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D Jaeck

Publications and source records attributed to D Jaeck.

At least 73 records · Page 4Linked to original sources
PubMed1997

Integration of in vitro data into allometric scaling to predict hepatic metabolic clearance in man: application to 10 extensively metabolized drugs.

In this study, we investigated rational and reliable methods of using animal data to predict in humans the clearance of drugs which are mainly eliminated through hepatic metabolism. For 10 extensively metabolized compounds, adjusting the in vivo clearance in the different animal species for the relative rates of metabolism in vitro dramatically improved the predictions of human clearance compared to the approach in which clearance is directly extrapolated using body weight. Using hepatocyte data to normalize the in vivo clearances led to lower median deviations between the observed and predicted clearances in man compared to the approach normalizing data with brain weight (30-40% vs 60-80%, respectively). In addition, the approach integrating in vitro data appeared to be superior with respect to the range of deviations: approximately 2-fold underestimation, in the worst case, was observed by using in vitro data, whereas normalizing data by brain weight led to up to 10-fold underestimation of clearance in man. In addition, the integration of in vitro data provides a more rational basis to predict the metabolic clearance in man and may be applicable to compounds undergoing phase I and phase II metabolism as well.

Animals↗
PubMed1997

The use of human hepatocytes to select compounds based on their expected hepatic extraction ratios in humans.

PURPOSE: The present investigation retrospectively evaluates the use of human hepatocytes to classify compounds into low, intermediate or high hepatic extraction ratio in man. METHODS: A simple approach was used to correlate the in vivo hepatic extraction ratio of a number of compounds in man (literature and in-house data) with the corresponding in vitro clearance which was determined in human hepatocytes. The present approach assumes that, for compounds eliminated mainly through liver metabolism, intrinsic clearance is the major determinant for their in vivo hepatic extraction ratio and subsequently their bioavailability in man. The test compounds were selected to represent a broad range of extraction ratios and a variety of metabolic pathways. RESULTS: The present data show that in vitro clearances in human hepatocytes are predictive for the hepatic extraction ratios in vivo in man. Most of the test compounds (n = 19) were successfully classified based upon human hepatocyte data into low, intermediate or high hepatic extraction compounds, i.e. compounds with potential for high, intermediate or low bioavailabilities in humans. CONCLUSIONS: The present approach, validated so far with 19 test compounds, appears to be a valuable tool to screen for compounds with respect to liver first-pass metabolism at an early phase of drug discovery.

Adult↗
PubMed1997

The effects of N-acetylcysteine and anti-intercellular adhesion molecule-1 monoclonal antibody against ischemia-reperfusion injury of the rat steatotic liver produced by a choline-methionine-deficient diet.

Abundant fat in the liver has been implicated in poor outcome after liver transplantation or liver surgery, but the reasons for this association are still unclear. The aim of the present study was to examine mechanisms that may be involved in hepatic dysfunction after ischemia-reperfusion (I/R) of the steatotic rat liver. Steatosis was produced by a choline-methionine-deficient (CMDD) diet. In the first experiment, isolated perfused rat livers, subjected to 24-hour cold storage followed by 120-minute reperfusion, were used to investigate hypothermic I/R injury of the steatotic rat liver. In the second experiment, livers were subjected to 60-minute partial left lobar vascular clamping to allow study of normothermic I/R injury. In the first experiment, compared with normal nonsteatotic liver, steatotic livers showed significantly greater injury, as assessed by amounts of hepatic enzymes released into the perfusate, bile production, the concentrations of reduced glutathione (GSH) in the perfusate, as well as in the livers themselves, and electron microscopic findings of sinusoidal microcirculatory injury. The addition of N-acetylcysteine (NAC), a precursor of glutathione, to the liver before cold storage significantly improved these parameters in steatotic livers. The second experiment showed that, compared with nonsteatotic livers, steatotic livers had lower concentrations of GSH and impaired rates of bile production. There was also evidence of increased oxidative stress in polymorphonuclear leukocytes (PMNLs) in liver or peripheral blood of rats with fatty livers. An anti-rat intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody inhibited neutrophil infiltration into pericentral sinusoids and improved these parameters in the steatotic rats. We conclude that sinusoidal microcirculatory injury is involved in hypothermic I/R injury, that oxidative stress produced by PMNLs is involved in normothermic I/R injury, and that NAC and anti-rat ICAM-1 monoclonal antibody restore liver integrity in I/R injury.

Acetylcysteine↗
PubMed1997

[An original case of simultaneous cardiac, pancreatic and renal transplantation. Results over 6 years].

Combined transplantation is actually performed on specific and rare indications. We are presenting here the results of a combined heart-kidney and pancreatic graft. It was performed in a patient presenting an idiopathic cardiomyopathy in end-stage failure and a post-diabetic nephropathy on dialysis. Today, organs function is quite satisfactory with a 6 year follow-up. Only one isolated heart rejection episode was observed at the 15th post-operative day. The patient has recovered a full-time professional activity at one year. This successful graft was obtained by an "homogeneous multiorgan approach" during all the pre-peri and postoperative time.

Adult↗
PubMed1996

Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Française de Chirurgie.

BACKGROUND: Five-year survival rates after resection of liver metastases from colorectal carcinoma are close to 25%. Recurrences occur in two-thirds of the patients after surgery. Selection of patients likely to benefit from surgery remains controversial and subjective. METHODS: Data from 1568 patients with resected liver metastases from colorectal carcinoma were collected. The prognostic value of different factors was studied through uni- and multivariate analyses. A scoring system was developed including the most relevant factors. RESULTS: Two- and 5-year survival rates were 64% and 28%, respectively, and were affected by: age; size of largest metastasis or CEA level; stage of the primary tumor; disease free interval; number of liver nodules; and resection margin. Giving one point to each factor, the population was divided into three risk groups three risk groups with different 2-year survival rates: 0-2 (79%), 3-4 (60%), 5-7 (43%). CONCLUSIONS: A simple prognostic scoring system was proposed to evaluate the chances for cure of patients after resection of liver metastases from colorectal carcinoma. The comparison between expected survival and estimated operative risk can help determine on an objective basis whether surgery is worthwhile. This system needs further prospective validation.

Aged↗
PubMed1996

Prospective study of microscopic lymph node involvement of the hepatic pedicle during curative hepatectomy for colorectal metastases.

Extensive lymph node dissection of the hepatic pedicle was undertaken in 100 consecutive patients undergoing curative hepatectomy for colorectal liver metastases in whom lymph node involvement of the hepatic pedicle was not macroscopically detectable. Microscopic lymph node involvement was found in 14 patients, in very different lymph node sites, and was related only to the number of metastases, extent of liver involvement and carcinoembryonic antigen level (all P < 0.05).

Adult↗
PubMed1996

Liver grafts can be preserved overnight.

The introduction of University of Wisconsin solution has made liver transplantation a semi-elective procedure. However, many studies have suggested that cold storage must not exceed 12 hours to avoid ischemic-type biliary complications, to reduce the incidence of primary nonfunction and to improve graft and patient survival. The aim of this study was to compare the function of livers transplanted as soon as possible after the liver was harvested and those preserved overnight. Over a 42-month period, we studied 133 elective orthotopic liver transplantation procedures. When cold ischemia started after 6 PM, patients underwent transplantation the following morning (group A), whereas the remainder underwent transplantation immediately (group B). Cold ischemia lasted 13.7 hours and 9.5 hours in groups A and B, respectively (P < .001). The two groups were comparable in terms of initial and late biochemical liver function, the rates of primary nonfunction (6.5% in group A, 6.8% in group B), acute rejection (45.6% in group A, 45.7% in group B), and vascular and infectious complications. No ischemic-type biliary complications were observed. Graft and patient survival were similar in both groups (72.4% v 75.4% and 72.9% v 75.8% in groups A and B, respectively). These results suggest that having taken a cut off at 6 PM to divide the groups into those that underwent transplantation consecutively and those deferred to the morning, the difference between the two groups in terms of storage is relatively modest. Elective liver transplantation can be performed after overnight graft storage without increasing short-term or long-term morbidity or mortality rates.

Adolescent↗
PubMed1996

Primary hepatic pheochromocytoma.

Pheochromocytomas are uncommon tumors that represent a potentially curable cause of hypertension. They are usually located in the adrenal glands, but 10% arise from extra-adrenal sites, located along the paravertebral sympathetic chains. We report a case of primary hepatic pheochromocytoma responsible for a severe hypertension in a 24-year-old man. Echotomography showed a lightly heterogeneous mass located in the segment 8 of the liver. Iodine 131-metaiodobenzylguanidine scintigraphy showed a large hepatic concentration of the tracer and no other localization. This tumor appeared highly vascularized on enhanced CT scan and on aortic angiography. Magnetic resonance imaging revealed a hepatic tumor with a high signal intensity on T2-weighted images and with a signal isointense to the liver on T1-weighted images. The hepatic venous sampling contained the highest catecholamine level, whereas the adrenal venous sampling was normal. After surgical resection of the hepatic tumor, the tension level and catecholamines plasmatic level normalized. No recurrent symptoms appeared during a 3-year follow-up.

3-Iodobenzylguanidine↗
PubMed1996

Comparison of resection, liver transplantation and transcatheter oily chemoembolization in the treatment of hepatocellular carcinoma.

BACKGROUND/AIMS: Resection and liver transplantation are currently considered as the most useful treatments for hepatocellular carcinoma. However, transcatheter oily chemoembolization may be favourably compared with these two surgical treatments in patients with anatomically operable tumors. METHODS: Between 1985 and 1991, 122 patients with an Okuda stage I tumor were hospitalized in two French hospitals. Among these patients, 33 remained untreated, 42 were treated by transcatheter oily chemoembolization, 30 by resection and 17 by liver transplantation. The four groups were closely comparable except for age, the patients in the two surgical groups being significantly younger. Moreover, the frequency of pTNM II tumor was significantly higher in the resection group. RESULTS: The 5-year probability of survival was close to 45% in each of the three treated groups and was significantly higher than in the untreated group (0% at 4 years, p < 0.0001). The probability of cancer recurrence and/or metastatic dissemination was lower after transcatheter oily chemoembolization than after surgery. CONCLUSION: Thus, transcatheter oily chemoembolization seems comparable at 5 years with resection or transplantation for the treatment of resectable hepatocellular carcinoma.

Aged↗
PubMed1996

Interspecies scaling of bosentan, a new endothelin receptor antagonist and integration of in vitro data into allometric scaling.

PURPOSE: The goal of this study was to find a rational and reliable method of using animal data to predict the clearance of metabolised drugs in humans. METHODS: One such approach is to use in vitro liver models (e.g. hepatocytes and microsomes) to determine the relative capacities of the various animal species and humans to metabolise the test compound. These data can then be combined with the in vivo clearances in animals, to calculate the in vivo clearance in humans using allometric scaling techniques. In this study, this approach was evaluated with a new endothelin receptor antagonist, bosentan, which is eliminated mainly through metabolism and is characterized by very large interspecies differences in clearance. Therefore, this compound provided a stringent test of our new extrapolation method for allometric scaling. RESULTS: The results obtained with bosentan showed that adjusting the in vivo clearance in the different animal species for the relative rates of metabolism in vitro gave a far better prediction of human clearance than an empirical correcting factor (brain weight). CONCLUSIONS: This approach provided a more rational basis for predicting the clearance of metabolised compounds in humans.

Animals↗
PubMed1996

Interspecies scaling of tolcapone, a new inhibitor of catechol-O-methyltransferase (COMT). Use of in vitro data from hepatocytes to predict metabolic clearance in animals and humans.

1. In the present study, in vivo pharmacokinetic data in animals were combined with in vitro metabolic data from animal and human hepatocytes to predict the human systemic plasma clearance and the kinetic profile of tolcapone, a compound metabolized by phase II reactions. 2. The integration of in vitro metabolic data from hepatocytes into allometric scaling gave satisfactory predictions of metabolic clearance in humans for tolcapone (74.2 ml/min predicted versus 118 ml/min observed). 3. Using combined time transformations and in vitro metabolic rates, the range of values predicted from the various animal species (90.4 to 242 ml/min, 0.60 to 2.2 h and 7.3 to 121 for clearance, half-life and volume of distribution, respectively) were in good agreement with the observed values in humans (118 ml/min, 1.3 h and 8.6 h, respectively). 4. Compared to the conventional correction factors (e.g. maximum life span, brain weight), in vitro metabolic data provide a more rational basis for extrapolating the metabolic clearance in humans.

Animals↗
PubMed1996

[Evaluation of a new technique of extracorporeal perfusion of the swine liver on a swine-primate model].

With the increasing success of liver transplantation there is an urgent need for developing an artificial liver support system to be used in patients with liver failure. An extracorporeal porcine liver perfusion machine was successfully tested in animals with experimental liver failure. Livers were flushed, removed from 35 kg pigs and placed in a heated sterile cassette. The portal vein and the hepatic artery of the graft were connected to the arterial system of the animals. The perfusion pressure of the hepatic artery was regulated via a pressure-flow computerized feed-back device. The venous flow was reinfused from the hepatic veins of the graft to the jugular vein of the animals. The experimental work consisted in two steps: 1. evaluation of clinical and biological consequences of liver perfusion in healthy animals (Group A = pigs, n = 3; group B = primates, n = 3); 2. evaluation of the efficiency of the liver perfusion in animals with ischemic liver failure (Groupe D = pigs, n = 6). The control group (Group C = pigs, n = 7) consisted of pigs with ischemic liver failure without hepatic support. No major clinical or biological adverse effects are reported in groups A and B excepted a thrombocytmia and a marked increase in serum transaminases levels in group B. Liver function as assessed by the bile flow was good in both groups. Comatose pigs with ischemic hepatic failure (group D) recovered a subnormal neurological status in five out of six cases. Serum ammoniemia level were significantly decreased (from 1076 +/- 163 to 255 +/- 32 umol/l). A decrease in serum bilirubine levels and an improvement in the coagulation profile were observed in the perfused animals. Pigs and primates tolerated the perfusion procedure well and beneficial effects were observed in perfused pigs with experimental liver failure.

Animals↗
PubMed1996

[Surgical treatment of synchronous hepatic metastases of colorectal cancers. Simultaneous or delayed resection?].

The surgical strategy for resectable synchronous hepatic metastases of colorectal cancer remains controversial. The retrospective analysis of our series of resectable synchronous hepatic metastases focused on the percentage of simultaneous resections, the circumstances, the indications and the results of the one-step procedure compared to the two-step strategy. From January 1, 1982 to December 31, 1995, 129 patients were operated on for resection of hepatic metastases of colorectal cancer. Forty one patients (32%) presented with synchronous hepatic metastases, 20 of whom (49%) underwent simultaneous resection of the primary tumor and the hepatic metastases (simultaneous resection group: SR). For the other 21 patients (51%), the hepatic resection was delayed for a mean interval of 5.2 +/- 4.2 months (delayed resection group: DR). The mean age of the 2 groups was not significantly different (54 years versus 58 years). When the primary tumor was located on the ascending colon, the hepatic excision was performed simultaneously in 9 out of ten cases. The need for blood transfusion and the volume required were not significantly different between the two groups. The length of each surgical operation was comparable between the two groups (331 +/- 76 minutes SR vs 330 +/- 88 minutes DR). Postoperative complications were observed in 20% of patients in the SR group and 10% of patients in the DR group (no significative difference). There was no postoperative mortality in either group. Survival was 83%, 44% and 37% at 1, 2 and 3 years respectively in the SR group and 79%, 59% and 49% in the DR group, with no significant difference between the groups. These results show that simultaneous resection of the primary tumor and the hepatic metastases did not increase either morbidity or mortality in our study, and that it should be proposed especially to patients presenting with a primary tumor of the ascending colon with metastases resectable by means of a minor hepatectomy.

Actuarial Analysis↗