Bariatric surgery and prevention of cardiovascular events and mortality in morbid obesity: mechanisms of action and choice of surgery.

AIMS: Obesity is associated with increased cardiovascular (CV) morbidity and mortality. Weight loss improves several risk factors for CV diseases, but anti-obesity medications and lifestyle interventions have failed to modify primary CV endpoints. This paper reviews bariatric surgery in prevention of CV diseases and CV mortality, and analyzes the possible mechanisms involved. DATA SYNTHESIS: In morbidly obese patients bariatric surgery results in stable weight loss and in long-term reduction in the prevalence and incidence of obesity-related comorbidities; controlled trials have shown superiority of bariatric surgery over medical therapy in inducing significant weight loss and improvement of CV risk factors. Bariatric surgery induces several metabolic improvements (resolution of type 2 diabetes mellitus, improvement of lipid metabolism and of insulin resistance, reduction of visceral fat, of subclinical endothelial dysfunction and inflammation), and functional improvements (reduction of hypertension, of sympathetic overactivity, of left and right ventricular hypertrophy), which can explain the protective effect towards CV disease. CONCLUSIONS: Reduction of CV diseases is mediated by the pleiotropic effects of weight loss through surgery. Available data do not allow conclusions on the comparative efficacy of different surgical techniques; the choice of the surgical technique for a single patient remains an open question, and it is likely that the degree of prevention of CV diseases depends, among other factors, on the baseline conditions of patients. Large prospective studies are needed to address this issue in morbidly obese patients.

Synthesis and pharmacological evaluation of aryl/heteroaryl piperazinyl alkyl benzotriazoles as ligands for some serotonin and dopamine receptor subtypes.

Thirteen [(aryl/heteroaryl-piperazinyl)alkyl]benzotriazoles were prepared as potential trazodone- and buspirone-like drugs. The synthesized compounds displayed from moderate to good affinity to the serotonin 5-HT1A receptor and only modest or poor affinity to the dopamine D2 receptor, similar to buspirone. The introduction of substituents on the benzotriazole ring did not improve the affinity to the 5-HT1A receptor, compared to the previously described unsubstituted derivatives. In a general pharmacological screening, which concerned only three of these compounds so far (5, 7 and 13), several in vitro and in vivo activities were observed. The guinea pig ileum contractions, induced either electrically or by several agonists, were strongly inhibited; at higher concentrations also the spontaneous tone of the guinea pig trachea was reduced. Compound 13 exhibited good analgesic activity in mice in the formalin-induced algesia and in the writhing test. The same at 30 mg kg(-1) p.o. also displayed antihypertensive activity probably related to calcium channel blockade and adrenergic alpha1 antagonism. In binding assays, 13 showed a IC50 = 580 nM for displacing [3H]prazosin from alpha1 receptor. Finally, compound 5 (and, to a minor extent, compound 13) protected mice against potassium cyanide induced hypoxia.

Preparation and local anaesthetic activity of N-[2-(tert-amino)ethyl]- and N-(lupinyl)-benzotriazol-1/2-ylacetamides.

Two sets of N-[2-(tert-amino)ethyl]- and N-[(quinolizidin-1 alpha-yl) methyl]-benzotriazol-2-ylacetamides, bearing substituents on position 5 or 5 and 6, were prepared and tested for local anaesthetic activity in comparison with lidocaine. Most of the prepared compounds exhibited a fairly good activity comparable or superior to that of lidocaine. The introduction of substituents on the benzene ring and the replacement of the usual tert-amino alkyl chains with the quinolizidin-1 alpha-ylmethyl (lupinyl) moiety were quite profitable for both the intensity and duration of activity. One selected compound was subjected to a large pharmacological screening and found endowed with a good level of the purported antiarrhythmic activity without any other disturbing activity.

Synthesis and antiinflammatory activity of some imidazolinylpyrazole derivatives.

Some new imidazolinyl-pyrazoles (4) were synthesized by condensation of 2-imidazolylhydrazine hydroiodid (1a) with beta-ketoesters to afford the intermediate 3 that, as free base, ring closes only to 4. The attempt to obtain the imidazo-triazepinone 5, starting from 2-imidazolinyl-2-methylhydrazine, was accomplished, in low yield, only in reacting with ethyl acetoacetate. The pharmacological evaluation of antiinflammatory and analgesic activities of pyrazoles 4a-f revealed an appreciable antiinflammatory activity.

Synthesis and CNS activities of pyridopyrazinone and pyridodiazepinone derivatives.

New tricyclic derivatives with cyclocondensed pyrido-pyrazine 7,10 and pyrido-diazepine 20a,20b skeletons were synthetized and biologically investigated. The compounds, preliminarily tested on explorative, muscle relaxing, antinociceptive, spontaneous motor activities and influence on the narcotic effect of Evipan, revealed interesting CNS depressant and analgesic activities. The pyrido[2,3-e]pyrrolo[1,2-a]pyrazine structure of 7 appeared the most promising for analgesic and neuroleptic activities. The above compounds were assayed also for their capacity to inhibit DNA synthesis in Ehrlich ascites tumor cells; 20a appeared to be able of inducing a significant inhibition.

Cyclopenta[e] [1,5] benzodiazepin-10 (9H)-one derivatives as CNS depressant agents.

A series of dialkylaminoalkyl derivatives of cyclopenta[e] [1,5] benzodiazepin-10(9H)-one (E1-4) and its 6-chloro derivative (E5-8) was prepared to evaluate their CNS activity in comparison with that of isosteric pyridodiazepinones (A1-4) previously described. The results of the pharmacological screening show a significant depressant activity more remarkable in 6-chloro derivatives, which also revealed a high and lasting analgesic activity. The replacement of pyridine with benzene nucleus did not show any significant or homogeneous activity variation.

Rosmaricine derivatives as potential antitumoral agents.

A group of N-(alkylaminoacyl)-O,O-dimethylrosmaricines was prepared and, together with a set of rosmaricine derivatives previously described by us, evaluated for activity against lymphocytic leukemia P 388. Only one compound exhibited a borderline activity, while all the others were inactive.

N-[(N-halogenoacyl)imino]acenaphthene-quinoxalines as potential antitumoral agents.

Applying a reaction formerly studied by the Authors between acenaphthenequinone and N1-(2-amino)phenyl-N2-acylhydrazines, a group of N-[(N-alpha- and beta- halogenoacyl)imino]acenaphthenequinoxalines were obtained. On account of the reactivity of the halogen atom, they are potentially interesting as antitumoral agents. In contrast with the beta-chloropropionyl derivative, the alpha-halogenoacyl derivatives were formed in low yields and with the simultaneous loss of the whole halogenoacylimino group. Thus, an alternative synthetic route was set up, consisting in the N-imination of acenaphthenequinoxalines by means of O-mesitylenesulfonylhydroxylamine, followed by acylation of the intermediate N-iminoacenaphthenequinoxalines. The National Cancer Institute of Bethesda evaluated the activity against lymphocytic leukemia P 388 on some of the numerous compounds now described. Only the N-chloroacetyliminoacenaphthenequinoxaline exhibited, at the dose of 50 mg/Kg i.p., 35% increase of the average survival time of treated mice. All the remaining compounds were inactive.

Preparation and pharmacological activity of some 1-lupinylbenzimidazoles and 1-lupinylbenzotriazoles.

Twelve new 1-lupinyl-benzimidazole and 1-lupinyl-benzotriazole derivatives were prepared and, together with some previously described analogues, were tested for analgesic (hot plate test), antiinflammatory (against carrageenan edema), diuretic and antihypertensive (in spontaneously hypertensive rats) activities. Several compounds exhibited a good degree of activity in one or in more than one areas.

[Preparation and pharmacologic activity of amido- derivatives of 3-methyl-3,4-dihydro benzo- and pyrido-1,2,4-triazin-3-acetic acids]. / Preparazione e attività farmacologica di ammidoderivati 3-metil-3,4-diidro benzo e pirido-1,2,4-triazin-3-acetici.

Thirteen amidoderivatives of 3-methyl-3,4-dihydro-6-R-benzo-1,2,4-triazin-3-yl-acetic acids and of 3-methyl-3,4-dihydro-pyrido [3,2-e]/[3,4-e]-1,2,4-triazin- 3-yl-acetic acids were prepared and submitted to a wide pharmacological screening. The dihydrobenzotriazine and dihydropyridotriazine moieties were endowed with a wide pharmacogenic capacity; in fact, several compounds exhibited high antiinflammatory [(I c), (I d), (II d), (V f), (VI f)], diuretic [(I f), (I g), (I h)] and antihypertensive activities [(I d), (III d)], as well as minor effects on the C.N.S.

[Preparation and pharmacologic activity of N-oxides of 4'-(benzotriazol-2-yl-phenylalkanoic and -phenoxyalkanoic acids]. / Preparazione e attività farmacologica di n-ossidi di acidi 4'-(benzotriazol-2-il)-fenilalcanoici e-fenossialcanoici.

A number of N-oxides of 4'-(benzotriazol-2-yl)-phenylalkanoic and -phenoxyalkanoic acids bearing various substituents on position 6 of benzotriazole together with 4'-(benzotriazol-2-yl) phenylacetic acid were prepared and subjected to a wide pharmacological screening. Several compounds exhibited significant antiinflammatory and diuretic activities, while one was endowed with antihypertensive activity.

[1,4-Disubstituted 1,3-dihydro-2H-1,5-benzo- and chlorobenzodiazepin-2-ones with activity on the central nervous system]. / 1,3-diidro-2H-1,5-benzo- e -clorobenzodiazepin-2-oni-1,4-disostituiti ad attività sul S.N.C.

In pursuing the study on pyridodiazepinone derivatives, in order to verify the variation of biological activity induced by replacement of the heteroaromatic with an aromatic nucleus and by the introduction of chlorine on the benzene ring, a series of 1-[(dialkylamino)alkyl]-4-phenyl-1,3-dihydro-2H-1,4-benzodiazepin- 2-ones and of 7-chloro-analogues were prepared. Some benzodiazepinones and their 7-chloro-analagous were subjected to pharmacological experimentation in order to evaluate and compare their effect upon mice with regard to exploratory activity, motor coordination and spontaneous motility. In addition their anti-strychnine, anti-cardiazole, anti-amphetamine and anti-reserpine activities were also evaluated.

[Pyrido[2,3-b][1,4]diazepinones with CNS activity]. / Pirido[2,3-b][1,4]diazepinoni ad attività sul S.N.C.

In the interests of developing our research on compounds with a pyrazinone nucleus, cyclohomologues, characterised by the presence of one diazepinone nucleus, were prepared. The 5-[(dialkylamino)alkyl]-3,5-dihydro-2-methyl/phenyl-4H-pyrido[2,3- b][1,4]diazepin-4-ones obtained by means of condensation of the 2-(dialkylamino)alkylamino-3-aminopyridines with ethyl acetyl- or benzoyl- acetate, were subjected to pharmacological experimentation in order to evaluate their effect upon mice with regard to exploratory activity, motor coordination, and spontaneous activity. In addition their analgesic activity was evaluated and also their anti-strychnine, anti-cardiazole, anti-amphetamine and anti-reserpine activities.

[Alkylation of 6-benzyl-5H-dibenzo(d,f)-(1,3)diazepine]. / Andamento dell'alchilazione della 6-benzil-5H-dibenzo(d,f)-(1,3)diazepina.

The alkylation of 6-benzyl-5H-dibenzo(d,f)-(1,3)diazepine (I) with propyl iodide and dimethylaminopropyl chloride in dimethylformamide solution and in the presence of sodium amide was investigated. In both instances the alkylation affected the methylene of benzyl group instead of the cyclic imino group, however the dimethylaminopropyl derivative does not stand the working up conditions, giving place to 2-amino-2'(alpha-phenyl-delta-dimethylamino)valerylamino-biphenyl (III).

[Preparation of 3,3-disubstituted-3,4-dihydro-1,2,4-benzotriazines]. / Preparazione di 3,4-diidro-1,2,4-benzotriazine-3,3-disostituite.

A compound formerly obtained through the reduction of cyclohexanone o-nitrophenylhydrazone has been defined as cyclohexane-3-spiro-3,4-dihydro-1,2,4-benzotriazine, and its formation has been interpreted via air oxidation of a cyclic form of o-aminophenylhydrazone formed first. The extension of such a reaction to several o-nitrophenylhydrazones of aliphatic, alicyclic and arylaliphatic ketones has been investigated. Formation of 3,4-dihydro-1,2,4-benzotriazines disubstituted in position 3 happens as a general rule; yields are good so long as bulky groups or aromatic nuclei are not close to the hydrazone double bond, hindering the amino group addition either sterically or by charge dispersion. Pharmacological screening has not shown any unusual activity for these new compounds; it is suggested that the formation of dihydrobenzotriazine derivatives be used to latentiate biologically active ketones.

[Quinolozidinylalkylamines with antihypertensive activity]. / Chinolizidinilalchilammine ad azione antiipertensiva.

Since lupinylamine [(I); R = H] exhibits hypotensive activity, mainly due to ganglionic blocking properties, and it is known that a high degree of steric hindrance around the basic function of other ganglioplegic amines is of paramount importance for optimal activity, several guinolizidine derivatives were prepared. They differ in the length of the alkyl chain connected to the ring and in the position of the amino group along the chain. Some N-substituted derivatives of 2-quinolizidin-1'alpha-yl-ethylamine (II) together with O-lupinylhydroxylamine and 2-quinolizidin-1'beta-yl-ethylamine, respectively isosteric and epimeric to it, were also prepared. When administered orally to spontaneously hypertensive rats, the amines (II), (III) and (XI) produced high and long-lasting antihypertensive activity, while the remaining compounds so far tested were inactive or had only modest effect on blood pressure. Compared with alpha-methyl-DOPA, amine (II) appears to be approximately two to three times as potent. The antihypertensive activity of (II) appears to be linked to glanglionic blocking properties, since this amine proved 1,2 times as potent as mecamylamine in the inhibition of cat nictitating membrane response to stimulation of the preganglionic sympathetic nerve.