Chemotherapy is not needed when complete evacuation of gestational choriocarcinoma leads to hCG normalization.

BACKGROUND: The standard treatment for gestational choriocarcinoma is chemotherapy. OBJECTIVE: To describe the risk of recurrence with expectant management of gestational choriocarcinoma that has reached a normal human chorionic gonadotropin level after tumor removal without adjuvant chemotherapy. METHODS: A retrospective multicenter international cohort study was conducted from 1981 to 2017 involving 11 gestational trophoblastic disease reference centers with patient's follow-up extended until 2023. Clinical and biological data of included patients were extracted from each center's database. The inclusion criteria were i) histological diagnosis of gestational choriocarcinoma in any kind of placental tissue retrieved, ii) spontaneous normalization of human chorionic gonadotropin level following choriocarcinoma retrieval, iii) patient did not receive any oncological treatment for the choriocarcinoma, iv) and at least 6 months of follow-up after the first human chorionic gonadotropin level normalization. RESULTS: Among 80 patients with retrieved gestational choriocarcinoma and whose human chorionic gonadotropin level normalized without any other oncological therapy, none had a recurrence of choriocarcinoma after a median follow-up of 50 months. The median interval between choriocarcinoma excision and human chorionic gonadotropin level normalization was 48 days. The International Federation of Gynecology and Obstetrics/World Health Organization risk score was ≤6 in 93.7% of the cases. CONCLUSIONS: This multicenter international study reports that selected patients with gestational choriocarcinoma managed in gestational trophoblastic disease reference centers did not experience any relapse when the initial tumor evacuation is followed by human chorionic gonadotropin level normalization without any additional treatment. Expectant management may be a safe approach for highly selected patients.

Impact of molecular genotyping on the diagnosis and treatment of human chorionic gonadotropin-producing tumors.

OBJECTIVES: To assess the use of molecular genotyping to accurately diagnose and treat human chorionic gonadotropin (hCG)-producing tumors and to evaluate the discriminating capacity of molecular testing on prognosis and overall survival. METHODS: We conducted a retrospective descriptive study of patients registered with the French Reference Center for Trophoblastic Disease between 1999 and 2021. We included all patients with hCG-producing tumors for whom results of molecular genotyping were available. RESULTS: Fifty-five patients with molecular genotyping were included: 81.2 % (n = 45) had tumors of gestational origin, 12.7 % (n = 7) of non-gestational origin and 5.5 % (n = 3) of undetermined origin. The results of molecular genotyping influenced the treatment decisions for 17 % of patients in this cohort. Overall survival was 93.3 % for patients with gestational tumors (after a median follow-up of 74 months) compared to 71.4 % for patients with non-gestational tumors (after a median follow-up of 23 months). CONCLUSION: In atypical presentations of hCG-producing tumors, molecular genotyping is a valuable tool to guide diagnosis and tailor treatment recommendations.

Risk of gestational trophoblastic neoplasia after hCG normalisation according to hydatidiform mole type.

OBJECTIVE: The risk of gestational trophoblastic neoplasia (GTN) after a hydatidiform mole (HM) is well known. However, the risk of GTN after normalisation of hCG in HM is poorly reported. The aim of this study was to evaluate the risk of GTN after normalisation of hCG according to HM types. METHODS: This prospective cohort study carried out between 2000 and 2010 used the database of the French Trophoblastic Disease Centre (FTDC). A total of 2008 registered patients with ascertained types of HM were analysed. Cases of GTN occurring after normalisation of hCG were analysed. RESULTS: A GTN developed in 239 out of 1980 HMs (12.1%) and 6 out of these 239 post-molar GTN (2.5%) were diagnosed after normalisation of hCG. The risk of GTN after normalisation of hCG was 0.34% (6/1747) following a HM, 0% (0/593) after a partial HM (PHM), 0.36% (4/1122) after a complete HM (CHM), and 9.5% (2/21) after a multiple pregnancy with HM. CONCLUSIONS: The risk of post-molar GTN justifies hCG monitoring in all women with HM. However, after normalisation of hCG, monitoring of PHM can be stopped safely while it should be maintained for CHM and more importantly for multiple pregnancies with HM.

Predictive values of hCG clearance for risk of methotrexate resistance in low-risk gestational trophoblastic neoplasias.

BACKGROUND: Early identification of patients at high risk for chemoresistance among those treated with methotrexate (MTX) for low-risk gestational trophoblastic neoplasia (GTN) is needed. We modeled human chorionic gonadotropin (hCG) decline during MTX therapy using a kinetic population approach to calculate individual hCG clearance (CL(hCG)) and assessed the predictive value of CL(hCG) for MTX resistance. PATIENTS AND METHODS: A total of 154 patients with low-risk GTN treated with 8-day MTX regimen were retrospectively studied. NONMEM was used to model hCG decrease equations between day 0 and day 40 of chemotherapy. Receiver operating characteristic curve analysis defined the best CL(hCG) threshold. Univariate/multivariate survival analyses determined the predictive value of CL(hCG) and compared it with published predictive factors. RESULTS: A monoexponential equation best modeled hCG decrease: hCG(t) = 3900 x e(-0.149 x t). Median CL(hCG) was 0.57 l/day (quartiles: 0.37-0.74). Only choriocarcinoma pathology [yes versus no: hazard ratio (HR) = 6.01; 95% confidence interval (CI) 2.2-16.6; P < 0.001] and unfavorable CL(hCG) quartile (< or =0.37 versus >0.37 l/day: HR = 6.75; 95% CI 2.7-16.8; P < 0.001) were significant independent predictive factors of MTX resistance risk. CONCLUSION: In the second largest cohort of low-risk GTN patients reported to date, choriocarcinoma pathology and CL(hCG) < or =0.37 l/day were major independent predictive factors for MTX resistance risk.

[Contribution of meb to endometriosis patients' diagnosis and treatment]. / Apport de la réunion de concertation pluridisciplinaire à la pertinence du diagnostic et du traitement de l'endométriose.

OBJECTIVES: Diagnosis and treatment of endometriosis may be complex and therefore justify the discussion of therapeutic decisions in a multidisciplinary endometriosis board (MEB). The development of endometriosis regional expert centers requires an assessment of the quality and relevance of MEB. METHODS: Qualitiative retrospective study on patients whose management was discussed in Centre Hospitalier Lyon-Sud between June 2013 and December 2017. RESULTS: Among 376 patients presented in MEB, 309 (80.2%) were painful and 184 (59.5%) had complex endometriosis. A complete clinical evaluation was performed in 120 (38.8%) patients. MRI was performed for 370 (98.4%) patients including 303 (81.9%) with a second reading by an expert radiologist. These second readings allowed a diagnosis correction in 88 (60.7 %) patients with complex endometriosis. MR enterography (27.8 %) and rectal endoscopic sonography (14.4%) were the most frequently used third-line exams to complete the initial imaging of digestive lesion in patients with rectal endometriosis. Surgery was proposed for 199 (52,9%) patients including 108 (58,7%) with complex endometriosis. CONCLUSION: One of the major interests of MEB in endometriosis is the second reading of MRI, which, by identifying complex endometriosis initially undiagnosed or underestimated, enabled to better discuss the benefits/risks of therapeutic choices, and to organize complex surgeries when those were retained. The development of MEB in regional expert centers will contribute to optimizing the relevance of care for patients with endometriosis.

[Evaluation of treatment relating to gestational trophoblastic tumor registered to the French Trophoblastic Disease Reference Center (TDRC) in Lyon from 1999 to 2005]. / Evaluation de la prise en charge des tumeurs trophoblastiques gestationnelles enregistrées au Centre de référence des maladies trophoblastiques de Lyon de 1999 à 2005.

OBJECTIVES: The aim of this study was both to analyse if gestational trophoblastic neoplasia (GTN) registered to the French Trophoblastic Disease Reference Center (TDRC) in Lyon (France) were managed according to the FIGO criteria for diagnosis of GTN and if chemotherapy was adapted to the 2000 FIGO prognostic scoring system. PATIENTS AND METHODS: Retrospective, descriptive analysis of 167 GTN registered to GTC of Lyon between 1999 and 2005. RESULTS: On the one hand, 66% of women (104/158) had a diagnosis of GTN according to FIGO criteria. One third (n=54) of the patients therefore had a premature or erroneous diagnosis of a tumor, when the treatment started. No supporting element of this premature diagnosis has been found out for 26 patients. The identification of lung and vaginal metastasis and histological diagnosis of invasive mole appeared as the most mentioned inappropriate criteria for diagnosis. On the other hand, chemotherapy was adapted to 2000 FIGO scoring in 91, 5% of cases. Twelve low risk GTN were treated with polychemotherapy and two high risk GTN were treated with monochemotherapy. Moreover 29% of the patients received a non adequate treatment due to deviations from the recommended protocol. DISCUSSION AND CONCLUSION: Non respect of FIGO criteria for the diagnosis of GTN can lead to erroneous diagnosis of tumors. Identification of lung or vaginal metastasis or diagnosis of invasive mole should not automatically justify the diagnosis of gestational trophoblastic neoplasia if the decrease in HCG occurs properly. Respect of FIGO criteria for the diagnosis of GTN and adaptation of chemotherapy to 2000 FIGO scoring are necessary to avoid inadequate treatment of gestational trophoblastic neoplasia.

Estimates of the number of cancer patients hospitalized in a geographic area using claims data without a unique personal identifier.

OBJECTIVE: In French national claims databases, claims are currently anonymous i.e. not linked to individual patients. In order to improve our estimate of the medical activity related to cancer in one French region, a statistical method was developed to use claims data to assess the number of cancer patients hospitalized in acute care. METHODS: This method used the medical and administrative information available in the claims (i.e. age, primary site, length of stay) to predict an average number of stays per patient, followed by a number of patients. It was based on a two-phase study design using an internal dataset which contained personal identifiers to estimate the model parameters. RESULTS: The predicted number of acute care patients hospitalized in one or several health care centers in one French region was 38,109 with a 95% predictive interval (37,990; 38,228) for the first six months of 2002. A prediction error of 24 per thousand was found. CONCLUSION: We provide a good estimate of the morbidity in acute care hospitals using claims data that is not linked to individual patients. This estimate reflects the medical activity and can be used to anticipate acute care needs.

[Elaboration of a national biobank for the study of gestational trophoblastic diseases]. / Création d'une biobanque nationale pour l'étude des maladies trophoblastiques gestationnelles.

AIM: To generate a national biobank made up of samples of the highest quality for the purpose of inciting basic research on gestational trophoblastic diseases (GTD). MATERIAL AND METHODS: Three priority axes of research were defined to optimize the nature, method of collection, and storage of the samples. These are: to enhance our understanding of GTD, develop new diagnostic tests, and identify new therapeutic targets. The protocol for patient inclusion and sample processing was determined after extensive literature review and collaboration with international experts in the field of GTD. RESULTS: For each patient with a GTD and for control patients (legally induced abortions), chorionic villi, decidua and tumor samples (fresh, immersed in RNA-protective solution and fixed in formaldehyde), blood (serum, plasma, RNA, and peripheral blood mononuclear cells), urine (supernatant), and cell cultures of villous cytotrophoblasts are prospectively collected. Associations are then made between the collected samples and numerous clinical and biological data, such as human chorionic gonadotropic plasma levels following curettage in the case of a hydatidiform mole. CONCLUSION: Such a collection of high quality samples and their associated data open up new perspectives for both national and international collaborative research projects.

Effects of intravenous infusions of commercial fat emulsions (Intralipid 10 or 20%) on rat plasma lipoproteins: phospholipids in excess are the main precursors of lipoprotein-X-like particles.

Like most commercial parenteral emulsions, Intralipid contains the same amount of phospholipids (12 mg/ml) to stabilize 100 or 200 mg of soybean oil (10 or 20% formula, respectively). By centrifugation, 10 or 20% Intralipid was separated into a supernatant, fat particles containing the bulk of triacylglycerols stabilized by a fraction of phospholipids and an infranatant--called mesophase--consisting mainly of phospholipids used in excess as emulsifier. We observed that the initial triacylglycerol/phospholipid ratio of the emulsion (100/12 and 200/12, respectively) determines the size of the triacylglycerol-rich particles (260 and 350 nm) as well as the phospholipid content of the mesophase (6.02 and 4.67 mg/ml). To understand the mechanism of the lipoprotein-X (LPX) accumulation generally reported after intravenous fat infusions, plasma lipid levels and lipoprotein profiles were first compared in the rats after infusion (at a constant rate of 0.5 or 1 ml/h for 43 h) of Intralipid 10 or 20%. For the same intravenous triacylglycerol load (100 mg/h), rats infused with Intralipid 10% at 1 ml/h displayed higher triacylglycerol levels than rats infused with the 20% emulsion at 0.5 ml/h, suggesting that the size of exogenous fat particles modulated the catabolic rate of their triacylglycerols. The plasma levels of LPX varied according to the infusion rate of phospholipids not associated with triacylglycerol-rich particles of the emulsion. Moreover, an apo E and apo B enrichment of plasma and an elevation of the apo B48/apo B100 ratio was always observed after Intralipid infusions. In order to confirm that phospholipids of the mesophase are the main LPX precursors, lipoprotein profiles were then compared in the rats after intravenous infusion, at a constant rate of 1 ml/h, of either the mesophase or a suspension of triacylglycerol-rich particles isolated from Intralipid 20%. As expected, significant LPX amounts were only detected in rats infused with the pure mesophase of the emulsion. It was concluded that products of the lipolysis of exogenous fat particles play only a minor role in the formation of LPX. In fact these abnormal lipoproteins are generated by phospholipids of the mesophase which, like infused liposomes, actively mobilize endogenous free cholesterol. Consequently, in order to be considered as true chylomicron models for safe fat delivery in parenteral nutrition and in order to prevent some detrimental effects on cholesterol metabolism, commercial emulsions should be cleared of phospholipid excess.

Total parenteral nutrition stimulates hepatic cholesterol synthesis in the rat.

Cholesterol synthesis was studied in parenterally fed rats, as compared to orally fed rats with or without saline infusion. Conditions of total parenteral nutrition (TPN) involved the intravenous infusion of a nutritive mixture containing 20% Intralipid as the lipid source (50% of non-protein energy) at the continuous rate of 2 ml per h, for five days. In rats maintained in isotopic steady state by daily injections of [3H]cholesterol, isotope dilution indicated that the endogenous plasma cholesterol input was significantly higher (+15%, P < 0.05) in TPN than in orally fed rats, which suggested a slight stimulation of whole body cholesterogenesis. Cholesterol synthesis was assessed in TPN and orally fed rats by the in vivo incorporation of [1,2-13C]- and [1-14C]acetate into hepatic and intestinal sterols, and by the activity of HMG-CoA reductase in microsomes isolated from liver and small intestine. Both methods demonstrated that TPN markedly stimulated the hepatic cholesterol synthesis, since the radioactivity of liver sterols was 6- to 10-fold higher, and the activity of HMG-CoA reductase 5-fold higher, in TPN than in orally fed rats. Despite the weight reduction of the small intestine, by about 20% after TPN, the incorporation of exogenous [14C]acetate into intestinal sterols was similar in TPN and orally fed rats. As the liver and intestine are the main organs responsible for the appearance of endogenous cholesterol in plasma, it may be concluded that the increased endogenous plasma cholesterol input was mainly due to a strong stimulation of hepatic cholesterol synthesis in TPN rats.

Total parenteral nutrition and plasma lipoproteins in the rat: evidence for accelerated clearance of apo-A-I-rich HDL.

The effect of total parenteral nutrition (TPN) containing fat on plasma lipoproteins and apo-A-I-rich HDL catabolism was studied in the rat. TPN rats were intravenously infused for 5 days with a nutritive mixture containing amino acids, lipids (Intralipid 20%) and glucose. In spite of similar plasma levels of total cholesterol in TPN and control orally fed rats, density gradient ultracentrifugation of plasma samples gave evidence of marked differences in the lipoprotein profiles. In the density range 1.010-1.040, were found elevated amounts of apo-B-100 and apo-B-48 containing lipoproteins, as well as an increase in free cholesterol and phospholipids, the latter indicating that the plasma of TPN rats contained abnormal lipoprotein-X-like particles. The level of apo-E-rich HDL (density: 1.040-1.063) was not markedly changed, whereas that of typical HDL (d > 1.063) was lowered, with less apo-A-I and apo-A-IV, and low amounts of cholesterol and phospholipids were found in the most dense HDL3 fractions (d > 1.090) containing the bulk of apo-A-I-rich particles. After intravenous infusion of homologous [14C]sucrose-labelled HDL3, the clearance of these particles was 2-fold faster in TPN than in control rats, with a tissue uptake increased in the liver (+40%) and decreased in the small and large intestines (-60%). Because the pool of apo-A-I-rich HDL was dramatically reduced after 5 days of artificial feeding, the absolute catabolic rate of these lipoproteins was similar in the two groups. These data suggest that, in TPN rats lacking of chylomicron coat components as a source for HDL material, the fall in plasma levels of apo-A-I-rich HDL resulted mainly from accelerated turnover of these particles, mediated by increased uptake by the liver. Conversely, mucosa atrophy was probably involved in the reduced uptake of apo-A-I-rich HDL by the gastrointestinal tract.

The acute phase response in apolipoprotein A-1 knockout mice: apolipoprotein serum amyloid A and lipid distribution in plasma high density lipoproteins.

In plasma, the bulk of apoSAA, a positive acute phase reactant protein, is transported in high density lipoproteins (HDL), especially HDLH (apoA1-rich HDL). In this study we tested whether apoA1 deficiency would adversely affect apoSAA concentration and lipid distribution in mouse plasma lipoproteins. Acute phase response (APR) was induced in C57BL/6J (apoA1+/+) and apoA1-knockout mice (apoA1-/-) by a subcutaneous injection of silver nitrate. The APR increased cholesterol concentrations in LDL of apoA1-/- mice and apoA1+/+ mice in a like manner. In contrast to apoA1+/+ mice, concentrations of cholesterol, phospholipids and proteins in both HDLL (1.063

A unique amyloidogenic apolipoprotein serum amyloid A (apoSAA) isoform expressed by the amyloid resistant CE/J mouse strain exhibits higher affinity for macrophages than apoSAA1 and apoSAA2 expressed by amyloid susceptible CBA/J mice.

CBA/J and other inbred strains of mice that express the amyloidogenic apolipoprotein serum amyloid A (apoSAA) apoSAA2, together with apoSAA1, are susceptible to amyloid A (AA) amyloidosis, whereas CE/J mice that express a single unique isoform, apoSAACEJ, are resistant. Studies indicate that CBA/JxCE/J hybrid mice that express apoSAA2 in the presence of apoSAACEJ are protected from amyloidogenesis. To define a mechanism by which expression of apoSAACEJ may protect from AA formation in the presence of apoSAA2, binding of recombinant apoSAA (r-apoSAA) isoforms, validated by N-terminal sequencing, to a murine macrophage cell line was investigated. Maximal specific binding occurred after incubation of radiolabeled apoSAA with IC-21 macrophages (1x105 cells/ml) for 30 min at 4 degreesC. The binding of 125I-r-apoSAA1, 125I-r-apoSAA2 and 125I-r-apoSAACEJ was specific and saturable, with an affinity (Kd) of about 2.8, 3.2 and 1.3 nM, respectively, and approximately 2-4x106 sites per cell. Competitive binding experiments indicate apoSAACEJ binds with higher affinity to macrophages than does either apoSAA1 or apoSAA2. We suggest that greater cellular affinity of apoSAACEJ compared to apoSAA2 may contribute to protection from AA amyloid in certain CBA/JxCE/J hybrid mice by interfering with interaction of apoSAA2 by macrophages and hence either membrane associated or intracellular degradation.

Lipid composition and structure of commercial parenteral emulsions.

In order to study the influence of the phospholipid/triacylglycerol (PL/TG) ratio of parenteral emulsions on the distribution and the physico-chemical properties of their fat particles, commercial 10, 20 or 30% fat formulas were fractionated by centrifugation into an upper lipid cake (resuspended in aqueous glycerol) and a subnatant or mesophase, from which a PL-rich subfraction (d = 1.010-1.030 g/l) was purified by density gradient ultracentrifugation. Chemical and 31P-NMR analyses of these fractions indicated that at least two types of fat particles coexist in parenteral emulsions: (i) TG-rich particles (mean diameter: 330, 400, 470 nm in the 10, 20, 30% emulsion) which contain practically all the TG and esterified phytosterols of native emulsions, but only a fraction of their PL, unesterified cholesterol and phytosterols, and other minor lipids; (ii) PL-bilayer particles or liposomes (mean diameter: 80-100 nm) which are constituted with the remaining PL and relatively very small amounts of TG and other lipids. The higher the oil content of the emulsion, the lower the amount of these PL-rich particles, which represent the major particle population of the mesophase. Indeed, minute amounts of TG-rich particles (probably the smallest ones) are also present in the mesophase, even in the PL-rich subfraction which contains the bulk of liposomal PL. Since the PL-rich particles of the infused emulsion generate lipoprotein X-like particles, only the large TG-rich particles can be considered as true chylomicron counterparts.

Quantitative ultrasound parameters as well as bone mineral density are better predictors of trochanteric than cervical hip fractures in elderly women. Results from the EPIDOS study.

RATIONALE: Hip fractures can be separated into cervical and trochanteric fractures. Trochanteric fractures have been associated with up to twice the short-term mortality of cervical fractures in the elderly. There is also evidence suggesting that the mechanisms are different. Evidence from the literature remains limited on the predictive power of bone mineral density (BMD) and quantitative ultrasounds (QUS) for both types of hip fractures. METHODS: 5703 elderly women aged 75 years or more, who were recruited from the voting lists in the EPIDOS study, and had baseline calcaneal ultrasounds (QUS) and DXA measurements at the hip and the whole body, were analyzed in this paper. Among those, 192 hip fractures occurred during an average follow-up of 4 years, 108 cervical and 84 trochanteric fractures. RESULTS: Femoral neck, trochanteric and whole body BMD were able to predict trochanteric hip fracture (RR's and 95% CI were, respectively, 3.2 (2.4-4.2); 4.8 (3.5-6.6); and 2.8 (2.2-3.6)) more accurately than cervical fractures (respectively, 2.1 (1.7-2.7); 2.3 (1.8-3.0); 1.2 (1.0-1.6)). All ultrasound parameters, SOS, BUA, and stiffness index (SI) were significant predictors of trochanteric (RR's respectively 3.0 (2.2-4.1), 2.5(2.0-3.1), and 3.5(2.6-4.7)) but not cervical fractures. After adjustment for femoral neck or trochanteric BMD ultrasound parameters were still significant predictors of trochanteric fracture, and stiffness tended to be a better predictor of trochanteric fractures than either BUA or SOS with a relative risk of 2.25 (1.6-3.1). CONCLUSIONS: A significant decrease of all bone measurements, BMD and QUS, was highly predictive of trochanteric fractures, whereas a decrease of femoral neck and trochanteric BMD were only associated with a slight increase in cervical fracture risk and a low total body BMD or QUS parameters were not significant predictors of cervical fractures. In women who sustained a hip fracture, the decrease of BMD and QUS values increases the risk of trochanteric fracture as compared to cervical fracture. Trochanteric fractures were mostly a consequence of a generalized low BMD and QUS, whereas other parameters might be involved in cervical fractures.

Role of CD36 in membrane transport and utilization of long-chain fatty acids by different tissues.

The transmembrane glycoprotein CD36 has been identified in isolated cell studies as a putative transporter of long-chain fatty acids. To examine the physiological role of CD36, we studied FA uptake and metabolism by tissues of CD36 null mice after injection with two fatty acid analogs. Compared to controls, uptake was substantially reduced (50-80%) in heart, skeletal muscle, and adipose tissues of null mice. The reduction in uptake was associated with a large decrease in fatty acid incorporation into triglycerides, which could be accounted for by an accumulation of diacylglycerides. Thus CD36 facilitates a major fraction of fatty acid uptake by myocardial, skeletal muscle, and adipose tissues, where it is highly expressed. Its role in other tissues where its expression is low and cell-specific could not be determined in these studies.

Saturated fatty acids and LDL receptor modulation in humans and monkeys.

It has been known for 40 years that dietary saturated fat (SAT FAT) increases plasma cholesterol, including LDL-C and HDL-C. In humans, where LDL-C is typically > 90 mg/dl this SAT FAT effect largely reflects changes in LDL-C pool size. The original human studies suggested that LDL-C expansion during SAT FAT consumption reflected reduced LDL clearance (LDL receptor activity) in hyperlipemics and increased LDL production rates in normolipemics (LDL-C < 100 mg/dl) . This dual explanation is supported by data from several animal models where specific saturated fatty acids (SFAs) have been the focus. However, the situation is complicated by the fact that polyunsaturated fatty acids (PUFAs) oppose SFAs, i.e. PUFAs decrease LDL-C and increase LDL receptor (LDLr) activity, so the effect of SAT FAT intake may represent the combined influence of increased SFAs and decreased PUFAs. In fact, careful scrutiny of primate data suggests a negligible effect of saturated fat on LDL clearance (and receptor activity) in the absence of dietary cholesterol when PUFA intake is adequate (5-10%en) and the lipoprotein profile is relatively normal (LDL-C < 90 mg/dl), i.e. normolipemic situations at the time of dietary intervention. In such cases increases in LDL-C due to SFAs (particularly 12:0+14:0) appear to reflect LDL overproduction associated with a shift in cholesterol from tissues to the plasma cholesteryl ester (CE) pool (both LDL-C and HDL-C) without altering whole-body cholesterol balance. The reason for this shift, which is accompanied by an increase in the plasma oleic/linoleic CE ratio, is unknown but may reflect a decreased rate of CE hydrolysis by the liver. When individuals or animals are rendered hyperlipemic by other factors (e.g. chronic caloric and dietary cholesterol excesses in humans or by cholesterol feeding in animals) specific SFAs (particularly 16:0) can contribute to decreased LDLr activity initiated by a primary factor, such as dietary cholesterol. However, LDLr down-regulation by dietary cholesterol greatly exceeds any contribution from SFAs.

Crilvastatin, a new 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, inhibits cholesterol absorption in genetically hypercholesterolemic rats.

Crilvastatin is a new drug from the pyrrolidone family, which acts as a non-competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The long-term effects of oral crilvastatin treatment (200 mg per day per kg body weight for 4 and 10 weeks) were investigated on in vivo cholesterogenesis in male adult normocholesterolemic (SW) and genetically hypercholesterolemic (RICO) rats. In both strains of rats, the treatment had no effect on the plasma cholesterol level, but efficiently inhibited cholesterol synthesis in liver and intestine, as shown by the decreased incorporation of exogenous [14C]acetate into hepatic (3.5-fold in SW, 1.7-fold in RICO rats) and intestinal (2.5-fold in SW, 3.3-fold in RICO rats) sterols. In RICO rats in which the dietary cholesterol absorption coefficient was two-fold lower in treated (38%) than in untreated (78%) rats, this drug reduced intestinal cholesterol absorption. As a result, the total plasma cholesterol input (absorption + synthesis), measured by isotope analysis in RICO rats, was markedly lower in treated (11.3 mg per day) than in untreated animals (28.8 mg per day).

Reduced cholesterol absorption in hamsters by crilvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.

Crilvastatin, a new drug from the pyrrolidone family, has been previously shown to inhibit the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, in vitro and in vivo, to reduce the absorption of dietary cholesterol and to stimulate the activity of cholesterol 7 alpha-hydroxylase in the rat. The aim of this study was to evaluate the effects of crilvastatin on cholesterol and bile acid metabolism in the hamster. In hamsters fed on a lithogenic diet for 8 weeks, crilvastatin treatment (200 mg/day per kg body weight) did not change plasma lipid levels, failed to improve bile parameters and did not prevent gallstone formation. In hamsters fed on a basal cholesterol-rich (0.2%) diet for 8 weeks, crilvastatin at the same dose reduced the cholesterol level in the plasma by 20%, with a decrease of both low-density and high-density lipoprotein cholesterol. The drug did not significantly stimulate the biliary secretion of bile acids but significantly decreased the activity of acyl coenzyme A:cholesterol acyltransferase in the small intestine by 64%. This effect was enhanced when cholestyramine, a bile acid-sequestering resin, was given in combination with crilvastatin. Crilvastatin alone did not change the activity of cholesterol 7 alpha-hydroxylase in the liver, despite the marked reduction in both hepatic cholesterogenesis and intestinal absorption of dietary cholesterol (the absorption coefficient was 44 +/- 2% in treated hamsters vs. 61 +/- 7% in controls).