A novel minimal invasive closed chest myocardial ischaemia reperfusion model in rhesus monkeys (Macaca mulatta): improved stability of cardiorespiratory parameters.

The aim of this study was to report the cardiorespiratory events observed during coronary artery occlusion and reperfusion in a minimally invasive closed chest myocardial occlusion-reperfusion model in rhesus monkeys. We hypothesized that a minimally invasive technique may lead to fewer cardiac arrhythmias and complications. Eight male rhesus macaques 10-15 kg and 10-15 years old were sedated with ketamine (2 mg/kg), midazolam (1.3 mg/kg), atropine (0.01 mg/kg) and buprenorphine 0.02 mg/kg intramuscularly. Etomidate 1-2 mg/kg was injected intravenously to allow tracheal intubation. Anaesthesia was maintained with isoflurane. Pulse oximetry, electrocardiogram (ECG), heart rate, mean arterial blood pressure (MAP), inspired isoflurane fractions (F(I)ISO) and core temperature were recorded every 10 min. The coronary artery occlusion was induced by a balloon-tipped catheter advanced via the femoral artery into the left anterior descending artery and inflated to completely occlude the vessel for 20-50 min (IT) before reperfusion. Sequences of elevated ST segment, QRS complex prolongation, ventricular premature complexes and ventricular fibrillation were observed with a lower incidence than previously described in the literature. IT was (min: 17; max: 50) min long. F(I)ISO was lower than the minimal alveolar concentration in these species. Hypotension (MAP < 70 mmHg) and hypothermia (T°C < 36°C) were observed in all macaques. This minimally invasive closed chest model was successful in providing better cardiorespiratory physiological parameters than reported in previous models. The benefit (achieving ischaemia) versus risk (lethal arrhythmia) of the duration of the coronary occlusion should be considered.

Pharmacokinetics of echocontrast agent infusion in a dog model.

Ultrasound contrast agents (UCAs) have a distinct diagnostic impact on transcranial Doppler (TCD) and duplex sonography. In addition to the properties of the UCA and ultrasound imaging modes, the duration of contrast enhancement depends on the administration mode. Infusion of UCAs may be appropriate for prolonging the diagnostically useful time of elevated Doppler intensity. Five sedated dogs were investigated by TCD during infusion with SonoVue, a new UCA consisting of sulfur hexafluoride microbubbles. The infusion rate was varied, and the time-intensity curves were analyzed. Infusion rate of 70 ml/h provided a stable mean level of increased Doppler intensity up to 24 to 26 dB over baseline, whereas a rate of 35 ml/h did not result in a stable plateau (range 8-19 dB over baseline [5 minutes after starting time]). The maximum increases in Doppler mean intensity (18.2 dB [35 ml/h] and 25.6 dB [70 ml/h]) were significantly different (P = .025). Pharmacokinetic analysis of SonoVue during inflow (by exponential functional fitting of the time-mean intensity curves) and elimination (by linear regression analysis) revealed no dose-related differences. This study demonstrated a dose-dependent level of increased Doppler mean intensity within the brain circulation during infusion of SonoVue. Unlike the bell-shaped course of Doppler signal enhancement seen after bolus injection, infusion generates a stable plateau, which is an important prerequisite for more advanced contrast applications.

Harmonic imaging of the brain parenchyma using a perfluorobutane-containing ultrasound contrast agent.

We evaluated the signal-enhancing effect of the novel perfluorobutane-based ultrasound contrast agent BR 14 (Bracco Research, Switzerland) in grey-scale harmonic imaging of the brain parenchyma. Six sedated male beagle dogs were investigated with transcranial grey-scale harmonic imaging (SONOS 5500, 1.8/3.6 MHz). After bolus injection of two different doses of BR 14, acoustic densitometry was performed to quantify changes in regional contrast intensity. In the dogs' brain parenchyma, the mean relative peak increase in acoustic intensity was +61% after administration of 0.05 ml/kg BW of BR 14 and +24% after 0.2 ml/kg BW. In the masticatory muscle, application of the higher dose resulted in a stronger increase in contrast intensity compared to the lower dose. Evaluation of the contralateral base of the skull showed a dose-dependent decrease in acoustic intensity. Bolus injection of BR 14 produces an increase in acoustic intensity, which can be used for the visualization of contrast agent in the brain parenchyma. Using high dosages, a strong signal-enhancing effect in the regions near the ultrasound probe leads to a consecutive attenuation of signals from structures being located beyond ("shadowing-effect"). This is the explanation for the paradoxical result that the higher dose leads to a lower peak signal increase in the brain parenchyma.

[Brief history of recent hemp cultivation in Switzerland and subsequent medico-legal problems resulting from hemp cultivation]. / Bref historique de la culture récente du chanvre en Suisse et problèmes médico-légaux engendrés par cette culture.

In March 1995, a decision about cultivation of cannabis was issued by the Swiss Federal Offices of Public Health, Police and Agriculture in order to satisfy the growing interest of farmers and other people in hemp farming. It pointed out that 1)... each hemp plant contains THC and must be therefore considered a drug, 2)... no permission is required for those who grow hemp without the intention to produce drugs ... meaning that the choice of the plant variety was not restricted to those which are characterized by a low THC concentration and grown in a few countries belonging to the European Union. Claiming that natural hemp must contain significant amounts of THC and thanks to the Swiss legislation, areas dedicated to hemp cultivation develop considerably. Most hemp plants which are submitted to our laboratories by the police for THC quantification belong to the drug-type. Nowadays, a great deal of goods (food and beverages, cosmetics, drugs) made of hemp are marketed in Switzerland. Strong suspicions exist however that several of these products could be used as a screen for the illegal market of cannabis. For instance, despite financial support from the state, fiber hemp cultivation remains unsuccessful. No advantage with regard to seed productivity, edible seed and essential oils qualities and yields have been found for drug hemp over fiber hemp by agricultural research stations up to now. Several clues about the possible illicit use of hemp goods rich in THC, especially hemp tea made of flower tops and "therapeutic" pillows filled with cannabis exist. Recently, two Federal edits were issued in order to restrict the selling of hemp seedlings and of hemp foods and beverages to those containing only low amounts of THC. However, the marketing of hemp plants used for decorating remains free partly explaining the recent success of these "beautiful" plants. Broadly speaking, the Swiss and European legislations about hemp have approached mutually during the last years.

Assessment of myocardial perfusion by intermittent harmonic power Doppler using SonoVue, a new ultrasound contrast agent.

RATIONALE AND OBJECTIVES: The authors evaluated the potential of SonoVue, a new echo contrast agent, for the detection of myocardial perfusion abnormalities using intermittent harmonic power Doppler (IHPD) imaging and different pulse repetition frequencies (PRFs). METHODS: Experiments were performed in vitro (in a tissue-mimicking phantom) and in vivo (in minipigs) in harmonic power Doppler using an ATL HDI 3000 with second harmonic software. SonoVue was injected intravenously in an auricular vein in bolus (dose range 0.01-0.05 mL/kg) in closed-chest animals or as an infusion (rate = 0.1 mL/kg/minute) in open-chest minipigs with reversible left anterior descending coronary artery (LAD) occlusion. The animals were imaged using IHPD gated on the electrocardiogram at end-systole (pulsing interval at each cardiac cycle). The efficacy of SonoVue was evaluated at six PRFs from 500 to 6000 Hz either qualitatively using a subjective scoring system or quantitatively using a digital image analyzer. RESULTS: SonoVue at a dose of 0.01 mL/kg produced a strong and homogeneous myocardial opacification in IHPD. Higher doses prolonged the duration of the contrast effect. Varying the PRF allowed the discrimination of flow velocities in vitro and the detection of perfusion differences within the myocardium during transient LAD occlusion and during immediate reperfusion in vivo. Low PRFs were particularly useful to differentiate the ischemic bed from the healthy one during LAD occlusion. The high flows caused by coronary hyperemia during immediate reperfusion were detected clearly in the reperfused area at high PRFs. CONCLUSIONS: SonoVue is a promising agent for myocardial opacification studies using IHPD. The latter imaging modality is particularly well suited for blood flow detection in tissues. Varying the PRF provides additional information on flow velocity and improves the detection of perfusion differences in the myocardium.

Gray-scale liver enhancement in VX2 tumor-bearing rabbits using BR14, a new ultrasonographic contrast agent.

RATIONALE AND OBJECTIVES: We evaluated the potential of BR14, a novel gas-based echo contrast agent, for gray-scale liver imaging and VX2 tumor detection/delineation in the conventional and harmonic imaging modes. METHODS: A single dose (0.2 mL/kg) of BR14 was administered to eight VX2 tumor-bearing rabbits. Imaging was performed with an ATL-HDI 3000. The B-mode gray levels were analyzed by videodensitometry in areas selected in the liver tissue, tumors, aorta, and the portal vein from frames recorded up to 1 hour after injection. The tumors were further assessed using subjective scores just before and after contrast injection, as well as 15 minutes later in both conventional gray-scale and harmonic imaging modes. RESULTS: Gray-scale enhancement of the liver tissue was detectable soon after BR14 injection and remained at a high level even after clearance of the agent from the blood stream. On precontrast, of 42 observed tumors, 4 were perfectly detected (4/42). After injection of BR14, the number rose to 10/20 in the vascular phase and 12/20 in the delayed phase. In harmonic imaging, the corresponding numbers were even higher, 17/22 in the vascular phase and 18/22 in the delayed phase. The number of tumors perfectly delineated increased after BR14 from 1/42 to 3/20 in the vascular phase and 5/20 in the delayed phase. In the harmonic mode, 9 of 22 tumors were perfectly delineated in the vascular phase and 10 of 22 in the delayed phase. CONCLUSIONS: BR14 is a promising new agent for the study of tissue perfusion and in particular for liver imaging. It shows not only strong, but also persistent gray scale enhancement of the parenchyma but not of the tumors. The increased conspicuousness allows considerable improvements in tumor detection and tumor delineation in conventional imaging and even more so in harmonic imaging.

BR1: a new ultrasonographic contrast agent based on sulfur hexafluoride-filled microbubbles.

RATIONALE AND OBJECTIVES: The basic characteristics of BR1, a novel echo contrast agent based on stabilized sulfur hexafluoride (SF6) microbubbles have been evaluated. METHODS: The authors determined the physicochemical properties (bubble concentration, bubble size distribution, resistance to pressure, and stability) and the acoustic properties (backscatter and attenuation coefficients) of BR1. The diagnostic value of BR1 was evaluated further in minipigs. Left heart images were recorded before and after injection of different doses of BR1. RESULTS: BR1 is formulated as a lyophilized product, which after addition of saline, provides a suspension containing 2 x 10(8) SF6 microbubbles/mL with a number mean diameter of 2.5 microns. More than 90% of the bubbles are below 8 microns. The use of SF6 rather than air provides an improved resistance to pressure increases such as the ones occuring in the left heart during systole. After reconstitution, the echogenicity and the bubble characteristics are unchanged for more than 8 hours. The high echogenicity remains almost constant over the entire medical frequency range (1-10 MHz). BR1 injections in animals resulted in a homogenous, dose-dependent opacification of the left heart. CONCLUSIONS: Considering its high echogenicity, outstanding stability, and resistance to pressure changes, BR1 is a very promising ultrasound contrast agent.

Sulfur dioxide induced bronchitis in rats.

The effects of subchronic inhalation of 300 ppm and 400 ppm SO2 gas on airway mucus production and the distribution and density of respiratory tract goblet cells was examined in rats. The changes in the goblet cell population and mucus hypersecretion were examined over a 6-week period, with interim sacrifices at 3 and 4 weeks. Subacute exposure to 300 ppm SO2 produced a bronchitic syndrome in rats similar to that observed in human bronchitis. Inhalation of 300 ppm SO2 produced predominantly a large airway mucus cell hyperplasia with practically no loss in cellularity, or ablation as was observed with 400 ppm. In addition, the inhalation of both 300 ppm and 440 ppm SO2 induced a hypersecretion of mucus resulting in mucus accumulation throughout the respiratory tract.

The metabolism and excretion of (+)-[14C]cyanidanol-3 in man following oral administration.

Following administration of a single dose of [U14C]cyanidanol-3 to human volunteers, a mean of 55% of the dose of 14C was excreted in urine; 90% of urine 14C was excreted within 24 h of drug administration. The major urinary metabolites were the glucuronides of (+)-catechin and 3'-O-methyl-(+)-catechin, and the sulphate of the latter. These three conjugates collectively accounted for three quarters of urine 14C. Urinary excretion of unchanged (+)-cyanidanol-3 was 0.1-1.4% dose. (+)-Cyanidanol-3 and metabolites containing the intact flavanol ring system accounted for 90% of urine 14C. Ring scission was, under these conditions, a minor metabolic pathway resulting in the excretion of small amounts of 3-hydroxybenzoic acid, 3-hydroxyhippuric acid and 3-hydroxyphenylpropionic acid. Unchanged (+)-cyanidanol-3 was detected in plasma between 30 min and 12 h after administration. Metabolites (as total 14C) persisted in plasma for at least 120 h after administration.

Inhibition of galactosamine induced edemas in the rat by drugs preventing macromolecular leakage from the hamster cheek pouch microvasculature.

We have shown that terbutaline and dimethpyrindene, 2 drugs which prevent macromolecular leakage in the in vivo--bio-assay of Hamster Cheek Pouch, either by direct action onendothelial cells or by blocking histamine receptors at the microvascular leakage sites, can also prevent macromolecular leakage in vivo in 2 different models of generalized edema.

Absorption, metabolism and excretion of safrole in the rat and man.

The metabolic disposition of different doses of [14C] safrole were studied in rat and man. In both species, small amounts of orally administered safrole were absorbed rapidly and then excreted almost entirely within 24 h in the urine. In the rat, when the dose was raised from 0.6 to 750 mg/kg, a marked decrease in the rate of elimination occurred as only 25% of the dose was excreted in the urine in 24 h. Furthermore, at the high dose level, plasma and tissue concentrations of both unchanged safrole and its metabolites remained elevated for 48 h probably indicating impairment of the degradation/excretion pathways. The main urinary metabolite in both species was 1,2-dihydroxy-4-allylbenzene which was excreted in a conjugated form. Small amounts of eugenol or its isomer 1-methoxy-2-hydroxy-4-allylbenzene were also detected in rat and man. 1'-Hydroxysafrole, a proximate carcinogen of safrole, and 3'-hydroxyisosafrole were detected as conjugates in the urine of the rat. However, in these investigations we were unable to demonstrate the presence of the latter metabolites in man.

[Phagocytosis of liposomes by mouse peritoneal macrophages (author's transl)]. / Phagocytose des liposomes par les macrophages péitonéaux de souris

Uptake of 14C-cholesterol or 3H-cholesterol labelled liposomes, stimulation of 14C-glucose oxidation, as well as ultrastructural and autoradiographical experiments have shown that liposomes are phagocytized by mouse peritoneal macrophages. Further results have shown that degradation of liposomes was not complete 2h after uptake.