the injection of particles, a response that is considered physiological rather than pathological in nature; it involves some products of arachidonic acid metabolism and can be controlled pharmacologically. Means of further stabilizing fluorocarbon emulsions, involving molecular-diffusion-controlling additives or fluorinated surfactants, including mixed fluorocarbon-hydrocarbon compounds, have been devised. Increased control over in vivo particle recognition, intravascular persistence and side effects, and at adapting emulsion characteristics to specific applications, is being investigated. The range of therapeutic applications is expanding. The concentrated emulsions will be able to serve as a temporary red blood cell substitute in many situations. Acute normovolemic hemodilution with fluorocarbon emulsions, used in conjunction with homologous predonation and other blood-sparing techniques, should afford greater flexibility, increase the margin of safety, and reduce or alleviate the need for autologous blood transfusion during surgical procedures. Fluorocarbon applications in the cardiovascular field include use during PTCA, for cardioplegia and reperfusion, and the treatment of myocardial infarction. Significant tumor growth delay has been achieved when concentrated emulsions are used in conjunction with cancer radio- or chemotherapy. Liquid ventilation has potential as a unique treatment for the adult and infant respiratory distress syndromes and for drug delivery. The radiopaque and versatile perflubron can also be used in contrast agents for diagnosis with computed X-ray tomography, magnetic resonance imaging and ultrasound, allowing the early detection and staging of cancer. Other potential applications investigated include the treatment of cerebral ischemia, organ and limb preservation, use as a tamponade during retinal repair, etc.

Biotechnology↗
PubMed1992

Stability and stabilization of fluorocarbon emulsions destined for injection.

The factors that have an impact on the stability, and the mechanisms of degradation of fluorocarbon emulsions suited for intravascular use, are briefly reviewed. Various ways of prolonging shelf stability are discussed. The effectiveness of perfluoroalkylated surfactants and/or co-surfactants as stabilizers is demonstrated. New means of stabilizing fluorocarbon-in-water emulsions using molecular dowels are presented.

Blood Substitutes↗
PubMed1992

Perfluoroalklylated phospholipids as surfactants and co-surfactants forinjectable fluorocarbon emulsions.

Highly fluorinated phospholipids were investigated as sole surfactant, and as co-surfactant with egg yolk phospholipids (EYP), in the formulation of 50% and 100% w/v perfluorodecalin emulsions. The surfactant's capability to stabilize such emulsions improves with the length of the perfluoroalklylated tail and with the increase of its relative weight in the hydrophobic chain. As sole surfactant, 2, which has the longest fluorinated tail has the highest efficacy. As co-surfactant with EYP, a strong stabilizing effect is found when the total hydrophobic chain length is adjusted to the EYP membrane's thickness, which is the case of 1. Dispersions of the F-phospholipids do not modify cell growth and viability and show no hemolytic activity on human red blood cells at concentrations in the 60-100g/L range. Acute toxicity tests in mice indicate - i.v. DL50 greater than 2.75 g/Kg body wt.

Animals↗
PubMed1992

Development of highly fluid, concentrated and stable fluorocarbon emulsions for diagnosis and therapy.

A challenging aim in developing injectable fluorocarbon emulsions is to combine good flow characteristics (especially at low shear rates) with the high fluorocarbon concentration required for high oxygen delivery or effective contrast in imaging, long shelf life, and biological acceptability. A good balance of these sometimes conflicting objectives has been achieved with 90% w/v concentrated emulsions of various fluorocarbons, including the radiopaque oxygen carrier perfluorooctylbromide (PFOB, perflubron). The sterile emulsions have viscosities of about 20 cPs at a shear rate of 1 sec-1; the viscosity decreases rapidly with fluorocarbon concentration, and at 60% w/v the viscosity is less than that of human blood. The emulsions are suitable for injection as prepared, and are stable unfrozen for over a year.

Blood Substitutes↗
PubMed1992

Telomeric THAM-derived perfluoroalkylated surfactants for fluorocarbon emulsions.

New fluorophilic and hydrophilic, cost efficient telomeric surfactants derived from tris(hydroxymethyl)acrylaminomethane were synthesized in 2 steps in 80% yield with respect to the perfluoroalkylated telogen. They demonstrate better ability to emulsify fluorocarbons than Pluronic f-68. The biological tolerance of these new surfactants is remarkable, the perfluorohexyl derivative was tolerated at doses of 4g/kg bw after i.v. injection in mice. None of the perfluoroalkylated THAM derivatives induces hemolysis of human red blood cells at concentrations up to 200g/l in physiological solutions.

Animals↗