Effects of some antianginal and vasodilating drugs on sodium influx and on the binding of 3H-batrachotoxinin-A 20-alpha-benzoate and 3H-tetracaine.

The effects of antianginal drugs, especially arylalkylamines and structurally related derivatives, on 3H-batrachotoxinin-A 20-alpha-benzoate (3H-BTX-B) binding and on 3H-tetracaine binding were studied on rat synaptosomal and heart membrane preparations. The effect of the same drugs on the Na+ influx induced by protoveratrine B was studied on the rat synaptosomal preparation. Antianginal drugs tested inhibited 3H-BTX-B binding in rat synaptosomes, arylalkylamine derivatives being the most potent: IC50 values were 27 nM for flunarizine, 32 nM for prenylamine, 79 nM for cinnarizine. Similarly, these drugs were the most potent when tested in cardiac membrane preparations. All the drugs tested were very weak inhibitors of 3H-tetracaine binding (IC50 ranging from 0.01 mM to more than 1 mM) except for guanabenz, which was more potent (IC50:0.3 microM on the synaptosomal preparation). The various drugs tested inhibited the 22Na+ influx induced by protoveratrine B, with IC50 values ranging from 15 microM (prenylamine) to 110 microM (verapamil), with the exception of nifedipine which had an IC50 of more than 0.1 mM. The inhibition of 22Na+ influx correlated well with the inhibition of 3H-BTX-B binding. These findings suggest that some antianginal drugs, especially the arylalkylamines may have, in addition to their calcium antagonist activity, direct effects on sodium channels.

Anti-anginal arylalkylamines and sodium channels: [3H]-batrachotoxinin-A 20-alpha-benzoate and [3H]-tetracaine binding.

[3H]-batrachotoxinin-A 20-alpha-benzoate ([3H]-BTX-B) and [3H]-tetracaine are useful ligands for the study of sodium channels. Inhibition of their binding by various anti-anginal drugs was tested on a rat synaptosomal preparation and on a heart membrane preparation. Diphenylalkylamines and structurally related drugs inhibited [3H]-BTX-B binding in both the synaptosomal preparation and heart membrane preparation. They were almost inactive on [3H]-tetracaine binding. These results suggest that activity of arylalkylamines could be mediated by an interaction on the sodium channel.

[Diuretics]. / Diurétiques.

Microaspiration techniques and clearance studies have shown that reabsorption of filtered sodium approximates 65% in the proximal tubule, 25 to 30% in the ascending limb of the loop of Henle and 5 to 10% in the dilution segment. Reabsorption in the Henle loop is of special significance as it governs the process of dilution-concentration of urine. Moreover, inhibition of sodium reabsorption in the loop of Henle necessarily produces a substantial loss of sodium since only a fairly small fraction of urinary sodium is reabsorbed beyond the Henle loop (dilution segment, distal tubule). Excretion of water and electrolytes is regulated by humoral factors, such as the renin-angiotensin-aldosterone system, some prostaglandins and certain kinins. Factors that promote excretion of sodium, produced in particular by the myocardium, have recently been demonstrated. The correlation between blood pressure and salt has been substantiated by many findings. Diuretics are commonly used to treat high blood pressure as well as edema. Recent evidence indicates that sodium transport is altered in idiopathic hypertension, at least in red blood cells. Clinical trials of diuretics are designed to localize the drug's action and quantify its saluretic activity (evaluation of potency and effectiveness--single doses, sustained treatment). Furthermore, the minimal efficient antihypertensive dosage should be determined. Diuretics can be divided into two groups according to whether they produce an increase or decrease in serum potassium. Diuretics that are capable of producing hypokalemia belong to two main families. One consists of the Henle loop diuretics that interfere with the mechanisms of dilution-concentration of urine. Action of these drugs is potent and short-lived. For instance, following a single dose of furosemide, excretion of sodium can reach 25-30% of filtered sodium; renal blood flow increases; CH2O and TCH2O decrease. With furosemide, induction of diuresis is rapid (within a few minutes after IV injection and 20 mn after oral ingestion); elimination half-life is 50 mn; absolute bioavailability is 50-70%; 95% of the drug is bound to plasma proteins; elimination is mainly through the kidneys. Other Henle loop diuretics include ethacrynic acid, whose elimination half-life is less than one hour; bumetanide, which is 40 times more potent than furosemide; muzolimine, whose action is more lasting despite the fact that only 65% of the drug is bound to plasma proteins; and ozolinone, which has a saliuretic action comparable to that of furosemide and in addition exerts a direct vasodilating effect.(ABSTRACT TRUNCATED AT 400 WORDS)

[3H]-tetracaine binding on rat synaptosomes and sodium channels.

[3H]-tetracaine binding was studied in a rat synaptosomal preparation. [3H]-tetracaine bound to a single class of binding sites with a mean KD of 188 +/- 28 nM and a mean maximal binding capacity of 13 +/- 0.7 pmol mg-1 protein. [3H]-tetracaine binding was inhibited by tetracaine, procaine and by beta-adrenoceptor blocking agents which possess local anaesthetic properties. [3H]-tetracaine binding was not modified by neurotoxins interacting specifically with the sodium channels.

Pharmacokinetic profile of benoxaprofen in subjects with normal and impaired renal function, prediction of multiple-dose kinetics.

The pharmacokinetic profile of benoxaprofen given as a single oral dose of 600 mg was determined comparatively in 5 healthy volunteers and in 15 patients with various degrees of renal insufficiency (5 of whom were undergoing maintenance hemodialysis). In normal subjects, the half-absorption period (Ka) was 0.63 hours. A mean maximum concentration of 47.3 micrograms/ml could be predicted at 3.6 hours after the dose intake. Serum level decrease was particularly slow. The overall elimination rate constant, Ke, was 0.0234(h-1) and biologic half-life amounted to 28.8 hours. Values for total clearance (Ct=4.8 ml/min/1.73 m2) and renal clearance (Cr=1.6 ml/min/1.73 m2) were low. Of the administered dose of benoxaprofen, 13.9% was recovered in the urine over a 24-hour period. Renal insufficiency did not induce major changes in pharmacokinetic parameters. Under such conditions, it seems advisable to reduce the dose to one-half only in patients with a creatinine clearance of less than 10-20 ml/min/1.73 m2. Predicted serum levels theoretically achieved after repeated administration of a 600-mg dose of benoxaprofen every 6, 12, 24, 36 and 48 hours were calculated. From this evaluation, it appears that therapeutically effective and adequate levels could be obtained after administration of a 600-mg dose every 12 ot 24 hours.

Pharmacokinetics of mezlocillin in patients with kidney impairment: special reference to hemodialysis and dosage adjustments in relation to renal function.

The pharmacokinetics of Mezlocillin were determined after the intramuscular injection of a single 1-gram dose in 10 subjects with normal renal function, in 10 patients with stabilized renal impairment and in 5 patients with end-stage renal disease submitted to repeated hemodialysis. In normal subjects, biological half-life, Tb1/2, was equal to 0.9 h; total clearance (Ct) to 449 ml/min/1.73 m2; renal clearance (Cr) to 263 ml/min/1.73 m2.72.2% of the administered dose was excreted in the urine within 12 h. In patients with renal insufficiency and in patients undergoing long-term hemodialysis, the serum concentration decrease was markedly slower. During a 6-hour dialysis session, 62% of the Mezlocillin present in the central compartment at the start of hemodialysis was removed. In the 25 subjects under study, a significant correlation was found between the values of Ke and those of creatinine clearance, Ccr (Ke = 0.1973+0.0046 Ccr). This relation was used to calculate the loading doses, the maintenance doses and the dosage intervals adjusted to the degree of renal impairment, allowing assessment of useful dosage recommendations.

[Benoxaprofene: pharmacokinetic profile in the normal subject and patients with renal insufficiency; evaluation of anticipated serum levels]. / Benoxaprofène: profil pharmacocinétique chez le sujet normal et l'insuffisant rènal, évaluation prévisionnelle des taux sériques.

The pharmacokinetic profile of benoxaprofene, administered in a single oral dose of 600 mg, has been determined comparatively in 5 normal subjects and 15 patients with renal insufficiency (five of whom were on chronic hemodialysis). In the normal subject, the half-absorption time (Ka) was 0.63 hours; a mean theoretical maximal concentration of 47.3 micrograms/ml was reached 3.6 hours after administration of the drug. The decrease in serum levels was particularly slow, the coefficient of total elimination (Ke) being 0.0241(h-1) and the biological half-life attaining 28.8 hours. :The total clearance (Ct = 4.8 ml/min/1.73 m2) and renal clearance (Cr =1.6 ml/min/1.73 m2) values were low. 13.9% of the ingested dose of benoxaprofene was recovered in the 24 hours urinary volume. Renal insufficiency does not significantly change the pharmacokinetic parameters. It appears advisable to reduce the dosage by half only in patients with a Cr clearance of less than 10-20 ml/min/1.73 m2. The theoretical serum values reached after administration of 600 mg benoxaprofene repeated every 6-12-24-36 or 48 hours have been calculated and it has been found that effective concentrations can be obtained by administration of 600 mg every 12 or 24 hours.

[Effect of propranolol on diuretic activity of furosemide hypertensive patients (author's transl)]. / Effets du propranolol sur l'action diurétique du furossmide chez l'hypertendu.

The effect of propranolol on water and sodium depletion provoked by frusemide was studied. Nine hypertensive patients were treated at 2-day intervals with a single dose of 40 mg of frusemide associated with a placebo or propranolol (320 mg given in 8 doses over a period of 24 hours). The association frusemide-propranolol is more hypotensive than frusemide alone. Propranolol reduced the rise in plasma renin activity and aldosteronuria provoked by the diuretic; total sodium output/24 h remained stable but sodium elimination was increased in the later samples. This prolongation of the natriuretic action is correlated with the inhibition of hyperaldosteronuria. Propranolol depresses urinary osmolality for a longer period than frusemide alone and water elimination tends to be higher. This action of the beta-blocker on urine concentration is independent of its effects on aldosteronuria but is correlated with the inhibition of the rise in plasma renin activity.

Cefamandole pharmacokinetics and dosage adjustments in relation to renal function.

The pharmacokinetic characteristics of cefamandole were determined after intravenous administration of a 1-Gm dose to 10 subjects with normal renal function, 10 patients with stabilized renal failure, and five chronic nephritic patients included in a intermittent hemodialysis program. In normal subjects, biological half-life (t1/2) averaged 0.94 hour, the overall elimination rate constant (Ke) was 0.7378 (hr-1), total clearance (Ct) was 223 ml/min/1.73 m2, renal clearance (Cr) was 164 ml/min/1.73 m2, and urine recovery of cefamandole over the 6 hours following a dose amounted to 74 per cent of the administered dose. In patients with stabilized renal failure and in patients on hemodialysis, biological half-life was markedly increased, with a theoretical value of 10.4 hours in case of a creatinine clearance of zero. The amount of antibiotic extracted over a 6-hour dialysis period accounted for 29 per cent of the cefamandole present in the vascular compartment at the beginning of the dialysis procedure. A significant correlation was established between the values of Ke and creatinine clearances, Ccr: Ke = 0.0289 + 0.0063Ccr (r = 0.937). This relationship was used to calculate the loading dose (LD), maintenance doses (D), and dosage intervals (tau) with regard to renal function. From these data recommendations regarding the adjustment of cefamandole dosage to the renal status can be made.

[Clinical and biological manifestations following the interruption of prolonged treatment with clonidine]. / Manifestations cliniques et biologiques l'arrêt d'un traitement prolongé par la clonidine

In 7 out of 14 patients there were marked subjective symptoms following the interruption of prolonged treatment with clonidine. A significant increase in blood pressure, systolic and diastolic, heart rate and urinary catecholamine excretion was seen in the majority of cases. The clinical and biological manifestations would appear to reflect a phenomenon of derepression of sympathetic activity: the increase in urinary catecholamines is the biological result. The findings are of practical importance since they indicate that the interruption of anti-hypertensive therapy with clonidine must be under taken with caution, i.e. progressively.

[Secreting paragangliomas of the organ of Zuckerkandl. A report on two cases (author's transl)]. / Paragangliomes sécrétants de l'organe de Zuckerkandl. Apropose de deux cas

The authors describe two cases of secreting paragangliomas of the organ of Zuckerkandl, beinging the number of known cases to 78. They underline the interest of arteriographic and phlebographic explorations which define more accurately the origin and spread of these tumours.

[Comparison of the pA2 of various beta blocking agents]. / Comparaison des pA2 de différents bêta-bloquants

The drug industry is now putting out specific beta 1 or beta 2 beta-blocking agents. The pA2 of various beta-blocking agents were determined on isolated organs-guinea pig atrium and trachea: practolol and acebutolol were considered as specific beta-1 inhibitors; butoxamine was a specific beta-2 inhibitor, while pindolol, oxprenolol, propranolol and alprenolol were specificity free. The pA2 quantifies the action exerted by an inhibitor. Cardioselectivity is expressed by the pA2 left atrium/pA2 trachea ratio. It exceeds 1 000 for practolol, it equals 30 for acebutolol, and is very slight for butoxamine. The pA2 therefore gives a good idea of the potential of the various drugs on the animal's isolated organ. However, these data cannot safely be extrapolated to man. Hence the necessity of conducting clinical pharmacological studies.