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Biomedical subjects

A F Lant

Publications and source records attributed to A F Lant.

At least 37 records · Page 2Linked to original sources
PubMed1995

Long-term safety of statin-fibrate combination treatment in the management of hypercholesterolaemia in patients with coronary artery disease.

OBJECTIVE: To evaluate the long-term safety profile of treatment with a statin-fibrate combination in a cohort of patients with documented coronary artery disease. DESIGN: Retrospective cohort analytical study. SETTING: District general hospital. PATIENTS: 102 (81 male and 21 female) hypercholesterolaemic (total cholesterol concentration > 6.5 mmol/l) patients with documented coronary artery disease and who had been treated with a statin-fibrate combination for over 1 year. Coronary artery disease was confirmed by angiography in 93 patients and by a positive (Bruce protocol) exercise test in the remainder. Fifty eight patients had a history of previous coronary bypass graft surgery. INTERVENTIONS: Twice daily lipid lowering treatment was given, with the fibrate administered in the morning (either bezafibrate 400 mg (n = 101) or fenofibrate 200 mg (n = 1)) and the statin in the evening (either simvastatin 10 mg (n = 23), 20 mg (n = 72), or 40 mg (n = 2) or pravastatin 10 mg (n = 1) or 20 mg (n = 4)). Treatment continued for 1 (n = 9), 2 (n = 58), or 3 (n = 35) years. MAIN OUTCOME MEASURES: Selected laboratory variables (total cholesterol concentration and liver (aspartate transaminase (AST)) and muscle enzyme (creatine kinase (CK)) activities) and documented symptomatology. RESULTS: A mean (SD) total cholesterol concentration of 5.2 (0.8) mmol/l was achieved after combined treatment for 1 year which was maintained at annual follow up. Over a maximum 3 year follow up no patient reported myalgic symptoms and none had a measured CK activity > 10 times above nomal. Four men on a simvastatin-bezafibrate combination had a CK activity rise to less than three times normal. Fourteen patients with a negative history of alcohol excess (consumption < 21 units/week) had borderline raised AST values. CONCLUSIONS: Statin-fibrate combination treatment for up to 3 years in a cohort of patients with coronary artery disease was not associated with serious disturbances in biochemical markers of muscle or liver function.

Adult↗
PubMed1995

Relation of sodium-lithium countertransport activity to markers of cardiovascular risk in normotensive subjects.

A study was undertaken in 298 normotensive, normolipidaemic and normoglycaemic subjects to define the range of erythrocyte sodium-lithium countertransport activity in this cohort and to determine the associations between countertransport activity and markers of vascular risk. Countertransport activity showed a positively skewed non-normal distribution with a median (95% confidence interval) of 0.197 (0.123-0.271) mmol Li/L erythrocytes per hour. Countertransport activity was elevated in women who were taking oral contraceptives (median (95% CI) mmol Li/L erythrocytes per hour, 0.270 (0.162-0.320) vs. 0.147 (0.110-0.201)). Countertransport activity was also found to be elevated in subjects who had alcohol intakes greater than the recommended weekly maximum (median (95% CI) mmol Li/L erythrocytes per hour, 0.193 (0.139-0.211) vs. 0.260 (0.148-0.317)). Positive correlations with sodium-lithium countertransport activity were noted with resting diastolic blood pressures (n = 298; P = 0.004) and maximal systolic blood pressure at peak exercise (n = 123; P = 0.003). In respect of serum biochemical variables, positive correlations were only found with triglycerides (P = 0.025) and creatinine (P = 0.005). These results support the view that elevation of erythrocyte sodium-lithium countertransport activity may reflect an alteration in the behaviour of cell membrane proteins through the influence of environmental factors associated with vascular risk.

Adult↗
PubMed1995

Association of angiotensin converting enzyme DD genotype with hypertension in diabetes.

Angiotensin converting enzyme (ACE) genotypes have been associated with hypertension in the general population. However, the relation of ACE genotype to the prevalence of hypertension in diabetic populations is less clear. This study investigated ACE genotypes in 100 patients with diabetes mellitus, of whom 41 were on anti-hypertensive medication. A significant association was found between the presence of the ACE-D allele and hypertension in both the overall diabetic group (D = 0.66, P < 0.01) and in the subset of diabetics who had non-insulin-dependent diabetes (D = 0.69, P < 0.001). There was no correlation of ACE genotype with hypertension in insulin-dependent diabetes (D = 0.57).

Adolescent↗
PubMed1995

Ethnic origin and hypertension-associated alterations in sodium-lithium countertransport kinetics.

In Caucasian subjects, elevated erythrocyte sodium-lithium countertransport (SLC) activity, displaying an increased affinity for external Na+ (decreased KNa), has a strong association with hypertension and has also been proposed as a potential marker for vascular disease. We have compared SLC activity and the kinetic components, KNa and maximal rate of turnover (Vmax), of the countertransporter in groups of Caucasian, Asian and Black hypertensive subjects matched for ethnicity, age and sex with healthy normotensive controls. SLC activity was the same in all ethnic groups irrespective of the presence of hypertension. Similarly, hypertension had no impact on Vmax values within each ethnic group (normotensive vs. hypertensives: Caucasian, 0.360 +/- 0.186 vs. 0.335 +/- 0.137; Asian, 0.324 +/- 0.078 vs. 0.273 +/- 0.105; black people, 0.192 +/- 0.123 vs. 0.178 +/- 0.082 mmol Li/l erythrocytes h). However, in black people compared with the other two ethnic groups, Vmax was lower for both controls and hypertensives (P < 0.05; ANOVA). Median KNa values in hypertensive subjects were consistently lower than their normotensive counterparts in all ethnic groups (P < 0.01; Kruskal-Wallis); Caucasians, (89.1 vs. 41.2 mmol Na; P = 0.01), Asians (121.1 vs. 33.1; P = 0.04) and black people (74.4 vs. 27.2 mmol Na; P = 0.02; Wilcoxon). The results show that Vmax is altered in black people independently of the presence of hypertension. This contrasts with KNa which, for each ethnic group studied, is reduced in the hypertensive compared with the normotensive state.

Adult↗
PubMed1993

Cholesterol-lowering drug therapy in a patient with receptor-negative homozygous familial hypercholesterolaemia.

Familial hypercholesterolaemia (FH) is caused by mutations in the gene for the low density lipoprotein (LDL) receptor. It is generally believed that homozygous FH patients do not respond well to lipid-lowering drug therapy with inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase because they cannot respond to an increased demand for hepatic cholesterol by up-regulation of LDL-receptor activity. In this paper we show that serum cholesterol in a homozygous FH patient with a receptor-negative LDL-receptor phenotype was reduced by 30% after treatment with simvastatin alone and by a further 11% with simvastatin in combination with probucol and nicotinic acid. The patient was a true homozygote, with two identical alleles of the LDL receptor gene in which a previously undescribed point mutation in exon 11 introduces a premature termination codon at residue 540 in the protein; the mutant protein is predicted to be truncated in the domain with homology to the epidermal growth factor precursor. Cultured cells from the patient were unable to bind, internalise or degrade LDL by the receptor pathway and there was no immunodetectable LDL receptor protein in the cells. Thus the lipid lowering effect of simvastatin in this individual must involve mechanisms other than stimulation of LDL receptors.

Adolescent↗
PubMed1993

Sodium-lithium countertransport activity is not affected by short-term insulin exposure in vivo or in a physiologic medium in vitro.

This study examined the acute effects of physiologic concentrations of insulin in vitro and in vivo on sodium-lithium countertransport (SLC) kinetics in nondiabetic subjects. SLC was measured at eight different external sodium concentrations including the standard 150 mmol/L, allowing calculation of both maximal velocity (Vmax) and external sodium affinity (Km). Incubation with insulin (50 mU/L) in 110 MgCl2 but not in 150 mmol/L NaCl decreased standard SLC activity. The decrease was accounted for by a reduction in Vmax, whereas Km remained constant. There was no difference in standard SLC activity, Vmax, or Km when endogenous insulin concentrations were altered either by fasting or by a carbohydrate load. Similarly, standard SLC activity, Vmax, or Km were not significantly different before or at the completion of a euglycemic hyperinsulinemic clamp. These findings provide no support for an action of physiologic concentrations of insulin either in vitro or in vivo on the kinetics of the countertransporter measured in vitro in isotonic sodium-containing media.

Adult↗
PubMed1992

Erythrocyte sodium-lithium countertransport and blood pressure in identical twin pairs discordant for insulin dependent diabetes.

OBJECTIVE: To investigate whether insulin dependent diabetes is responsible for the abnormal behaviour of the carrier in sodium-lithium countertransport and whether the diabetic state is associated with rise in blood pressure. DESIGN: Case-control study. SETTING: London teaching hospital. SUBJECTS: 44 twin pairs discordant for insulin dependent diabetes living in United Kingdom and 44 healthy control subjects matched for age, sex, and body mass index. None of the twin pairs or the controls had evidence of microalbuminuria. MAIN OUTCOME MEASURES: Sodium-lithium countertransport activity in erythrocytes and arterial blood pressure. RESULTS: The mean (95% confidence interval) sodium-lithium countertransport activity (mmol Li per litre of red blood cells per h) of the diabetic twins (0.291 (0.244 to 0.338)) was similar to that of their non-diabetic cotwins (0.247 (0.204 to 0.290)); both values were significantly higher than that of the controls (0.187 (0.157 to 0.216); p < 0.05). In addition, systolic blood pressure was higher in those twins with diabetes (127 (122 to 133) mm Hg) than in the non-diabetic cotwins (122 (117 to 127) mm Hg; p < 0.01). There were no significant differences in mean diastolic blood pressure between any of the groups studied. CONCLUSIONS: The raised erythrocyte sodium-lithium countertransport activity in the diabetic twins compared with the controls seems to be inherited rather than a consequence of overt diabetes. The higher systolic blood pressure in diabetic twins than non-diabetic cotwins indicates that insulin dependent diabetes does exert a small influence on systolic blood pressure.

Adult↗
PubMed1992

Neuropsychological and psychiatric abnormalities in myalgic encephalomyelitis: a preliminary report.

Ten patients attending one general medical hospital clinic who fulfilled operational criteria for the diagnosis of myalgic encephalomyelitis (ME) and with a history longer than three months, underwent a series of standardized neuropsychological and psychiatric tests. Nine were able to complete the tests and were individually matched with a normal control group for age, sex, educational background and premorbid intelligence. The ME subjects showed inferior performance to the controls on two tests of verbal memory. Their personality scores displayed less extraversion and less psychoticism. This is the first report of objective neuropsychological abnormalities in patients with ME, suggesting a discrete deterioration of short-term memory. The findings may also suggest a concurrent psychiatric component of the condition, but the direction of causality remains to be clarified.

Anxiety Disorders↗
PubMed1992

Importance of routine measurement of HDL with total cholesterol in diabetic patients.

The prevalence of hypercholesterolaemia and the frequency of a reduced HDL-cholesterol (at different cholesterol concentrations) were evaluated in a group of 400 diabetic patients attending a single diabetic clinic. Despite regularly supervised diabetes, including dietary advice, over one quarter of the patients had a serum total cholesterol concentration greater than 6.5 mmol/l, while over a quarter of the non-insulin treated and one eighth of the insulin treated diabetic subjects had an HDL-cholesterol less than 0.9 mmol/l, with a greater prevalence in the males compared with the females. More than 60% of all the diabetic patients who had a reduced HDL-cholesterol less than 0.9 mmol/l also had a total cholesterol concentration less than 6.5 mmol/l. When the total/HDL-cholesterol ratio was calculated more non-insulin treated subjects had a value greater than 4.5 as compared with insulin treated diabetic patients. When comparisons were made between an age matched group of diabetic patients (n = 185) and a group of non-diabetic subjects attending for a health screen (n = 155), the frequencies of serum cholesterol concentrations greater than 5.2, 6.5, and 7.8 mmol/l were similar for both groups. Significantly greater numbers of diabetic patients had a reduced HDL-cholesterol less than 0.9 mmol/l (at any level of serum cholesterol) and a total/HDL cholesterol ratio greater than 4.5. This study has shown that the measurement of serum total cholesterol concentration alone will not characterize many subjects who are at risk of macrovascular complications due to a reduced HDL-cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Steroid trials in the assessment of reversibility of air flow limitation: a survey of current clinical practice of chest physicians.

To evaluate how steroid trials are currently used in the assessment of reversibility of air flow limitation, a postal questionnaire was sent to 355 consultant members of the British Thoracic Society working in England and Wales; 253 questionnaires were returned (71% response rate). Two respondents did not undertake steroid trials; of the remaining 251, 75% prescribed 30-40 mg oral prednisolone, with the commonest treatment period being 2 weeks. A high dose steroid inhaler was sometimes used as an alternative by 31% of respondents. Although 71% of respondents made lung function measurements on several occasions before starting steroids and 76% made measurements during treatment, 78% assessed patients on only one occasion at the end of the trials to ascertain its outcome. Weight, blood pressure and glycosuria were measured less frequently after the steroid treatment compared to the pre-trial period. Blood glucose and serum electrolytes were infrequently measured both before and after treatment. Wide variations exist in steroid trial regimens and current practice may neither provide definitive evidence of treatment benefit nor an adequate safeguard for patients against potential side-effects.

Chronic Disease↗
PubMed1991

Muzolimine: renal site of action and interaction with probenecid in humans.

Muzolimine (60 mg, administered orally) was administered to eight healthy volunteers, under conditions of altered fluid load, to elucidate its renal site of action. The duration of action and the effect of probenecid pretreatment on muzolimine response was also investigated. Muzolimine had a rapid onset of action, with the diuresis complete within 4 hours after dosing. At peak natriuresis, under hydrated conditions, fractional excretion of free water remained unaltered (9.72% +/- 0.59% versus 9.07% +/- 0.44%; difference not significant) but was accompanied by a significant increase in the delivery of sodium out of the proximal tubule, as measured by fractional excretion of lithium (22% +/- 2% to 31% +/- 1%; p less than 0.01). The fraction of sodium reabsorbed in the distal tubule also decreased from 94% +/- 1% to 67% +/- 1% (p less than 0.001) of the delivered load. The fractional reabsorption of free water during hydropenia decreased after muzolimine (5.63% +/- 0.26% to 2.00% +/- 0.81%; p less than 0.05). Pretreatment with probenecid resulted in a prominent decrease in urinary sodium excretion (246 +/- 25 mmol/24 hr for muzolimine alone 161 +/- 24 mmol/24 hr for muzolimine and probenecid; p less than 0.01). These findings suggest that muzolimine has a major site of action in the medullary portion of the thick ascending limb of Henle with additional inhibitory activity on the proximal tubule. It is likely that the active secretion of one or more of the acidic metabolites of muzolimine, by way of the probenecid sensitive organic acid pathway, is responsible for mediating the renal actions this basic drug.

Administration, Oral↗
PubMed1991

Analysis of the natriuretic action of a loop diuretic, piretanide, in man.

1. The renal responses to a loop diuretic, piretanide, were investigated in a group of fourteen healthy volunteers. The effect of fluid replacement on the drug-response relationship was evaluated in the absence and in the presence of probenecid pretreatment following both oral and intravenous administration of piretanide. 2. Urinary excretion of piretanide was greater when volume losses were replaced than in the absence of volume replacement (i.v. dose: 3.32 +/- 0.15 vs 2.55 +/- 0.23 mg 6 h-1, P less than 0.01; oral dose: 2.57 +/- 0.09 vs 1.87 +/- 0.27 mg 6 h-1, P less than 0.01). With intravenous piretanide urinary excretion of sodium was likewise greater in the fluid replaced group (198 +/- 4 vs 141 +/- 10 mmol 6 h-1, P less than 0.01); these differences caused by fluid replacement did not however occur after oral dosing of piretanide (181 +/- 12 vs 167 +/- 14 mmol 6 h-1). 3. Probenecid pretreatment significantly decreased the renal excretion of piretanide in all subjects and consistently decreased the natriuretic response with the exception of intravenous piretanide challenge in subjects not undergoing fluid replacement. In this situation, despite probenecid causing a decrease in the amount of drug excreted (2.55 +/- 0.23 vs 1.63 +/- 0.15 mg 6 h-1, P less than 0.05) the sodium output was unaltered (141 +/- 10 vs 152 +/- 16 mmol 6 h-1, NS). 4. Complete replacement of the induced fluid losses resulted in the enhancement of the renal response, without affecting the shape of the diuretic response curve, of either the intravenous or orally administered piretanide.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1991

Management choices for hypertension with coexistent hypercholesterolaemia.

Guidelines for the management of either hypertension or hyperlipidaemia have been widely published. However, recent data have shown the high frequency of an abnormal lipid profile in hypertensive subjects. We have therefore surveyed 195 general practitioners throughout Britain to determine current community-based attitudes and management approaches to hypertension with coexistent hypercholesterolaemia. Routine screening for lipids in hypertensive subjects was recommended by 40% of respondents. First-line antihypertensive drug choices were influenced by the knowledge of a hypercholesterolaemia, with preference for drugs known to have no adverse effects on the lipid profile. When first-choice drug failed to effectively lower blood pressure, the additional drug or the substitute choices were not influenced by the metabolic profiles of the alternative selected. The current wide choice of antihypertensive drugs and the complexity of metabolic complications of treatment plus the relationship of risk factor clustering has made the formulation of management strategies very difficult. This was supported by the finding that 88% of respondents in our survey felt that there was a clear need for consensus management guidelines for the treatment of hypertension with coexistent hypercholesterolaemia.

Aged↗
PubMed1990

Pharmacokinetic and pharmacodynamic studies of glibenclamide in non-insulin dependent diabetes mellitus.

1. The pharmacokinetic and pharmacodynamic properties of oral glibenclamide have been studied in 31 hospitalised in-patients and 79 ambulant out-patients with diabetes mellitus. 2. Breakfast was found to have no significant influence on the kinetic behaviour of glibenclamide or on the effect of this drug on blood glucose utilisation. 3. The time course of glibenclamide kinetics after 20 mg dosing was adequately described by a two-compartment open model, yielding mean half-lives of 3.3 +/- 1.5 h (t1/2, lambda 1) and 9.7 +/- 1.2 (t1/2, z) for the initial and terminal elimination phases respectively. 4. No significant accumulation or change in kinetic profile occurred in patients who had normal renal and hepatic function, were treated continuously with glibenclamide, and then rechallenged after 8-12 weeks. 5. Despite inter-individual variations in drug absorption, peak plasma concentrations (Cmax) and the area under the plasma concentration-time curve (AUC(0-24] were dose-dependent over the dose range 5-20 mg. No significant dose-response behaviour was observed in respect of glucose utilisation, suggesting that there is little clinical benefit in using doses of glibenclamide above 5 mg day-1. 6. Comparison of plasma glibenclamide concentrations at different time-bands following doses of 5 and 10 mg showed a wider range in ambulant out-patients than in age-, sex-matched in-patients treated with the same dosages of drug. Mean plasma drug concentrations attained at all time bands up to 8 h after dosing were higher in out-patients than in in-patients, suggesting a tendency to 'over-compliance' by patients in anticipation of attendance at clinic.

Administration, Oral↗
PubMed1990

Pharmacokinetic and pharmacodynamic actions of enalapril in humans: effect of probenecid pretreatment.

The pharmacokinetic and pharmacodynamic profiles of oral enalapril (20 mg), in absence and in presence of probenecid pretreatment (1 g twice daily for 5 days), were investigated in 12 healthy volunteers on normal salt intake (150 mmol/24 hr). Mean peak serum concentration of enalapril rose from 158 +/- 7 to 216 +/- 1 ng/ml (P less than .01), whereas that of its metabolite, enalaprilat, rose from 62 +/- 6 to 84 +/- 8 ng/ml (P less than .01) in the presence of probenecid pretreatment. Area under the curve of both enalapril and enalaprilat increased by 50% (P less than .001), which was accompanied by a reduction in renal excretion of both compounds. The renal clearance of enalapril decreased from 229 +/- 19 to 61 +/- 4 ml/min (P less than .001) and that of enalaprilat from 108 +/- 4 to 66 +/- 2 ml/min (P less than .001). The total drug recovery fell from 48 +/- 3 to 38 +/- 2% (P less than .01) of the administered dose with no accompanying changes in plasma elimination half-lives of the parent drug or metabolite. The pharmacodynamic response of enalapril such as fractional excretions of sodium, calcium, magnesium and urate were enhanced by probenecid pretreatment. Absolute urinary excretion of sodium increased from 51 +/- 5 to 91 +/- 8 mmol/6 hr (P less than .001) after enalapril and from 55 +/- 4 to 113 +/- 13 mmol/6 hr (P less than .01) after enalapril in presence of probenecid pretreatment, despite a significant decrease in the renal excretion of enalapril and enalaprilat over the same interval.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Renal responses and pharmacokinetics of piretanide in humans: effect of route of administration, state of hydration and probenecid pretreatment.

The influence of route of administration, state of hydration and transport inhibitor probenecid on the renal responses of a loop diuretic, piretanide, were investigated in 14 healthy volunteers. Maximally achieved plasma concentrations after i.v. and oral piretanide were higher in the nonhydrated state [+54% (i.v.); + 68% (oral)], accompanied by significant decreases in mean residence time, renal clearance and fraction of unchanged drug excreted with nonsignificant decreases in t1/2, steady-state volume of distribution and total clearance when compared with the hydrated state. Relative differences between the two hydrated states in maximal plasma concentrations of piretanide remained after probenecid [+26% (i.v.); +55% (oral)] but changes in kinetic parameters did not. Pretreatment with probenecid produced significant increases in absolute peak and plasma diuretic concentrations, t1/2 and mean residence time while decreasing steady-state volume of distribution, total clearance, renal clearance and fraction of unchanged drug excreted without affecting the bioavailability of piretanide. Urinary drug recovery was greater after i.v. than after oral piretanide, the recovery being consistently lower in nonhydrated state [iv: 2.78 (nonhydrated) versus 3.41 mg/24 h (hydrated); oral: 1.93 (nonhydrated) versus 2.76 mg/24 h (hydrated)]. Probenecid pretreatment reduced the overall urinary recovery of piretanide without altering the i.v./oral differences. Excretion of sodium paralleled piretanide excretion throughout the study except after i.v. dosing in the nonhydrated state where changes in drug excretion after probenecid (2.55 versus 1.63 mg/6 h) failed to influence sodium output (167 versus 152 mmol/6 h). These results demonstrate the importance of route of administration and state of hydration in determining the pharmacocological response of loop diuretics within the kidney.

Administration, Oral↗