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Biomedical subjects

W J Louis

Publications and source records attributed to W J Louis.

At least 91 records · Page 5Linked to original sources
PubMed1990

Regulatory demands for cost-benefit studies.

In 1987 to 1988 there was a significant increase in drug costs in Australia. This was largely the result of the introduction of angiotensin-converting enzyme inhibitors into clinical practice. In this article the implications of escalating drug costs are examined. The impact of revolutionary new drugs is considered, and it is questioned whether even a relatively wealthy country, such as Australia, can afford the high costs of these new agents. The Australian Pharmaceutical Benefits Scheme is discussed, and modification of this into a two-tier system is proposed. A two-tier system could preserve the present list and the essential elements of the current scheme but would introduce a second list of new drugs for which a premium would be charged. Such a system could recoup costs generated by new drugs and also restrict overprescribing but may limit the prescription of new drugs to less well-off persons. The article concludes by considering the total health care budget, taking into account the relative cost-benefit expenditures of hospital care and drug therapy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Acute myocardial uptake of digoxin in humans: correlation with hemodynamic and electrocardiographic effects.

Acute myocardial uptake of digoxin was measured at a constant paced heart rate (75 beats/min) for 30 min after an intravenous bolus injection of 500 micrograms of digoxin in 14 patients with ischemic heart disease. Myocardial digoxin content, determined by serial measurement of aortocoronary sinus digoxin concentration gradients and coronary sinus blood flow, was expressed relative to coronary sinus blood flow at rest and correlated with simultaneous hemodynamic and electrocardiographic changes. Myocardial digoxin uptake was extensive (4.1 +/- 0.7% of total injected dose at 30 min) and prolonged, with rapid initial uptake (75.3 +/- 6.6% of maximum at 3 min), followed by a variable phase of slower accumulation. Peak left ventricular positive first derivative of left ventricular pressure (dP/dt) increased progressively (p less than 0.01), with a similar time course to that of myocardial digoxin accumulation; maximal change was 18.5 +/- 4.7% at 27 min. The ratio of inotropic effect to myocardial digoxin content did not vary significantly over the period of the experiment. However, peak inotropic effects in individual patients were not significantly related to peak myocardial digoxin content. The spontaneous PR interval increased transiently, with a peak increase of 5.9 +/- 1.8% (p less than 0.05) 12 min after digoxin administration. It is concluded that after intravenous bolus administration, 1) peak effects of digoxin on atrioventricular (AV) conduction occur early, whereas positive inotropic effects increase progressively for greater than or equal to 27 min; and 2) digoxin accumulation in the human myocardium is prolonged and is a determinant of inotropic effects, but not of prolongation of AV node conduction.

Aged↗
PubMed1990

The effect of hepatic cirrhosis on the pharmacokinetics and blood pressure response to nicardipine.

The present study was designed to compare the pharmacokinetic handling of a single oral dose of nicardipine in normal subjects and in patients with hepatic cirrhosis and to compare the sensitivity of the two groups to its hypotensive effect. Nicardipine plasma concentrations were substantially higher in the subjects with hepatic cirrhosis with impaired antipyrine clearance, as shown by a significantly higher average Cmax and AUC. The terminal elimination half-life in this group varied from 0.8 to 60.2 hours (median, 11.7 hours), compared with 0.6 to 4.1 hours (median, 1.4 hours) in the group of eight subjects with normal liver function. In the cirrhotic patients with impaired antipyrine clearance, the AUC of the pyridine metabolite averaged 10% of that of the parent drug, whereas in normal subjects the ratio averaged 48%. This finding suggests less conversion of nicardipine to this metabolite in subjects with impaired hepatic function. Peak blood pressure decreases were greater in the cirrhotic group, which was in keeping with the higher plasma levels in these subjects.

Adult↗
PubMed1990

Nitrate tolerance induced by nicorandil or nitroglycerin is associated with minimal loss of nicorandil vasodilator activity.

In the current study, the vasodilator and tolerance-inducing actions of a recently developed organic nitrate vasodilator, nicorandil, were compared to nitroglycerin (NTG) in an isolated coronary artery preparation. The order of potency for relaxing U46619-constricted bovine-isolated coronary artery rings was NTG greater than isosorbide dinitrate (ISDN) greater than nicorandil. NTG was approximately 250-fold more potent than nicorandil (mean EC50 values for relaxation; 0.044 and 11.2 microM, respectively; n = 6-8). Coronary artery rings preexposed for 60 min to NTG (30 microM) were subsequently markedly less responsive to the relaxant effects of NTG (7.5-fold increase in mean EC50 value, 68.4% decrease in Emax; p less than 0.001) and ISDN (14.1-fold increase in mean EC50 value; p less than 0.001), although only marginally less responsive to nicorandil (1.75-fold increase in mean EC50 value; p less than 0.05). Thus, the coronary artery relaxant actions of nicorandil were significantly less affected by NTG-induced tolerance than were the relaxant actions of the related organic nitrate compounds, NTG and ISDN. To compare the tolerance-inducing actions of NTG and nicorandil, the relaxant actions of a series of nitric oxide (NO)-containing vasodilators were determined in control coronary artery rings and in rings preexposed for 60 min to either 30 microM NTG or 5,000 microM nicorandil. Quantitatively, similar changes in coronary artery ring responsiveness were produced by tolerance induced by NTG and nicorandil; marked attenuation of responsiveness to NTG and to the nonnitrate compound 3-morpholinosydnonimine (SIN-1), but only marginal attenuation of responsiveness to nicorandil and NO.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Determinants of acute hemodynamic and electrophysiologic effects of verapamil in humans: role of myocardial drug uptake.

To examine the relationship between myocardial verapamil content (MVC) and acute effects in humans, coronary sinus catheterization was used in 22 patients to determine myocardial uptake of verapamil after bolus intravenous (i.v.) verapamil (4 mg) injection. Verapamil-induced effects on hemodynamic and electrophysiologic parameters were measured simultaneously and correlated with MVC per unit baseline coronary sinus blood flow (MVC:F). Myocardial uptake of verapamil was rapid: peak MVC (1.2 +/- 0.2% of injected dose) occurred at 5.4 +/- 0.4 min; at 30 min, residual MVC was 71.1 +/- 3.4% of maximum. Peak MVC:F in individual patients was inversely related to the extent of coronary artery disease (p less than 0.005) but not to left ventricular (LV) systolic function. Verapamil produced significant (p less than 0.001) early reductions in arterial pressure and systemic vascular resistance (SVR); cardiac index (CI) increased, left ventricular (LV) positive dP/dt was unchanged. Verapamil prolonged (p less than 0.01) PR and AH intervals (maximum at 12-18 min) and atrioventricular (AV) nodal effective and functional refractory periods (ERP, FRP) (maximum at 30 min). In individual patients, the extent of changes in AH intervals (r = 0.69; p less than 0.05) and LV dP/dt (r = 0.62; p less than 0.05) correlated with peak MVC:F. We conclude that after i.v. injection, verapamil uptake by the human myocardium is rapid and more extensive in patients with minor coronary artery disease. Despite the hysteresis between MVC and drug effects, MCV is a determinant of inotropic and electrophysiologic effects of verapamil.

Adult↗
PubMed1990

The effects of a single dose of dilevalol on [3H]-noradrenaline plasma kinetics and plasma lipoprotein cholesterol concentrations.

1. A single oral dose of dilevalol (200 mg or 400 mg) or placebo was administered to 15 normal male volunteers in a double-blind, random order crossover study. 2. Dilevalol had no significant effect on supine blood pressures or heart rates, but caused a significant fall in systolic blood pressure 1 and 30 min following standing, and attenuated the rise in diastolic blood pressure and heart rate that accompanies standing. 3. Dilevalol caused a dose dependent increase in plasma noradrenaline levels from arterialized blood which was due to an increase in noradrenaline spillover with no change in clearance. 4. Dilevalol increased plasma levels of the noradrenaline metabolite 3,4-dihydroxyphenylethylene glycol (DHPG) (which is formed in sympathetic nerves following neuronal uptake of noradrenaline), indicating that the increase in noradrenaline spillover was not due to the blockade of neuronal uptake. 5. Acute dilevalol administration had no effect on total plasma cholesterol, HDL-cholesterol or LDL-cholesterol levels.

Adult↗
PubMed1990

Relationship between systemic and coronary vascular responses to digoxin and concurrent drug therapy with verapamil/beta-adrenoceptor antagonists in humans.

1. In 24 patients who were undergoing coronary arteriography for the assessment of ischaemic heart disease, the relationship between the systemic and coronary vascular responses to acute intravenous digoxin administration (500 micrograms) and concurrent drug therapy with the calcium antagonist verapamil (group I) or a beta-adrenoceptor antagonist (group II) or neither of these agents (group III) was examined. 2. Systemic vascular resistance (SVR) tended to rise rapidly after digoxin injection in patients in groups II and III, and tended to decline initially in patients in group I; however, these differences were not statistically significant (variance ratio [VR] = 0.77). 3. No significant differences were observed in coronary vascular responses to acute digoxin administration between the three groups of patients (VR = 0.34). 4. For the entire group of 24 patients, no statistically significant digoxin-induced effects on resistance could be demonstrated in either the systemic or coronary circulations, although in individual patients vasoconstrictor effects were observed. 5. We conclude that acute intravenous administration of digoxin does not consistently cause systemic or coronary vasoconstriction in patients with ischaemic heart disease. Variability in vasomotor responses to digoxin is not clearly related to concurrent drug therapy with verapamil or a beta-adrenoceptor antagonist. The observation that systemic vascular resistance tends to increase in the first few minutes after digoxin injection should be addressed in future studies.

Adrenergic beta-Antagonists↗
PubMed1990

Steady state plasma [3H]-noradrenaline kinetics in quadriplegic chronic spinal cord injury patients.

1. Steady state plasma noradrenaline kinetics were measured in eight male quadriplegic patients and in eight age and sex matched controls. 2. Plasma noradrenaline levels were significantly lower in quadriplegic patients compared to controls. Noradrenaline spillover rate was markedly reduced in quadriplegics compared to controls while noradrenaline clearance was similar in both groups. 3. Noradrenaline kinetics in quadriplegic patients differ from peripheral autonomic neuropathy patients where reductions in both the spillover and clearance of noradrenaline are present.

Adult↗
PubMed1990

Genealogy of the spontaneously hypertensive rat and Wistar-Kyoto rat strains: implications for studies of inherited hypertension.

The spontaneously hypertensive rat (SHR) is the most commonly used animal model of hypertension. For many years, it has been widely accepted that the most appropriate control strain is the Wistar-Kyoto (WKY) rat to which SHR rats are genetically related. However, recent concerns have been raised about genetic differences between the various colonies of SHRs and, in particular, genetic differences between colonies of WKY rats. It has been further emphasized that the only way to establish that a genetic trait is an etiological factor in the development of hypertension is through studies of F2 backcrosses between SHR and WKY rats. The present article details the history of the SHR and WKY strains and demonstrates why there is high likelihood of genetic variability between rats of both strains from different colonies around the world. It suggests that the WKY strain is not the most suitable for backcross studies because of the incidence of spontaneous hypertension and the somewhat higher levels of blood pressure in these rats. A central reference strain is proposed using SHRs inbred at Kyoto University, where brother/sister inbreeding has continued for more than 80 generations.

Animals↗
PubMed1990

Impaired arterial baroreceptor reflex and cardiopulmonary vagal reflex in conscious spontaneously hypertensive rats.

The activity of baroreceptor reflexes and cardiopulmonary reflexes was examined in conscious spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) rats. The baroreceptor heart rate reflex, elicited by phenylephrine- and nitroprusside-induced changes in blood pressure, had a reduced range and lower heart rate plateau in SHR than in WKY rats, which suggests impaired vagal control of the heart rate in SHR. Cardiopulmonary receptor reflex activity was assessed by intravenous injections of phenyldiguanide which evoke the Bezold-Jarisch reflex. Phenyldiguanide elicited dose-dependent bradycardic and hypotensive responses in WKY rats, but these were significantly attenuated in SHR. This is the first demonstration of impaired Bezold-Jarisch responses in conscious SHR and provides evidence of both impaired vagally mediated arterial baroreceptor activity and impaired cardiopulmonary receptor activity in this rat strain.

Animals↗
PubMed1989

Excitotoxin-induced lesions of the central but not basolateral nucleus of the amygdala modulate the baroreceptor heart rate reflex in conscious rats.

The present study has examined the influence of the central nucleus of the amygdala (Ce) and the basolateral nucleus of the amygdala (BL) on the baroreceptor heart rate (HR) reflex in conscious, unrestrained rats. Baroreceptor HR reflex activity was examined in rats with bilateral excitotoxin (N-methyl-D-aspartate; 40 nmol/side)-induced lesions of the Ce or the BL and in control rats (artificial cerebrospinal fluid). After lesioning, the reflex HR responses were recorded following intravenous bolus doses of the pressor agent phenylephrine and the depressor agent sodium nitroprusside. Baroreceptor reflex parameters were determined by sigmoidal computerized curve-fitting. Lesions of either the Ce or the BL failed to affect resting mean arterial pressure (MAP) or HR. However, the Ce lesion reduced the maximum and average gain (sensitivity) of the baroreceptor reflex, and diminished the range of the reflex by altering the minimum, but not the maximum HR plateau. The upper and lower reflex thresholds and the MAP value corresponding to the midpoint of the HR range were not affected. Bilateral lesions of the BL failed to modify any baroreceptor reflex parameters. These results suggest that despite previous evidence for the involvement of the BL in cardiovascular regulation this nucleus does not exert a tonic influence on vasomotor neurons nor does it influence the baroreceptor HR reflex. In contrast, neurons projecting from the Ce appear to provide excitatory input to medullary neurons involved in baroreceptor reflex are regulation.

Amygdala↗
PubMed1989

Pharmacokinetics and antihypertensive effects of low dose clonidine during chronic therapy.

Using a sensitive and specific radioimmunoassay the pharmacokinetic disposition of clonidine was determined in hypertensive patients after a single dose and then after 5, 28 and 56 days of chronic dosing with 75 micrograms bd. Following a single dose of clonidine maximal plasma concentrations of 0.34 +/- 0.06 ng/ml were achieved after 3.6 +/- 1.2 hours. After 5 days of repetitive dosing the maximal concentration was significantly higher, 0.66 +/- 0.06 ng/ml and remained so throughout chronic therapy (P = 0.018). The AUC, Tmax and T1/2 did not differ significantly between the acute dose and the chronic dosing pharmacokinetic studies. Clonidine also produced a significant fall in blood pressure. Supine diastolic blood pressure fell from 106 +/- 5 mmHg predose to 99 +/- 6 mmHg 2 hours after the first dose (P less than 0.05). The corresponding values after cyclopenthiazide alone were 108 +/- 8 and 105 +/- 8 mmHg (P = 0.13). Similar falls in blood pressure were produced during chronic therapy.

Adult↗
PubMed1989

Prediction of acute myocardial disposition of antiarrhythmic drugs.

Using peripheral blood concentration and myocardial content data (from coronary sinus catheterization and serial determination of transmyocardial drug concentration gradients) from a previous clinical study of the antiarrhythmic drugs lidocaine and mexiletine, we tested the hypothesis that two prospectively defined models of myocardial drug disposition could be used to predict myocardial drug content, in the first 30 min following bolus iv injection, from peripheral blood concentrations alone. Compartmental analysis of peripheral blood concentration data from prolonged blood sampling (three-compartment model) and from the first 30 min after drug injection (two-compartment model) was used to calculate drug content, during the first 30 min, in the second compartment of each of the models. The time course of calculated compartmental content was similar to that of the measured myocardial content in 16 of the 18 patients studied, although there were some differences in the time of peak content. This relatively noninvasive method may therefore be useful in predicting the time course of myocardial drug content after acute iv drug administration.

Anti-Arrhythmia Agents↗
PubMed1989

Excitatory amino acid receptors in the caudal ventrolateral medulla mediate a vagal cardiopulmonary reflex in the rat.

The importance of the caudal ventrolateral medulla (CVLM) in mediating vagal cardiopulmonary (Bezold-Jarisch reflex) reflex activity was studied in urethane-anaesthetized rats. Unilateral electrolytic lesion of the CVLM markedly attenuated Bezold-Jarisch reflex responses (hypotension and bradycardia) elicited by intravenous injections of 5-HT. Bilateral lesion of the CVLM virtually abolished the reflex responses. Microinjection of the excitatory amino acid (EAA) receptor antagonist kynurenate (KYN), but not the inactive analogue xanthurenate, into the CVLM markedly attenuated the reflex responses to 5-HT. The N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 also markedly attenuated reflex activity. Furthermore, lesions, KYN and MK-801 all tended to elevate resting blood pressure and to reduce resting heart rate. These findings support the hypothesis that the CVLM is an important medullary locus mediating cardiovascular reflex integration and that an EAA synapse in the CVLM is important in the cardiopulmonary reflex arc.

Animals↗
PubMed1989

The cost of new drugs in the treatment of hypertension--the Australian experience.

The treatment of hypertension by costly new drugs such as the angiotensin converting enzyme inhibitors, means that careful monitoring of health care expenditure is essential. If drugs like simvastatin come to be widely used, costs will mount even more. New drugs cannot be used indiscriminately.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Blood pressure variability in tetraplegic patients with autonomic hyperreflexia.

Autonomic hyperreflexia (AH) is a syndrome characterised by profound pressor responses, sweating and headache which occurs in tetraplegic patients in response to a variety of stimuli below the level of cord injury. The pathogenesis of this syndrome is unclear but may be associated with increased blood pressure (BP) variability in these patients. To investigate this possibility, 24 hour ambulatory BP monitoring was performed utilising the Spacelabs 5300 Ambulatory BP system in 30 patients: 10 normal subjects, 10 spinal cord injury (SCI) patients who had never experienced AH and 10 SCI patients who had experienced recent episodes of AH (but with no symptoms during the study period). There were no statistically significant differences in systolic BP (SBP), diastolic BP (DBP) or heart rate (HR) between the three groups. The average of the coefficients of variation of SBP, DBP and HR within each subject over the study period were calculated. Tetraplegic patients who had recently experienced episodes of AH had greater SBP, DBP and HR variability than normal persons (p less than 0.01, p less than 0.005, p less than 0.005) and greater DBP and HR variability than SCI patients who had never experienced AH (p less than 0.01, p less than 0.05). AH may represent the symptoms associated with the upper extremes of this BP variability. The increased variability may be the result of enhanced cardiovascular responsiveness to noradrenaline and arginine vasopressin or because of the absence of descending inhibitory pathways in the decentralised cord that would normally suppress spinal sympathetic reflexes.

Adult↗