PubMed Health⌕ Search

Biomedical subjects

A Barchowsky

Publications and source records attributed to A Barchowsky.

48 records · Page 3Linked to original sources
PubMed1984

Simultaneous determination of lidocaine and its metabolites in plasma and myocardium.

No validated method exists for measuring lidocaine and its metabolites in myocardial tissue. We modified a previously described high-performance liquid chromatographic assay and applied it to plasma and to homogenized myocardial samples obtained from dogs that had received lidocaine by a double-infusion technique. Recovery of lidocaine, monoethylglycylxylidide and glycylxylidide after homogenization and extraction is reported. Assay variability, sensitivity and linearity over a wide range of sample sizes are also described. The results obtained with high-performance liquid chromatographic analysis are compared to quantitation of 14C-labeled lidocaine plus metabolites measured by an oxidation-scintillation technique. Myocardium to plasma partition coefficients for lidocaine, monoethylglycylxylidide and glycylxylidide were 2.16, 4.27, and 2.91, respectively.

Animals↗
PubMed1984

The effect of prostaglandin synthesis inhibition on the direct stimulation of renin release from rabbit renal cortical slices.

Prostaglandins have been hypothesized to have several mechanistic functions in sympathetically mediated release of renin. The rabbit renal cortical slice system was chosen to examine the prostaglandin dependency of renin release directly stimulated by either a direct adenylate cyclase activator, forskolin, or a beta-agonist, isoproterenol. In this study, we demonstrate that with forskolin (1 X 10(-5) M) or isoproterenol (1 X 10(-6) M), renin release was elevated 2-3 fold above control, and that this increase was shown to accompany a substantial increase in the tissue levels of cAMP (19.5 fold and 3.5 fold respectively). We also demonstrate that the increase in renin release produced by these compounds was not inhibited by cyclooxygenase inhibitors, indomethacin (25 microM) or eicosatetraynoic acid (30 micrograms/ml), nor was it inhibited by the selective prostacyclin synthesis inhibitor, U-51605 (30 micrograms/ml). Each of these inhibitors was demonstrated to block the synthesis of prostaglandins in the cortical slices at the concentrations used. Thus we propose that prostaglandins do not play a role in the induction of renin release resulting from elevated cyclic nucleotide levels or beta-adrenergic stimulation.

Adenylyl Cyclase Inhibitors↗
PubMed1982

Mechanism of bradykinin-stimulated prostacyclin synthesis in porcine aortic endothelial cells.

Porcine aortic endothelial cells studied at confluence were found to synthesize both prostacyclin and prostaglandin E2. Addition of arachidonic acid, bradykinin, the calcium ionophore A23187 or thrombin stimulated prostaglandin formation, whereas addition of angiotensin II did not. Bradykinin was found to stimulate very potently arachidonic acid release from cells prelabelled with [3H]arachidonate, the response being dose-dependent and half-maximal at 8 ng/ml. The rate of release of label (primarily arachidonate) from cells was increased by bradykinin (100 ng/ml) approximately 8-fold, with a return to control levels by 10 min. The calcium ionophore, A23187, similarly released [3H]arachidonic acid from prelabelled cells; the rate of release was approximately linear for 15 min. Both bradykinin and ionophore A23187 stimulated [3H]arachidonate release from endothelial cell phospholipids, an effect which was abolished in a dose-dependent manner by mepacrine. Release in response to bradykinin was prevented by incubation in Ca2+-free medium. Trifluoperazine, a compound which can inhibit calmodulin-mediated events, blocked the release of label stimulated by bradykinin. These data indicate that the likely mechanism of bradykinin-stimulated prostaglandin production in endothelial cells involves the activation of a phospholipase via a Ca2+-calmodulin-dependent pathway.

Animals↗
PubMed1982

Control of lidocaine therapy: new perspectives.

Although lidocaine has been available for clinical use for 30 years, it still retains an important place amongst antiarrhythmic drugs. It is still widely regarded as the first line of therapy in ventricular arrhythmias occurring after myocardial infarction or cardiac surgery. Recently, however, its use has been advocated in the prophylaxis of primary ventricular fibrillation occurring after myocardial infarction. This recommendation is based primarily on the well-designed and controlled study of Lie and co-workers (1). The results of this study have been reviewed and compared with the results of 11 other studies showing no significant effect of lidocaine in this situation (2). One other study did show that lidocaine gave protection against primary ventricular fibrillation (3). The authors concluded, however, that all the other studies had major defects in trial design, and were prepared to accept the conclusion that lidocaine was effective in preventing primary ventricular fibrillation after myocardial infraction. Similar conclusions were made by De Silva and co-workers (4). As a result, the drug is given in several centres in the U.S.A. to patients admitted with suspected acute myocardial infarction, particularly those aged less than 70 years who are seen within 6 h of the onset of chest pain (5,6).

Blood Proteins↗
PubMed1982

Saliva concentrations of lidocaine and its metabolites in man.

The plasma concentrations of lidocaine and its two major active metabolites, monoethylglycylxylidide (MEGX) and glycylxylidide (GX), were measured in simultaneously mixed saliva and plasma samples from 16 patients who had received the drug intravenously for at least 12 h. The concentrations of each compound in saliva tended to be greater than those in the corresponding plasma sample, so that the mean saliva-to-plasma ratio for lidocaine was 2.9 (median, 2.65); for GX, 4.7 (median 2.2); and for MEGX, 7.0 (median, 6.4). There was a statistically significant, although rather weak, relationship between the saliva and the total plasma lidocaine concentrations (r = 0.700; n = 16; p less than 0.01) and between the saliva and the free (unbound) plasma lidocaine concentrations (r = 0.509; n = 16; p less than 0.05). When the latter was corrected for the effect of pH, the relationship was significant but still weak (Spearman's P = 0.619; p less than 0.05). It appears that mixed salivary lidocaine concentrations are a relatively poor guide to free drug concentrations at steady state, even if correction is made for pH changes. Other rapid and convenient methods of estimating free plasma lidocaine concentrations are clearly needed.

Biotransformation↗
PubMed1982

On the role of alpha 1-acid glycoprotein in lignocaine accumulation following myocardial infarction.

1 Blood plasma and free lignocaine concentrations have been measured 12 h after beginning a constant infusion of 2 mg/min and again at the end of the infusion (36-72 h) in five patients with myocardial infarction (MI) and compared with five control patients who did not develop objective evidence of MI. 2 In MI patients, total plasma concentration rose significantly between 12 h and the end of infusion. Because of an increase in alpha 1 acid glycoprotein (AAG) plasma binding increased, so that free drug concentration did not change. The rise in whole blood concentration was less than that in plasma as a result of drug redistribution out of red cells due to enhanced binding. 3 In control patients, neither blood nor plasma concentrations changed with time and plasma binding remained constant. Free drug concentrations, however, rose slightly. 4 The concentrations of GX and MEGX remained unchanged in all patients, but the ratio of lignocaine/MEGX concentrations fell in controls but rose in MI patients. 5 Pharmacokinetic modelling suggested that at least some of the rise in blood lignocaine concentration was due to reduced clearance resulting from enhanced plasma binding. 6 We conclude that the rise in AAG following MI is responsible for increased plasma binding and drug redistribution within blood. These changes, together with a reduction in lignocaine clearance, can explain much of the phenomenon of lignocaine accumulation in MI.

Adult↗
PubMed1981

Clinical comparison of rapid infusion and multiple injection methods for lidocaine loading.

A rapid infusion regimen for lidocaine loading (150 mg infusion over 18 minutes following a 75 mg priming injection) was evaluated in 12 patients. This was compared with multiple injection loading method in six patients involving three 50 mg injections over 18 minutes following the same priming dose. Both loading regimens were followed by a maintenance infusion of 2 mg/min. Predictably, the multiple injection method produced wide variations in lidocaine concentrations compared to the rapid infusion method. Some evidence of lidocaine toxicity (drowsiness, tinnitus) was seen in 13 of the 18 patients after the priming injection. During multiple injection loading, all six patients experienced side effects (drowsiness, tinnitus, dysarthria, or paresthesias.) Only 1 of 12 patients experienced a side effect (drowsiness) during rapid infusion loading. The difference in incidence of adverse reactions was significantly greater with the multiple injection regimen (p less than 0.01) but was associated with measurably greater drug levels.

Adult↗
PubMed1981

Relationship between alpha 1-acid glycoprotein and lidocaine disposition in myocardial infarction.

The effects of myocardial infarction (MI) on lidocaine disposition were investigated in eight patients during a constant infusion of 2 mg/min. Plasma lidocaine binding and total plasma and free lidocaine concentrations were measured 12, 24, 36, and 48 hr after beginning therapy and were related to alpha 1-acid glycoprotein (AAG) concentrations. By 48 hr total plasma lidocaine and AAG concentrations had risen, as had plasma lidocaine binding. Because of enhanced binding, free lidocaine concentrations did not change significantly over this time. There was a correlation between AAG and the binding ratio for lidocaine (r = 0.87) and between AAG and total plasma lidocaine concentrations (r = 0.81). The data suggest that the rise in AAG seen after MI is responsible for enhanced plasma lidocaine binding and may, at least in part, be related to lidocaine cumulation.

Adult↗
PubMed1981

Sex-related differences in the plasma protein binding of lignocaine and diazepam.

1 The percentage of lignocaine free in the plasma of ten females receiving oral contraceptive medication was significantly greater than in 17 males of similar age (18--42 years). 2 In the same subjects the percentage of diazepam free in plasma was significantly greater in the contraceptive treated group than in 11 contraceptive-free females and significantly greater in contraceptive-free females than in males. 3 The differences in lignocaine binding were almost completely attributable to changes in alpha 1-acid glycoprotein concentration, which is reduced by oestrogens. The binding of diazepam was significantly related to albumin, alpha 1-acid glycoprotein and non-esterified fatty acid concentrations which together were related to 55% of the variation in the binding of this basic compound.

Adult↗
PubMed1981

Lignocaine disposition in blood in epilepsy.

1 The plasma concentration of alpha 1-acid glycoprotein (AAG) was significantly greater in 27 epileptic subjects receiving anticonvulsants compared with 27 age- and sex-matched drug-free control subjects. 2 Increased AAG concentration was associated with enhanced lignocaine binding in the plasma of epileptics. 3 Increased AAG concentration was also associated with a redistribution of lignocaine out of red cells and into plasma thus lowering the blood to plasma concentration ratio. 4 Enhanced lignocaine binding in epileptics receiving anticonvulsant therapy may result in lower free (unbound) plasma concentrations of the drug compared to normal subjects with equivalent total plasma lignocaine concentrations.

Adult↗
PubMed1980

Lidocaine plasma protein binding.

The percent of unbound lidocaine in the plasma of 24 healthy subjects was measured by equilibrium dialysis after addition of 3 microgram/ml C14 lidocaine hydrochloride. The percentage of unbound lidocaine varied from 19.9 to 38.8 (30.2 +/- 5, mean +/- SD) was inversely related to the concentration of alpha 1-acid glycoprotein (AAG) in the plasma (r = -0.931, p less than 0.001). The binding ratio (number of moles bound divided by number of moles unbound) of lidocaine was directly related to the plasma AAG concentration (r = 0.960, p less than 0.001). The binding ratio of lidocaine in solutions containing AAG but no albumin, prepared from the plasma of subjects in the study, was also directly related to the concentration of this acute-phase protein (r = 0.909, p less than 0.001). Human serum albumin solution (4 gm/100 ml) bound lidocaine to the extent of 20% under the same conditions. There was no relationship between the binding ratio of lidocaine and the albumin concentration in the plasma of the 24 subjects. In 7 normal subjects variation in AAG between 2 samples collected at least 1 mo apart was associated with a concomitant change in plasma lidocaine binding (r = 0.943, p less than 0.01). Thus even in normal subjects there is considerable interindividual and intraindividual variation in lidocaine binding, and measurements of AAG concentration in plasma may be a useful predictor of the extent of lidocaine plasma binding.

Adult↗