Protective effect of the nitrate ester ITF 296 against methacholine-induced myocardial ischemia in the anesthetized rat.

The activity of ITF 296 against methacholine-induced myocardial ischemia was investigated in anesthetized rats in comparison with the organic nitrates nitroglycerin (NTG) and isosorbide dinitrate (ISDN), the K(+)-channel openers nicorandil and cromakalim, the Ca(2+)-channel blocker amlodipine, and the vasodilator dipyridamole. Given as i.v. boluses, ITF 296 (0.1-100 micrograms/kg) dose-dependently prevented methacholine-induced ST-segment elevation without affecting mean arterial blood pressure or heart rate to a significant extent. In this situation, ITF 296 was 10- to 30-fold more potent than the other coronary vasodilators tested. The protective effect of ITF 296 and ISDN against myocardial ischemia was also observed after oral administration, demonstrating good absorption and a limited first-pass metabolism of the two drugs. The anti-ischemic action of ITF 296 at 1 and 10 micrograms/kg/min was well maintained during 2 h of continuous i.v. infusion, whereas the effect of NTG and ISDN was attenuated or abolished by the end of the infusion. The new nitrate ester ITF 296 has a potent and long-lasting cardioprotective action in the anesthetized rat. The anti-ischemic effect displayed by this compound is probably mediated by an improvement of myocardial blood supply caused by pronounced coronary dilatation, whereas the contribution of systemic vasodilation is not important. Moreover, the maintenance of the anti-ischemic action during continuous i.v. infusion suggests a reduced "tolerance" development for ITF 296 compared with other nitrovasodilators.

Protective effects of ITF 296 in the isolated rabbit heart subjected to global ischemia.

The anti-ischemic action of ITF 296 was evaluated in isovolumic, electrically driven rabbit heart preparations subjected to temporary ischemia and reperfusion. Reduction of perfusion rate from 20 to 0.2 ml/min produced a sharp decrease of peak systolic pressure, left ventricular (LV)-developed pressure, and LV dP/dt, which culminated in complete ventricular arrest within 3-4 min. Thereafter, LV end-diastolic pressure (LVEDP) progressively increased, suggesting a severe ischemic episode. Reperfusion with 20 ml Krebs solution/min after 40 min of low-flow perfusion produced only minimal recovery from the rhythm disturbances associated with cardiac mechanical activity. During reperfusion, loss of myocardial elasticity was associated with a significant increase in coronary vascular resistance, as indicated by the augmentation of coronary perfusion pressure. Injection of ITF 296 (0.3-10 microM) into the perfusion system dose-dependently inhibited the increase in LVEDP that took place during ischemia and progressively improved the recovery of a regular rhythm in the isolated heart. Isosorbide dinitrate (ISDN) at a concentration of 10 microM exerted a protective action on the myocardium similar to that obtained with ITF 296 (3 microM). Treatment with ITF 296 (1 and 10 microM) resulted in a dose-dependent increase in the rate of 6-keto-PGF1 alpha biosynthesis during both the ischemia and the reperfusion period (+157% over basal values). Similar results were obtained when hearts were pretreated with ISDN (10 microM). Infusion of a buffer containing NG-monomethyl-L-arginine (L-NMMA; NO synthase inhibitor at 10 microM) just before reduction of flow, markedly exacerbated the effects of ischemia and reperfusion on the myocardium and increased coronary perfusion pressure. The effects of L-NMMA were clearly antagonized by ITF 296 (10 microM) or L-arginine (100 microM). Mechanical activity and sinus rhythm during reperfusion were rapidly and completely restored, and coronary resistance values were close to the preischemic values. As with ISDN, ITF 296 significantly increased the rate of synthesis of 6-keto-PGF1 alpha both under basal conditions and during reperfusion.

Reversible inhibition of thromboxane A2 production by imidazole 2-hydroxybenzoate (ITF 182) in the arachidonic acid injected rat. A comparison with acetylsalicylic acid and indometacin.

The behavior of imidazole 2-hydroxybenzoate (ITF 182), acetylsalicylic acid (ASA) and indometacin (INN; in some pharmacopoeias called indomethacin) in inhibiting thromboxane A2 (TXA2) and prostaglandin (PGs) production in the blood of the rat intravenously injected with arachidonic acid was studied. ITF 182 caused a selective inhibition of TXA2 production with a time-dependent reversible action. An irreversible inhibition of PGs production was shown by ASA whereas a reversible inhibition could be observed with indometacin. The PGs involved in the physiological processes, may be spared after ITF 182 administration contrary to what occurs after ASA or indometacin administration.

Pharmacological and toxicological studies on an iron succinyl-protein complex (ITF282) for oral treatment of iron deficiency anemia.

ITF282, a soluble iron succinyl-protein complex, orally administered to the rat elevates the concentration of iron in the serum to a greater extent than ferritin. The serum iron increase induced by ITF282 is delayed when compared with ferrous sulphate. The ITF282 absorption process, like that of ferritin, proceeds along the physiological pathways without bypassing the transfer system of the intestinal mucosal cells since no further increase of serum metal is observed when giving high doses of ITF282 to the rat pretreated with a saturating dose of ferrous sulphate. Hypochromic and microcytic anemia induced in growing rats by bleeding and feeding a low iron diet is sensitive to both prophylactic and therapeutic oral treatment with ITF282. Iron deficiency anemia and cardiomegaly induced in suckling rats by feeding the pregnant and lactating dams with the low iron diet are reversed by oral treatment of the dams with ITF282. Comparative investigations of the therapeutic efficacy of ITF282 and ferritin made on uncomplicated iron deficiency anemia show that the drugs, p.o. administered during 4 weeks, are equally effective. Preliminary toxicological data in the rat, after single and chronic administrations, show that ITF282 is well tolerated. These findings prove that ITF282 gives an adequate supply of iron from which to make hemoglobin.

Penetration of imidazole 2-hydroxybenzoate (ITF 182) into experimentally inflamed pleural and knee joint exudates.

The penetration of the two components of imidazole 2-hydroxybenzoate (ITF 182), imidazole and salicylate, into inflamed sites induced by intrapleural injection of carrageenin in the rat and by a urate-cotton pellet implantation in the knee joint of the rabbit is studied. The results obtained show that the two components of the salt penetrate rapidly the inflamed sites and display different kinetic profiles: imidazole diffuses throughout inflamed and non-inflamed fluids without any specific localization, salicylate shows preferential localization in inflamed fluids and remains longer than imidazole.

Different sensitivity of basilar and saphenous arteries to thromboxane A2-induced contractions. Effect of imidazole 2-hydroxybenzoate (ITF 182).

Superfused rings of rabbit basilar arteries are more sensitive than those of saphenous arteries to the contractions induced by a prostaglandin endoperoxide analogue (U-46 619) and by a thromboxane A2 (TXA2) generating system. 5-Hydroxytryptamine aggravates the latter. Prostaglandin I2 (PGI2) on the other hand, relaxes only the basilar rings without affecting the saphenous. Imidazole 2-hydroxybenzoate (ITF 182), at doses that do not interfere with platelet cyclooxygenase, reduces the contractions induced by the TXA2 generating system on both arteries because it reduces the platelet TXA2 synthetase enzyme. TXA2 is involved in the aetiology of strokes and cerebral vasospasms while PGI2 plays a physiological role in the maintenance of cerebral arterial tone. The high sensitivity of cerebral arteries to contractures caused by TXA2 together with the ability of ITF 182 to reduce them by inhibiting TXA2 production and to spare physiological PG production suggest a beneficial effect of the drug in cerebral vasospasms.

[Derivatives of 1,3-bis-(methlendioxyphenoxy)propane with antispastic activity]. / Derivati dell'1,3-bis-(3,4-metilendiossifenossi)propano ad attività antispastica.

A number of amines derived from 1,3-bis(3,4-methylen-dioxyphenoxy)propane have been prepared from 1,3-bis-(3,4-methylendioxy-phenoxy)propan-2-one. The acute toxicity and the activity of these compounds on isolated guinea pig ileum have been studied. The majority of the compounds showed clear antagonist activity towards BaCl2, histamine and acetylcholine contracting responses, generally grater than that of papaverine; on the contrary, their antagonist activity towards 5-HT responses was slightly lower.

[Action on the isolated guinea-pig ileum and toxicity of some derivatives of 1,5-bis-(3,4-methylendioxyphenyl)-n. pentane]. / Attività sull'ileo isolato di cavia e tossicità di alcuni derivati dell'1,5-bis-(3,4-metilendiossifenil)-n.pentano

The acute toxicity and the activity on isolated guinea pig ileum of some derivatives of 1,5-bis-(3,4-methylendioxyphenyl)-n.pentane are reported. The majority of such compounds showed clear antagonist activity towards BaCl2, acetylcholine, histamine and 5-HT contracting responses, generally greater than that of papaverine. In almost all cases the therapeutic index of these compounds, calculated as the ratio between mouse i.v. LD50 and ileum ED50, was greater than the therapeutic index of papaverine.