[Changes in blood pressure after introduction of an antidepressant in a public institution of mental health]. / Évolution de la pression artérielle après introduction d'un antidépresseur en établissement public de santé mentale.

INTRODUCTION: Primary prescribing of antidepressants is common in general practice. The relationship between antidepressant introduction and blood pressure (BP) changes is not well established in the literature. The purpose of our study was to examine the short-term course of AHR with and without the introduction of an antidepressant into a public institution of mental health (EPSM). MATERIALS AND METHODS: An exposed/non-exposed single-centre analytical epidemiological study on a retrospective cohort, with a collection of data on stays between 2013 and 2015 at the EPSM in Armentières. The stays were divided into two groups: antidepressant treatment (introduced during the stay) and control (without antidepressant). BP measurements were taken over a 30-day period per stay. To assess the evolution of AHR across groups, we used a nested mixed linear regression model with multivariate adjustment. RESULTS: Out of 1241 stays analysed, 124 were in the treated group and 1117 in the control group. The average age was 44.6±14.7 years. The two groups were comparable on most of the variables analyzed. The change in systolic BP was associated with systolic BP values at baseline, history of hypertension, presence of an antihypertensive drug and BMI; the change in diastolic BP was associated with diastolic BP values at baseline, presence of an antihypertensive drug, BMI and history of bipolar disorder. We find no significant difference in the evolution of BP over time between the treated group and the control group over the 30 days of measurement per stay, after adjustment (evolution coefficient of +0.12mmHg systolic BP and -0.1mmHg diastolic BP, P=0.45 and 0.38 respectively). CONCLUSION: These results are reassuring on the early development of BP after the introduction of antidepressants. They should not overlook the frequent effects of depression and antidepressants on cardiovascular risk (decreased physical activity, dyslipidemia, weight gain, etc.).

Pharmacomodulation of 7-(2-methylene-butyryl)-2,3-dihydrobenzoxazin-[1,4]-3-one structure and normolipemic activity.

A series of compounds from 7-(2-methylene butyryl)-2,3-dihydro benzoxazin-[1,4]-3-one was synthesized and evaluated for its lipid lowering action in animal models. Substitutions in positions 2, 4 and 7 were performed. The results of the structure-activity relationships are very difficult to be interpreted. The different modifications tested did not show any improvement in the normolipemic activity.

Lipid lowering actions of 7-(2-methylene butyryl)-(2H)-1,4-benzoxazin-3-(4H)-one derivatives in mice, rats and Syrian hamsters.

A series of compounds derived from 7-acyl-(2H)-1,4-benzoxazin-3-(4H)-one was synthesized and evaluated for its lipid lowering actions in animal models. These of three 7-(2-methylene butyryl) 4-methyl and 2,4 dimethyl or 2,2,4 trimethyl benzoxazinone showed very potent activity. Their hypocholesterolemic and hypotriglyceridemic activities were tested in normolipemic and in cholesterol-induced hyperlipidemic mice, rats and Syrian hamsters. Two key enzymatic activities (ACAT, HMG CoA Reductase) of the most active compound were also determined. Additional investigation with these products and other derivatives will be performed using a variety of hepatic enzyme activities to better determine their mechanisms of action.

Effects of fenofibrate on lipoprotein metabolism and fatty acid distribution in Zucker rats.

The short term effects of fenofibrate (150 mg/kg per day), administered by gavage, on lipoprotein and fatty acid distribution have been investigated in an hypertriglyceridemic model, the Zucker rat. Lean rats were compared to control obese and treated obese rats, and control obese animals to treated obese littermates. Classically, plasma cholesterol and triacylglycerol increased by 1.8- and 7.9-fold, respectively, in control obese versus lean rats. Treatment of the Zucker obese rats with fenofibrate reduced their plasma cholesterol by 10% and raised triacylglycerol by 47% (P less than 0.001) in comparison to untreated control obese rats. These effects were accompanied by a change in the composition of all plasma lipoproteins. The cholesterol/triacylglycerol ratio in VLDL rose by 32% while that in LDL and HDL fell by 43 and 47%, respectively. Drug therapy altered the fatty acid profile in both plasma and liver; the percentage of polyunsaturated fatty acids fell while monounsaturated fatty acids increased. The increased proportion of monounsaturated fatty acids in plasma suggests that the fatty acid composition of circulating lipoproteins is modified, particularly in VLDL. This, in association with the altered lipid distribution in VLDL may reflect an abnormal metabolism of this lipoprotein. In view of these abnormalities, we conclude that this rat is not an appropriate model for the short-term study of clofibrate analogues.

Aspects of cholesterol metabolism in normal and hypercholesterolemic Syrian hamsters. Influence of fenofibrate.

This study reports the short-term effects of fenofibrate in golden Syrian hamsters receiving a standard or cholesterol enriched (0.5%) diet. In chow fed control animals, the plasma cholesterol (132 mg/dl) was transported essentially by LDL (27%) and HDL (56%). Conversely, the bulk of triglycerides (114 mg/dl) circulated in VLDL (54%). One week of hypercholesterolemic diet increased plasma cholesterol (+80%) and it is reflected in a 3.3-fold increase in VLDL, 2.8-fold in IDL, 1.6-fold in LDL and 1.5-fold in HDL, accompanied by a rise in cholesterol hepatic level by a factor of 4.5. 15 days of treatment with fenofibrate (300 mg/kg/d) produced a decrease in free plasma cholesterol (-21%) without modification in total cholesterol level in chow fed animals. In liver, cholesterol was reduced by 27% and triglycerides were raised by 58%. In animals receiving the hypercholesterolemic diet, fenofibrate increased hepatic and plasmatic triglyceride levels (55 and 54%, respectively), although it slightly reduced plasma cholesterol levels and more markedly the hepatic cholesterol content (-55%). In chow fed animals, cholesterol biosynthesis was decreased by fenofibrate treatment by 40%. The effects of fenofibrate on triglyceride levels are in contrast to experiences in other animal species, including man, and indicate a hypersecretion of chylomicrons and/or a hypersecretion of VLDL, although the explanations are not yet obvious. The results concerning cholesterol metabolism indicate similarities between man and hamster.

Effects of fenofibrate, gemfibrozil and nicotinic acid on plasma lipoprotein levels in normal and hyperlipidemic mice. A proposed model for drug screening.

These studies examine the effects of a hypercholesterolemic diet (with butter and cholesterol added), or a hypertriglyceridemic diet (30% sucrose (w/v) in drinking water), on murine plasma lipids and lipoproteins prepared either by sequential ultracentrifugation or gel exclusion chromatography. The hypercholesterolemic diet increased plasma cholesterol (186%), particularly that associated with very low (VLDL) and low (LDL) density lipoproteins. In addition, the cholesterol/triglyceride ratio in the VLDL fraction rose significantly from 0.10 to 4.0. The hypertriglyceridemic diet raised markedly plasma triglyceride levels (46%) by expanding the circulating VLDL pool (+39%). These dietary modifications were used to provide a model for the examination of 3 classical hypolipidemic drugs (fenofibrate, gemfibrozil and nicotinic acid). In animals receiving the standard diet, fenofibrate, gemfibrozil and nicotinic acid decreased the triglyceride (TG) level (-28%, -31%, and -38%) by lowering VLDL-TG (-37%, -42%, and -49%), fenofibrate and gemfibrozil increased HDL-cholesterol by 18% and 31%, respectively. In animals receiving the hypercholesterolemic diet fenofibrate lowered the total plasma cholesterol level by 40%, at the same time increasing HDL-cholesterol by 23%. In animals fed sucrose, on the other hand, fenofibrate (100 mg/kg per day) and nicotinic acid (900 and 600 mg/kg per day) reduced plasma triglyceride levels (-20%, -40% and -33%), and nicotinic acid (900 mg/kg per day) decreased VLDL-TG by 58%. These results are in good agreement with clinical data from studies in man and suggest that this animal model may provide a useful and rapid screening system for testing new lipid lowering drugs.