Abnormal liver cholesteryl ester storage in a strain of golden hamsters. Possible model for studies on cholesterol metabolism.

Very high values of hepatic cholesteryl esters were found in a strain of golden hamsters isolated in our laboratory: 2 g/100 g in animals kept at 22 degrees C and more than 10 g/100 g in starved cold-adapted animals. The rate of incorporation of labelled mevalonate was not increased, but the esterification of the newly-synthetized cholesterol was markedly stimulated.

Relationship between aorta cholesterol content and plasma lipids in guinea pigs fed an atherogenic diet.

Guinea pigs fed a diet enriched with 0.5% cholesterol for 15 weeks developed a 25% increase in their aorta cholesterol content. This increase was positively correlated with the mass of all the LDL components, but inversely correlated with the mass of the VLDL phospholipids and triglycerides. No clear relationship was detected with the HDL constituents. The partial correlation coefficients suggested that the harmful influence of the LDL or VLDL cholesterol generally depends on the actual variation of the other components of the lipoproteins, with the exception of triglycerides.

Hepatic acylcoenzyme A:cholesterol acyltransferase activity is low in hamsters fed apples in addition to a standard diet.

The effect of consumption of apples as a supplement to a standard diet on hepatic acylcoenzyme A: cholesterol acyltransferase (ACAT) activity was investigated in adult golden hamsters (Mesocricetus auratus). The experimental diet was given for 2 months. IN response to the high-fruit intake, the level of cholesteryl esters was reduced in the liver, and hepatic ACAT activity, determined in vitro under various conditions of incubation, was lowered by about 30%. Moreover, plasma cholesterol was redistributed among the lipoproteins, with a decrease in the cholesterol transported in the ApoB-rich lipoproteins.

Reduction of cholesterol transported in apo B-rich lipoproteins in spontaneously hypercholesterolemic hamsters fed an apple-supplemented diet.

The influence of an apple-supplemented diet on the distribution of cholesterol among the lipoproteins in plasma was studied using a special animal model: FEC hamsters which spontaneously develop hypercholesterolemia with aging when fed a commercial balanced diet. This metabolic disorder did not occur in animals freely consuming apples in addition to the standard diet. This combined diet essentially decreased the cholesterol content in the VLDL and LDL, the apo B-rich lipoproteins in plasma.

Steroid pattern of bile and feces in response to a fruit-enriched diet in hypercholesterolemic hamsters.

The effect of a fruit (apple)-enriched diet on bile secretion and on fecal steroid excretion was studied in two strains of hamster: normal hamsters with normal cholesterolemia and spontaneous hypercholesterolemic hamsters with high-level hepatic cholesterol esters (FEC hamsters). Quantitative and qualitative alterations in the steroid composition in bile and feces were accompanied by changes in intestinal morphology. The fruit diet displayed a choleretic effect and increased the output of bile acids from liver in FEC hamsters. In addition, bile collected continuously from cannulated apple-fed animals was enriched with conjugates of cholic acid. Moreover, apple consumption lowered the lithogenic index of the bile. In response to the fruit diet, fecal excretion of bile acids and neutral sterols increased, essentially in the form of primary bile acids and sterol esters, respectively.

Dietary cholesterol fails to stimulate acylcoenzyme A: cholesterol acyltransferase activity in the liver of hamsters with a spontaneous high level of cholesterol.

The effect of exogenous cholesterol on acylcoenzyme A:cholesterol acyltransferase (ACAT) was investigated in conventional golden hamsters (NH) and in FEC hamsters characterized by a high level of cholesterol esters in the liver. ACAT activity was determined in liver microsomal fractions obtained from control animals, in animals fed 0.1% cholesterol diet or in microsomes preincubated with exogenous cholesterol. NH responded to cholesterol feeding by increasing the rate of cholesterol esterification in the liver, and exposure of the NH microsomes to media containing cholesterol stimulated ACAT activity. By comparison, whatever the conditions, cholesterol failed to alter the rate of cholesterol esterification in FEC hamsters. This finding raises several questions about cholesterol metabolism in the liver of these animals that does not fit into the well-established schemes of hepatic cholesterol metabolism.

Marked elevation of HDL-cholesterol in cold-adapted golden hamsters.

Golden hamsters with spontaneous hypercholesterolemia at 22 degrees C developed a further increase in plasma cholesterol when they were maintained at 6 degrees C. This hypercholesterolemia was associated with a redistribution of plasma cholesterol between VLDL and HDL. Plasma cholesterol transported in the VLDL decreased while cholesterol in the HDL increased by 45%. The LDL profile was not significantly modified.

[Diminution of blood and hepatic cholesterol induced by an apple-supplemented diet in the hamster. Trials in man]. / Diminution du cholestérol sanguin et hépatique induite chez le hamster par un régime alimentaire complémenté en pommes. Essais chez l'Homme.

The effects of an apple-supplemented diet on plasma and liver cholesterol were investigated in two strains of Hamster, a normal one and another which exhibits a spontaneous accumulation of cholesteryl esters in the liver (FEC animals). Adding of apples to the standard diet promoted a 20 % decrease of cholesterolemia in normal animals and normalized the high level of plasma cholesterol in the FEC animals. Similarly, the cholesterol content of the liver was diminished. The levels of cholesteryl esters were strongly lowered, threefold and tenfold respectively in normal and in FEC animals. Incorporation of labelled mevalonate into cholesterol was increased, but esterification of the neosynthesized sterol was markedly reduced in the liver from FEC animals. In human daily ingestion of apples caused a significative reduction (16 %) of cholesterolemia.

Comparative aspects of lipid metabolism in two shrews (Suncus etruscus and Crocidura russula).

1. The amounts of tissue lipids were higher in S. etruscus than in C. russula. 2. The level of liver phospholipids was specially low in C. russula, 2650 mg/100 g as opposed to 3725 g in S. etruscus. 3. This is in good agreement with a reduced rate of the labelled acetate incorporation into the lipids of C. russula. 4. The proportion of unsaturated fatty acids was greater in the liver of S. etruscus; however, the percentage of arachidonic acid was higher in C. russula--15% as opposed to 8%.

Reduced synthesis and rapid esterification of cholesterol in the liver of hamsters with spontaneous hypercholesterolemia.

The rates of in vitro incorporation of [2-14C]mevalonate and of [2-14C]acetate were determined in the liver and in the ileum obtained from two groups of hamsters. The first (N-H) were conventional hamsters with normal cholesterolemia, the second (FEC-H) were hamsters which develop high levels of cholesterol in plasma and in the liver with age. In FEC-H, the levels of cholesterol reached 130 to 220 mg/100 ml in plasma and 600-2400 mg/100 g fresh tissue in the liver in contrast to about 100 mg and 350 mg respectively in the N-H group. The accumulation of cholesterol in the tissues of FEC-H was found to be associated with a strong decrease in the incorporation rate of the precursors into cholesterol, but above all, the distribution of the radioactivity derived from [2-14C]mevalonate between free cholesterol and esterified cholesterol was markedly different in the two groups of hamsters. In FEC-H, 78% of the radioactivity was found in the esters, as opposed to 10% found in the N-H group. Thus, the development of hypercholesterolemia with age in FEC-H might be related to alterations in the enzyme systems (ACAT, CEH) which modulate the level of cholesterol esters in the liver. No significant difference was observed between the two groups of hamsters either in the concentration of cholesterol or in the rate of cholesterogenesis in the ileum.

Hepatic cholesterogenesis and cholesterol 7 alpha-hydroxylase activity in hamsters fed diets enriched with pectins and/or cholesterol.

Cholesterol 7 alpha-hydroxylase activity was determined in parallel with the rate of cholesterogenesis from acetate and mevalonate in the liver of hamsters fed diets enriched with pectins (5%) and/or cholesterol (0.1%). Cholesterol feeding reduced the rate of incorporation of the precursors into cholesterol. Moreover, the radioactivity derived from mevalonate was found mainly in the esterified form of the newly synthesized molecules. In parallel, cholesterol 7 alpha-hydroxylation decreased by 50%. Pectins did not greatly affect hepatic cholesterogenesis or 7 alpha-hydroxycholesterol formation. In contrast, the fibers prevented to a large extent the metabolic alterations resulting from cholesterol feeding. Cholesterogenesis from mevalonate remained active; ester formation declined and the activity of cholesterol 7 alpha-hydroxylase persisted. Pectins could maintain the activity of this enzyme through multiple mechanisms, one of them being the channeling of substrate into the specific compartment of cholesterol which is destined to form bile acids.

Comparative studies of the circulating lipoproteins in hamster (Mesocricetus auratus) with a normal or spontaneous high level of cholesterol in the plasma.

The lipoprotein profile and the distribution of plasma cholesterol were studied comparatively in two strains of hamster, a normal one, and a second, developing spontaneous hypercholesterolemia associated with a high level of cholesterol esters in the liver. In the hypercholesterolemic animals, the amount of cholesterol was increased by 40, 84 and 69% in the circulating VLDL, LDL and HDL respectively. Moreover, the VLDL were particularly rich in cholesterol esters, 21% of their weight in contrast to 11% in controls. A close positive correlation existed between the enrichment of the VLDL with the esters and the accumulation of cholesterol in the hepatic tissue. In the two strains of hamster, there was similar participation of the various classes of lipoprotein in cholesterol transport, that of HDL being particularly high. These lipoproteins carried more than 50% of the circulating cholesterol.

Tratamiento del dolor oncológico irruptivo con citrato de fentanilo transmucosa oral / Treatment of breakthrough cancer pain with oral transmucosal fentanyl citrate

El dolor oncológico está insuficientemente tratado y su incidencia suele aumentar a medida que progresa la enfermedad, oscilando entre el75 a 80% en los pacientes con enfermedad avanzada. Se presenta como un dolor persistente que puede controlarse con una pauta analgésica establecida y un dolor irruptivo que precisa dosis de rescate de analgésicos. El citrato de fentanilo transmucosa oral es un opioide agonista puro que se presenta en forma de matriz edulcorada que se disuelve en la boca liberando su contenido con una absorción inmediata a través de la mucosa oral. Objetivos: evaluar los efectos del tratamiento con citrato de fentanilo transmucosa oral (CFTO) en 8 pacientes con dolor irruptivo oncológico. Métodos: revisión retrospectiva de 8 pacientes afectos de dolor oncológico con crisis de dolor irruptivo tratadas con CFTO. Se registraron la edad, sexo, diagnóstico, EVA basal, tratamiento opioide de base y dosis, medicación concomitante, número de crisis de dolor irruptivo durante 3 días (1 por semana), EVA inicial y final de las crisis, dosis de CFTO, tiempo de alivio del dolor, efectos secundarios, valoración del tratamiento en cuanto a efectividad y tolerabilidad por parte del paciente. Resultados: se incluyeron en el estudio 8 pacientes, 5 mujeres y 3 hombres. La edad media fue de 58,5 años (rango: 38-74). Todos estaban siendo tratados con fentanilo transdérmico de base con una dosis media de 93,75 µg/hora (rango: 50-200). La EVA basal media fue de 31/100 (rango: 20-40/100). El número total de crisis de dolor irruptivo fue de 27 con una media de 3,3 por paciente (rango: 2-5). La EVA inicial media fue de 80/100 (rango: 60-100/100). La EVA final media fue de 10/100 (rango: 0-30/100). De los 27 episodios de dolor irruptivo registrados, en 5 (18,5%) se obtuvo un alivio total del dolor, en 20 (74,07%) se obtuvo un alivio del dolor superioral 75%, y en 2 (7,4%) un alivio del dolor superior al 50%. La dosis media de CFTO fue de 325 µg (rango: 200-600). Tres pacientes presentaron efectos secundarios (somnolencia en 2 pacientes, xerostomía y estreñimiento en 1 paciente). La valoración del tratamiento en cuanto a efectividad fue: buena en 5 pacientes y excelente en 3 pacientes, y en cuanto a tolerabilidad fue: buena en 5 pacientes y excelente en 3 pacientes. Conclusión: el CFTO es un buen fármaco para el tratamiento del dolor irruptivo de origen oncológico, con una muy buena efectividad y tolerabilidad (AU)

Cancer pain is generally poorly controlled and its incidence usually increases with illness; it varies among 75-80% in patients with advanced illness. It features as a persistent pain that could be controlled with an usual analgesic therapy and an incidental pain that need a salvage analgesic treatment. The oral transmucosal fentanyl citrate is a pure opioid agonist. Its presentation is an edulcorate matrix that dissolves in mouth with an immediate absorption. Aims: to assess the effects of the therapy with oral transmucosal fentanylcitrate (OTFC) in eight patients with breakthrough cancer pain. Methods: this is a retrospective study of 8 patients with cancer pain with episodes of incidental pain treated with OTFC. Age, gender, diagnosis, baseline VAS, baseline opioid therapy and dose, number of pain episodes during 3 days (once a week during 3 weeks), VAS at onset and at the end of the episode, OTFC doses, pain relief time, side effects, self assessment of effectiveness and tolerance by the patient were registered. Results: eight patients, five women and three men, were included in study. Mean age was 58.5 years (range 38-74). All patients were treated with transdermic fentanyl with a baseline dose of 93.75 µg/hour (range 50-200). The mean baseline VAS was 31/100 (range 20-40/100). The total number of episodes of incidental pain was 27, being the mean number foreach patient 3.3 (range 2-5). Mean VAS at onset was 80/100 (range 60-100/100). Mean VAS at the end of the study was 10/100 (range 0-30/100). Total pain relief was obtained in 5 cases out of 27 episodes of incidental pain (18.5%). The relief was higher than 75% in 20 cases (74.07%) and higher than 50% in 2 cases (7.4%). The mean dose of OTFC was 325 µg(range 200-600). Three patients reported side-effects (sedation in 2patients, xerostomy and constipation in 1 patient). The self assessment for effectiveness was as follows: good for 5 patients and excellent in 3 patients. The assessment for tolerance was good for 5 patients and excellent in 3 patients (AU)

Tratamiento del dolor neuropático de origen neoplásico con topiramato / Treatment of neuropathic pain of neoplastic origin with topiramte

El dolor neuropático está causado por una lesión o disfunción del sistema nervioso. La fisiopatología es muy compleja y representa el intento del sistema nervioso de reestablecer las propiedades que han sido alteradas. Existen muchas similitudes entre los fenómenos fisiopatológicos observados en algunos modelos de epilepsia y los modelos de dolor neuropático. Esto justificaría la utilización de fármacos antiepilépticos en el tratamiento sintomático del dolor neuropático. Objetivos: valorar la efectividad del topiramato en 4 pacientes con dolor neuropático de origen oncológico. Métodos: estudio prospectivo de 4 pacientes afectos de dolor neuropático de causa oncológica tratados con topiramato. Se registró la edad, sexo, diagnóstico, topografía del dolor, tiempo de duración del dolor, EVA inicial y EVA final, dosis media y efectos secundarios. Resultados: se revisaron los datos de 4 pacientes, 3 hombres y 1 mujer. La edad media fue de 68,7 años (rango 65-73). Todos estaban siendo tratados con analgésicos opioides mayores, AINE y adyuvantes (antiepilépticos, antidepresivos y corticoides). El tiempo medio con dolor fue de11 meses (rango 4-15). El diagnóstico fue de 1 paciente con neoplasia de pulmón con plexopatía braquial, 1 paciente con neoplasia de mama con plexopatía braquial, 1 paciente con neoplasia de vejiga con infiltración de plexo sacro y 1 paciente con neoplasia de recto con plexopatía sacra. La localización del dolor era perineal en 2 pacientes y extremidad superior derecha en 1 paciente y extremidad superior izquierda y cervical en 1paciente. La EVA inicial media fue de 87,5/100 (rango 70-100/100). La EVA final media fue de 17,5/100 (rango 0-40/100). En 1 paciente (25%) se observó una desaparición total del dolor, 2 pacientes (50%) mostraron una mejoría superior al 75% y 1 (25%) paciente una mejoría superior al 50%. La dosis media de topiramato fue de 200 mg/día (rango 100-300). Se observaron efectos secundarios en 2 pacientes: somnolencia en ambos que no obligó a retirar el fármaco y que fue desapareciendo progresivamente. Conclusión: el topiramato es una buena opción en el tratamiento de pacientes con dolor neuropático de origen oncológico, con una buena efectividad y efectos secundarios tolerables (AU)

Neuropathic pain is originated by a nervous system lesion or dysfunction. Pathophysiology is quite complex and it is an attempt of nervous system to restablish the altered properties. There are so many agreements between the physiopathological phenomena that have been found in some epilepsy models and the neuropathic pain models. This issue would warrant the antiepileptical drugs use in the symptomatic therapy of the neuropathic pain. Aims: to assess the topiramate efficacy in four patients with oncological origin neuropathic pain. Methods: this is a prospective study of 4 patients that suffered from oncological neuropathic pain and they were treated with topiramate. Age, gender, diagnosis, pain location, lasting of pain, baseline and final EVA score, mean drug dose and side-effects were all registered. Results: data from all 4 patients (3 men and a woman) were reviewed.The mean age was 68.7 years (range 65-73). All of them were treated with major opioid analgesics, NSAID and others (antiepileptics, antidepressants and steroids). The mean time with pain was 11 months (range 4-15). The diagnosis included 1 patient with lung cancer with brachial plexopathy, 1patient suffering from breast cancer and brachial plexopathy, 1 patien twith bladder carcinoma with sacral plexus infiltration and, finally, a patient with rectal neoplasia with sacral plexopathy. The pain location was in perineum in 2 patients, and right upper limb in 1 patient and left upper limb and cervical en the remaining one. The mean baseline EVA score was 87.5 (range 70-100/100). The mean final score was 17.5 (range 0-40/100). The pain totally disappeared in one patient, 2 patients showed an improvement higher than 75% and the remaining patient demonstrated an improvement higher than 50%. The topiramate mean dose was 200mg/day (range 100-300). Side-effects were found in two patients that presented drowsiness. However, the drug administration was not discontinued and the side-effect disappeared progressively. Conclusions: topiramate is a good option in the treatment of patients with neuropathic pain from oncological origin with a good efficacy and tolerable side-effects (AU)