We studied the influence of posterior pituitary extract, vasopressin, and somatostatin on hepatic elimination function. Hepatic clearance and its two biological determinants, hepatic blood flow and metabolic activity (clearance Vmax/Km), were determined from hepatic indocyanine green elimination at steady-state in cirrhotic patients. Intravenous infusion of posterior pituitary extract (oxytocin, 59%; vasopressin, 41%) at the constant rate of 0.3 unit per kg per hr decreased hepatic clearance (p less than 0.05) and Vmax/Km (p less than 0.05) but did not change hepatic blood flow. Intravenous infusion of vasopressin (0.3 unit per kg per hr) decreased hepatic clearance (p less than 0.05), Vmax/Km (p less than 0.05) and hepatic blood flow (p less than 0.05). Intravenous infusion of somatostatin (250 micrograms per hr following a bolus i.v. injection of 250 micrograms) decreased hepatic clearance (p less than 0.05), Vmax/Km (p less than 0.05), and hepatic blood flow (p less than 0.05). This study shows that the vasoactive agents used in the management of upper digestive bleeding in cirrhotic patients may have deleterious effects on the metabolic activity of the liver in addition to their effects on hemodynamics. The results suggest that the vasoactive substances either increased the fraction of total hepatic blood which bypassed intact hepatocytes or directly impaired metabolic activity of hepatocytes. Reduction in the metabolic activity of the liver produced by vasoactive agents may have important implications in therapy of portal hypertension.

Female↗

PubMedDate not supplied

Effect of vasodilators on hepatic microcirculation: a study of the inhibition of norepinephrine-induced vasoconstriction in the isolated perfused rat liver.

We studied the effects of a series of 16 vasodilators on the intrahepatic vasoconstriction induced by norepinephrine in the isolated perfused rat liver. The vasodilators were nonselective alpha-adrenergic antagonists (phentolamine, ifenprofil, isoxsuprine and buflomedil), a nonselective beta-adrenergic antagonist (propranolol) and an agonist (isoproterenol), an alpha 2-adrenergic agonist (clonidine), calcium channel blockers (verapamil and diltiazem), nitrovasodilators (nitroglycerin, sodium nitroprusside), papaverine and other unclassified vasodilators, some of them with rheological properties (diazoxide, vincamine, cinepazide, naftidofuryl and pentoxifylline). The most potent drugs were ifenprofil, phentolamine, isoxsuprine, clonidine, sodium nitroprusside and buflomedil. Diazoxide, papaverine, pentoxifylline and trinitrine were less powerful. Verapamil, diltiazem, propranolol, isoproterenol, vincamine, cinepazide and naftidofuryl were ineffective. We conclude that different classes of pharmacological agents have significant vasodilatory properties on the hepatic microvasculature. This offers interesting perspectives in the treatment of cirrhosis and stressful states where high levels of circulating norepinephrine may contribute to the altered liver perfusion.

Animals↗

PubMedDate not supplied

Pharmacokinetics of hydroxy-3(S)-dihydroquinidine in healthy volunteers after intravenous and oral administration.

The pharmacokinetics of hydroxy-3(S)-dihydroquinidine (HDHQ) were studied in 6 healthy volunteers following a 15 min intravenous infusion of a 300 or 400 mg dose, a 300 mg oral dose in solution and a 300 mg tablet administration on three separate occasions (random order) with at least one week intervals. Using a specific HPLC assay for HDHQ, the post-infusion and post-absorption plasma HDHQ concentrations declined bi-exponentially. Both oral forms of HDHQ were absorbed rapidly (tmax 1 h-1.2 h) with an absolute bioavailability of the oral solution (F = 0.54 to 0.93) which was not significantly different from that of the tablet (F = 0.66 to 0.90). HDHQ was rapidly and extensively distributed to the tissues with a high steady-state volume of distribution (6.82 +/- 1.85 l X kg-1). Mean elimination half-life was 6.7 +/- 1.4 h after IV infusion, 8.4 +/- 1.7 h after the oral solution and 11.3 +/- 4.4 h after the tablet administration. HDHQ was partially eliminated from the body in the unchanged non-conjugated form by the urine and renal clearance represented approximately 50% of the total body clearance. These results show that HDHQ is rapidly and almost completely absorbed and has potential for a twice daily administration regimen for the treatment of cardiac arrhythmias.

Administration, Oral↗

PubMedDate not supplied

Amiodarone pharmacokinetics in coronary patients: differences between acute and one-month chronic dosing.

The pharmacokinetics of amiodarone (A) and its desethylamiodarone metabolite (DEA) were compared in the same coronary patients after a first 1000 mg dose and one-month chronic oral dosing. Terminal half-life (t1/2 el) of amiodarone increased from a mean (SD) 24.1 +/- 19.5 h after the first dose to 20.4 +/- 4.8 days after the last dose. Desethylamiodarone slowly appeared in the plasma after the first oral dose and its apparent t el was 61.6 +/- 26.6 h. After one-month dosing apparent t1/2 el of desethylamiodarone increased to 29.5 +/- 9.7 days. Mean maximal plasma amiodarone/desethylamiodarone concentration ratio decreased from 9.2 +/- 5.0 to 2.0 +/- 0.6 after chronic dosing. This change was mainly related to an increase in the plasma concentration of desethylamiodarone. These data suggest that after long-term treatment with amiodarone, the complete elimination of the drug and its metabolite may need 3-4 months in some patients. The results of this study were presented in part at the meeting of the Societe Francaise de Therapeutique et de Pharmacologie Clinique, Paris, December 1985.

Administration, Oral↗

PubMedDate not supplied

Assessment of the sustained release properties of a new oral formulation of trimetazidine in pigs and dogs and confirmation in healthy human volunteers.

The pharmacokinetics of immediate (IR) and modified release (MR) trimetazidine (TMZ) in dogs and pigs, have been compared under single dose conditions, then predicted at steady-state under conditions mimicking an actual human pharmacokinetic study. In both animal species, the MR tablet has demonstrated sustained release properties, as assessed by delayed time to peak and increased mean absorption times. Multiple dose simulations in dogs revealed a delayed time to peak (3.0 vs. 1.0 h), a decrease in peak plasma concentration (544 vs. 659 microg/L), an increase in trough concentrations (115 vs. 63 microg/L), a decrease in peak-trough fluctuation (141 vs. 193%), and an increase in plateau time (5.5 vs. 4.9 h). Qualitatively similar changes were simulated in pigs. These properties have then been verified in humans where a TMZ MR 35 mg b.i.d regimen did provide similar total exposure, increased plateau time (11 vs. 4 h), decreased peak-trough fluctuation (86 vs. 121%), a 31% increase in trough concentrations, and no increase in inter-individual variability as compared to a TMZ IR 20 mg t.i.d. regimen. Furthermore, the TMZ MR 35 mg b.i.d. regimen is likely to result in improved patient compliance and better patient anti-ischemic protection in the early morning.

Administration, Oral↗

PubMedDate not supplied

Is diclofenac a valuable CYP2C9 probe in humans?

INTRODUCTION: Besides the low therapeutic index drug tolbutamide, there is no validated in vivo probe to assess the genetically determined CYP2C9 activity in humans. The in vitro CYP2C9-specific substrate diclofenac might be a valuable, well-tolerated probe candidate. In order to validate diclofenac as an in vivo CYP2C9 probe, we planned to show that urinary 4'-hydroxydiclofenac/diclofenac metabolic ratio (MR) would correlate to the apparent partial metabolic clearance of diclofenac into 4'-hydroxydiclofenac (Clmet). PATIENTS AND METHODS: Eighteen healthy volunteers received a single oral dose of 50 mg diclofenac in its enteric-coated form. Blood and urinary pharmacokinetics of diclofenac were studied over 48 h. Identification of the CYP2C9 alleles (CYP2C9*1, CYP2C9*2, and CYP2C9*3) was performed with genomic DNA sequencing. RESULTS: We observed a dramatic inter-individual variability in the delay of diclofenac intestinal absorption since its first detectable blood concentration ranged from 0.5 h to more than 12 h after drug intake. The Clmet of diclofenac could not be determined in two subjects who started to absorb the drug after 12 h. No correlation could be observed between Clmet of diclofenac and the different MRs calculated at 0-4 h, 0-8 h, 0-12 h, 0-24 h and 0-48 h urinary collections. The Clmet of diclofenac in heterozygous subjects tended to be lower than among wild-type homozygous subjects, but this difference did not reach statistical significance due to an insufficient number of subjects studied. CONCLUSION: Diclofenac, in its enteric-coated form, is not a useful in vivo CYP2C9 probe probably because of its highly variable intestinal absorption rate. However, since we found a lower metabolic clearance of diclofenac in heterozygous CYP2C9 subjects, as observed with other CYP2C9 substrates, diclofenac, in another galenic form, might be a potential probe to quantify CYP2C9 activity in humans.

Adult↗

PubMedDate not supplied

Effects of encainide (MJ9067) on the ventricular fibrillation threshold in anesthetized dogs.

The right ventricular epicardial ventricular fibrillation threshold (VFT) was determined during paced supraventricular rhythm using 100 Hz trains of stimuli at 15 min intervals in dogs before and during the intravenous administration of encainide, a new antiarrhythmic drug. With each VFT determination, simultaneous blood samples were obtained for determination of drug concentration. In 6 control dogs, VFT determined every 15 min during a 210 administered as a 90 min intravenous infusion at three successive rates (0.01, 0.02 and 0.04 mg/kg/min) for 30 min each. VFT measured at 5 and 20 min of each infusion increased from a mean control of 11.5 +/- 1.5 (+/-SE) to 20.2 +/- 2.2 mA (p less than 0.01) after 20 min of the third infusion. The maximal effect occurred during the second infusion with plasma concentration of 594 +/- 46 ng/ml and then reached a plateau. In group II (n = 6), encainide was administered in four successive sequences, each one including a bolus loading intravenous dose followed by a 45 min intravenous infusion. VFT measured at 30 and 45 min of each infusion when the encainide plasma concentration was close to a steady state increased significantly (p less than 0.01) after the second infusion from 11.8 +/- 2 to 27.3 +/- 4 mA. Two dogs in group II developed transient complete atrioventricular block at an encainide plasma concentration of greater than 800 ng/ml. These results show that the new antiarrhythmic drug encainide increases the VFT in anesthetized dogs.

Anesthesia↗

PubMedDate not supplied

Cardiac electrophysiologic effects of quinidine and propranolol isomers in anesthetized dogs: concentration-response relationships.

Electrophysiological properties of quinidine and the two isomers of propranolol were compared in pentobarbital-anesthetized dogs using His bundle recordings and programmed stimulation in order to differentiate the effects resulting from beta-blockade from those related to nonspecific membrane-stabilizing effects. Quinidine in the plasma concentration range of 2.7-20 microM/liter resulted in concentration-dependent increases in atrionodal and His-Purkinje system conduction times and in the atrial effective refractory period. Quinidine did not produce any significant concentration-dependent change in atrioventricular (AV) nodal and ventricular refractory periods, sinus node automaticity, or QTc interval duration. Propranolol isomers in concentration range of 0.03-0.85 microM/liter produced a concentration-dependent increase in atrionodal conduction time but exerted no significant effect on His-Purkinje conduction time, QTc duration, or ventricular refractory period. Both isomers increased the atrial effective refractory period, but with slopes of concentration-response regression lines which were significantly different from those of quinidine. Only l-propranolol produced concentration-dependent increases in AV nodal refractory period, Wenckebach cycle length, and sinus node recovery time. These results suggest that the electrophysiological effects of propranolol isomers are related to beta-blockade and are significantly different from those resulting from the membrane-stabilizing effect of quinidine.

Anesthesia↗

PubMedDate not supplied

Acute effects of intravenous prifuroline and amiodarone on canine cardiac automaticity, conduction, and refractoriness.

We compared the acute electrophysiologic properties of prifuroline (P), a new aminopyrroline derivative, to those of amiodarone (A) in pentobarbital-anesthetized dogs using His bundle recordings and programmed stimulation. Ten dogs received in randomized order four cumulative doses of P (2.5-20 mg/kg) and of A (1.25-10 mg/kg) with a 14-day interval between drug administrations. In a control group of four dogs receiving the diluent of the drugs, no significant changes occurred in cardiac automaticity, conduction, and refractoriness except for the atrioventricular (AV) nodal functional refractory period (RP), which increased with time (p less than 0.05). P and A produced a significant dose-related decrease in heart rate and in sinus node recovery time, with A being 3.7-3.1 times more potent than P. While atrionodal conduction time increased with both drugs, only P resulted in a significant dose-related increase in the His-Purkinje system conduction time. Prifuroline was 2.9 times more potent than A in increasing the atrial effective refractory period, while A was 2.5 times more potent than P in increasing the ventricular effective refractory period. Both drugs increased the AV nodal refractoriness in a dose-dependent way. These results suggest that the new compound prifuroline possesses some properties similar to intravenous amiodarone on sinus automaticity, atrionodal conduction, and atrial and ventricular refractoriness. However, its effects on the His-Purkinje System are typical of those of a class I quinidine-like agent.

Amiodarone↗

PubMedDate not supplied

beta- and alpha-Adrenoceptor antagonism by medroxalol in healthy volunteers: relationship to dose and plasma concentration.

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Administration, Oral↗

PubMedDate not supplied

Cardiac electrophysiological effects of medroxalol in anesthetized dogs.

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Adrenergic alpha-Antagonists↗

PubMedDate not supplied

Comparative cardiac electrophysiologic study of PK 10139, a new antiarrhythmic agent, and quinidine in anesthetized dogs: plasma concentration-response relationships.

Cardiac electrophysiologic effects of PK 10139 (PK), a new quinoleic antiarrhythmic agent, were compared with those of quinidine sulphate (Q) after three cumulative intravenous doses of 0.75, 1.5, and 3 mg/kg of PK and 5, 10, and 20 mg/kg of Q in anesthetized dogs. A control group of animals received saline solution only. Both PK and Q provoked an increase, correlated with plasma concentrations, in atrionodal (St-H), His-Purkinje system (HV), and auriculoventricular (QS) conduction times, and auricular effective and functional refractory periods (AERP, AFRP). The effects of PK on conduction times were more marked than those of Q. Slopes of the plasma concentration-effect curves were similar for the two drugs for HV and QS but different for St-H. PK was 42.5 times more potent than Q in increasing HV and 46 times more potent than Q in increasing QS. Effects of PK on AFRP and nodal FRP did not differ from those observed in control animals. These findings demonstrate more marked effects of PK, when compared with Q, at doses 6.7 times lower and at plasma concentrations 15 to 42 times less, without chronotropic effects or significant alterations in blood pressure, and without adverse reactions on the central nervous system.

Anesthesia↗