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Biomedical subjects

D G Shand

Publications and source records attributed to D G Shand.

At least 37 records · Page 2Linked to original sources
PubMed1983

Efficacy, safety, and pharmacokinetics of a concentration-maintaining regimen of intravenous pirmenol.

A 3-stage, concentration-maintaining intravenous infusion regimen of pirmenol, a new antiarrhythmic agent, was tested for efficacy and safety in 8 subjects with chronic, stable premature ventricular beats. The regimen, which consisted of (1) a priming bolus of 50 mg over 2 minutes, followed by (2) a rapid loading infusion of 2.5 mg/min for 1 hour, and (3) a maintenance infusion of 0.25 mg/min, rapidly achieved and maintained stable plasma pirmenol levels from 0.94 to 2.75 micrograms/ml, during infusions lasting up to 48 hours. Therapeutic efficacy was evaluated during 4-hour infusions in 5 patients utilizing a randomized, double-blind, placebo-controlled study design. Pirmenol suppressed average premature ventricular beat frequency 93 +/- 6% compared with control values (p = 0.03). Pirmenol infusions were unassociated with toxicity. There were slight but significant increases in diastolic blood pressure, QRS duration, and corrected Q-T interval. No significant changes occurred in systolic blood pressure, heart rate, P-R interval, or laboratory variables. Pirmenol is a promising therapeutic agent that warrants further evaluation. The 3-stage infusion satisfactorily achieves and maintains therapeutic plasma pirmenol levels.

Adult↗
PubMed1983

Evidence for cardiac beta 2-adrenoceptors in man.

We compared the effects of single doses of 50 mg atenolol (cardioselective), 40 mg propranolol (nonselective), and placebo on both exercise- and isoproterenol-induced tachycardia in two experiments involving nine normal subjects. Maximal exercise heart rate was reduced from 187 +/- 4(SEM) after placebo to 146 +/- 7 bpm after atenolol and 138 +/- 6 bpm after propranolol, but there were no differences between the drugs. The effects on isoproterenol tachycardia were determined before and after atropine (0.04 mg/kg IV). Isoproterenol sensitivity was determined as the intravenous dose that increased heart rate by 25 bpm (CD25) and this was increased from 1.8 +/- 0.3 micrograms after placebo to 38.9 +/- 8.3 micrograms after propranolol and 8.3 +/- 1.7 micrograms after atenolol. The difference in the effects of the two was significant. After atropine the CD25 was unchanged after placebo (2.3 +/- 0.3 micrograms) and atenolol (7.7 +/- 1.3 micrograms); it was reduced after propranolol (24.8 +/- 5.0 micrograms), but remained different from atenolol. This change with propranolol sensitivity was calculated as the apparent Ka, this was unchanged by atropine (11.7 +/- 2.1 and 10.1 +/- 2.5 ml/ng). These data are consistent with the hypothesis that exercise-induced tachycardia results largely from beta 1-receptor activation that is blocked by both cardioselective and nonselective drugs, whereas isoproterenol activates both beta 1- and beta 2-receptors so that after cardioselective blockade there remains a beta 2-component that can be blocked with a nonselective drug. While there appear to be beta 2-receptors in the human heart, their physiologic or pathologic roles remain to be defined.

Adult↗
PubMed1983

Verapamil plasma binding: relationship to alpha 1-acid glycoprotein and drug efficacy.

The relationship between alpha 1-acid glycoprotein (AAG) plasma concentration and plasma verapamil binding was examined in samples obtained 15 minutes after 10 mg IV verapamil to 15 subjects. There was a good correlation (r = 0.83) between the binding ratio and AAG concentration, suggesting that AAG could bind verapamil. This was confirmed in vitro by the addition of AAG to an albumin solution, which resulted in a strong correlation between binding ratio (r = 0.99) and AAG concentration. The relationship between both free and total plasma concentrations and the effects of verapamil on the PR interval was also examined several times after 10 mg IV verapamil in seven of the subjects. While there was a correlation between log of both concentrations and the percent prolongation in PR interval (P less than 0.001), the correlation was stronger with free drug concentration (r2 = 0.58) than with total plasma concentration (r2 = 0.36). The range of free concentrations associated with a given effect (220%) was also narrower than that for total concentration (300%). While these data indicate that AAG is responsible for most of the variability in plasma verapamil binding, which in turn contributes somewhat to variation in effectiveness of a given total plasma concentration, neither of these causes of individual variations is likely to have a major clinical impact in patients who, apart from arrhythmia, are otherwise healthy.

Chromatography, High Pressure Liquid↗
PubMed1983

Differentiation of hemodynamic, humoral and metabolic responses to beta 1- and beta 2-adrenergic stimulation in man using atenolol and propranolol.

The respective contributions of beta-adrenoceptor subtypes to the hemodynamic, humoral and metabolic consequences of adrenergic stimulation during graded exercise in man were investigated using nonselective beta-adrenoceptor blockade with propranolol and beta 1-adrenoceptor blockade with atenolol. Doses of these agents that produced comparable suppression of beta 1 response as measured by antagonism of cardioacceleration during exercise were selected. Six healthy, nonsmoking males received these drugs in a placebo-controlled, Latin-square, randomized manner using a double-blind protocol. Both drugs produced comparable reductions of systolic blood pressure and elevation of diastolic blood pressure compared with placebo as exercise load increased. Propranolol produced higher peak epinephrine levels than atenolol or placebo (808 +/- 162, 640 +/- 190 and 584 +/- 153 pg/ml, respectively, p = 0.03), but norepinephrine levels did not show significant differences. Plasma renin activity was similarly suppressed both at rest and during all grades of exercise by both drugs. Lactate levels during moderate exercise were significantly lower after propranolol than after either atenolol or placebo (p = 0.03), but were similar at heavy work loads. Plasma glucose values rose on placebo (from 96.5 +/- 2.1 to 97.7 +/- 2.7 mg/dl) and on atenolol (from 99.7 +/- 2.2 to 102.1 +/- 4.8 mg/dl), but fell on propranolol (from 96.4 +/- 1.9 mg/dl to 87.2 +/- 2.5 mg/dl, p less than 0.01). These results indicate that blockade of vascular smooth muscle beta 2 receptors does not substantially alter hemodynamics during intense short-term exercise. Stimulation of renin release and lipolysis are produced through beta 1-adrenoceptor mechanisms, whereas beta 2 adrenoceptors are important in the provision of carbohydrate as an energy substrate for exercising muscle.

Adult↗
PubMed1983

Clinical pharmacology of the beta-blocking drugs: implications for the postinfarction patient.

All available beta-adrenergic blocking agents share the property of blocking beta 1 adrenoceptors, including those in the heart. They differ, however, in their ability to block beta 2 receptors (cardioselectivity), their membrane stabilizing action, intrinsic sympathomimetic activity and their pharmacokinetic properties. The strongest evidence for efficacy in secondary prevention has been obtained with timolol, metoprolol and propranolol. Timolol and propranolol block all beta-receptor-mediated responses and are therefore nonselective, whereas metoprolol is relatively cardioselective. Propranolol and metoprolol have membrane stabilizing action, but timolol does not; none of these agents show intrinsic sympathomimetic activity. Thus, no ancillary property is a requirement for efficacy. All of these agents may precipitate heart failure, but this problem has been exaggerated, and transient failure during the early course of myocardial infarction is no longer a contraindication to therapy. Cardioselective agents cause less bronchospasm, but this can still occur, especially with higher dosages. In addition, these agents probably cause somewhat less fatigue and result in less hypertension during hypoglycemia than nonselective agents. The availability of at least three effective agents allows for a choice of therapy to offer individual patients.

Adrenergic beta-Antagonists↗
PubMed1982

Pharmacokinetics of verapamil: experience with a sustained intravenous infusion regimen.

Disappearance kinetic characteristics of verapamil were determined in 9 patients after a single intravenous dose. From the pharmacokinetic variables determined, we designed an intravenous regimen to maintain a plasma verapamil concentration of 150 ng/ml consisting of (1) a loading bolus (10 mg over 2 minutes), followed by (2) a rapid loading infusion (0.375 mg/min) for 30 minutes, and finally (3) a maintenance infusion (0.125 mg/min). We tested this regimen in 7 patients for 2 to 12 hours, and found it to be safe and to produce stable prolongation of the P-R interval. Verapamil concentration was highest immediately after the bolus administration and was prevented from falling below 67 ng/ml by the rapid infusion. Maintenance concentration remained between 77 and 156 ng/ml for all patients, and averaged 122 ng/ml. Transient and slight decreases in brachial blood pressure and sinus cycle length occurred coincident with the maximum verapamil concentration. Maximum P-R prolongation lagged behind peak plasma concentration but was sustained for the duration of the infusion. Prolongation of the P-R interval was not significantly different at the end of the infusion from that 90 minutes after the start of the regimen. No patient demonstrated significant side effects, arrhythmia, or clinically important hypotension. Although the specified regimen produced a final concentration averaging 125 ng/ml, it is predicted that infusion regimens producing other plasma concentrations can be similarly devised by changing the bolus, rapid loading infusion, and maintenance infusion doses in proportion to the desired final plasma concentration.

Adult↗
PubMed1982

Hemodynamic effects of the antiarrhythmic drug pirmenol.

We examined the hemodynamic effects of pirmenol, a new antiarrhythmic drug, for the first time in man. Right and left heart pressures, Fick cardiac output, and radionuclide ejection fraction were measured before and during infusion of pirmenol in 10 patients with coronary artery disease who were undergoing routine diagnostic cardiac catheterization. Pirmenol was given as a 50-mg IV injection over 2 min followed by a constant infusion of 2.5 mg/min for up to 36 min. Plasma pirmenol levels were within or near the previously determined therapeutic range in all patients. There were no significant changes in systolic blood pressure or cardiac output. Diastolic blood pressure rose from a mean (+/- SD) 78 +/- 7 during the control period to 82 +/- 6 during the infusion, heart rate rose from 66 +/- 6 during the control period to 75 +/- 7 during infusion and ejection fraction fell from 60 +/- 8 during control to 55 +/- 12 during infusion. Although the left ventricular end-diastolic pressure rose from 6 +/- 2 during control to 8 +/- 3 during the infusion, the left ventricular stroke work index fell and the left ventricular work index per minute did not change. The fall in ejection fraction did not correlate with the control ejection fraction, plasma pirmenol levels, or the change in heart rate. The decline in ejection fraction and the failure of the left ventricular work index per minute to rise despite a small rise in left ventricular end-diastolic pressure may indicate a potential myocardial depressant effect of pirmenol.

Anti-Arrhythmia Agents↗
PubMed1982

Pirmenol kinetics and effective oral dose.

The oral form of pirmenol has not been administered to man. Pirmenol was given by mouth to eight patients with chronic, stable premature ventricular beats (PVBs) to determine effective dose and kinetics. The patients were evaluated with a dose-ranging protocol following by a double-blind, crossover, placebo-controlled study of doses that were effective during dose ranging. Oral doses of 150 to 250 mg induced at least 90% suppression of PVBs 18 of the 19 times they were administered during both protocols. During the double blind experiment, a single oral dose of pirmenol suppressed 95 +/- 8% PVBs/hr (mean +/- SD) for 3 consecutive hr, while placebo suppressed 4 +/- 42% PVBs/hr (P less than 0.01). a 90% or greater reduction in PVBs persisted for a median of 6 hr (range 1 to 8 hr). The range of plasma pirmenol concentrations associated with an at last 90% reduction in PVBs was 0.7 to 2.0 micrograms/ml. Median half-life (t1/2) was 9.3 hr (range 6.0 to 12.4) with 86.6 +/- 2.4% protein binding and 82.6 +/- 23.6% bioavailability. At peak drug level there was lengthening of the QTc interval (0.036 sec, P less than 0.05), but no change in heart rate, blood pressure, PR interval or QRS duration, or symptoms. In this single-dose study, pirmenol effectively reduced PVBs, has a relatively long t1/2, and was minimally toxic.

Administration, Oral↗
PubMed1982

Comparison of intravenous and oral verapamil dosing.

To compare the effects of intravenous and oral verapamil we examined the prolongation of the PR interval in 11 patients after (1) a single 10 mg IV bolus given over 2 min, (2) a single oral dose of 120 mg, and (3) a sustained concentration-maintaining infusion. Maximal PR interval prolongation was delayed relative to peak plasma verapamil concentration in all patients after the bolus and in seven of 11 patients after oral dosing. In all 11 patients oral verapamil was less potent than a single intravenous bolus of verapamil; the plasma verapamil concentration corresponding to a 10% prolongation of the PR was 39.5 +/- 21.7 ng/ml after the bolus and 146.3 +/- 75.1 ng/ml after the oral dose (P = 0.001). However, there was no such difference between oral verapamil and an infusion in six patients. The plasma verapamil concentration corresponding to a 10% PR prolongation was 35.7 +/- 24 ng/ml after the bolus, 132.5 +/- 80.8 ng/ml after the oral dose, and 85.2 +/- 29.9 ng/ml after the infusion. Maximum PR prolongation (drug efficacy) was comparable for the three methods of administration. There was no evidence of tachyphalaxis during prolonged infusions. We conclude that both oral doses and infusions of verapamil are less potent then bolus doses, but that drug efficacy at the concentrations reached is equivalent for the three. Plasma verapamil concentrations determined after bolus doses appear to underestimate effective plasma concentration when the drug is given by the oral or infusion methods.

Administration, Oral↗
PubMed1982

Diazepam and lidocaine plasma protein binding in renal disease.

The plasma protein binding of diazepam and lidocaine was measured in patients with renal disease (those with uremia, nephrotic syndrome, or who had received a transplant) and in age- and sex- matched control subjects. Percentage unbound diazepam in plasma was increased over control in all three groups of patients as follows: uremic patients 3.23%, control, 1.64% (P less than 0.001), nephrotic patients, 3.55%, control, 1.63% (P less than 0.001); and transplant recipients, 2.11%, control 1.50% (P less than 0.001). The binding ratio (molar concentration of bound to unbound drug) in patients was related to albumin concentration (r = 0.609, P less than 0.001). Percentage of unbound lidocaine did not differ substantially from control in nephrotic patients (34.2%, control 30.8%), but was reduced in the uremic patients (20.8%, control 30.7%, P less than 0.001) and transplant recipients (24.6%, control 33.7%, P less than 0.005). These increases were associated with increases in alpha 1-acid glycoprotein (AAG) concentration (uremic patients 134.9 mg/dl, control 66.3, P less than 0.001; transplant recipients 106.5, control 65.6, P less than 0.001). The binding ratio of lidocaine was closely related to the AAG concentration in patients (r = 0.933, P less than 0.001) and controls (r = 0.719, P less than 0.001). Thus, the binding of basic drugs may be increased or decreased in patients with renal disease, depending on the relative contribution of the individual plasma to the total binding and the type of disease.

Adult↗
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↗
PubMed1982

Biological determinants of altered pharmacokinetics in the elderly.

The biological determinants of drug disposition have been clearly identified and methods are available to quantify what effects altering them will have on drug kinetics. The factors include blood flow and intrinsic clearance of the organ of elimination, drug binding in blood and tissues, and, in the case of drugs eliminated by the liver, the oral route of administration. The effects of these various factors on drug elimination depend on the efficiency of the elimination process. At one end of the spectrum, some drug elimination is very efficient as it is largely flow-dependent, while at the other elimination depends largely on intrinsic clearance. The oral route of elimination may be important for drugs which undergo efficient hepatic extraction, when a large "first-pass" effect results. In addition, that fraction of the drug escaping first-pass elimination is largely dependent on intrinsic clearance and not flow. Finally, plasma drug binding may affect both elimination and drug distribution. The way in which these factors can be affected by the aging process will be discussed and illustrated with examples showing how changes in organ blood flow, intrinsic clearance and plasma drug binding can produce pharmacokinetic changes seen in the elderly.

Aged↗
PubMed1982

Pirmenol, a new antiarrhythmic agent: initial study of efficacy, safety and pharmacokinetics.

Pirmenol (CI-845), a new antiarrhythmic drug, was studied for the first time in humans to establish a minimum effective i.v. dose in 10 patients with chronic, stable premature ventricular complexes (PVCs) and to evaluate toxicity and pharmacokinetics. Infusions of 70-150 mg were associated with a 90% or greater reduction in PVCs nine of the 12 times they were administered to six patients. Peak plasma concentrations were 1.0-3.8 micrograms/ml at the end of these infusions. At the same time, small but significant increases in diastolic blood pressure (4 mm Hg) and QTc interval (0.01 second) were seen, but both values were within the normal range. Pirmenol was associated with no change in heart rate, systolic blood pressure, PR interval or QRS duration, renal, hepatic or hematologic function, or symptoms. Blood, plasma and free drug concentrations declined biexponentially after cessation of a 150-mg infusion (n = 4), with a terminal half-life of 7-9.4 hours. The therapeutic response, lack of toxicity, and relatively long half-life indicate that pirmenol is a promising antiarrhythmic agent.

Anti-Arrhythmia Agents↗