Indenopyridazinone derivatives as potential antisecretory and antiulcer agents.

A series of substituted indenopyridazinones (4b-h) has been synthesized and tested for their antisecretory and antiulcer activity, in comparison with ranitidine, as reference drug. While the monomethoxy (4b-d), as well as the benzyloxy (4f) and the 6,9-dimethoxy (4g) derivatives were found to be devoid of overt antisecretory properties, the 9-methoxy (4e) was weakly active. The most interesting compound of this class was the 7,8-dimethoxy substituted (4h), which at an oral dose of 30 mg/kg still retains a significant activity. The dihydroderivatives of 4g,h (compounds 1g,h) were more active (1g) or comparable (1h) to the parent compounds, thus proving that the 4, 4a-double bond, which was an essential requirement in the analogues 2 and 3, is not necessary in this new series. The disubstituted derivatives (1g,h; 4g,h) were also tested as antiulcer agents, in two different models. All compounds were able to prevent haemorragic lesions induced in rats by 90% ethanol in a dose dependent manner. In the indomethacin model they still showed a significant activity, though lower than in the previous test. Attempts have been made to elucidate their mechanism of action.

Synthesis and bone resorption effect of alkoxy-substituted xanthones.

A topological modification of ipriflavone 1, a recent antiosteoporotic drug, is described. The flavone moiety of 1 has been replaced by a xanthone one. Among the new derivatives, the 3,6-diisopropoxyxanthone (2a) has shown significant bone resorption inhibition in in vitro and in vivo tests.

Effects of 3'-hydroxyfarrerol (IdB 1031), a novel flavonoid agent, on phagocyte products.

The novel flavonoid compound 3'-hydroxyfarrerol (IdB 1031) was tested in a number of in vitro experiments in order to ascertain its effects on some functions and products of human phagocytes. We found that IdB 1031 did not depress neutrophil phagocytosis and chemotaxis, whereas at a concentration of 10(-4) M it significantly (p < 0.05) reduced the fMLP-triggered neutrophil production of superoxide anion. At the same concentration, the compound decreased the release of neutrophil elastase and myeloperoxidase from neutrophils (p < 0.05). We also found evidence that IdB 1031 is a non competitive, reversible inhibitor of human neutrophil elastase (Ki 200 microns). Finally, IdB 1031 at the concentration of 10(-5) M significantly reduced the release of tumor necrosis factor-alpha and interleukin-8 from monocytes (p < 0.05). We conclude that, in spite of the moderate activity displayed by IdB 1031, these findings add to our current knowledge on the spectrum of the antiinflammatory activities of flavonoids.

Scavenging effect of silipide, a new silybin-phospholipid complex, on ethanol-derived free radicals.

Ethanol metabolism by cytochrome P4502E1 (CYP2E1) produces free radical intermediates, identified as hydroxyethyl radicals. We have observed that in vitro addition or in vivo pretreatment of rats with Silipide, a new 1:1 complex of silybin with phosphatidyl-choline, is able to decrease the spin trapping of hydroxyethyl radicals in microsomes from chronic alcohol-fed rats. This effect is not due to an interference with the metabolism of ethanol by CYP2E1, but is rather related to the capacity of the silybin molecule to scavenge hydroxyethyl radicals. However, such an effect is lost when pure silybin in amounts comparable to those present in Silipide is administered instead, due to the low bioavailability of uncomplexed flavonoid. Further experiments in vivo have shown that Silipide administration also decreases hydroxyethyl radical signals detectable in the bile of rats acutely treated with ethanol. The ability of Silipide to scavenge ethanol-derived radicals along with its antioxidant activity suggests that this drug might be potentially useful in counteracting free radical-mediated injuries involved in the development of liver damage caused by alcohol abuse.

Effects of the natural flavonoid delphinidin on diabetic microangiopathy.

The purpose of the present study was to investigate the effects of the flavonoid delphinidin chloride (CAS 528-53-0, IdB 1056) on diabetic microangiopathy. Hamsters were injected with alloxan and cheek pouch microcirculation was observed by a fluorescent microscopy technique 90 days from alloxan. The increase in permeability, the number of adhering leukocytes to venular vessel wall and vasodilatory responses to acetylcholine (Ach) and sodium nitroprusside (SNP) were measured. In diabetic group microvascular permeability and the number of sticking leukocytes to the venular endothelium were increased. Vasoconstriction by Ach was observed while the vasodilation by SNP was significantly attenuated in diabetic animals. These results are consistent for a decreased relaxation and suggest also an impairment in the smooth muscle cell function in diabetic arterioles. IdB 1056 exhibited an inhibitory effect on increased microvascular permeability and on leukocytes adhering to the venular vessels. Indeed, the treatment with IdB 1056 in diabetic hamsters pretreated or not with indometacin, a cyclooxygenase inhibitor, restored the relaxant responses to Ach and SNP. In conclusion, the effects of IdB 1056 observed in vivo at the microcirculatory level prevent the injury to endothelial cell function associated with diabetes and/or oxidative stress.

Effect of Vaccinium myrtillus anthocyanosides on ischaemia reperfusion injury in hamster cheek pouch microcirculation.

The effects of Vaccinium myrtillus anthocyanosides (VMA) on ischaemia reperfusion injury were investigated in the hamster cheek pouch microcirculation. Ischaemia was induced by clamping the cheek pouch for 30 min followed by 30 min of reperfusion. The microvasculature was visualized by a fluorescence technique. VMA [10 mg (100 g body weight)-1] were orally administered for 2 and 4 weeks. The number of adhering leukocytes to venular vessel walls, the perfused capillary length, the increase in permeability, the arteriolar diameter changes were determined. Ischaemia and reperfusion were associated with increased number of leukocytes sticking to venules, decreased number of perfused capillaries, and increased permeability. VMA decreased the number of leukocytes sticking to the venular wall and preserved the capillary perfusion; the increase in permeability was significantly reduced after reperfusion. VMA saved the arteriolar tone and induced the appearance of rhythmic diameter changes of arterioles. These results demonstrate the ability of Vaccinium myrtillus anthocyanosides to reduce microvascular impairments due to ischaemia reperfusion injury, with preservation of endothelium, attenuation of leukocyte adhesion and improvement of capillary perfusion.

Effect of 3'-hydroxyfarrerol on airway hyperreactivity induced by acute cigarette smoke exposure in guinea pigs.

The (+/-)-3'-hydroxyfarrerol (IdB 1031) is a new drug endowed with an interesting mucokinetic activity. In this study the effectiveness of IdB 1031 has been verified in a model of airway hyperreactivity and lung inflammation induced in anaesthetized guinea pig by active cigarette smoke exposure. IdB 1031 (500 mg/kg per os) completely inhibited the capacity of cigarette smoke to induce airway hyperreactivity. IdB 1031 also inhibited the recruitment of proinflammatory cells within the airway lumen as showed in bronchoalveolar lavage fluids. In line with these experiments IdB 1031 inhibited 5-lipoxygenase with an IC50 of 7.36 x 10(-6) M in human leukocytes challenged by A-23187 (2 microM). A significant reduction of the above parameters was observed also in animals exposed to smoke after repeated treatment with IdB 1031 at 200 mg/kg per os for 15 days. These results show that IdB 1031 is a promising drug with a favourable spectrum of activities on the respiratory tract.

Synthesis and diuretic activity of (E)-2-methyl-6-phenylimidazo[2,1-b]-1,3,4-thiadiazole-5-carboxald ehyde dimethylaminoacetohydrazone.

(E)-2-Methyl-6-phenylimidazo[2,1-b]-1,3,4-thiadiazole-5-carboxalde hyde dimethylaminoacetohydrazone was synthesized and its configuration determined. The diuretic activity of this compound, evaluated in rats in a dosage range of 2.5, 10 and 40 mg/kg, was higher than that of the reference compounds hydrochlorothiazide and furosemide.

Synthesis and antiulcer activity of uvaol hemiphthalate derivatives.

Disodium salts of the dihemiphthalates of urs-12-ene-3 beta, 28-diol 3b and of ursa-9(11), 12-diene-3 beta,28-diol 4b were synthesized from uvaol and examined for their gastroprotective activity in rats. The effects showed by 3b and 4b, given p.o. in two antiulcer tests (ethanol induced gastric lesions and diclofenac induced gastric ulcers), were 5-25 times better than those of carbenoxolone. When given p.o. in the rat once a day for 5 days at a gastroprotective dose, 3b and 4b did not induce any change in urine excretion, whereas carbenoxolone significantly reduced urine volume, Na+ excretion and Na+/K+ ratio. In conclusion, 3b and 4b are effective antiulcer agents, devoid of mineral-corticoid activity and therefore provided with a good therapeutic index.

Comparative pharmacokinetics of silipide and silymarin in rats.

The plasma level profile and the biliary excretion of silybin, the main flavanolignan component of silymarin, were evaluated in rats after single equimolar oral doses (200 mg/kg, expressed as silybin equivalents) of the silybin-phosphatidylcholine complex silipide (laboratory code IdB 1016) and of silymarin. Silybin was assayed by using a specific HPLC method which allowed also the determination of other flavanolignans present in the biological fluids after administration of silymarin (i.e. silydianin, silycristin and isosilybin). After oral silipide, silybin reached peak plasma levels within 2 h, with a Cmax of 9.0 +/- 3.0 micrograms/ml for unconjugated drug and 93.4 +/- 16.7 micrograms/ml for total (free + unconjugated drug). Maximum total biliary concentrations of silybin (2989 +/- 568 micrograms/ml) were observed within 2 h and the biliary recovery after 24 h accounted for about 13% of the administered amount. After administration of silymarin, unconjugated and total plasma silybin levels as well as biliary excretion were several-fold lower than those observed after treatment with silipide. Silybin recovered over a 24 h period after silymarin intake accounted for about 2% of the administered dose. Plasma and bile obtained after administration of silymarin contained also silydianin, silycristin and, to a greater extent, isosilybin. The concentrations of the latter compound in plasma and in bile were higher than those of silybin itself. The relative bioavailability of silipide (calculated in the target organ as the ratio between AUCs of cumulative biliary excretion curves) was 10-fold higher than that of silymarin.

Protective activity of silipide on liver damage in rodents.

The activity of silipide, a silybin-phosphatidylcholine complex (IdB 1016), was tested in different models of liver damage in rodents. After oral administration, silipide exhibited a significant and dose-related protective effect against the hepatotoxicity induced by CCl4, praseodymium, ethanol and galactosamine. The ED50 values for inhibition of the rise in ASAT and ALAT levels caused by CCl4 and praseodymium and for antagonism of the increase in liver triglycerides caused by ethanol ranged from 93 to 156 mg/kg (as silybin). At a dose of 400 mg/kg (as silybin), silipide was also active in protecting against paracetamol-induced hepatotoxicity. Silybin and phosphatidylcholine at doses equivalent to those contained in the active doses of silipide failed to show any significant protective activity in these models. The liver protective effect of silipide is probably related to its antioxidant activities and to a stimulating effect on the hepatic synthesis of RNA and proteins.

Synthesis and antihypertensive activity of imidazo[2,1-b]-thiazoles bearing a 2,6-dichlorophenyl group.

A number of imidazo[2,1-b]thiazoles bearing a 2,6-dichlorophenyl group as hydrazone or as amide were prepared and tested in rats as antihypertensive agents. Only compounds bearing a chlorine at position 6 were active.

Synthesis and pharmacological activity of imidazo [2,1-b] thiazole nitriles, amides and p-sulfamidophenylhydrazones.

The synthesis of three series of new imidazo [2,1-b] thiazoles (nitriles 1-7, amides 8-14 and p-sulfamidophenylhydrazones 15-24) is reported. Among the compounds tested, only 12 showed a borderline diuretic activity. Compounds 15-24, possible prodrugs of sulfanilamide, were devoid of antibacterial activity.

Vaccinium myrtillus anthocyanosides pharmacokinetics in rats.

The pharmacokinetics of Vaccinium myrtillus anthocyanosides (VMA) have been investigated in male rats. After intravenous administration anthocyanosides undergo a rapid body distribution and their disappearance from the blood is suitably fitted by a three-compartment pharmacokinetic model. The elimination occurs mostly through urine and bile. After a single oral administration the plasma concentrations of anthocyanosides reach peak level after 15 min and then rapidly decline within 2 h. The extent of cumulative urinary and biliary elimination together with the gastrointestinal recovery demonstrates an absorption of about 5%. No hepatic first-pass effect has been observed. Despite of the modest gastrointestinal absorption and the low absolute bioavailability (1.2% of the administered dose), the plasmatic peak levels (2-3 micrograms/ml) measured after the oral treatment are in the range of biological activity reported for these substances.

Synthesis and antiinflammatory activity of indole carboxylic acids and esters.

1-Phenylalkylindole-3-carboxylic acids 1-4, indole-1-acetic acids/esters 5-10 and the hydrazones 11-15 were prepared and submitted to the rat paw edema test using carrageenin. In the first two groups of compounds, the 2-chloro indoles were more active than the corresponding indole derivatives. In the third group the activity seemed to be determined largely by the substituent at the 1-position.

Effect of a natural flavonoid on gastric mucosal barrier.

The effects of 3,5,7-trihydroxy-2-(3,4-dihydroxyphenyl)-1-benzopyrylium chloride (IdB 1027) on the rat gastric mucosa were evaluated. IdB 1027 administered intragastrically at doses ranging from 100 to 400 mg/kg inhibited the fall in transmucosal potential difference and the increase in H+ back-diffusion induced by acetylsalicylic acid. Moreover, IdB 1027 at doses of 50 and 200 mg/kg by intragastric route increased the gastric bicarbonate secretion. These results suggest that the gastroprotective activity of IdB 1027 is mediated by an increase in the efficiency of gastric mucosal barrier.

General pharmacology of the new antitussive levodropropizine.

The general pharmacological profile of levodropropizine (S(-)3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol, DF 526), a new antitussive drug, was compared with that of dropropizine racemate. Levodropropizine had weaker central sedative effects than the racemate and it did not induce physical dependence in rats. When given intravenously or intraperitoneally, levodropropizine did not exert any significant effects on the cardiovascular and respiratory systems. Receptor binding data excluded interaction with beta-adrenergic, muscarinic and opiate receptors. On the contrary, levodropropizine has affinity for H1-histaminic and alpha-adrenergic receptors. The affinity was also confirmed with isolated organ preparations. On the basis of this study, levodropropizine appears to have a better tolerability index than the racemate.

Antitussive properties of levodropropizine.

The antitussive activity of levodropropizine (S(-)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol, DF 526), was evaluated in anaesthetized guinea-pigs and rabbits and in unanaesthetized guinea-pigs. Levodropropizine was shown to have good antitussive activity. Intravenously, it was 1/10 to 1/20 as active as codeine and comparable to dropropizine, from which it is derived, on mechanically and electrically induced coughing in rabbits and guinea-pigs. After oral administration to the guinea-pig the antitussive activity of levodropropizine was comparable with those of both dropropizine and codeine against coughing induced by irritant aerosols.

Role of endogenous prostaglandins in protection of rat gastric mucosa by tripotassium dicitrate bismuthate.

Gross and microscopic examination of rat gastric mucosa demonstrated that intragastric administration to rats of tripotassium dicitrate bismuthate (TDB), a colloidal bismuth compound, protects against gastric lesions induced by 85% ethanol. Indomethacin, a prostaglandin synthetase inhibitor, significantly blocked the gastric mucosal protective effect of TDB. The release of gastric mucosal prostaglandins was greater in animals treated with TDB than in control animals, both time- and dose-dependently. These results seem to indicate involvement of prostaglandins in the action of TDB.

Effectiveness and tolerability of ketoprofen lysine, once a day, in patients with rheumatic disorders.

Ketoprofen lysine (KL) at a dose of 160 mg b.i.d. has been shown to have favourable anti-inflammatory and analgesic properties in a large number of patients. In the present paper investigators describe their experience with a new therapeutic schedule of KL, 320 mg given once a day to patients with various rheumatic disorders. With this new schedule there was satisfactory clinical improvement of most of the clinical parameters and good tolerability, with a low incidence of gastric troubles. The favourable clinical effects and the patients' good compliance with once-a-day KL make it a useful drug for successful treatment of rheumatic disorders.