Biomedical subjects
Publications and source records attributed to J G Kelly.
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Greater health consumer awareness and increasing levels of concern for the rights of patients have led to patient care technology being more strictly regulated. This article analyses both the general law issues and the particular statutes that will be of relevance to those involved in evaluating and implementing such technologies. There are three main elements to this analysis. Firstly, there is the issue of liability for a product fault, which will in many cases be directed by legislation back to the manufacturer of the goods. Secondly, those involved in placement of patient care technology should be aware of anti-discrimination legislation when making placement decisions. Finally, occupational health and safety legislation sets minimum standards for technology used in healthcare facilities. The author suggests ways of complying with the laws for each regulatory regime.
A high-performance liquid chromatographic (HPLC) method was developed which involves the use of two 5-microns BDS silica gel columns (15 cm x 4.6 mm I.D.) in series for increased resolution and sensitivity, and an organic mobile phase for both extraction and elution of diltiazem. Plasma samples (400 microliters) were extracted using the organic mobile phase [n-hexane-methanol-dichloromethane-ammonia (370:35:30:0.3)] and the extracts were monitored at 240 nm. Desipramine (30 micrograms ml-1) was the internal standard. The limit of quantification in plasma was 20 ng ml-1 with a correlation coefficient of > or = 0.999 within the 20-800 ng ml-1 standard window. The inter- and intra-assay R.S.D.s were within 5%. The recovery of diltiazem varied from 101.1% at 20 ng ml-1 to 93.7% at 400 ng ml-1. The method was applied to the investigation of diltiazem absorption in a rat. Drug absorption was based on the intestinal single-pass perfusion model. The concentration of diltiazem in all test perfusion solutions was 1 mg ml-1 (2.4 mM) and the flow-rate through the system was 3.33.10(-3) ml s-1. A non-specific mucolytic absorption enhancer was also added to a diltiazem solution and studied in the in situ system. The pharmacokinetics of diltiazem hydrochloride were investigated in two study groups of Wistar rats (n = 4). A two-sample Student's t-test was employed to compare values of the area under the curve (AUC). The pharmacokinetic data indicated that the AUC in the group which received the enhancer [18.12 +/- 5.43 ng ml-1 h-1 (+/- S.D.)] was higher than that in the control group (11.49 +/- 3.67 ng h-1 ml-1), t-test; p = 0.0483. Hence it was shown that administration of an enhancer could increase the oral bioavailability of diltiazem.
An open, randomised, cross-over study was performed to investigate the pharmacokinetics of enalaprilat, administered as 20 mg enalapril both as monotherapy and in combination with hydrochlorothiazide (HCTZ 12.5 mg). Three groups of 6 hypertensive patients were enrolled [untreated diastolic blood pressure (DBP) 90-115 mm Hg]; normal renal function [glomerular filtration rate (GFR) > 81 ml min-1 1.73 m-2], mild renal impairment (GFR 51-80 ml min-1 1.73 m-2), and moderate renal impairment (GFR 31-50 ml min-1 1.73 m-2). The pharmacokinetics of enalaprilat and enalaprilat plus HCTZ correlated predictably with renal impairment with increased plasma concentrations and decreased urinary elimination at lower values of GFR. The coadministration of HCTZ had no significant effect on the pharmacokinetics of enalaprilat in any group. We conclude that although the pharmacokinetics of both enalaprilat and HCTZ are related to renal function, HCTZ has no significant effect on the pharmacokinetics of enalaprilat and that dosage adjustment for both regimens should be based on renal function.
We describe a miniature electrochemically driven, wrist-worn infusion pump. Generation of gas by an electrolytic reaction compresses a reservoir containing medication and provides a predictable and controllable infusion rate. The pump was used for patient-controlled analgesia (PCA) in women who required analgesia after Caesarean section. It was accepted readily and was convenient for both patients and nursing staff. This portable system, using a novel motive force, has advantages of convenience over larger systems and has sophisticated features not present in existing small systems. It has potential as a routine PCA device and it may have uses in other situations requiring convenient infusion or intermittent injection in an ambulatory setting.
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.
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.
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.
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.
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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.
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.
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)
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.
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.
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.
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.