Journal de pharmacologie最新文献

The properties of some tricyclic and non-tricyclic antidepressants on antagonist histamine H1 and muscarinic acetylcholine receptors have been evaluated on guinea-pig ileum. They act like competitive antagonists on histamine H1 receptors. Some of them show a competitive antagonism and others a non-competitive antagonism on muscarinic acetylcholine receptors. A few of them are very potent antagonists on histamine H1 and/or muscarinic acetylcholine receptors, while others, especially the non-tricyclic antidepressants, have a small potency. All antidepressants have a higher histamine H1 activity than muscarinic acetylcholine activity. These results cannot explain the therapeutic effect of these drugs, but they can account for some side effects and drug interactions.

The effect of an i.v. administration of some beta-adrenergic blocking drugs on blood pressure has been investigated in rats after blood-brain barrier (BBB) opening. Practolol and atenolol which do not penetrate the BBB, induced an immediate hypotensive effect after BBB breakdown by intracarotid (i.c.) injection of cetrimonium. In 39 week-old spontaneously hypertensive rats, practolol (15 mg/kg i.v.) and atenolol (3 mg/kg i.v.) induced a large drop in blood pressure while only a slight decrease was shown in normotensive ones. Likewise, acebutolol induced a significantly greater hypotension after BBB damage. On the other hand, the effects of dl-propranolol (5 mg/kg), quinidine (2.5 mg/kg) and isoproterenol (3 micrograms/kg) on blood pressure were not modified by pretreatment with cetrimonium i.c., while the hypotension induced by d-propranolol (5 mg/kg) was shortened. These results indicate that beta-adrenergic blocking agents with a low degree of lipophily can induce a hypotensive effect when their penetration into brain is largely enhanced after BBB opening either by prolonged hypertension or by cetrimonium. This effect is only dependent on their action on beta-adrenoreceptors; membrane stabilizing effect and intrinsic sympathomimetic activity do not seem to be involved.

The presence of alpha 1-receptors has been demonstrated in numerous venous fragments for various animal models. On the other hand, the presence of alpha 2-receptors in the saphenous of the dog is a matter of debate. Beta 2-receptors are activated by isoproterenol, noradrenaline and adrenaline in precontracted veins (part of the facial vein of the rabbit may be an exception). Preferential blocking by atenolol of beta 1-receptors in the jugular veins of the rat suggests that these receptors may mediate vasodilation. The saphenous veins of the dog provide the only example where specific dopaminergic receptors have been noted following partial antagonism with haloperidol. The vasoconstrictive action of acetylcholine has been seen in venous segments of numerous species and indicates the presence of muscarinic receptors. The existence of angiotensin receptors can be postulated despite the weak and inconstant in vitro and in vivo (the dorsal cerebral sinus in the dog excepted) reactions observed and the use of a non-specific antagonist. The same is true for bradykinin and vasopressin. The marked vasoconstrictive action of serotonin on all veins studied is evidence for the presence of receptors. The nature of the antagonists is subject to some divergence of opinion. Nevertheless, D tryptamine muscular receptors (or 5 HT2) can be identified due to the lack of morphine-mediated response and the efficacy of methysergide. The presence of a third type of serotoninergic receptor has only been reported once, following observations of vasodilation in the sheep. H1 receptors are involved in histamine-mediated vasoconstriction. The presence of H2 receptors which mediate vasodilation in precontracted veins remains hypothetical. Prostaglandins exhibit different efficacies in producing contraction in isolated veins; PGF2 alpha is more efficacious than PGE1 and PGE2. Prostacyclin induces contraction of human saphenous veins in a dose-dependent manner. PGE2 and particularly PGE1 can induce relaxation in precontracted veins, as is also true for prostacyclin. Receptors for these prostaglandins must exist at the post-junctional level. P2-receptors mediate transmission of the vasoconstrictive action of various purine derivatives.

Sudden cardiac death (SCD) due to acute myocardial infarction (AMI) is mostly the result of ventricular fibrillation (VP) which is an electrical accident appearing on the basis of electrical instability of the myocardium. In addition to the chronic electrical instability predisposing to ventricular arrhythmias the trigger effect of a precipitating factor also seems necessary which may disrupt the normal sequence of cardiac contractions. In view of this hypothesis the following strategy of therapeutic interventions aimed at preventing SCD from AMI seems to be logical: Prophylactic measures to prevent pathological processes underlying chronic electrical instability of the heart i.e. elimination of identified risk factors of ischemic heart disease. Protection from SCD due to AMI: by using drugs which could, prevent further electrical destabilization as shifts in myocardial and plasma ionic balance, in pH, in pCO2, accumulation of potentially arrhythmogenic metabolites: Inhibit the trigger effect of sudden changes: in hemodynamics, in the autonomic nervous outflow and balance. The general supportive measures include therapeutic interventions which are not directly connected with appearance of lethal arrhythmias but may indirectly contribute to their development as pain, arterial Hb desaturation, deep vein thrombosis. Some of the measures listed above are capable of limiting the size of the developing infarct, a major determinant of the future conditions of life and prognosis of the patient. In the prehospital phase of AMI when two thirds of all coronary deaths occur general supportive measures and drug treatment of life threatening arrhythmias should be applied simultaneously. Sedatives and anxiolytics, furthermore analgetics are widely used. They are however often associated with bradycardia and sometimes with hypotension. This latter is dominant in patients with inferior infarction, showing a parasympathetic hyperactivity, when atropine treatment is needed. Sympathetic hyperactivity responds to analgesia and sedation but beta blockers may be required to reduce increased MVO2. These agents belong to the group of anti-ischemic drugs. The beneficial anti-ischemic action of beta-blockers is mostly due to their negative chronotropic and inotropic effect. A direct metabolic action was shown by use as well as the presence of a positive steal phenomenon in the experimental angina model in dogs. Anti-ischemic action of coronary vasodilators. The most reliable drug for preventing or abolishing anginal attack is still the classic nitroglycerin. On the other hand persantine a potent coronary dilator failed to protect against anginal attack in man.

The determination of the dose regimen of a new antibiotic is difficult because a dose/effect relationship cannot be established in patients with an infectious disease. The optimal dose is usually extrapolated from combined data provided by in vitro and in vivo microbiologic toxicologic and kinetic studies. Additional data ought to be produced in the future such as: kinetics of cidal effect in vitro, of the post antibiotic effect, of drug concentrations at the sit of infections itself, of the cidal serum activity in volunteers and patients; how these parameters are modified when modulating the mode of administration of the drug ought to be studied as well. The optimal dose, once it is roughly evaluated from classical studies, has to be adjusted: either by decreasing the dose, through an appropriate program of clinical trials with non-threatening life infections; or by increasing the dose in severe infections, through an in-depth analysis of new data available because of the improvement of: the design of clinical trials, the sensitivity of analytical techniques, the standardized serum bactericidal tests, the sophisticated monoparametric animal models simulating human infections, our knowledge of drugs mechanisms of toxicity. Establishing a rational dose regimen obviously requires a long-term multidisciplinary approach of the problem.

The pharmacokinetics, metabolism and disposition of doxorubicin and daunorubicin were studied for periods up to 100 hr in rabbits with (group II) or without a biliary fistula (groups I and III) and with (group I) or without (groups II and III) ligatured ureters using high-performance liquid chromatography to separate parent drug and metabolites. The plasma decay of doxorubicin and daunorubicin was triexponential. Metabolites appearing in the plasma after doxorubicin and daunorubicin bolus i.v. injection were respectively doxorubicinol and daunorubicinol, the latter being the major compound after daunorubicin injection. The elimination of daunorubicin was faster than that of doxorubicin. No differences in the elimination were observed between the 3 groups. In bile, 21% of the injected dose of doxorubicin were excreted mainly as the parent drug and 60% of the injected dose of daunorubicin were excreted, mainly as daunorubicinol. Enterohepatic circulation did not affect the biliary excretion of both doxorubicin and daunorubicin. Ligature of ureters increased slightly the biliary excretion of doxorubicin. The hepatic clearance of daunorubicin was greater than that of doxorubicin. The total urinary excretion was not different between the II and III groups and amounted to 11.6 and 12.8% of the injected dose of doxorubicin and daunorubicin, respectively. Metabolic ratios of doxorubicinol/doxorubicin and daunorubicinol/daunorubicin were similar in bile and urine.