Selection of cholesterol absorption inhibitors devoid of secondary intestinal effects.

The digestive tolerance of cholesterol absorption inhibitors, which requires a constant improvement, was the main purpose of this study. Given the known hypocholesterolemic and antiatherosclerotic properties of some steroid glycosides, we synthesized a series of sterol derivatives by coupling some phytosterols known to interact with sterol absorption and also to be poorly absorbed to a cationic group. The first derivative was a potent inhibitor of cholesterol absorption and a potent hypocholesterolemic agent in different animal models, but was responsible for severe gastro-intestinal side-effects. In order to control the tolerance of the newly synthesized compounds, cholesterol and taurocholate absorption were measured in the jejunum and in the ileum, respectively. The intestinal water and ionic transport and the estimation of histological changes in the intestinal mucosae were determined simultaneously. The in-situ isolated loop technique, in anaesthetized rats, allowed the simultaneous control of these three parameters which were used to select the best derivative, inhibitor of cholesterol absorption devoid of any deleterious effect, as seen via a three-dimensional representation. The results showed that it was possible to obtain a specific cholesterol absorption inhibitor without secretory and deleterious effects and suggested that the amphiphilic characteristics of the molecules were responsible for their deleterious effects on digestive tract.

Extracorporeal high-intensity focused ultrasound for VX2 liver tumors in the rabbit.

High-Intensity Focused Ultrasound (HIFU) can produce radical tissue necrosis. We wanted to assess tumor destruction, proliferation, and tumorigenesis after HIFU, in an animal model of hepatic tumor. New Zealand rabbits bearing VX-2 solitary liver tumors were treated with extracorporeal HIFU under ultrasound (US) guidance and standardized conditions. Groups differed only for the administration of either one or two consecutive HIFU procedures. Tissue destruction was assessed by stereomicroscopy and planimetry, cell proliferation was estimated by in vivo intra-arterial injection of 1200 muCi [3H]thymidine, and tumorigenesis was tested by reimplantation of treated or untreated pieces of liver tumors into the thighs of nontumor-bearing animals. Mortality was 0. Tumor destruction rates were 76.3% +/- 16% after one procedure and 94.2% +/- 7.3% after two procedures. Nuclear staining was heavy in control tumors and was absent in treated tumors. Untreated hepatic tumors induced measurable tumors at 3 weeks in thighs of all recipients, 7.8 +/- 2.4 cm3 in volume. Hepatic tumors treated with one HIFU procedure induced tumors in the thigh of recipients in 31.3% of cases (0.47 +/- 0.06 cm3), and those treated with two HIFU procedures induced tumors in 0% even after 8 weeks of follow-up. In conclusion, HIFU allows a noninvasive approach to the destruction of liver tumors in this model, with little toxicity but significant effects on proliferation and tumorigenesis. The repetition of HIFU procedures may improve results.

Pharmacokinetic, metabolic, and antidiarrheal properties of (D and L) heptapeptides of sorbin in rodent.

The C-terminal heptapeptide-amide (C7-sorbin) is the minimal biologically active fragment of sorbin inducing an increase in intestinal hydroelectrolytic absorption. An analogue (D7-sorbin), characterized by the replacement of the ultimate C-terminal amino acid L-alanine-amide by D-alanine-amide, was synthetized. For pharmacokinetic studies, D7-sorbin and C7-sorbin were tritium labeled. After IV injection, clearances were 10.6 and 30.2 ml-1 for D7-sorbin and C7-sorbin, respectively, and MRT were 34 and 18 min. After SC administration, Cmax attained 0.41% and 0.12% of the dose/ml, respectively. The IP route showed a 45-min delay before Cmax and a 100% bioavailability for both peptides. D7-sorbin was principally excreted in urine, as shown by balance study, and in part in intact form, as controlled by mass spectrometry. D7-sorbin induced a significant decrease of the VIP-induced ileal secretion, previously observed with C7-sorbin. The change of L-Ala to D-Ala increased the stability of the synthetic C-terminal peptide of sorbin whereas its biological activity, bioavailability, and route of elimination were unchanged.

Focused liver ablation by cavitation in the rabbit: a potential new method of extracorporeal treatment.

A new device was used to achieve focused tissue ablation by shockwave induced cavitation. The device produced a half cycle of negative pressure followed by a shock wave, thus enhancing cavitation. Twenty eight New Zealand rabbits were treated. Therapeutic ultrasound was targeted at the centre of the liver under ultrasound guidance. The focal volume was scanned with a computer operated x-y-z micropositioner. The number and frequency of bursts as well as the distance between two x-y-z displacements were preselected. The relation of tissue ablation seen to preselected parameters, effects on surrounding tissues, biological side effects, and mode of healing were studied. Macroscopy, planimetry, and quantitative microscopy were used. Focused and homogeneous tissue ablation was achieved within well defined limits. Maximal tissue ablation was seen in the centre of the target. Liver surrounding the target remained unaffected. Lesions were made of a-cellular spots surrounded by disorganised rims of necrotic hepatocytes; 24 hours after treatment, the changes (mean (SEM)) in alanine transaminase and haemoglobin were +225 (36)% and -2.4 (2)% respectively. Serum transaminases, haemoglobinaemia, and packed cell volume were normal 21 days after treatment and the target area was replaced by a fibrous scar. It is concluded that ultrasound cavitation may achieve extracorporeal intrahepatic tissue ablation inside a predetermined target. This technique should now be tested in an animal hepatic tumour model.

Extracorporeal ablation of liver tissue by high-intensity focused ultrasound.

High-intensity focused ultrasound (HIFU) may produce a well-delineated lesion of coagulation necrosis in deep organs, by means of an extracorporeal transducer. Applications of this method to the liver in animal models have been studied for many years. The effects of HIFU on the normal liver parenchyma and on hepatic tumors are reviewed. In the normal rabbit liver in vivo we showed the relation between intensity levels and exposure times and the need to adapt intensity to the depth of the target. No severe complications were observed when an intensity of 1,000 W/cm2 was used. HIFU is a noninvasive method for the local destruction of liver tumors. In experimental models, safety and efficacy were demonstrated. HIFU may be interesting for the treatment of some human liver tumors.

Characterization of extracorporeal ablation of normal and tumor-bearing liver tissue by high intensity focused ultrasound.

Treatment parameters of extracorporeal high intensity focused ultrasound (HIFU) were analysed in normal and tumor-bearing rabbit liver. HIFU was generated with a 1 MHz transducer and energy was provided by a 7.5 kW power amplifier. In vivo experiments were conducted on 74 New Zealand rabbits. Normal rabbits and rabbits bearing an intrahepatic VX2 tumor were used. In group 1, spatial peak temporal peak (SPTP) intensities ranging from 1470 to 5500 W cm-2 and exposure times from 0.5 to 5 s were tested at a constant depth in the liver; in group 2, the output power was adjusted as a function of the target depth in order to keep constant the focal in situ intensity in the liver; in group 3 (liver tumors), the focal in situ intensity was 1365 W cm-2 in eight rabbits and 500 W cm-2 in nine. In groups 1, 2 and 3, rabbits were sacrificed 48 h after the treatment. Groups 4 and 5 were designated for analysis of the lesion in the normal liver 4 weeks after treatment at 1000 W cm-2 and 3000 W cm-2 SPTP intensities, respectively. In normal rabbits, the lesion volume increased with exposure time at constant intensity; there was a negative correlation between intensity and exposure time (group 1). When the output power was adjusted as a function of the path length, the lesion size was nearly constant (group 2). In VX2 rabbits, tumor destruction rates were significantly higher in rabbits treated at 500 W cm-2 than in rabbits treated at 1365 W cm-2 (p < 0.05; group 3). As in the normal liver, the lesion volume increased with the exposure time at constant intensity. HIFU lesions treated at 1000 w cm-2 (SPTP) healed as thin fibrous scars, and no severe complication occurred (group 4); at 3000 W cm-2 (SPTP), scars were larger and perforation of a neighbouring organ was seen in 7 of 11 rabbits (group 5).