Synthesis of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4- tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid (6-10) and their 1-[2-hydroxy-3(4-phenyl-1-piperazinyl)propyl] derivatives (11-15) are described. Some of them displayed strong analgesic activity.

Amides↗

PubMedDate not supplied

Modulation of the protective efficacy of common antiepileptic drugs by xanthine derivatives: implications for the clinical use of xanthines in epileptic patients.

Aminophylline and caffeine (methylxanthines) in non-convulsive doses considerably reduced the protective efficacy of common antiepileptic drugs against maximal electroshock-induced convulsions. On the other hand, a new xanthine derivative, enprofylline (3-propylxanthine) which is devoid of convulsive potential and is four to five times more potent as a bronchodilator than aminophylline, remained without influence upon the protection offered by a variety of antiepileptics against electroconvulsions. Similar results were obtained when diprophylline and pentoxifylline were used. The only difference was in the case of pentoxifylline which moderately diminished the protective activity of diphenylhydantoin. It is suggested that the clinical use of aminophylline in epileptic patients for pulmonary reasons should be limited or even stopped. Furthermore, enprofylline, diprophylline and to the lesser degree pentoxifylline seem to possess no dangerous potential to epileptic patients on anticonvulsive therapy.

Animals↗

PubMedDate not supplied

Effect of aminophylline on the protective action of common antiepileptic drugs against electroconvulsions in mice.

The increasing amount of data tends to suggest that adenosine-mediated inhibition may play a role in the anticonvulsant activity of a number of antiepileptic drugs. Consequently, we tried to reverse the protective action of acetazolamide [(40 and 80 mg/kg) i.p.; 60 min before the test]; carbamazepine (20 and 30 mg/kg i.p., 60 min); diazepam (5 and 10 mg/kg i.p., 60 min); diphenylhydantoin (8 and 12 mg/kg i.p., 120 min), phenobarbital (20 and 30 mg/kg i.p., 120 min) and valproate (200 and 300 mg/kg i.p., 30 min) with aminophylline (50 and 100 mg/kg i.p., 30 min) against electroconvulsions in mice. Aminophylline markedly decreased the anticonvulsant efficacy of almost all drugs studied, acetazolamide (40 and 80 mg/kg) and carbamazepine (30 mg/kg) being the only exceptions. The ethylenediamine component of aminophylline did not modify the anticonvulsant activity at all. These results seem to support the suggestion that aminophylline-induced blockade of adenosine receptors might be involved in the reversal of the protective action of at least some drugs studied. Regardless of the nature of the aminophylline-induced impairment in the anticonvulsant efficacy of a number of antiepileptic drugs, the use of methylxanthines in epileptic patients for the treatment of obstructive lung diseases should be avoided.

Aminophylline↗

PubMedDate not supplied

Effect of aminophylline and enprofylline on the protective efficacy of common antiepileptic drugs against electroconvulsions in mice.

The anticonvulsant potency of phenobarbital (PB) (120 min before the test), phenytoin (PHT) (120 min), carbamazepine (CBZ) (60 min), valproate (VPA) (30 min), and acetazolamide (60 min) alone or in combination with either aminophylline (50 mg/kg, 30 min) or enprofylline (46.2 mg/kg, 30 min) was measured against maximal electroshock-induced convulsions in mice. All drugs were administered intraperitoneally (i.p.), and the protective efficacy of each drug was expressed as ED50 in milligrams per kilogram. Aminophylline decreased anticonvulsant activity of PB, PHT, CBZ, and VPA, increasing the respective ED50 values from 16 to 28 mg/kg, 7.4 to 14 mg/kg, 18 to 26 mg/kg, and 260 to 335 mg/kg. On the contrary, enprofylline in the equimolar dose did not exert such effect. Furthermore, neither aminophylline nor enprofylline affected anticonvulsant action of acetazolamide. The present data favor enprofylline as a preferable drug for treatment of obstructive lung diseases in epilepsy patients. However, accurate pharmacokinetic data in mice and men for both xanthines are necessary if one attempts to compare their cerebral and pulmonary actions.

Aminophylline↗