Diffusion-weighted MR imaging: diagnostic accuracy in patients imaged within 6 hours of stroke symptom onset

We evaluated the agreement between wedged hepatic vein pressure (WHVP), portal vein pressure (PVP), and its relationship with portal hemodynamics in 21 patients with HCV-related cirrhosis with esophageal varices. Direct measurements of the portohepatic gradient (HVPG) were obtained by ultrasound-guided fine needle puncture of the right hepatic and the portal veins. In five cases PVP was 6.4-10.4 mm Hg higher than WHVP. In 12 cases measurements were similar (WHVP - PVP < or = 3 mm Hg). In the remaining four cases WHVP was 3.6-9.6 mm Hg higher than PVP. WHVP and PVP agreement was not related to HVPG mean value, Child-Pugh score, or grading of esophageal varices. By contrast, the difference between WHVP and PVP was inversely related to the portal flow velocity (P = 0.053) and directly related to the portal vascular resistance (P = 0.02). Whereas the portal branches were visualized in patients with WHVP lower or similar to PVP, a predominant left portosystemic collateral flow was observed in patients with WHVP > PVP. Our data point out that, in patients with cirrhosis due to hepatitis C virus infection, discrepant HVPG values reflect true hemodynamic differences.     

Transcatheter liver lobar ablation: an experimental trial in an animal model

Complete embolization of tumor tissue together with surrounding liver sufficiently prevents collateral blood supply to the tumor, offering curative treatment for hepatic malignancies. The present experiment was designed to test the feasibility of hepatic lobar ablation by means of the transcatheter chemoembolization technique. Five groups of rats (n = 6) were treated with a mixture of iodized oil/ethanol in ratios of 5:1, 4:1, 3:1, 1:1, and 1:0, which was injected selectively into the right-lobe artery until saturation during open surgery. Another group (n = 6) was studied using in vivo microscopy to observe the distribution of the mixture in the liver and changes in hepatic microcirculation. Ethiodol/ethanol mixture entered the portal vein after injection into the hepatic artery creating dual, complete arterial and portal venous embolization. Lobar ablation effects were achieved in 2 weeks in the 5:1, 4:1, and 3:1 ratio groups, indicated by the lobe/liver weight measurements (p < 0.001 vs normal liver). Hepatic arterial administration of the Ethiodol/ethanol mixture creates dual hepatic arterial and portal venous embolization, achieving a lobar ablation effect.     

Antibody mediated lung targeting of long-circulating emulsions

Monoclonal antibody 34A, which specifically binds to a surface glycoprotein (thrombomodulin) of the pulmonary endothelial cell surface in mice, has been conjugated to the surface of long-circulating emulsions composed of Castor oil, phosphatidylcholine and polyethylene glycol coupled to distearoylphosphatidyl-ethanolamine. These antibody-containing emulsions were found capable of binding to the lung when injected into mice through the tail vein. The level of lung accumulation of these emulsions depends on the amount of antibodies conjugated to the surface of the emulsions. With an input antibody to lipid ratio of 2:1 (w/w), 30% injected emulsions were found in the lung 30 minutes after administration. Such high level accumulation can be blocked by co-administration of free 34A antibody, indicating that the binding is specific and 34A antibody mediated. Kinetic studies showed that emulsion targeting to the lung was very rapid. Five minutes after tail vein injection, the total amount of emulsion found in the lung was the highest among the time points examined, indicating the completion of lung binding. However, about 50% of the initially bound emulsions remained bound for more than 4 hours. These results indicate that the targeted drug delivery using oil-in-water emulsions could be very useful to enhance the therapeutic efficacy of lipophilic drugs.     

Low-field NMR determinations of the properties of heavy oils and water-in-oil emulsions

Low-field (< 50 mT) nuclear magnetic resonance (NMR) well-logging measurements are beginning to be used to obtain estimates of oil viscosity in situ. To build an interpretive capability, we made laboratory T1 and T2 relaxation measurements on a suite of high-density, high-viscosity crude oils. These measurements were also used to estimate oil viscosity and water fraction from T1 and T2 measurements on stable, water-in-oil emulsions. High-density, high-viscosity oils have components that relax faster than can be measured by nuclear magnetic resonance logging tools. This requires corrections to T2 logging measurements for accurate estimates of oil saturation and porosity.     

Newcastle disease oil emulsion vaccines prepared with animal, vegetable, and synthetic oils

Animal, vegetable, and synthetic oils were tested as potential replacements for mineral oil in Newcastle disease oil emulsion vaccines. Emulsifying surfactants of seed oil origin comprised 10% of the the oil phase that was used to prepare water-in-oil emulsion vaccines that contained a final concentration of 20% aqueous antigen. The hemagglutination inhibition responses of chickens inoculated with 46 of the newly formulated oil vaccines were, in most cases, not significantly different from those of control chickens inoculated with mineral oil vaccine. Tissue reactions associated with animal, vegetable, and synthetic oil vaccines were less severe than those associated with mineral oil vaccines. Viscosity of the mineral oil formulations ranged from 1/2 to 3 1/2 times that of the mineral oil control vaccines. These findings indicate that any of several oils may be more suitable than mineral oil for preparation of immune adjuvants for poultry vaccines.     

The effects of intra-arterial and intraportal injections of vasopressin on the simultaneously perfused hepatic arterial and portal venous vascular beds of the dog

The hepatic arterial and hepatic portal venous vascular beds of the chloralose-urethane anesthetized dog were perfused simultaneously in situ. Vasopressin (10 mU = 1 unit) was injected in graded increasing doses into the hepatic artery and into the portal vein. Both intra-arterial and intraportal vasopressin elicited both hepatic arterial vasoconstriction and hepatic venous dilation; the delay in onset of both hepatic vascular effects was significantly shorter than that for any succeeding systemic effects (a rise in systemic arterial pressure and fall in heart rate), showing that they were not attributable to recirculation or to arterial baroreceptor reflexes. Injections of vasopressin into the inferior vena cava at the level of the hepatic veins consistently produced smaller hepatic vascular effects than either intra-arterial or intraportal injections of the same doses. The results are discussed in the context of the therapeutic role of vasopressin in controlling gastrointestinal bleeding and portal hypertension.     

Stable lipiodolized emulsions for hepatoma targeting and treatment by transcatheter arterial chemoembolization

We attempted to develop lipiodolized emulsions that remain in the tumour for a long period, release drug in a sustained release pattern, and thus improve the conventional treatment of hepatocellular carcinoma (HCC) [1]. Polyoxyethylene derivatives of hydrogenated castor oil (HCO) were the most suitable emulsifiers in stabilizing emulsions containing Lipiodol as an oil phase. The length of ethylene oxide coupled to HCO rather than the hydrophilic-lipophilic balance (HLB) values was an important factor in preparing stable emulsions and in achieving sustained-release characteristics. When distilled water was replaced with Iopamiro, a heavy water soluble contrast medium with a specific gravity of 1.335, more stable lipiodolized emulsions with longer sustained release behaviour could be prepared with smaller amount of HCO. To study the in vivo stability of the w/o Lipiodol emulsion and the sustained-release characteristics of doxorubicin from the emulsion, the pharmacokinetic study was performed with normal dogs using transcatheter arterial chemoembolization technique. The area under the plasma concentration-time curve for the first eight hours (AUC0-8) and AUCtotal values of the stabilized emulsion were three to four times higher than those of the coarse emulsion prepared lacking HCO 60. From the in vitro and in vivo studies, Lipiodol based water in oil emulsion with HCO 60 containing doxorubicin showed higher stability and released doxorubicin in a sustained fashion.     

Cerebral hemodynamic response to CO2 after severe head injury: clinical and prognostic implications

PURPOSE: To evaluate the efficacy and safety of transcatheter oily chemoembolization therapy (TOCE) via the inferior phrenic artery (IPA) in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Fifty patients with HCC underwent a total of 82 procedures of TOCE of the IPA, as well as of the hepatic artery. In 16 patients, additional extrahepatic collaterals were depicted and were also embolized in 10 patients. TOCE was performed with an emulsion of iodized oil and doxorubicin hydrochloride, and gelatin sponge particle embolization was added in 32 patients. RESULTS: Initial response showed complete or partial remission of the tumor in 31 patients. The cumulative survival rates after combined TOCE of the hepatic artery, IPA, and other extrahepatic arteries were 89% (6 months), 78% (1 year), 46% (2 year), and 30% (3 year), when calculated from the time of IPA chemoembolization. Liver abscess and empyema developed in one case of combined IPA and multiple intercostal artery chemoembolization. There were no serious complications after IPA chemoembolization alone. CONCLUSION: TOCE of the IPA has a potential therapeutic role as a safe adjunct to TOCE of the hepatic artery in the management of HCC supplied by the IPA.     

Retrograde transport of nerve growth factor from olfactory bulb to olfactory epithelium

OBJECTIVE: The purposes of this study were to determine if splenic perfusion measurements obtained using dynamic CT are useful in the evaluation of portal hypertension. MATERIALS AND METHODS: Forty-four patients with chronic liver disease (29 men and 15 women, 49-81 years old) and 38 control subjects (17 men and 21 women, 21-79 years old) underwent dynamic CT of the spleen. Regions of interest were drawn on images of the spleen and aorta, and splenic perfusion was calculated by dividing the peak gradient of the splenic time-attenuation curve by the peak aortic CT measurement increase. In 11 patients with chronic liver disease and three patients with normal livers, we measured the wedged hepatic vein pressure (WHVP) of the right or right accessory hepatic vein to estimate portal vein pressure. RESULTS: Splenic perfusion was less in patients with chronic liver disease (0.894 +/- 0.324 ml/min) than in the control group (1.299 +/- 0.429 ml/min; p < .0001). We found a significant negative correlation between splenic perfusion and WHVP (r = .741; p = .0024). CONCLUSION: A significant decrease in splenic perfusion in patients with chronic liver disease negatively correlated with WHVP. Measurement of splenic perfusion may be useful in the evaluation of portal hypertension.     

Sodium butyrate induces NIH3T3 cells to senescence-like state and enhances promoter activity of p21WAF/CIP1 in p53-independent manner

PURPOSE: To evaluate the diagnostic efficacy of computed tomography (CT) after hepatic intraarterial injection of iodized oil in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Forty patients who underwent CT with iodized oil before orthotopic liver transplantation (OLT) were evaluated prospectively. All patients underwent digital subtraction angiography and injection of iodized oil during chemoembolization. CT during arterial portography (CTAP) was performed in 34 patients. The number of neoplastic nodules was assessed in explanted livers and compared with the radiologic results. RESULTS: Sixty-six HCC nodules were present in the explanted livers. CT with iodized oil enabled correct diagnosis in 38 of 66 lesions (58%), and the results were false-positive in two lesions (3%). Digital subtraction angiography had a sensitivity of 67% (44 of 66 nodules) and CTAP had a sensitivity of 85% (45 of 53 nodules). Four (6%) false-positive diagnoses were made at digital subtraction angiography and three (6%) at CTAP. The diagnostic efficacy of CT with iodized oil was significantly related to lesion diameter greater than 2 cm (P < .0001) and hypervascularity (P < .0001). CONCLUSION: CT with iodized oil failed to provide any substantial information in the pre-OLT staging of HCC: It was inaccurate for small HCC nodules (<2 cm) and intrahepatic metastases. Its sensitivity matched that of digital subtraction angiography and was statistically significantly inferior to that of CTAP.     

Development of non-iodized oily agent in targeting chemoembolization for hepatocellular carcinoma

The purpose of this study was to evaluate a new oily agent in targeting chemoembilization for hepatocellular carcinoma. The oily preparation was made by mixing non-iodinated poppy seed oil and a thickener to obtain the same viscosity as Lipiodol. The oily preparation and Lipiodol were compared by injecting them into the hepatic artery of rabbits inoculated with VX 2 carcinoma in their liver. On the CT scan following intra-arterial injection, tumors were visibly stained in the non-iodinated preparation group, whereas the Lipiodol group was not evaluable because of excessively high attenuation. The non-iodinated oily preparation was concluded to be of clinical significance.     

Prolonged release of tegafur from S/O/W multiple emulsion

To develop a prolonged and sustained release preparation, we prepared an albumin microsphere-in-oil-in-water emulsion (S/O/W) and examined sustained release from it in comparison with other control preparations such as water-in-oil (W/O) emulsions and microspheres in vitro and in vivo, respectively. Tegafur was used as a model drug. A microsphere-in-oil emulsion was prepared by adding albumin microspheres to soybean oil containing 20% Span 80. To prepare an S/O/W emulsion, the microsphere-in-oil emulsion was added into an aqueous solution of hydroxypropyl methylcellulose containing Pluronic F68. The mean particle size of the albumin microspheres was 3 microns, and the ratio of entrapment of tegafur into albumin microspheres was about 25%. In an in vitro release test, the t75 of the S/O/W emulsion was fourfold greater and in an in vivo release test the mean residence time of tegafur from the S/O/W emulsion was more than twofold that from a W/O emulsion or microsphere system. The mean residence time of 5-fluorouracil (5-FU) from an S/O/W emulsion was also greater than with other dosage forms. These results suggest the possible usefulness of an S/O/W emulsion for the sustained and prolonged release of tegafur.     

Preferential in vivo accumulation of sn-2,3-diacylglycerols in postheparin plasma of rats

The stereochemical course of in vivo hydrolysis of triacylglycerols by lipoprotein lipase was investigated by determining the structure of diacylglycerol intermediates in postheparin plasma of rats which had been fed [3H]glycerol-labeled Intralipid 2 h before an injection of heparin or had been given an injection of a mixture of [3H]glycerol-Intralipid and heparin. During the clearance of both the natural chylomicrons and the artificial emulsion, sn-2,3-diacylglycerols (60-80%) were found to be the dominant enantiomers. Similar results were obtained when the contribution of the hepatic lipase was altered, either by tying off the mesentery artery and portal vein before injection of heparin, or by injection of heparin directly into the portal vein. These findings are consistent with a preferential release of the acyl group from the sn-1 position of the triacylglycerol molecule as demonstrated previously in vitro. A preferential orientation of the substrate in the enzyme-substrate complex or at the oil-water interface is discussed as a possible basis for these effects.     

Lipid emulsions of palmitoylrhizoxin: effects of composition on lipolysis and biodistribution

Four types of lipid emulsion for highly lipophilic antitumour agent RS-1541 (13-O-palmitoylrhizoxin) with mean particle diameters of 200-260 nm were prepared using soybean oil (SOY) or dioctanoyldecanoylglycerol (ODO) for the oil phase and lecithin (LEC) or polyoxyethylene-(60)-hydrogenated castor oil (HCO-60) for surfactants. The lipolysis rate of HCO-60-emulsified emulsions by lipoprotein lipase was much slower than that of LEC-emulsified emulsions. Particle sizes of emulsions incubated in plasma with the lipase for six hours were 75%, 79%, 101%, and 93% of initial values for SOY/LEC, ODO/LEC, SOY/HCO-60, and ODO/HCO-60 emulsions, respectively, showing an apparent size decrease for LEC-emulsified emulsions. In rats, uptake clearance values of SOY/LEC and ODO/LEC emulsions of RS-1541 in the reticuloendothelial system (RES) were 81.2 and 135.3 mL h(-1), respectively, and AUC values were 4.0 and 1.3 microg h mL(-1), respectively. In contrast, RES uptake clearances of HCO-60 emulsions of RS-1541 were considerably lower (4.2 mL h(-1) for SOY/HCO-60; 2.2 mL h(-1) for ODO/HCO-60), resulting in high AUC values (35.4 microg h mL(-1) for SOY/ HCO-60; 63.9 microg h mL(-1) for ODO/HCO-60). The concentrations of RS-1541 in tumour tissues after an intravenous administration of ODO/HCO-60 emulsions of RS-1541 to mice bearing solid tumour M5076 sarcoma were about ten times higher than those after the administration of SOY/LEC emulsions. These results indicate that HCO-60 emulsions, compared with conventional LEC emulsions, are more stable to lipoprotein lipase and show low uptakes by RES organs, long circulations in the plasma, and high distributions in tumours. Thus, these sterically stabilized emulsions could show potential as effective carriers for highly lipophilic antitumour agents to enhance the drug delivery in tumours.     

Solubilization and stabilization of an anti-HIV thiocarbamate, NSC 629243, for parenteral delivery, using extemporaneous emulsions

The O-alkyl-N-aryl thiocarbamate, I, (2-chloro-5-[[(1-methyl-ethoxy)thioxomethyl]amino]benzoic acid, 1-methylethylester, NSC 629243, also known as Uniroyal Jr.) is an experimental anti-HIV drug with very low water solubility (1.5 micrograms/mL). Early clinical studies required an injectable solution at approximately 15 mg/mL, representing a solubility increase of approximately 10(4)-fold. Adequate solubilization of this hydrophobic drug was achieved in 20% lipid emulsions. Extemporaneous emulsions were prepared by adding a concentrated drug solution to a commercially available parenteral emulsion. Various methods of preparation to minimize drug precipitation during its addition and enhance redissolution of precipitated drug were evaluated. The stability and mechanism(s) of decomposition of NSC 629243 in both 20% lipid emulsions and in natural oil vehicles were examined. In lipid emulsions, the shelf life at 25 degrees C varied from 1 to > 10 weeks, depending on the extent to which air was excluded from the preparation. The shelf life of 50 mg/mL solutions in natural oils at 25 degrees C varied from < 1 to > 100 days depending on the oil and its supplier. A qualitative correlation was found between the initial rate of oxidation and the peroxide concentration in the oil. The primary degradation product in both systems was shown to be a disulfide dimer, II, formed via oxidation. Oxidation was inhibited by vacuum-sealing of emulsion formulations or incorporation of an oil-soluble thiol, thioglycolic acid (TGA), into oil formulations. TGA may inhibit oxidation by consuming free radicals or peroxide initiators or by reacting with the disulfide, II, to regenerate the starting drug.     

Randomized controlled trial for hepatocellular carcinoma with portal vein thrombosis: intra-arterial iodine-131-iodized oil versus medical support

Portal vein thrombosis is a poor prognostic factor in patients with hepatocellular carcinoma (HCC) and a contraindication for chemoembolization. Intra-arterial injection of 131I-iodized oil which does not modify arterial flow, is feasible in this condition. The aim of this prospective randomized controlled trial was to compare the efficacy of treatment with radiolabeled oil (treated group) versus medical support (control group) in patients with stage I or II HCC (classification of Okuda) with portal vein thrombosis. METHODS: Twenty-seven HCC patients (26 males, 1 female), aged 53-79 yr, with portal vein thrombosis were randomly assigned to Lipiocis group (n = 14) or Control group (n = 13). Additional injections of radiolabeled oil were given 2, 5, 8 and 12 mo after initial therapy. Medical support treatment consisted of: tamoxifen (n = 5), 5 FU intravenously (n = 1), NSAIDs or corticosteroids (n = 5). Efficacy was evaluated according to survival rate (Kaplan-Meier method; log rank test), AFP serum values (measured at 2, 5, 8 and 12 mo) and angiography. RESULTS: The two groups were comparable (Child's classification, Okuda's classification, liver function tests, location of the thrombus). Tolerance was excellent in the Treated group. The actuarial survival curves were significantly different (p < 0.01) between the two groups, the survival rates (Cl 95%) at 3, 6 and 9 mo being 71% (48%-95%), 48% (12%-55%), 7% (1%-31%) for the Treated group; and 10% (1%-33%), 0% and 0% for the Control group. CONCLUSION: Intra-arterial hepatic injection of 131I-labeled iodized oil is a safe and effective palliative treatment of HCC with portal vein thrombosis.     

Repeated arterial embolization of rat livers by degradable microspheres

A transient arrest of arterial blood flow can be accomplished by intra-arterial injection of a new type of degradable microsphere. The effects of single and multiple injections of these microspheres into rat hepatic arteries were studied by measurements of fractional cardiac output distribution and 133Xe washout from the liver before and after embolization. Injection of these microspheres into the hepatic artery caused a significant but transient reduction of the arterial blood flow to the liver. Repetition of the injection several times over several days produced identical effects on each embolization. No signs of hepatic cell damage were detected after repeated embolization, as suggested by assay of the serum enzymes or the Bromsulphalein retention test.     

Iodized oil enhances the thermal effect of high-intensity focused ultrasound on ablating experimental liver cancer

The influence of the biological medium on high-intensity focused ultrasound (HIFU) therapy for ablating experimental liver cancer was studied. In study 1, the temperature rise in the focal zone in the presence of iodized oil or castor oil was observed in vitro. The results showed that HIFU with iodized oil produced a higher and faster temperature rise than did HIFU with castor oil, whether high-power (500 W/cm2) or relatively low-power (136 W/cm2) conditions were used (P = 0.0008 and P = 0.0004 respectively). With the excised liver samples, the temperature also rose higher and more rapidly after injection of iodized oil into the liver than when castor oil was injected (P = 0.0239), and the target liver tissue revealed more radically and extensive destruction with iodized oil than with castor oil. In study 2, 48 nude mice, bearing primary liver cancer LTNM4 implanted subcutaneously, were randomly divided into four groups. Group I (n = 12) were the controls, group II (n = 12) were injected with iodized oil alone, group III (n = 12) received HIFU treatment, and group IV (n = 12) were exposed to HIFU after iodized oil injection. Significant inhibition of tumor growth was seen in groups III and IV as compared with group I or group II (P < 0.05), the tumor growth inhibition rate on the 28th day after treatment being 87% and 93% respectively. Significantly improved survival was noted in groups III and IV compared with groups I and II (P < 0.05). Histologically, group IV showed more complete tumor necrosis than did group III. These data suggest that HIFU combined with iodized oil might have achieve of synergism, location and targeting in the treatment of liver cancer.     

Kinetics and thermodynamics of emulsion delivery of lipophilic antioxidants to cells in culture

Oil-in-water emulsions are being used increasingly for the delivery of lipophilic drugs, but the fundamental physicochemical principles governing such delivery have not been explored. We determined the kinetics and thermodynamics of delivery from emulsions to cells in culture for two lipophilic compounds, U74006 and U74500. Two fundamental properties dominate the delivery, (a) the concentration of the compound in the lipid phase of the emulsion is directly proportional to the concentration of the compound in cells at equilibrium, and (b) the rate of transfer is directly proportional to the concentration of particles in contact with the cells. Thus, the transfer is consistent with direct partitioning from the lipid phase of the emulsion to cells and occurs by the direct collision of emulsion particles with cells. The details of the mechanism of delivery differ between the two compounds. Specifically, delivery of U74006 is first-order with respect to the drug accumulating in the cells. The transfer of U74500 is best described as a sum of two simultaneous pseudo first-order processes consistent with delivery from a single donor compartment to two receiver compartments. Furthermore, two molecules of U74500 appear to be involved in each transfer event. Our results show that relatively simple principles govern the delivery of compounds from oil-in-water emulsions to cells.     

Age-associated alterations in calcium current and its modulation in cardiac myocytes

Stimulatory effects of several types of adjuvants on secondary antibody response to inactivated Newcastle disease virus (iNDV) were examined in chickens. For this purpose, animals were primed with iNDV without adjuvant resulting in a low but significant antibody response, boosted with iNDV plus adjuvant 3 weeks later, and analysed for specific antibody titres in serum 3 weeks after the booster. Water-in-mineral oil emulsion (W/O) caused significant increase in antibody titres measured in an indirect enzyme-linked immunosorbent (ELISA), haemagglutination inhibition (HI), and virus neutralisation (VN) assay. The adjuvants tested included three oil-in-water emulsions (i.e. mineral oil-in-water, sulpholipo(SL)-Ficoll400/squalane-in-water and sulpholipo-cyclodextrin/squalane-in-water), three negatively-charged polymers with high molecular weight (i.e. polyacrylate, polystyrenesulphonate and sulpho(S)-Ficoll400) and two surface-active agents (i.e. dimethyldioctadecylammonium bromide (DDA) and Quil A). These adjuvants enhanced significantly the secondary immune response but none reached the titre obtained with W/O. Combinations of adjuvants with distinct physicochemical properties, i.e. polyacrylate and DDA revealed only slight, beneficial effects. We concluded that the various types of adjuvants tested can stimulate secondary immune responses in primed animals but that W/O is superior.