Accumulation of caffeine in healthy volunteers treated with furafylline.

The pharmacokinetics and tolerance of repeated oral doses of furafylline were investigated in normal volunteers. In accord with predictions from single dose studies, steady state was achieved on the first day following the administration of 90 mg and maintained by subsequent daily doses of 30 mg. When corrected for body weight there were no significant differences in minimum and maximum plateau levels of furafylline between males (1.2-2.0 micrograms ml-1; mean body weight 67.2 kg) and females (1.6-2.6 micrograms ml-1; mean body weight 54.9 kg). The half-life of elimination was less when the plasma concentration was lower than 600 ng ml-1 than during the stationary phase of treatment. Despite constant plasma levels the repeated administration of furafylline appeared to be associated with the onset of adverse xanthine-like side effects, a finding which was subsequently traced to the presence of, and possible synergism with, accumulating serum levels of caffeine in those volunteers drinking caffeine containing beverages. Subsequent studies showed that a single dose (90 mg) of furafylline results in a rapid accumulation of caffeine given orally (100 mg twice daily) and that this is accompanied by an elimination half-life of some 50 h and an abrupt decrease in metabolite levels. The furafylline-induced accumulation of caffeine was not influenced by the smoking habits of the subjects, implying that the metabolite pathway blocked by furafylline is the demethylation of caffeine in position 3, an implication confirmed by the reduced formation of paraxanthine. This demonstration of an unacceptable level of adverse side effects resulting from a potent inhibiting effect of furafylline on the metabolism of a normal dietary constituent has obvious implications in the interpretation of drug-induced toxicity.

Characterization of a new crystalline synthetic gastric antacid, almagate.

A new crystalline hydrated aluminium-magnesium hydroxycarbonate, almagate (Almax) is described. It has been shown to have an empirical formula Al2 Mg6(OH)14(CO3)2 X 4 H2O X. X-ray diffraction spectra indicate that it is different from other related antacids and that its crystal structure is made up of brucite layers, in which magnesium is replaced by aluminium in the ratio of 3 to 1, interposed with negatively charged layers containing carbonate ions and water. Analysis of the IR spectra suggests that the interstitial carbonate is coordinated to both metals. Differential thermal analysis demonstrates that almagate has good thermal stability and measurement of its antacid activity shows that it has a rapid neutralization velocity and a high acid consuming capacity.

Evaluation of a new antacid, almagate.

Almagate (Al2Mg6(OH)14(CO3)2 X 4 H2O, Almax), a crystalline hydrated aluminium-magnesium hydroxycarbonate, was compared with a number of other known antacids in a battery of tests designed to demonstrate the properties of an ideal antacid. In dynamic tests for measurement of velocity of neutralization, total acid consuming capacity and duration of activity, almagate like other crystalline aluminium magnesium hydroxide derivatives such as hydrotalcite and magaldrate was rapidly acting, neutralized a high proportion of its theoretical acid consumption and maintained gastric pH between 3 and 5 for a prolonged period of time. It was more active than these two substances in respect of rapidity of action and did not lose antacid activity as the pH was raised. Like these compounds it had considerable advantages over the amorphous gels and co-gels of aluminium and magnesium hydroxides or hydroxycarbonates in respect of both rapidity of action and acid consuming capacity. It inhibited the activity of pepsin and was shown to adsorb bile acids and had a low sodium content.

Dopaminergic activity in a series of N-substituted 2-aminopyrimidines.

A series of N-substituted 2-aminopyrimidines were prepared and tested for pharmacological activity associated with stimulation of central and peripheral dopamine receptors using piribedil as the reference standard. Most of the new compounds showed some degree of dopaminergic activity although in many cases central activity was not accompanied by peripheral activity and vice versa. Clear relationships between structure and activity were not apparent and none of the new compounds possessed dopamine receptor blocking properties.

Synthesis and pharmacological properties of a series of antidopaminergic piperidyl benzamides.

The synthesis and pharmacological screening for anti-apomorphine, stomach emptying and local anaesthetic activities of some new piperidylbenzamides is described. One of these, N-(1'-benzyl-4'-piperidyl)-2-methoxy-4-amino-5-chlorobenzamide (clebopride) is more potent than metoclopramide in tests related to blockade of cerebral dopamine receptors.