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Biomedical subjects

D W Holt

Publications and source records attributed to D W Holt.

At least 91 records · Page 5Linked to original sources
PubMed1994

Creatine kinase MB isoforms: sensitive markers of ischemic myocardial damage.

We investigated the use of creatine kinase (CK) MB isoforms as a marker of myocardial cell injury in a preliminary study of 16 patients with chronic stable angina after successful percutaneous transluminal coronary angioplasty (PTCA) and 25 patients after coronary artery bypass grafting (CABG). Three control groups were studied: apparently healthy volunteers (n = 31), patients undergoing thoracotomy (n = 10), and patients undergoing routine coronary angiography (n = 9). Patients in the PTCA group showed an association between ischemic ST segment changes lasting > 3 min and a transient increase in the MB2/MB1 ratio; however, all had total CK-MB activity within normal limits. Routine coronary angiography subjects had no significant change in MB2/MB1. In the CABG patients, MB2/MB1 peaked within 1 h after the cross-clamp release and returned to baseline by 24 h postoperatively. The median time to peak MM3/MM1 and total CK-MB activity was 2 and 8 h after reperfusion, respectively, returning to baseline values by 2 and 5 days, respectively. After thoracotomy, MB2/MB1 was increased only in elderly patients (n = 5) with risk factors for ischemic heart disease; total CK-MB activity was increased in only three of these. Apparently, CK-MB isoforms can detect myocardial damage in clinical settings with less overt damage than myocardial infarction.

Adolescent↗
PubMed1993

Quality assurance programs for immunosuppressive drugs: cyclosporine and beyond.

Monitoring blood cyclosporine concentrations as a guide to therapy has become established as a useful guide for optimal prescription of the drug. Quality assurance programs for external assessment of cyclosporine measurements have helped to clarify many of the methodological problems associated with measurement of the drug. A number of new immunosuppressive agents are in development and, although experience in their routine monitoring in clinical practice is still at an early stage, some observations regarding external assessment of their measurement can be made. This article summarizes the lessons to be drawn from the experience of cyclosporine quality assurance programmes and suggests some areas in which these lessons could be applied in the field of new immunosuppressive drugs.

Cyclosporine↗
PubMed1993

Urinary protein excretion and the diagnosis of graft rejection or renal dysfunction in renal transplant patients.

Urinary proteins have been found to be a sensitive marker of renal damage caused by nephrotoxic agents. An electrophoretic method was used to investigate the potential value of the pattern of urinary protein excretion in 14 cyclosporin-treated renal transplant patients, to differentiate between graft rejection episodes and other causes of renal dysfunction. Urinary protein excretion consistent with renal damage was observed in all of the patients studied, with no marked differences between those with signs of graft rejection, those with renal dysfunction, or those with stable renal function.

Adult↗
PubMed1993

Class III antiarrhythmics in overdose. Presenting features and management principles.

Class III (Vaughan-Williams classification) antiarrhythmic drugs prolong the cardiac action potential without affecting depolarisation. The 3 class III drugs currently in general use are amiodarone, sotalol and bretylium. The presenting features of acute toxicity are different for each agent and are, therefore, discussed separately. Several new class III antiarrhythmic agents are under development, including dofetilide and d-sotalol, but specific data on overdoses of these potent class III drugs are not yet available. Amiodarone toxicity following acute overdose is rare because poor bioavailability and a large volume of distribution limit the peak serum concentration. Toxicity is low even if high serum concentrations are reached. The major risks from acute overdose are hypotension (intravenous administration only) and arrhythmia if other factors, such as hypokalaemia or additional antiarrhythmic agents are present. Management is chiefly directed at reducing absorption with activated charcoal or cholestyramine, and monitoring for arrhythmia. Sotalol is a beta-blocker with additional class III activity. Oral bioavailability is high, and overdosed patients can present with bradycardia, hypotension and major haemodynamic collapse. The combination of bradycardia and prolongation of the QT interval is associated with malignant arrhythmias such as torsade de pointes. Management principles include observation and correction of bradycardia with endocardial pacing, intravenous adrenergic drugs and glucagon. The risk of arrhythmia can be substantially reduced by intravenous potassium and magnesium supplements. d-Sotalol is a potent class III drug devoid of beta-blocking activity and may be expected to share the proarrhythmic affects of the racemic mixture in overdose, without pronounced hypotension and bradycardia. Intravenous bretylium in overdose causes an initial hypertensive effect, followed by profound hypotension from systemic vasodilation. Management is directed at controlling hypotension with volume expansion and norepinephrine (noradrenaline).

Amiodarone↗
PubMed1993

External quality assessment scheme for cyclosporin in body fluids.

The United Kingdom Cyclosporin Assessment Scheme has over eight years experience in the measurement of cyclosporin and has over 176 participants World wide. The scheme provides a source of reference material which has been assayed by many laboratories and, thereby, provides external quality assessment for the clinical measurement of cyclosporin. The results also allow the direct comparison of the available analytical methodologies. The data presented are a summary of the results received during the period July 1990 to July 1991, inclusive.

Blood Chemical Analysis↗
PubMed1992

Smoking and decreased fertilisation rates in vitro.

To examine possible mechanisms for the association between cigarette smoking and reduced fertility, we have measured the concentration of the nicotine metabolite cotinine in ovarian follicular fluid collected at the time of oocyte recovery during treatment for in-vitro fertilisation. In a group of women in whom follicular fluid cotinine could not be detected (limit of accurate measurement 20 ng/ml) 116 oocytes were collected, of which 84 became fertilised (72%), whereas among women with cotinine concentration greater than 20 ng/ml 20/45 (44%) oocytes did so (p < 0.01). The median fertilisation rates for individuals (range 1-8 eggs each) in the high and low cotinine groups were 57% and 75%, respectively (p < 0.05). These findings suggest that infertile women should be advised to stop or reduce smoking generally, and especially before treatment by in-vitro fertilisation.

Adult↗
PubMed1992

Myocardial magnesium depletion associated with prolonged hypomagnesemia: a longitudinal study in heart transplant recipients.

OBJECTIVES: This study was carried out to establish prospectively the incidence and relation of hypomagnesemia and myocardial magnesium depletion after heart transplantation. BACKGROUND: No serial in vivo study of the relation of serum with tissue magnesium has been described. Myocardial magnesium depletion is associated with intracellular calcium overload, an increased incidence of cardiac arrhythmia and changes in coronary vasculature similar to those seen in the accelerated atherosclerosis that compromises graft survival after transplantation. METHODS: In a prospective study in 19 consecutive patients, serum and myocardial magnesium content were measured serially for 9 months after heart transplantation. Blood cyclosporine was assayed simultaneously. RESULTS: The incidence of hypomagnesemia was 100% during the 9-month study period, with lowest levels at 3 months (mean 0.80 vs. 0.64 mmol/liter, p less than 0.002). Myocardial magnesium depletion developed in 94% and was persistent in 55%; the lowest levels occurred at 6 months (mean 33.6 vs. 30.1, mumol/g, p less than 0.04). Hypomagnesemia predated decreases in myocardial magnesium by 2 to 6 weeks. Peak cyclosporine levels correlated positively with the decrease in serum magnesium. Clinical events were rare. CONCLUSIONS: This is the first report of serial measurement of tissue magnesium. Persistent hypomagnesemia is invariably accompanied by myocardial magnesium depletion in the transplanted heart. Reciprocal calcium overload and adverse changes in coronary vasculature would be expected from previous studies and merit further investigation. Should the implications of this study extend to the native heart, myocardial magnesium depletion may contribute to the high incidence of fatal arrhythmic events observed in patients with heart failure, who commonly have persistent hypomagnesemia.

Cyclosporine↗
PubMed1992

Cyclosporin monitoring: its role in autoimmune indications.

This paper describes some of the methodological problems related to the measurement of cyclosporin. The clinical value of the measurements following organ transplantation are discussed and those areas also applying to autoimmune indications are highlighted. It is concluded that the routine use of cyclosporin monitoring in samples from patients receiving the drug for autoimmune indications is unlikely to be of significant value as a guide to efficacy or toxicity. However, some settings, such as suspected poor patient compliance, for the avoidance of potential drug interactions and for research on the absorption of new formulations are considered to be useful applications of the methodology.

Autoimmune Diseases↗
PubMed1992

Radioimmunoassays for spirapril and its active metabolite spiraprilate: performance and application.

Radioimmunoassays for a nonsulfhydryl angiotensin converting enzyme inhibitor prodrug--spirapril--and its active metabolite--spiraprilate--are described. Nonextraction equilibrium assays using antibodies with a high specificity for spirapril or spiraprilate were used, with charcoal separation of bound and free tracer. Within-assay reproducibility (CV%) was less than 20% in the concentration range 0.5-40 micrograms/L for both analytes and the comparable value for between-assay reproducibility was less than 25%. Results for external quality control samples were in good agreement with the expected values of 0-250 micrograms/L (spirapril, r = 0.997) and 0-300 micrograms/L (spiraprilate, r = 0.999). Overall, samples circulated to four laboratories gave good agreement for measured values, including one center using gas chromatography-mass spectrometry analysis for the two compounds. Data are presented to show the suitability of these two assays to the measurement of spirapril and spiraprilate in clinical samples from assays to the measurement of spirapril and spiraprilate in clinical samples from dose-ranging and bioequivalence studies. Results are also shown relating drug plasma concentration data to a measurement of the pharmacodynamic effects of spiraprilate, namely inhibition of angiotensin converting enzyme activity. It is concluded that these assays have the sensitivity for use in studies to model the relationship between the pharmacokinetics and pharmacodynamics of the two compounds.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

The effect of age on the pharmacokinetics of pentisomide.

The effects of age on the pharmacokinetics of pentisomide (CM7857), an orally effective antiarrhythmic agent, were studied in two groups of volunteers. Sixteen young volunteers (mean age 26.4 years) and 10 elderly volunteers (mean age 67.8 years) received a single 200 mg oral dose of pentisomide. Mean AUC was larger and terminal elimination half-life longer in the elderly subjects, due to a decrease in total plasma clearance of pentisomide in the elderly. This decrease was due to a reduction in renal clearance of the drug which was paralleled by a significantly lower creatinine clearance in the elderly subjects. Dosage reduction, or a reduced frequency of dosing of pentisomide would be necessary in the elderly or those with impaired renal function.

Administration, Oral↗
PubMed1991

Monitoring cyclosporin: is it still important?

This paper reviews the current data which provide a rationale for the measurement of cyclosporin as a guide to therapy. Methodological problems related to sample matrix and analytical technique are considered, and the most commonly used methods considered. Factors which could influence the clinical interpretation of cyclosporin measurements are examined, including other drug therapy, compliance with therapy, cyclosporin metabolites, pharmacokinetic variables and sample timing. It is concluded that, whilst isolated measurements do not offer a definitive diagnostic tool, taken in context they can be of considerable value in optimising therapy.

Cyclosporine↗