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This study was supported by a grant from AIRC (Italian Association for Cancer Research) (to C.F.) and by the European GENAGE Project, by MURST (Ministry for University and Technological Research) Cofinanziamento 1998, and by POP (Regional Operative Project) 94/99 from regione Calabria, Italy.

The diuretic effect of dopamine (DA) was compared with that of other DA receptor stimulants in rats. While apomorphine (APO) and (±)N-n-propyl-norapomorphine (NPA) failed to increase urine excretion, (3, 4-dihydroxyphenylamino) -2-imidazoline (DPI), a supposed st i mulant of DA inhibitory receptors, exerted a far greater diuretic e f fect than DA itself. The diuretic effect of DA and that of DPI were antagonized by a-adrenergic receptor antagonists such as phentolamine and yohimbine and by bulbocapnine. In contrast, DA receptor blockers such as haloperidol, pimozide, sulpiride and ergometrine were totally ineffective. It is concluded that the diuretic effect of DA and DPI are mediated by stimulation of a-adrenergic receptors.

A series of 4-propylderivatives of 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c] [1,2,4]benzothiadizine-5,5-dioxide substituted or unsubstituted in the benzene ring was synthesized. Derivatives of these compounds together with those of the corresponding 4-methyl and 4-ethyl derivatives prepared previously were tested for cardiovascular effects in the anesthesized rat. All the compounds studied showed hypotensive activity which was particularly intense for compounds (X), (XIX), (XXII), (XXV), and produced an increase in differential pressure marked for (XXV) and (XXVIII) which was often accompanied by pronounced bradycardia (XVII), (XVIII) and (XIX). The results prove that derivatives of 2,3,3a,4-tetrahydro-1H-pyrrolo-[2,1-c][1,2,4]benzothiadiazine-5,5-dioxide have hypotensive and bradycardizing activity. Structure-activity relationships are discussed.

The in vitro antibacterial activity of quinolone compounds was assessed on strains of Pseudomonas aeruginosa isolated from clinical infections. The bactericidal effect of quinolones was high and their respective antibacterial properties with adriamycin remained unimpaired on strains both sensitive and resistant to betalactam and aminoglycoside antibiotics. The cytotoxic effect of the combination of adriamycin and quinolones was determined in cultured P388 leukemia cells: no interference with the cytotoxic activity of adriamycin was observed.

Analbuminemia or better hypoalbuminemia is a rare disease, first described in 1954 by Bennhold et al. (1), and is characterized by the almost total absence of albumin. This disease is inherited and is probably transmitted by a recessive autosomal gene (2,3). The defect is not complete. The albumin traces present in circulation on Immunoelectrophoresis show the same mobility as normal albumin (4) and no antigenic differences between normal albumin and that in subjects with analbuminemia have been detected (5). In this desease an increased catabolism or loss of this protein may also be ruled out: perfusion of albumin labelled with radioactive iodine has in fact shown a remarkable increase in the half-life of albumin (6,7).

In recent years the study of plasma lipoproteins has significantly broadened our understanding of lipid metabolism and lipid transport1,2.

Several authors have reported that Gemfibrozil decreases the plasma concentration of triglycerides (TG) and (to a lesser extent) cholesterol (CT) and raises HDL in hyperlipoproteinemias (Olsson et al. 1976; Manninen 1983; Pickering 1983; Samuel 1984).

(+/-)N-n-Propyl-norapomorphine (NPA), a potent agonist of brain dopamine receptors, influences aggressive behavior, but the type of influence depends on the experimental conditions. In rats, NPA increases aggression elicited by electrical foot shock, but decreases predatory aggression against turtles as well as isolation-induced aggression in male mice. NPA proves more potent than apomorphine in both the foot shock and predatory test. A per se ineffective dose of haloperidol (0.05 mg/kg-1 IP) antagonizes NPA in the rat foot shock test as well as in the isolated male mouse test. The relevance of stereotyped movements for NPA influence on aggressive behavior is briefly discussed.

A series of 4-dimethylaminoethyl and 4-diethylaminoethyl derivatives of 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c] [1,2,4] benzothiadiazine-5,5-dioxide substituted or unsubstituted in the benzene ring was prepared and subjected to preliminary investigation using the cardiovascular system of the anesthesized rat. Introduction of a basic group in the alkyl chain on N4 gives compounds with good hypotensive activity, this being most pronounced for (III, IV a and XIV) and an increase in differential pressure, marked for (V a, X, XII). These effects are sometimes accompanied by some bradycardizing activity, most marked for (V a) and (X). The results therefore confirm that derivatives of tetrahydropyrrolbenzothiazine have cardiovascular activity. Structure-activity relationships are discussed.

Apolipoprotein C-II (apoC-II), a 79 amino acid protein, is a cofactor for lipoprotein lipase, the enzyme which catalyzes the lipolysis of triglycerides on plasma chylomicrons and VLDL. Patients with apoC-II deficiency have marked elevations in plasma triglycerides, chylomicrons, VLDL, and a type I hyperlipoproteinemia. In order to evaluate the molecular defect in apoC-II deficiency, genomic DNA was analyzed using Southern Blot from 2 independent apoC-II deficient patients and compared to normal controls. Restriction digests of genomic DNA were performed with five different enzymes and the restriction fragments analyzed utilizing a 354 base pair nick-translated apoC-II probe for hybridization following Southern blotting. The restriction fragments varied from 0.8 to 21 Kb, and the pattern with normal DNA was identical to that of the two apoC-II deficient patients. The present study reveals that the apoC-II gene is present in patients with apoC-II deficiency. In addition, no insertional or deletional polymorphism was detected in the apoC-II gene of apoC-II deficient patients.

A series of quaternary ammonium salts of 3-alkylaminoderivatives of 1,2,4-benzothiadiazine-1,1-dioxide were prepared and tested for cardiovascular activity. Almost all the substances tested proved to have some measure of depressant activity on arterial pressure and the most interesting compounds in this respect were (XII), (XIII), (XV) and (XIX) for which hypotensive values between 60 and 70% with respect to the base level were recorded. Compound (XV) also caused increase in the differential pressure and decrease of cardiac frequency. The later however was increased by some other compounds [(XII), (XVIII)]. The structure-activity relationships are discussed taking into account also the activity of the parent tertiary amines.

The effect of different lipoproteins (lipoprotein-X and lipoprotein-B; LP-X and LP-B) on hepatic cholesterol synthesis was studied in vivo in rats. Lipoproteins were continuously infused into rats for 16 hours so that 24 mg cholesterol/100 g body weight were applied. Serum cholesterol level was nearly doubled after the infusion period. Lipoprotein electrophoresis revealed the predominance of the infused lipoprotein in the serum. LP-B infusion caused a reduction of cholesterol synthesis (42% of control values) and reduced the increased cholesterol synthesis of bile fistula rats to values below normal. LP-X did not reduce hepatic cholesterol synthesis significantly nor did it normalize the enhanced synthesis following biliary diversion. However, hepatic free cholesterol concentration increased after LP-X infusion. The effect of LP-X on liver cholesterol synthesis is similar to that of lecithin: cholesterol dispersions. The failure of LP-X to exert a feedback inhibition on cholesterol synthesis may therefore contribute to the mechanism of hypercholesterolemia in obstructive iaundice.

A series of (3-oxodihydro-1,2,4-benzothiadiazin-1,1-dioxide-3-yl)acetic acids [compounds of type (A)] and (1,2,4-benzothiadiazin-1,1-dioxide-3-yl)oxyacetic acids [compounds of type (B)] were synthesised and tested for antiinflammatory activity. Preliminary tests showed certain compounds to have a significant level of antiinflammatory activity in rat paw edema induced by carrageenan. It was found that the antiinflammatory activity of this series of compounds depends on the nature, number and position of the substituents on the benzene ring.

A series of (1,2,4-benzothiadiazin-1,1-dioxide-3-yl)acetic acids was prepared so that antiinflammatory activity could be tested. Some of the compounds synthetized showed marked activity against plantar edema induced by carrageenin and/or dextran. It was found that in this series antiinflammatory activity is related to the nature of the substituents on the benzene ring as well as their number, dihalogen substitution being the most favourable modification and dichlorosubstitution in particular giving the compounds most active against both types of edema.

Publisher Summary This chapter discusses a potent aphrodisiac drug combination which is naloxone and N-n-propyl-norapomorphine (NPA). Studies have shown that low doses of dopamine (DA) receptor stimulants, such as apomorphine, N-n-propyl-norapomorphine, amphetamine, L-Dopa, and amantadine, injected to adult male rats produce repeated episodes of penile erection (PE). NPA is by far the most potent compound to induce such a response, the minimum active dose being in the order of tenths of micrograms per kilogram. Moreover, apomorphine and NPA produce a bell-shaped dose-response curve, in that the effect is proportional to the dose up to the maximum active dose, then higher doses are progressively less effective until the stimulant effect ceases, and finally, even the normal occurrence of PE is suppressed. The sexual stimulant effect of apomorphine and NPA seems to be because of the stimulation of central DA receptors. They are prevented by the centrally acting neuroleptics but not by domperidone which fails to cross the blood–brain barrier. Experimental evidence suggests that endogenous peptides may play an antagonistic role against DA in the control of sexual behavior.

Imidazole (IMID), (9.37-75 mg/Kg) and yohimbine (YOH), (0.5-2.5 mg/Kg), strongly potentiated lisuride-induced mounting, scored as a percentage of animals affected and mean number of mounts per animal, while clonidine (150 micrograms/Kg) significantly antagonized the phenomenon. A high (2 mg/Kg) but not a low (50 micrograms/Kg) dose of B-HT 920 and DPI (100 and 500 micrograms/Kg) also inhibited lisuride-induce mounting. While, at present, IMID specific activity on monaminergic system is not yet conclusive, it is demonstrated that, at the doses used, YOH and clonidine are selective alpha 2 antagonist and agonist, respectively; B-HT 920 preferentially stimulates D2 receptors at 50 micrograms/Kg and alpha 2 receptors at 2 mg/Kg; finally DPI, proposed as DAI agonist, also activates alpha 2 receptors. Therefore, in view of the dose-related receptorial selectivity of action of the drugs tested, neurochemical mechanisms on specific receptors involved for modulation of this form of sexual behaviour are briefly discussed.

We have used a cDNA clone for human apolipoprotein CII (apo CII) to study the apo CII genes in two independent individuals with familial apo CII deficiency. With all the restriction enzymes so far used, gene fragments hybridising with apo CII cDNA are observed that are indistinguishable from normal samples. This demonstrates that in neither of these individuals is the defect due to a major deletion of DNA in or around the apo CII gene. We have used a common polymorphism of the apo CII gene detected with the enzyme TaqI to follow the inheritance of the gene in the families of these apo CII deficient individuals. The pattern of inheritance that we observe is consistent with the defect causing apo CII deficiency being in, or closely linked to the apo CII structural gene.

We have evaluated the relationships between adipose tissue lipoprotein-lipase activity (AT-LPL) or post-heparin plasma lipolytic activity (PHLA) and the composition of circulating lipoproteins in 7 patients with multiple symmetric lipomatosis (MSL). In addition we have investigated the behaviour of serum triglycerides after an oral fat load (1 g triglycerides/kg body weight) in 5 MSL patients and in 5 age and sex matched controls. We found significantly higher values of HDL, HDL2 and HDL3 cholesterol in MSL patients than in controls. Moreover, HDL2/HDL3 cholesterol ratio was higher in MSL patients than in controls, which indicate a predominant increase in HDL2 subfraction. The mean values of AT-LPL in lipomatous tissue was significantly higher than in control tissue. A positive statistically significant correlation was found between AT-LPL activity and HDL, HDL2 and HDL3 cholesterol values. After the fat load the maximal increments of serum triglyceride levels and the triglyceride areas over 8 and 12 h are lower in MSL patients than in controls; there was an inverse, statistically significant correlation between the total PHLA or the extrahepatic PHLA values and the triglyceride areas after lipid load. We conclude that MSL represents a useful naturally occurring model for the study of the role of AT-LPL in the metabolism of triglyceride-rich lipoproteins and in the clearance of lipoproteins in the post-prandial phase.

Familial chylomicronemia (type I hyperlipoproteinemia) is a rare genetic disease due to the absence of the lipoprotein lipase activity. This genetic error involves either the extrahepatic lipoprotein lipase (lipoprotein lipase deficiency) or its obligatory co-factor, i.e. the apoprotein C-II (apo C-II deficiency). The clinical features of this disease, wich is usually diagnosed in infancy or childood, are hepatosplenomegaly, recurrent abdominal pain, pancreatitis, eruptive xanthomata and lipemia retinalis.

Die Regulation der Cholesterinsynthese auf der Stufe der HMG-CoA-Reduktase geschieht durch zahlreiche Faktoren, deren wichtigster wohl die „feed-back“-Regulation durch Cholesterin selbst ist. Dieser Effekt kann durch exogenes, uber den Darm aufgenommenes Cholesterin wie auch durch das endogen synthetisierte Cholesterin vermittelt werden [1]. In Untersuchungen an Zellkulturen von menschlichen Fibroblasten und Leberzellen konnte gezeigt werden, das es fur die Vermittlung des „feed-back“ entscheidend ist, durch welches Lipoprotein das gebundene Cholesterin an die Zellen gelangt [2, 3]. So konnte bei den Untersuchungen mit Fibroblasten eine deutliche Reduktion der Aktivitat der HMG-CoA-Reduktase durch die Lipoproteine LDL und VLDL erreicht werden [2], wahrend die Leber in vivo starker durch intestinal gebildete Lipoproteine gehemmt wurde [1].

In rats the intraperitoneal injection of imidazole (IMID) induced shaking behaviour, the effect appearing to be age- and sex-linked; younger animals responded less vigorously than older animals, while females always exhibited a significantly weaker response than males of the same age. After ovariectomy, however, the number of shakes of the two sexes was very similar. A number of drugs were examined for their antagonism of this highly reproducible syndrome. IMID-shakes were antagonized by reserpine, clonidine, high doses of B-HT 920, propranolol, haloperidol, morphine and diazepam, were not affected by apomorphine, (+)3-PPP, physostigmine, naloxone or methysergide, and were potentiated by sulpiride and scopolamine. The results are considered in the light of the possible neurochemical mechanisms underlying the IMID-syndrome; the suggested usefulness of this test for the study of human dyskinetic movements is disputed.

Familial chylomicronemia is a rare genetic disorder attributable to the absence of lipoprotein lipase activity or the absence of apo-CII, i.e., the cofactor for the same enzyme. Plasma lipoproteins were analyzed by zonal ultracentrifugation under rate flotation conditions in four patients with lipoprotein lipase deficiency and two patients with apo-CII deficiency. Lipoproteins of density less than 1.006 gm/ml, and particularly lipoproteins with Sf greater than 100, were present in very high concentrations. Low levels of density greater than 1.006 gm/ml lipoproteins were observed. This fraction was composed of some different and discrete lipoprotein populations: intermediate-density lipoproteins (in three of six patients, density = 1.006 to 1.019 gm/ml); low-density lipoprotein LDL2 (in all patients, density = 1.019 to 1.045 gm/ml); low-density lipoprotein LDL3 (in all patients, density = 1.045 to 1.063 gm/ml); high-density lipoprotein HDL2 (in four of six patients); and high-density lipoproteins HDL3 (in all patients). LDL3 was never observed in normal participants by means of zonal ultracentrifugation; this subclass of low-density lipoproteins seems to correspond to LDL particles of very low Sf (2 to 5) previously identified by analytical ultracentrifugation in patients with severe hypertriglyceridemia. LDL3 was isolated by means of zonal ultracentrifugation as a single and discrete peak in all patients. Lipoproteins of density greater than 1.006 gm/ml were rich in triglycerides and poor in cholesterol in comparison with normal lipoproteins. The heterogeneity of low-density lipoproteins (particularly the appearance of LDL3), low levels of total high-density lipoproteins, and lower HDL3 flotation rate than normal are typical aspects of serum lipoproteins in these patients. No significant differences in the lipoprotein profiles of the patients with lipoprotein lipase deficiency in comparison with patients with apo-CII deficiency were found. In both groups of patients, the plasma lipoproteins profile and the altered lipoprotein composition could be related to the impaired catabolism of triglyceride-rich lipoproteins caused by the absence of lipoprotein lipase activity.

Kinetic studies were performed incubating lipoprotein lipase and hepatic triacylglycerol lipase from human postheparin plasma with triacylglycerol-rich lipoproteins from two patients with apolipoprotein C-II deficiency. These lipoproteins differed in their lipid and apolipoprotein composition from normal very-low-density lipoproteins and chylomicrons. The addition of isolated apolipoprotein C-II and normal or apolipoprotein C-II-deficient high-density lipoproteins caused an increase of Vmax and a decrease of the Km for lipoprotein lipase-induced hydrolysis. Hepatic triacylglycerol lipase activity was not influenced by the presence of apolipoprotein C-II in the incubation medium, but was inhibited by increasing amounts of high-density lipoproteins. Binding studies were performed in order to analyze the interactions between lipolytic enzymes, apolipoprotein C-II, and triacylglycerol-rich lipoproteins. Apolipoprotein C-II was, as expected, rapidly taken up by apolipoprotein C-II-deficient very-low-density lipoproteins and chylomicrons when they were incubated with normal high-density lipoproteins or with the purified apolipoprotein. This uptake was inhibited by the addition of increasing amounts of lipoprotein lipase in conditions in which no lipolysis could occur. Binding of lipoprotein lipase to apolipoprotein C-II-deficient very-low-density lipoproteins or chylomicrons was not affected by the addition of apolipoprotein C-II when an excess of triacylglycerol-rich lipoprotein was present. The stability of lipoprotein lipase was also studied. Apolipoprotein C-II and high-density lipoproteins were unable to prolong the half-life of the enzyme activity, while triacylglycerol-rich particles effectively stabilized lipoprotein lipase. We conclude that binding of lipoprotein lipase to the substrate surface is not affected by apolipoprotein C-II. It is more likely that the peptide catalyzes the conversion of lipoprotein lipase from a less to a more active form.

The prevention of Atherosclerosis (ATS) is generally divided into primary and secondary. Primary prevention is the set of interventions carried out on the asymptomatic patient before the appearance of atherosclerotic complications (angina, myocardial infarction, stroke, etc.), whereas by secondary prevention it is usually indicated any intervention after a clinical event has already occurred(1). Thus, pharmacological studies for the prevention of ATS should be divided into primary and secondary, even though this division is not always present in all the epidemiological trials.

Using the agar dilution technique, we examined the in vitro antibacterial activity of 5-fluorouracil and norfloxacin alone and in association against several bacterial strains. When administered in association, the two drugs did not antagonize each other in tests carried out on strains both sensitive and resistant to penicillins, cephalosporins, aminoglycosides, tetracyclines; furthermore their respective antibacterial properties remained largely unimpaired. The cytotoxic activity and the antitumoral effect of a combination of 5-fluorouracil and norfloxacin was determined in cultured tumor cells, and in mice bearing Ehrlich ascites carcinoma. No significant interference with the cytotoxic activity and antitumoral activity of 5-fluorouracil was observed.

A series of dialkylamino, pyrrolidyl and morpholyl-alkyl-derivatives of 3-amino-1,2,4-benzothiadiazine-1,1-dioxide, 7- or 5,7-halogen substituted in the benzenoid moiety, was prepared and their cardiovascular activity studied. Most of the substances in question were capable of inducing a significant decrease in mean arterial blood pressure; some of them tended to increase pulse pressure or to cause bradycardia, an effect which was noted particularly in the case of compound 10 which reduced heart-rate by 85%. The structure/activity relationship of these substances, of the 6- and 6,7-halogen substituted isomers and of their corresponding non-substituted progenitors is examined.