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Biomedical subjects

J G Kelly

Publications and source records attributed to J G Kelly.

At least 19 recordsLinked to original sources
PubMed1992

Object classification and acoustic imaging with active sonar.

The theoretical underpinnings of underwater acoustic classification and imaging using high-frequency active sonar are studied. All essential components of practical classification systems are incorporated in a Bayesian theoretic framework. The optimum decision rules and array processing are presented and evaluated. A systematic performance evaluation methodology is derived. New results quantify the relationship between classifier performance and object geometry, acoustic imaging, and the accuracy of a priori knowledge infused into the processor.

Algorithms↗
PubMed1992

Clinical pharmacokinetics of calcium antagonists. An update.

The calcium antagonists are valuable and widely used agents in the management of essential hypertension and angina. There is an increasing number of new agents to add to the 3 prototype substances nifedipine, diltiazem and verapamil. These new agents are dihydropyridines structurally related to nifedipine. However, they tend to have longer elimination half-lives (t 1/2 beta) and may be suitable for twice-daily administration. Amlodipine is an exception with a t 1/2 beta in excess of 30h. Apart from elimination rates, however, the pharmacokinetic characteristics of the newer agents have a notable tendency to resemble those of the established agents. They are highly cleared drugs, are relatively highly protein bound. As they are subject to significant first-pass metabolism, old age and hepatic impairment will increase their plasma concentrations due to a reduced first-pass effect. Renal impairment does little to their pharmacokinetics since the fraction eliminated unchanged by the kidney is small. For most agents, plasma concentration-response relationships have been described. Interesting areas for further research include chronopharmacokinetics, stereoselective pharmacokinetics and lipid solubility. Drugs affecting hepatic blood flow and drug metabolising capacity have predictable interaction potential. Some of the newer calcium antagonists will, like verapamil, increase plasma digoxin concentrations. Verapamil and diltiazem decrease phenazone (antipyrine) metabolism and therefore tend to decrease the metabolism of other drugs.

Calcium Channel Blockers↗
PubMed1992

Vasodilator therapy for acute heart failure: haemodynamic comparison of hydralazine/isosorbide, alpha-adrenoceptor blockade, and angiotensin-converting enzyme inhibition.

Haemodynamic comparison of three vasodilation regimens [intravenous (i.v.) hydralazine and isosorbide dinitrate (ISDN) combined, i.v. doxazosin, and i.v. enalaprilat] was undertaken in 36 patients with acute left ventricular (LV) failure due to recent myocardial infarction. Each regimen achieved similar reductions in pulmonary artery occluded pressure (PAOP, preload) and systemic arterial pressures (afterload), with increased cardiac and stroke volume (SV) indexes (p less than 0.01). Only the hydralazine and isosorbide combination induced resting tachycardia. Balanced vasodilatation after selective alpha-adrenoceptor blockade (doxazosin) and angiotensin-converting enzyme (ACE) inhibition (enalaprilat) without increase in heart rate (HR) suggests that these therapies may have definite haemodynamic advantages over the hydralazine/ISDN combination.

Adrenergic alpha-Antagonists↗
PubMed1991

Pharmacokinetic properties and antihypertensive efficacy of once-daily diltiazem.

The pharmacokinetic and clinical characteristics of a once-daily formulation of diltiazem are described. In a 20 subject, 5 day, steady-state pharmacokinetic study, 120 and 240 mg of once-daily diltiazem were bioequivalent on a dose-adjusted basis and were bioequivalent to a conventional reference product administered four times daily. The conventional formulation showed marked diurnal variation in its pharmacokinetics. Plasma concentrations following its administration at 2100 and 0300 h were significantly lower than following administration at 0900 and 1500 h. One hundred forty-four hypertensive patients completed a 16 week placebo-controlled, dose-titrated study examining the effects of once-daily diltiazem at doses of 120, 240, and 360 mg. Blood pressure was measured manually and (in 121 patients) by ambulatory evaluation. Following dose titration, diltiazem given once daily reduced blood pressure with significant effects present at 24 h following drug administration. Ambulatory blood pressures were lower than those measured manually and data from the manual measurements demonstrated a placebo effect suggested to result primarily from investigator bias. The placebo-adjusted reduction in blood pressure 24 h following a dose of diltiazem was approximately 5 mm Hg and was comparable for manual (supine and standing) and ambulatory measurements. Diltiazem was well tolerated. The only significant findings were of tiredness/dizziness (9 patients of 144) or oedema (also 9 of 144). The incidence of headache was not different than placebo. On both pharmacokinetic and pharmacodynamic grounds, the results indicate that diltiazem can be formulated in a manner suitable for once-daily antihypertensive use.

Adult↗
PubMed1990

Pharmacokinetics of oral acetyl-L-carnitine in renal impairment.

Acetyl-L-carnitine 1.5 g and 3.0 g was administered as three divided doses on each of two occasions to 24 people with varying renal failure (creatinine clearance 127-8 ml.min-1). Plasma and urinary concentrations of total-L-carnitine, free (non-esterified) carnitine, short-chain esters and acetyl-L-carnitine were measured. The baseline (pre-study) concentrations of all four substances were related to renal function. Patients whose creatinine clearance was below about 30-40 ml.min-1 were had the highest concentrations. Renal elimination of all four substances was related to dose and to renal function. There was evidence for dose-related elimination, with greater elimination of the larger dose.

Acetylcarnitine↗
PubMed1990

Clinical and pharmacokinetic properties of a transdermal nicotine patch.

We examined the pharmacokinetics of a transdermal nicotine patch and evaluated the usefulness of such a patch in a pilot smoking-cessation program. Use of the patch was associated with plasma nicotine concentrations that were comparable to smoking or to the use of other smoking-cessation devices. However, these plasma concentrations were maintained for 24 hours, and the patch appeared to be suitable for use once a day. Its use in a 6-week placebo-controlled double-blind study resulted in a significant degree of smoking cessation or in reduction of smoking activity. The findings suggest that it may be valuable to extend investigations to a larger population and that transdermal nicotine may have a useful role in smoking-cessation therapy.

Administration, Cutaneous↗
PubMed1990

Clinical pharmacokinetics of the newer ACE inhibitors. A review.

The orally active angiotensin-converting inhibitors (ACE inhibitors) such as captopril and enalapril represent a significant therapeutic advance in the treatment of hypertension and congestive heart failure. Enalapril differs from captopril in several respects. It is a prodrug converted by hepatic esterolysis to the active (but more poorly absorbed) diacid, enalaprilat. Enalaprilat is more potent than captopril, more slowly eliminated and does not possess a sulfhydryl (SH) group. Enalapril was rapidly followed by a number of newer ACE inhibitors, the majority of which are similar to enalapril in that they are prodrugs, converted by hepatic esterolysis to a major active but poorly absorbed diacid metabolite. In one case (delapril) there are 2 active metabolites; in another (alacepril) the prodrug is converted in vivo to captopril. Lisinopril is an exception in that it is an enalaprilat-like diacid but with acceptable oral bioavailability, so that the prodrug route is not employed. The newer ACE inhibitors are at widely different stages of development, and it is not yet clear how many will reach regular clinical use. Of these newer drugs, lisinopril is the longest established and is the subject of the widest published literature. For a number there is as yet little published pharmacokinetic information. A variety of assay methods have been employed to characterise the pharmacokinetics of the ACE inhibitors, including enzymatic techniques, radioimmunoassay and chromatography. The peak plasma concentrations of the prodrugs are generally observed at around 1 hour and those of the diacid metabolites at about 2 to 4 hours. However, there is considerable variation within and between drugs, with benazepril and benazeprilat reaching peak concentrations early and enalapril and enalaprilat typical of later times to peak. Absorption of the active diacids is generally poor, and moderate (typically 30 to 70%) for the prodrugs. The bioavailability of lisinopril is about 25%. It is difficult to talk meaningfully about half-lives of the active drugs. The declines in their plasma concentrations are polyphasic and, if analytical sensitivity allows, active drug may be found at 48 hours or more following administration. This may reflect binding to ACE in plasma. Half-lives of accumulation are of the order of 12 hours; protein binding varies from little (lisinopril) to 90% (benazeprilat). Elimination is mostly renal but there may be biliary elimination for some, such as benazeprilat and fosinopril. The half-lives of the prodrugs are short. Impaired renal function decreases the elimination rate of the diacids.(ABSTRACT TRUNCATED AT 400 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

The pharmacokinetics of dilevalol in renal impairment.

Dilevalol, 200 mg, was administered orally as seven daily doses to three groups of six participants, with differing degrees of renal impairment. Values of Cmax, Tmax, half-life or renal elimination did not significantly change with decreased renal function. Values of area under the plasma concentration-time curves and pre-dose concentrations tended to increase with renal impairment and there was a significant, if small, correlation between these and glomerular filtration rate. The practical clinical consequences of these results is that impairment is not likely to be associated with significant accumulation of dilevalol.

Administration, Oral↗
PubMed1989

Pharmacokinetic properties and clinical efficacy of once-daily sustained-release naproxen.

The pharmacokinetics and clinical efficacy of a once-daily sustained-release formulation of naproxen (sodium salt) have been compared with those of conventional-release agents. In a single dose pharmacokinetic study, the rate of absorption of the sustained-release preparation was less than that of a conventional-release preparation but the extent of absorption was the same. As is the case with conventional-release naproxen, food decreased the rate but not the extent of absorption of the sustained-release formulation. On multiple dose administration for 7 days, the AUC and average concentrations of the sustained release preparation (1 g daily) were the same as those for conventional release preparations of naproxen sodium (250 mg four times daily) and naproxen free acid (500 mg daily). The conventional-release sodium salt was absorbed more quickly with no differences in bioavailability. A double-blind clinical comparison in patients with osteoarthritis showed the sustained-release preparation (1 g daily) to be equivalent in efficacy to conventional naproxen capsules (500 mg twice daily) but to have a significantly lower incidence of gastrointestinal side-effects. The results suggest that sustained-release naproxen sodium has potential for use as a once-daily treatment for inflammatory disease.

Adolescent↗
PubMed1989

Metabolism and disposition of intravenously administered acetyl-L-carnitine in healthy volunteers.

The pharmacokinetics of acetyl-L-carnitine hydrochloride were investigated in 6 healthy volunteers of both sexes after i.v. injection of 500 mg of the drug, expressed as inner salt. Plasma concentrations and urinary excretion of acetyl-L-carnitine (A), L-carnitine (B) and total acid soluble L-carnitine fraction were evaluated over a period lasting from 24 h before to 48 h after the administration. Plasma concentrations of A increased quickly after administration and then declined reaching base values within 12 h. Conversely, plasma concentrations of B rose more slowly, reaching a peak in 30-60 min, and then declined to base values within 24 h. Most of the injected dose of acetyl-L-carnitine was recovered in the urine during the first 24 h after administration as B and A. Mean renal clearance of both A and B during the first 12 h after injection was higher than the base values, suggesting the presence of a saturable tubular reabsorption process which may counterbalance major changes occurring in plasma concentrations of L-carnitine pattern.

Acetylcarnitine↗
PubMed1989

Lisinopril population pharmacokinetics in elderly and renal disease patients with hypertension.

1. The population pharmacokinetics of lisinopril were investigated using data collected from two multicentre trials of lisinopril in the treatment of hypertension in elderly patients (n = 40) and patients with renal disease (n = 20). 2. Lisinopril was started at doses of 2.5-5 mg daily and increased at 2-4 weekly intervals as required for control of blood pressure. Steady-state concentration-time profiles were measured after at least 2 weeks at a constant dose. 3. All concentration-time data were analysed simultaneously using the program NONMEM and the influence of clinical factors on clearance/F and volume of distribution/F was tested. 4. Clearance was significantly influenced by creatinine concentration, age, weight and cardiac failure. No clinical features tested were found to influence volume of distribution. 5. The influence of renal function and cardiac failure on lisinopril clearance has been confirmed using a population pharmacokinetic analysis technique.

Age Factors↗
PubMed1988

Antihypertensive and renal effects of lisinopril in older patients with hypertension.

The antihypertensive efficacy and safety of lisinopril were assessed in 60 older patients with a mean age of 75 years (range, 65 to 85 years) in a 12-week open study. Mean ( +/- SEM) blood pressure while sitting was reduced from 190/106 +/- 3.3/1.8 mm Hg at entry to 162/89 +/- 3.2/1.6 mm Hg after 12 weeks of treatment (p less than 0.001). There was no significant alteration in heart rate, and postural hypotension did not occur. Mean glomerular filtration rate at entry was 61.6 +/- 3.4 ml/minute and was unchanged after 12 weeks of therapy at 62.2 +/- 3.0 ml/minute. Fourteen patients continued to receive lisinopril for a period of one year. Blood pressure remained controlled throughout and heart rate remained unchanged. There was a significant reduction in mean arterial pressure from 128.8 +/- 1.9 mm Hg to 105.1 +/- 1.5 mm Hg (p less than 0.001). Biochemical parameters remained unaltered. There was a significant increase in renal blood flow (p less than 0.025) and a corresponding reduction in renovascular resistance (p less than 0.001) following long-term therapy with lisinopril. Thus, lisinopril was generally well-tolerated and highly effective in lowering blood pressure in older hypertensive patients, whereas at the same time renal function was not adversely changed.

Aged↗
PubMed1988

Pharmacokinetics of amlodipine in renal impairment.

The pharmacokinetics of amlodipine was studied in 27 subjects with renal function ranging from normal to dialysis-dependent. Amlodipine (as a single 5-mg capsule) was administered once daily for 14 days and its plasma concentrations were measured by gas chromatography during and after treatment. Renal impairment had little or no effect on the pharmacokinetics of amlodipine. The elimination half-life was of the order of 50 h, similar to previously observed values, and did not vary with differences in renal function. Steady-state predose concentrations were observed after the ninth dose. Accumulation of amlodipine to steady-state levels was not significantly different from that expected on theoretical grounds and did not significantly change with renal function. These results suggest that once-daily administration of amlodipine is suitable for all degrees of renal function and that dosage adjustment is not necessary in renal impairment.

Adult↗
PubMed1988

Pharmacokinetics of lisinopril, enalapril and enalaprilat in renal failure: effects of haemodialysis.

1. Lisinopril and enalapril were administered as 2.5 mg single doses and as eight single daily 2.5 mg doses to separate groups of six patients with chronic renal failure. Patients were receiving regular haemodialysis. 2. In the absence of haemodialysis, the decline in plasma concentrations of lisinopril and enalaprilat was extremely slow and plasma concentrations were generally high. 3. Haemodialysis had large effects on plasma concentrations of lisinopril and enalaprilat. A 4 h period reduced plasma concentrations of both drugs by around one-half and often by significantly more than this. Even 1 or 2 h of haemodialysis had significant effects. 4. Haemodialysis plasma clearance was similar for both drugs with mean values of the order of 40 ml min-1. Clearance did not markedly differ when measured after 1, 2 or 4 h of haemodialysis or after single or multiple doses of lisinopril or enalapril. 5. The design of dosage regimens of both lisinopril and enalapril for patients with severe renal impairment or chronic renal failure should take into consideration the use and effects of haemodialysis.

Adult↗
PubMed1988

Chronic dose urinary and serum pharmacokinetics of norfloxacin in the elderly.

1. Norfloxacin was administered as two daily 400 mg oral doses to eight elderly patients requiring treatment for urinary tract infections. Blood specimens were obtained for pharmacokinetic profiles following the first and fifteenth doses. Further specimens were obtained before each morning's dose of norfloxacin. Specimens of urine were obtained to ascertain if adequate antimicrobial concentrations were reached in these patients with diminished renal function. 2. Norfloxacin half-life was consistent with that expected in mild renal impairment and was not different between the first and fifteenth doses. Based on ratios of AUC values, accumulation is probably related to renal function, being greatest for creatinine clearance values below 30 ml min-1. 3. On the great majority of occasions, the urinary concentrations of norfloxacin exceeded 20 micrograms ml-1. On days 2-7, the mean percentage 12 h renal elimination of norfloxacin was 18.6 +/- 1.47 (mean of 82 separate observations). Norfloxacin 400 mg twice daily was well tolerated in this group of elderly patients and produced adequate antimicrobial concentrations in urine.

Aged↗
PubMed1988

A study of the potential pharmacokinetic interaction of lisinopril and digoxin in normal volunteers.

1. The pharmacokinetics of single oral doses of 20 mg lisinopril and 0.25 mg digoxin, given alone and together, have been studied in 12 normal young male volunteers. 2. Peak serum conc of lisinopril occurred at 6 to 8 h and were slightly higher during combined treatment. Subsequent elimination proceeded moderately rapidly in both cases, concn declining to approx. 25% of peak values in 24 h. The AUC of lisinopril was similarly slightly higher during combined treatment. 3. After lisinopril alone, urinary elimination of unchanged lisinopril was 13% dose in 72 h, and after combined therapy was 17% dose. 4. Although there were no statistically significant differences in lisinopril pharmacokinetics during single or combined treatment, serum and urinary parameters suggest that bioavailability may be enhanced slightly during combined treatment. 5. Plasma concentrations of digoxin were slightly lower and urinary excretion slightly higher during combined treatment, the mean renal clearance being 20% higher.

Adult↗