Pharmacological studies in animals of beta-hydroxyethyltheophylline, the major metabolite of doxofylline in humans.

beta-HET (beta-Hydroxyethyltheophylline), the major metabolite of the antibronchospastic, antiasthmatic drug doxofylline was studied in several in vitro and in vivo trials to characterize its pharmaco-toxicological profile. When compared to the parent compound, beta-HET was found to be significantly less active. It was also discovered to be a very weak inhibitor of phosphodiesterase activity. Its affinity for A1- and A2-adenosine receptors was even lower than that of doxofylline, which was quite low. The oral toxicity of beta-HET was about three times lower than that of doxofylline. The pharmacological activity of doxofylline is due to the drug in its original form and not to its major metabolite.

Doxofylline differs from methylxanthines in its movement of cytosolic calcium.

This paper contributes to the pharmacological profile of doxofylline (Ansimar), a new xanthine derivative with high antibronchospastic activity and no extrapulmonary or cardiac side-effects, clearly demonstrating its inability to mobilize intracellular calcium stores, unlike other xanthines. In vitro, doxofylline does not cause rabbit ear artery contraction under Ca(++)-free conditions. In vivo, doxofylline does not induce a decrease in the calcium concentration of rabbit washed blood platelets. In the same trials theophylline showed opposite results. Furthermore, doxofylline does not antagonize receptors of Ca-antagonists, and does not interfere with the influx of calcium into the cell. Doxofylline also has a very low affinity for adenosine receptors inhibiting cAMP-phosphodiesterase as does theophylline. The absence of typical methylxanthine side-effects is undoubtedly due to doxofylline's low affinity for adenosine receptors, although this does not explain the absence of cardiovascular effects. The present study presents clear evidence that the inability of doxofylline to cause positive inotropism can be linked to its inability to induce calcium movement from intracellular stores.

Synthesis of a new anti-anaemic iron lysozyme glutarate complex and pharmacological studies in animals.

Iron lysozyme glutarate (ABC 1020) is a new soluble complex with an anti-anaemic activity superior to that of ferritin, ferrous sulphate and iron succinyl protein. Iron serum concentrations after treatment with ABC 1020 are higher than after ferritin and iron succinyl protein and lower than after ferrous sulphate treatment. Anaemic adult rats and rats born from dams with anaemia induced by an iron-deficient diet and by repeated bleeding showed considerable, dose-related improvement when treated with ABC 1020, which gave markedly better results than ferritin, iron succinyl protein and ferrous sulphate. Treatment with all four compounds improved the hematological and blood chemistry parameters considered, and reversed cardio- and splenomegaly. Preliminary data show that ABC 1020 is well tolerated, does not induce gastric lesions and has a high bioavailability.

In vivo anti-inflammatory activity of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine.

A new methylxanthine derivative [7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine, ABC 99] with mucoregulatory and antibronchospastic properties has been studied. ABC 99 was observed to have marked anti-inflammatory activity in a series of experimental trials involving the principal mediators of inflammation (PAF, histamine, serotonin, LTC4-like substances, etc). It inhibits the formation of oedemas induced both by carrageenin and PAF in the rat paw, and reduces the increase in vascular permeability induced by histamine and serotonin. ABC 99 was also found to inhibit PAF-induced pleurisy, reducing the volume of pleural exudate and the presence of LTC4-like substances in the pleural cavity. When administered subacutely, ABC 99 checks the formation of granulation tissue caused by the subcutaneous implantation of cotton pellets in the rat. These experimental results indicate ABC 99 may be of particular interest in the treatment of respiratory disorders involving obstructive inflammation and bronchial hypersensitivity.

Pharmacological and toxicological activities of a new methylxanthine derivative [7-(1,3-dithiolan-2-ylmethyl)1,3-dimethylxanthine] with antibronchospastic and mucoregulatory properties.

7-(1,3-Dithiolan-2-ylmethyl)-1,3-dimethylxanthine (ABC 99) has been studied in the animal to evaluate its pharmacological activity. This compound was found to have antibronchospastic activity in vitro and in vivo markedly greater than aminophylline. The new compound also had moderate antitussic properties and was an active mucoregulator. ABC 99 acts as an intestinal muscle relaxant, but it has no cardiovascular, urinary, or CNS side effects. The mechanism of ABC 99 could be explained by its inhibition of guinea-pig lung phosphodiesterases and affinity for adenosine receptors, particularly A2 receptors. ABC 99 had a low acute toxicity in animals, indicating it may be useful for treating asthma and chronic bronchitis.

Doxofylline in rat brain in relation to locomotor activity.

Doxofylline is a new xanthine derivative with significant bronchodilatatory activity. We have studied in HPLC the distribution of doxofylline in various areas of rat brain (cortex, cerebellum, limbic system) and its activity on the central nervous system by using a spontaneous motility test comparing it with aminophylline administered orally in equimolar doses (4.7 - 9.4 - 19 x 10(-5) mol/kg). Doxofylline is absorbed 3 or 4 times less than aminophylline at the same doses. Nevertheless, the quantity of doxofylline that goes to the brain is equivalent to that absorbed, whereas the quantity of aminophylline is about one-third. This is due to the greater liposolubility of doxofylline in comparison to aminophylline. In spite of the fact that doxofylline is easily distributed in the brain, spontaneous motility in animals is not modified, whereas aminophylline increases this activity significantly. The low affinity of doxofylline with adenosine receptors (A1 and A2) in comparison with aminophylline explains the lack of side effects on the central nervous system which has been amply documented for theophylline and for other methylxanthine derivatives.

[Histologic evaluation of gastric tolerability in rats of ferritin compared with ferrous sulfate]. / Valutazione istologica della tollerabilità gastrica nel ratto della ferritina in confronto col solfato ferroso.

The gastric tolerance of ferritin has been studied in Wistar rats and compared with a conventional antianaemic product (ferrous sulphate). The oral administration of the same amount of elementary iron (10-50-100 mg/kg 3 times in 24 h) from each compound produces different anatomopathological results. The treatment with ferritin caused only a moderate gastritic process. In contrast, the administration of ferrous sulphate induced a dose-dependent progression from incipient gastritis to intense gastritis, focal haemorrhagic gastritis and focal necrotizing gastritis. Ferritin did not produce other secondary effects, and is well tolerated even at the highest dosages.

Synthesis, antilipidemic and platelet antiaggregatory activity of 2-aminobenzimidazole amide derivatives.

The synthesis and preliminary pharmacological evaluation of 2-aminobenzimidazole amide derivatives are reported. None of these compounds showed antilipidemic or platelet antiaggregatory activity comparable to that of drugs used in therapy.

Biological properties of pancreatic elastase in relation to atherosclerotic disease.

The inhibitory effect of elastase on experimental atherosclerosis has been reported in numerous studies. In our investigation, performed in the rat, a pancreatic extract provided with elastolytic activity has been shown to possess an anti-aggregative effect in vitro and ex vivo and anti-thrombotic properties. In addition, the elastase was capable of inhibiting endothelial exfoliation induced by the desquamatory agent sodium citrate. This agent was tested for its microhaemorrhoeological activity in acute and subacute experiments. In both these conditions, elastase was able to increase the flexibility of red blood cells and their resistance to lysis provoked by hypotonic solutions. In animals fed on an atherogenic diet, this substance limited the lipoprotein accumulation in the aorta wall. Moreover, it reduced the enhanced calcium content, induced by vitamin D administration, in the tissue of arteries. These data indicate that elastase can counteract some pathobiological aspects that characterize atherosclerotic events.

Effect of teomorfolin [N-(7'-theophylline acetyl)morpholine], a new drug, on dislipidaemic conditions induced in the rat.

A study of a new compound with an original structure, teomorfolin [N-(7'-theophylline acetyl)morpholine], was performed in the rat to investigate interaction with experimentally induced dislipidaemic disturbance related to atherosclerotic disorders. The drug succeeded in normalizing the cholesterol and triglyceride serum levels in acute as well as in chronic hyperlipaemia, and, in this connection, it provoked a significant increase of serum alpha-lipoproteins and a decrease of serum beta-lipoproteins, with a consequent improvement of the beta/alpha ratio. In addition, it significantly limited the lipolytic effect produced by adrenaline. Moreover, the drug demonstrated in vitro and in vivo platelet anti-aggregant activity and was able to increase erythrocyte flexibility. Finally, the drug inhibited prostacyclin biosynthesis; this action could explain the anti-aggregant activity demonstrated by teomorfolin. In conclusion, the chemical under investigation showed a wide spectrum of biological properties that interfere with metabolic disturbances involved in atherosclerotic conditions.

Influence of non-steroidal anti-inflammatory compounds on the hepatic tryptophan pyrrolase activity in hypo- and hyperthyroid rats.

Hypothyroid state induced in the rat by thyroparathyroidectomy does not modify the activity of hepatic tryptophan pyrrolase (TPO) while hyperthyroidism, obtained after daily injection of 3, 3', 5-triiodo-L-thyronine, inhibits significantly the liver TPO activity. Treatment with oxametacine, indomethacin, phenylbutazone, flufenamic acid and acetylsalicylic acid, increases the activity of hepatic TPO in hypothyroid state, whereas, in hyperthyroid rats, the same drugs are able to restore the normal enzymatic activity, except for acetylsalicylic acid. During the development of an acute inflammatory process, provoked by carrageenan injection, the treatment with non-steroidal anti-inflammatory agents induces an enhancement of hepatic TPO activity. On the contrary, such enzymatic activity appears unaffected in chronic inflammation induced by cotton-pellet implantation.

[Stimulating action of hematoporphyrin on motor coordination and resistance to fatigue in rats]. / Azione stimolante dell'ematoporfirina sul coordinamento motorio e sulla resistenza alla fatica nel ratto.

The pharmacological activity of hematoporphyrin has been studied on two experimental models which are able to monitor the motor coordination in the rat, namely the natatory exhaustion and the Rota-Rod tests. A dose related effect of hematoporphyrin in increasing resistane to motor fatigue has been observed in the Rota-Rod between 2-8 mg/kg i.p. Higher doses of hematoporphyrin seem to be less effective (difasic effect). In both tests hematoporphyrin was able to potentiate the stimulating effect of d-amphetamine (6 mg/kg s.c.). The potentiation appeared to be dose related between 2 and 8 mg/kg in the Rota Rod and between 2 and 16 mg/kg in the natatory test.