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M MacMahon

Publications and source records attributed to M MacMahon.

At least 19 recordsLinked to original sources
PubMed2005

Safety, pharmacokinetics, and immunogenicity of single-dose rFXIII administration to healthy volunteers.

BACKGROUND: Factor XIII (FXIII) is a transglutaminase that cross-links fibrin and other proteins to improve clot strength and resistance to fibrinolysis. Both congenital and acquired FXIII deficiency may result in a bleeding diathesis, and plasma-derived FXIII has been used to treat many of these clinical conditions. OBJECTIVES: A clinical study was designed and performed to evaluate the safety, pharmacokinetics, and immunogenicity of recombinant FXIII (rFXIII) administration to healthy adult volunteers. PATIENTS AND METHOD: Fifty healthy adult volunteers were enrolled in this randomized, double-blinded, placebo-controlled study. A single dose of rFXIII, ranging from 2 U kg(-1) to 50 U kg(-1), or placebo was administered. Safety was evaluated by capturing adverse events, clinical safety laboratory studies, and clinical score for deep venous thrombosis. Blood samples were taken for pharmacokinetic and immunogenicity analysis throughout the 28-day follow-up period. RESULTS: Recombinant FXIII was well tolerated, with no serious adverse events or dose-related toxicities. Following a single i.v. injection of 50 U kg(-1) rFXIII, the estimated terminal half-life was 270-320 h, the volume of distribution ranged from 40 to 75 mL kg(-1), and FXIII activity increased 1.77% per 1 U kg(-1) rFXIII administered. Increase in circulating A2B2 and decrease in free FXIII-B subunit indicate in vivo formation of FXIII heterotetramer. An immunogenic response to rFXIII or yeast, the production host, was not observed. CONCLUSIONS: Recombinant FXIII was well tolerated at doses of up to 50 U kg(-1) in healthy adult volunteers. The safety, pharmacological and immunological profile of rFXIII suggests it should be studied in patients with congenital FXIII deficiency as well as evaluated as a systemic hemostat in patients with acquired FXIII deficiency or hemorrhage.

Adolescent↗
PubMed2000

Pharmacodynamics and pharmacokinetic-pharmacodynamic relationships of atorvastatin, an HMG-CoA reductase inhibitor.

The objective of this study is to determine the relationships between plasma atorvastatin concentrations, LDL (low-density lipoprotein) cholesterol reduction, and atorvastatin dose; the earliest time at which lipid levels change when atorvastatin treatment is initiated or discontinued; and alterations in LDL particle composition. Twenty-four subjects with elevated LDL-cholesterol were treated with escalating daily doses of 5, 20, and 80 mg atorvastatin for 6 weeks each. Serial plasma lipid and lipoprotein analyses were performed during the initiation and discontinuation of atorvastatin therapy, as well as at steady state. LDL-apolipoprotein B and LDL-cholesterol were measured directly after ultracentrifugation, and LDL-cholesterol also was estimated by the method of Friedewald. Steady-state atorvastatin pharmacokinetic parameters were estimated on the last day of each dosing period. LDL-cholesterol (Friedewald) reductions of 34%, 43%, and 57% were produced by atorvastatin doses of 5, 20, and 80 mg, respectively. The mean dose-response relationship was log linear, and almost all individual dose-response curves paralleled the mean curve. LDL-apolipoprotein B reductions were slightly less than those of LDL-cholesterol. Atorvastatin area under the curve (AUC(0-24) values increased proportionally with dose, while values of Cmax (maximum concentration) increased more than proportionally, and Cmin (minimum concentration) increased less than proportionally. Following initiation of dosing, statistically significant decreases in total cholesterol, LDL-cholesterol (beta quant), and LDL-apolipoprotein B were observed within 24 hours and in LDL-C (Friedewald) within 72 hours. Following discontinuation of drug dosing, statistically significant increases were observed in total cholesterol and LDL-cholesterol (Friedewald) within 48 hours and in LDL-cholesterol (beta quant) and LDL-apolipoprotein B within 72 hours. At each dose, an individual's LDL-cholesterol response was not correlated with AUC(0-24). In conclusion, atorvastatin produces marked LDL-cholesterol reductions, the mean dose-response relationship is log linear, almost all individual dose-response curves parallel the mean dose-response curve, onset and cessation of action are rapid, the estimated and measured LDL-cholesterol are the same, LDL-cholesterol and LDL-Apo B reductions are similar, and plasma concentrations are not correlated with LDL-cholesterol reduction at a given dose.

Adult↗
PubMed2000

A pilot study with simvastatin and folic acid/vitamin B12 in preparation for the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH).

BACKGROUND AND AIM: This study was conducted in preparation for the Study Evaluating Additional Reduction in Cholesterol and Homocysteine (SEARCH). SEARCH is a 12,000 patient 2X2 factorial study in post-myocardial infarction patients that will compare simvastatin 20 mg with simvastatin 80 mg to evaluate whether greater LDL-C reductions with simvastatin provide greater coronary event reductions. SEARCH will also test the hypothesis that lowering plasma homocysteine with folic acid and vitamin B12 will reduce coronary events. This pilot study was performed to determine whether any clinically meaningful interaction between simvastatin and folic acid/vitamin B12 exists. METHODS AND RESULTS: Following a 2-week diet/placebo run-in period, 141 patients with primary hypercholesterolaemia were randomised to one of three treatments for 6 weeks: 80 mg/day simvastatin and 2 mg folic acid/0.8 mg vitamin B12 daily (combination group); or 80 mg/day simvastatin and placebo vitamins (simvastatin alone group); or 2 mg folic acid/0.8 mg vitamin B12 daily and placebo simvastatin (vitamins alone group). The combination group and simvastatin alone group experienced similar serum lipid changes with reductions in LDL-cholesterol of 55.2% and 51.5% respectively. The combination group and vitamins alone group experienced similar homocysteine lowering with reductions in homocysteine of 25.3% and 23.1% respectively. All therapies were well tolerated. CONCLUSIONS: There was no detectable antagonistic effect when simvastatin and folic acid/vitamin B12 were administered concomitantly.

Cholesterol↗
PubMed1998

Low-dose antihypertensive therapy with 1.5 mg sustained-release indapamide: results of randomised double-blind controlled studies. European study group.

OBJECTIVE: In accordance with international recommendations on the need to decrease doses of antihypertensive drugs, a low-dose (1.5 mg) sustained-release (SR) formulation of indapamide was developed to optimize the drug's efficacy : safety ratio. The aim of this work was to evaluate the benefit of a low-dose diuretic by consolidating the efficacy and safety results of two clinical trials with a similar design. PATIENTS AND METHODS: Clinical data were obtained in two European randomized double-blind studies with 690 mild to moderate hypertensive patients (95 mmHg < or = supine diastolic blood pressure < or = 114 mmHg using a mercury sphygmomanometer) treated respectively for 2 and 3 months, with a mean age of 53 and 57 years, 44 and 57% males, mean supine diastolic blood pressure of 100.6 and 102.5 mmHg and mean supine systolic blood pressure of 161.0 and 164.5 mmHg. RESULTS: The first study, a dose-finding study with indapamide SR at 1.5, 2 and 2.5 mg versus placebo and the immediate-release (IR) formulation of indapamide, showed that the 1.5 mg dosage of the new indapamide formulation had an improved antihypertensive efficacy : safety ratio. The second study confirmed the equivalence of blood pressure reductions with 1.5 mg indapamide SR and 2.5 mg indapamide IR, and better acceptability with 1.5 mg indapamide SR, particularly in the number of patients with serum potassium levels < 3.4 mmol/l, which was reduced by more than 50%. The long-term efficacy of 1.5 mg indapamide SR was observed through a 9-month open-treatment follow-up to the second study. CONCLUSION: The 1.5 mg SR formulation of indapamide has an improved antihypertensive efficacy : safety ratio, which is in accordance with international recommendations for the use of low-dose antihypertensive drugs and diuretics in first-line therapy of hypertension.

Adult↗
PubMed1998

Ispaghula husk in the treatment of hypercholesterolaemia: a double-blind controlled study.

BACKGROUND: Lowering cholesterol levels by natural dietary modification is an attractive first-line option for the treatment of mild-to-moderate hypercholesterolaemia. However, results have been less than impressive. The addition of soluble fibre - for example, psyllium or oat bran - to a modified diet has produced better results. In this study, the cholesterol-level-lowering effect of ispaghula husk and dietary advice was compared with placebo and dietary advice in treating patients with mild-to-moderate hypercholesterolaemia. METHODS: The double-blind, placebo-controlled, randomized comparison was conducted in 42 general practices and three hospital centres in the UK. There was an initial 8-week diet-only period and then a 1 2-week treatment period. Ispaghula treatment (7.0 or 10.5 g/day) was continued for a further 12 weeks for some patients. A total of 340 patients, aged 18 to 65, with mild-to-moderate hypercholesterolaemia [low-density lipoprotein (LDL) cholesterol levels of 4.1 mmol/l or more] entered the 12-week treatment phase. Levels of LDL cholesterol, total cholesterol, high-density lipoprotein cholesterol, triglycerides and apolipoproteins A1 and B were determined. RESULTS: LDL cholesterol and total cholesterol levels fell during the diet-only period. In members of the intention-to-treat population after the 8-week diet period, LDL cholesterol levels had fallen by 0.42 mmol/l (8.7%) for the 7.0 g ispaghula/day group after 12 weeks of treatment, whereas LDL cholesterol levels had fallen by 0.48 mmol/l (9.7%) for the 10.5 g ispaghula/day group. Ispaghula at both doses produced significantly greater reductions in LDL cholesterol levels than did placebo (7.0 g/day versus placebo, P=0.009; 10.5 g/day versus placebo, P<0.001). Ispaghula and modification of diet together reduced LDL cholesterol levels by 10.6-13.2% and total cholesterol levels by 7.7-8.9% during the 6-month period. CONCLUSIONS: Ispaghula husk as an adjunct to diet is effective and well tolerated in the management of appropriate patients with mild-to-moderate primary hypercholesterolaemia.

Adolescent↗
PubMed1998

The effect of cholesterol reduction with fluvastatin on aortic compliance, coronary calcification and carotid intimal-medial thickness: a pilot study.

BACKGROUND: Regression of atheroma with reduction of cholesterol levels is recognized to occur, but less is known about reversal of sclerosis. Non-invasive indices of sclerosis have largely been based on carotid ultrasound measurements. OBJECTIVE: To measure aortic compliance, coronary calcification and carotid intimal-medial thickness during reduction of cholesterol level in patients with and without coronary artery disease. METHODS: We studied 64 hypercholesterolaemic patients, 24 with and 40 without coronary artery disease. All were administered fluvastatin for 1 year. Aortic compliance was assessed using magnetic resonance and coronary calcification score was determined by electron beam computed tomography. Carotid intimal-medial thickness in 34 patients was measured by carotid ultrasound means. RESULTS: There was a rise in high-density lipoprotein cholesterol level and falls in total cholesterol level, low-density lipoprotein cholesterol level, low: high-density lipoprotein ratio, triglyceride level and very-low-density lipoprotein cholesterol level. Coronary artery disease patients had a higher coronary calcification score (442 +/- 551) than did other patients (269 +/- 724, P = 0.0002). For both groups there was a small rise in coronary calcification score during the study. Mean aortic compliance rose and blood pressure and carotid intimal-medial thickness fell. Analysis revealed significant correlations between change in mean aortic compliance and changes in high-density lipoprotein level (r = 0.3, P = 0.036), very-low-density lipoprotein level (r = -0.31, P = 0.038) and low: high-density lipoprotein ratio (r = -0.35, P = 0.014). There was no significant difference in these changes between the two patient groups. CONCLUSION: An improvement in aortic compliance over 1 year indicates that increase in high-density lipoprotein level, decrease in very-low-density lipoprotein level and improvement in low: high-density lipoprotein ratio caused by administration of fluvastatin beneficially influenced vascular pathophysiology in hypercholesterolaemic patients with and without coronary artery disease. In those patients studied with carotid ultrasound means, carotid intimal-medial thickness decreased from 1.09 to 0.87 mm (P = 0.004), corroborating these results.

Anticholesteremic Agents↗
PubMed1996

Syncope: driving advice is frequently overlooked.

Consecutive referrals to a syncope clinic were asked about the frequency of enquiries about driving status by referring general practitioners and/or hospital specialists. Although 40% were drivers, only 13% of patients had been previously asked about driving, and 12% of drivers had experienced symptoms whilst driving. This represents an important oversight on the part of referring doctors.

Adult↗
PubMed1996

[Evaluation of trough/peak ratio of indapamide 1.5 mg sustained-release form assessed by ambulatory blood pressure monitoring].

Because of the high variability of casual blood pressure measurements. ABPM has become a complementary clinical tool for evaluating antihypertensive treatment. Nevertheless, there is still a lack of practical guidelines to interpret the data. A review of the literature shows that ABPM efficacy data are analyzed differently, especially the trough-to-peak ratio proposed by the Food and Drug Administration. Published trough-to-peak ratios are widely disparate due to the diversity of the calculation methods which are most often not justified. Thus inappropriate comparisons of these results can easily produce incorrect conclusions. The aim of this review is to select, through the literature, basic methodological requirements commonly agreed on for accurate assessment of trough-to-peak ratio, and to apply them to the ABPM data on indapamide, a diuretic related to the thiazides. Six methodological requirements commonly agreed on at this time are the following: 1. study design: placebo-controlled study with a placebo run-in period; 2. patients selection: compliance with the study protocol, record obtained before and after treatment for each patient; 3. population analysis: whole and responder population: 4. quality control of the records: 5. placebo effect subtraction; 6. global and individual calculation with the indication of median values. Given that, no T/P ratio, especially for a diuretic, has yet been calculated according to these requirements, the above methodological points were taken into account for the T/P calculation of indapamide, from a placebo-controlled dose-finding study involving 285 patients.

Adult↗
PubMed1995

Combined bezafibrate and simvastatin treatment for mixed hyperlipidaemia.

The safety and efficacy of combined bezafibrate-simvastatin therapy was evaluated in 49 patients with diet-resistant mixed hyperlipidaemia (type IIb). After a two-month placebo phase, patients were randomized to receive either Bezafibrate Slow Release (SR) 400 mg mane or simvastatin 20 mg nocte followed by three months combination therapy. Total cholesterol, triglycerides and high-density lipoprotein (HDL) cholesterol were measured at monthly intervals. Apolipoproteins (apo) A1 and B, lipoprotein (a) [Lp(a)] and fibrinogen were measured before and after each treatment. Simvastatin was more effective than Bezafibrate SR in reducing total cholesterol (2.0 vs. 1.1 mmol/l, p = 0.003) and lowering LDL cholesterol (1.7 vs. 0.4 mmol/l, p = 0.0001) whereas Bezafibrate SR was more effective in reducing triglycerides (by 41% vs. 17%, p = 0.001) and fibrinogen (by 23% vs. 3%, p = 0.004). Compared with simvastatin monotherapy, combined drug therapy induced further reductions in triglycerides (by 26%, p = 0.0003) and apoB (by 11 mg/dl, p = 0.03) and an increase in apoA1 (by 21 mg/dl, p = 0.0008). Symptomatic and biochemical adverse events did not occur more frequently on combined drug therapy than on monotherapy. The combination of bezafibrate and simvastatin was more effective in controlling mixed hyperlipidaemia than either drug alone and did not provoke more adverse events.

Adolescent↗
PubMed1995

Haemodynamics, cardiac conduction and pharmacokinetics of mibefradil (Ro 40-5967), a novel calcium antagonist.

OBJECTIVES: Mibefradil (Ro40-5967) is a chemically novel non-dihydropyridine calcium antagonist. In this phase II study we compared its acute and chronic effects on blood pressure, heart rate and atrioventricular conduction (electrocardiographic PQ interval) with those of verapamil and diltiazem. PATIENTS AND METHODS: After a 4-week placebo run-in, 18 patients with mild to moderate essential hypertension were given single doses of mibefradil (150 mg), slow-release (SR) verapamil (240 mg), diltiazem (240 mg) and placebo at weekly intervals; pharmacokinetics and the effects on blood pressure, heart rate and PQ interval were studied on four 10-h study days. Seventeen of the same patients subsequently underwent 4 weeks of treatment with either mibefradil (100 mg daily; n = 10) or verapamil SR (240 mg daily; n = 7), and on the last day, they attended a further 10-h study day. Two studies were conducted: an acute, single-dose, double-blind, randomly allocated, placebo-controlled, crossover study and a chronic, open-label, randomly allocated, parallel-group study. RESULTS: Mibefradil was well tolerated. In the acute study, the antihypertensive effect (difference from placebo) of mibefradil 150 mg was of slower onset than that of verapamil or diltiazem, but comparable blood pressure reductions had been achieved by 6 h. The mean +/- SD maximal PQ prolongation (difference from placebo) was 15.6 +/- 16.1 ms, compared with 44.0 +/- 22.6 ms for verapamil and 56.0 +/- 48.9 ms for diltiazem (P<0.05 mibefradil versus verapamil; P<0.01 mibefradil versus diltiazem). In the chronic study there were no significant differences during steady-state conditions between mibefradil at 100 mg and verapamil SR at 240 mg in their effects on blood pressure, PQ and heart rate. The mean +/- SD elimination half-life (t1/2) of mibefradil under steady-state conditions was 26.8 +/- 5.5 h (versus an apparent t1/2 of 16.9 +/- 11.1 h for verapamil SR, P<0.05). CONCLUSIONS: Mibefradil is a well-tolerated and efficacious antihypertensive agent well suited to single daily dosing because of its intrinsic long plasma half-life. The effects on both blood pressure and PQ interval are of more gradual onset than those of unmodified verapamil and diltiazem after single doses.

Adolescent↗
PubMed1994

Small intestinal bacterial overgrowth--an incidental finding?

OBJECTIVES: To assess the prevalence of typical clinical features and need for treatment of small intestinal bacterial overgrowth (SIBO) in the elderly. DESIGN: Random selection of patients, regardless of their nutritional status. SETTING: Acute admissions ward in the Dept. of Medicine for the Elderly. PATIENTS: Thirty elderly patients between 68 and 90 years of age. MEASUREMENTS: Active clinical problems, including the presence of recent weight loss and diarrhea, were recorded. Routine blood tests, including serum vitamin B12, red cell folate, albumin and calcium, and qualitative small bowel bacteriology results, were analyzed. The effect of age on all variables was studied. RESULTS: Twenty of the 30 small bowel aspirates had proven SIBO, and strict anaerobes were isolated in 15. The mean blood test values did not differ significantly between culture-positive and culture-negative patients. There was no significant correlation between those variables and the total bacterial counts. Of the 20 proven SIBO cases, eight had anemia, five had hypoalbuminemia, five had diarrhea, four complained of recent weight loss, and none had B12 deficiency. Alternative causes other than SIBO were identified for many of these abnormalities. Advancing age correlated significantly with rising counts of small bowel strict anaerobes. CONCLUSIONS: These data suggest that age may be a predisposing factor in the development of anaerobic overgrowth but that SIBO is a benign entity in the elderly. Contrary to previous recommendations, treatment of this condition is not routinely indicated.

Age Factors↗
PubMed1993

Observing the brachial artery through a pressure cuff.

A technique is described which enables ultrasonic imaging of the brachial artery whilst pressure is applied via a pressure cuff. This involves a new instrument--a sphygmomanometer, which uses water as opposed to air as the pressure medium, in order to permit ultrasonic imaging through the cuff. The technique was found to be acceptable in the clinical setting, and gave a measurement of the systolic blood pressure which correlated with the conventional cuff measurement in eleven elderly subjects (r = 0.89, p < 0.001). The technique should have an important role to play in studying the origin of differences which occur between direct and indirect blood pressure measurements.

Blood Pressure Determination↗
PubMed1993

Measurement of arterial closing pressure.

It has been suggested that certain artifacts in blood pressure measurement by auscultation stem from stiffness of the tissues underneath the pressure cuff, resulting in a component of cuff pressure being required to overcome resistance to brachial artery collapse. This paper describes a technique for measuring the pressure required to collapse a segment of the brachial artery which has been isolated from central arterial pressure. This measurement is termed the arterial closing pressure. In a study of eleven elderly subjects, the artery collapsed spontaneously (zero closing pressure) after being isolated from central pressure in seven subjects. The remaining four required external pressures ranging from 4.6 to 10.7 kPa (35 to 81 mmHg) in order to collapse the artery. Thus arterial closing pressure may frequently be a significant fraction of arterial blood pressure in the elderly population, and may contribute to error in the measurement of blood pressure by auscultation. Arterial closing pressure may be a useful tool for investigating the origin of differences between indirect and direct blood pressure measurements, and also in the investigation of spontaneous arterial closure.

Aged↗
PubMed1993

Endoscopic retrograde cholangiopancreatography in the elderly: a single unit audit.

Endoscopic retrograde cholangiopancreatography (ERCP) has an established role in the management of pancreato-biliary disease, but its role in elderly patients has not been evaluated. A prospective study was carried out in 50 elderly patients, aged between 65 and 94 years, to compare the sensitivity and specificity of ERCP in this age group with ultrasound and liver blood tests, and to examine its safety and therapeutic effectiveness. ERCP was successful in 46 of 50 (92%) procedures. Thirty-four patients had abnormal findings, and 18 sphincterotomies were performed. No complications were recorded. There was a poor correlation between ultrasound and ERCP with agreement in only 45% of cases; sensitivity 35% and specificity 75%. Liver blood tests, alkaline phosphatase and gamma-glutamyl transferase were elevated in all 30 cases with obstructed ducts on ERCP. Ultrasound revealed obstruction in only 10 (33%) of these. Thus, liver biochemistry proved a more reliable indicator of biliary obstruction than ultrasound. In 22 cases endoscopic stone clearance or demonstration of inoperable lesions obviated surgery while in 9 cases surgery was indicated, because of multiple large stones not cleared at ERCP, or for bypass of a malignant stricture. ERCP is therefore safe and effective with a high diagnostic and therapeutic yield even in the poor risk elderly.

Aged↗
PubMed1981

Rectal mercury.

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Child, Preschool↗