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Biomedical subjects

R Laaksonen

Publications and source records attributed to R Laaksonen.

At least 19 recordsLinked to original sources
PubMed2002

Desire for information about drugs: relationships with patients' characteristics and adverse effects.

INTRODUCTION: Adverse effects of drugs are known to cause problems both in hospital and general practice settings, contributing to longer stays in a hospital, and increased costs of hospitalisation. By developing both a greater understanding of adverse drug reactions and effects and developing ways to reduce them will assist pharmacists in managing medicines more effectively. The aim of this study was to explore the relationships between patient characteristics, information requirements and perceptions about adverse drug effects to assist pharmacists in identifying patients most at risk of ADRs. METHODS: The study took place on medical wards at a London teaching hospital during an eight week period in Autumn 2000. Patients were recruited using convenience sampling during the recruitment period. Once eligible patients consented to take part, standardised interviews were conducted at their bedside. The interviews included the use of the previously validated scale which measures the extent of information desired (EID), patient characteristics including age, gender, socio-economic status etc and the presence of an adverse drug effect was assessed using the Naranjo algorithm. Patients were also asked semi-structured questions to explore past and present experiences of adverse drug effects. RESULTS: 82 patients were recruited, 80 were eligible for adverse effects of drugs assessment. Fifteen percent (12/80) of patients were assessed as having "definite" and "probable" adverse drug effects, based on the Naranjo algorithm. The previously validated EID scale was found to be both valid and reliable in this patient sample. There was an association between high scores on the EID scale and the presence of an adverse drug effect (chi-squared = 4.97, p = 0.02). CONCLUSION: The results show an association between the occurrence of an adverse drug effect on admission (identified by the Naranjo scale), the experience of an adverse drug effect in the past and a patient's desire for information. The EID-scale could be developed into a useful tool for assessing and addressing patients' drug information needs for pharmacists to use when assessing adverse drug effects in everyday practice.

Adult↗
PubMed2002

Oestrogen receptor gene variation is a determinant of coronary reactivity in healthy young men.

BACKGROUND: Oxidised low-density lipoprotein (ox-LDL) is a determinant of impaired coronary function and oestrogens inhibit its formation probably throughout genetically-variable oestrogen receptor 1 (ESR1) in artery wall. We hypothesized that the ESR1 polymorphism might influence coronary function and reactivity as measured by positron emission tomography (PET), which allows the detection of coronary dysfunction before appearance of angiographic lesions. MATERIALS AND METHODS: Fifty-one healthy young men (aged 35 +/- 4 years), with normal or slightly-elevated serum cholesterol, underwent PET with intravenous adenosine. ESR1 PvuII genotypes P/P, P/p, and p/p in addition to the plasma autoantibody titre against ox-LDL, a marker of in vivo oxidation, were determined. RESULTS: The ESR1 genotype persisted as the only significant predictor of adenosine stimulated coronary flow (P = 0.035) after adjustment for other coronary risk factors. Subjects with P/P genotype had 33.4 and 41.8% lower adenosine-stimulated flow values than subjects with P/p and p/p genotypes (P = 0.030). Furthermore, plasma levels of ox-LDL titre were on average 59 and 77% higher in subjects with P/P genotype than in subjects with P/p or p/p genotypes (P = 0.049). CONCLUSIONS: These tentative findings from our pilot study provide evidence that genetic variation in ESR1 may modify coronary reactivity and LDL oxidation and reflect differences in the early pathogenesis of coronary dysfunction in these healthy young men.

Adult↗
PubMed2002

High oxidized LDL and elevated plasma homocysteine contribute to the early reduction of myocardial flow reserve in healthy adults.

BACKGROUND: Impairment of coronary blood flow reserve has been shown to be an early manifestation of atherosclerosis and coronary artery disease (CAD). We studied more closely the contribution of various risk factors on early deterioration of coronary function. MATERIALS AND METHODS: Fifty-one young, apparently healthy adults, with normal or mildly elevated serum cholesterol levels but without other major risk factors for CAD, such as diabetes or hypertension, underwent positron emission tomography (PET) studies. Coronary flow reserve (CFR) was measured using O15-water. In addition to the classical risk factors, the role of several new risk indicators, such as low-density lipoprotein (LDL) oxidation, infection (Chlamydia pneumoniae antibodies), and inflammation parameters (adhesion molecules, ICAM, VCAM, selectin, and C-reactive protein), homocysteine and body iron stores were investigated. RESULTS: Elevated lipid and lipoprotein levels were not associated with reduced coronary reactivity. However, high autoantibody titers against oxidized LDL (oxLDL) were associated with 21% lower CFR than low oxLDL (P < 0.05). Furthermore, high homocysteine levels predicted low CFR (P < 0.05). The other measured parameters, Chlamydia pneumoniae antibody levels, C-reactive protein and adhesion molecule concentrations did not associate with myocardial blood flow. In a stepwise regression model, oxLDL (P = 0.03), homocysteine (P = 0.04) and triglycerides (P = 0.018) were significant predictors of CFR. CONCLUSIONS: The present study suggests an important role for oxidized LDL and plasma homocysteine on early impairment of coronary reactivity in young adults.

Adenosine↗
PubMed2001

Paraoxonase gene polymorphisms and coronary reactivity in young healthy men.

This study examined the relationships between paraoxonase genotypes, coronary artery reactivity, and indices of low-density lipoprotein oxidation in healthy men. Impairment in coronary flow reserve, as assessed by positron emission tomography, is associated with lipoprotein oxidation, which is affected by high-density lipoprotein bound enzyme, paraoxonase. Paraoxonase has two common polymorphisms (M/L55 and R/Q192) that change the activity of the enzyme. Forty-nine healthy men (mean age 35 +/- 4 years) were divided by paraoxonase genotype into low (Q192/Q192, or M55/M55, M55/L55) and high-active (R192/Q192, R192/R192, or L55/L55) groups and related to the myocardial blood flow, to the susceptibility of low-density lipoprotein to oxidation, and the autoantibody titer against oxidized low-density lipoprotein. The blood flow was measured by positron emission tomography at rest and during adenosine infusion. The low-active Q192/Q192 genotype was associated with higher resting blood flow corrected for rate-pressure product compared to the high-active R192/R192 and R192/Q192 genotypes (P=0.011). The blood flow stimulated by adenosine was not significantly different in the low- and high-active genotype groups. Paraoxonase genotypes had no effect on low-density lipoprotein susceptibility to oxidation or autoantibody formation against oxidized low-density lipoprotein. Genotypes of paraoxonase may not clearly contribute to the early changes in coronary reactivity. Coronary vasomotor tone at rest appears to be modulated by paraoxonase R/Q192 polymorphism through mechanism(s) unrelated to low-density lipoprotein oxidation.

Adult↗
PubMed2001

Hepatic lipase gene variation is related to coronary reactivity in healthy young men.

BACKGROUND: Impaired coronary flow reserve (CFR) can be used to indicate vascular dysfunction before the appearance of angiographic lesions. The hepatic lipase (HL) gene has a functional promoter polymorphism at position C-480T, which affects transcription and leads to high activity (C/C) and low activity (C/T, T/T) genotypes. These genotypes modulate HL activity, but their role in coronary artery disease is controversial and the effect on coronary function has not been studied. We investigated whether HL genotypes are associated with coronary artery function in healthy young men. MATERIALS AND METHODS: We studied 49 healthy, mildly hypercholesterolemic men (aged 35 +/- 4 years). Myocardial blood flow was measured at rest and during adenosine induced hyperaemia with positron emission tomography using [15O] H2O. HL genotype was determined by PCR and Nla III enzyme digestion. RESULTS: Resting myocardial blood flow was not statistically different in subjects with high and low activity HL genotypes. However, CFR (the ratio of adenosine flow to resting flow) was 24% higher (4.62 +/- 1.52 vs. 3.73 +/- 1.08 mL g-1 min-1, P = 0.024) in men with the high activity genotype (n = 26) than in those with low activity (n = 23). In multivariate analysis, the HL genotype remained a significant predictor of CFR (P = 0.038) after adjusting for age, body mass index, serum lipids and smoking. CONCLUSIONS: The findings of our preliminary study suggest that the C-480T polymorphism of the HL gene may modify coronary reactivity and reflect differences in the early pathogenesis of coronary dysfunction in these healthy young men. If the association between HL polymorphism and impaired CFR is also present in subjects with other dyslipoproteinemias, the HL polymorphism could be a new risk factor for cardiovascular disease.

Adult↗
PubMed2001

Effect of lipid-lowering therapy with pravastatin on myocardial blood flow in young mildly hypercholesterolemic adults.

Serum low-density lipoprotein cholesterol concentration is an important regulator of vascular reactivity. This double-blinded study examined the effect of lipid-lowering therapy on myocardial vasodilatory function in young hypercholesterolemic but otherwise healthy men. Fifty-one men (age 35 +/- 4 years) with mild hypercholesterolemia (total cholesterol, 5.6 +/- 0.8 mM ) were randomly assigned to receive pravastatin, 40 mg/day, or placebo for 6 months. Myocardial blood flow was measured at rest and during adenosine-induced hyperemia using positron emission tomography and oxygen-15-labeled water at baseline and after treatment. Pravastatin lowered low-density-lipoprotein cholesterol by 33% from 3.77 +/- 0.76 mM (p < 0.001), whereas placebo had no effect. At baseline, resting and adenosine-induced flow values were 0.85 +/- 0.27 and 3.61 +/- 1.00 ml/min per gram in the pravastatin group and 0.83 +/- 0.18 and 3.17 +/- 0.69 ml/min per gram in the placebo group. Despite significant low-density-lipoprotein cholesterol lowering, resting and adenosine-stimulated blood flow values remained similar at follow-up: 0.86 +/- 0.23 and 3.79 +/- 1.31 vs. 0.78 +/- 0.20 and 3.20 +/- 0.86 ml/min per gram, in the pravastatin and placebo groups, respectively. An improvement in adenosine-induced flow after pravastatin, but not after placebo, was seen only in a subgroup of subjects (n = 15) with relatively low adenosine flow (<4.0 ml/min per gram) at baseline. Six months of cholesterol-lowering therapy with statin treatment has no overall significant effect on coronary vasodilator capacity in healthy subjects with mildly elevated cholesterol levels. A controlled study is needed to further test whether improvement in coronary function is obtained in subjects with initially reduced hyperemic flow response.

Adult↗
PubMed2001

Paraoxonase genotype modifies the effect of pravastatin on high-density lipoprotein cholesterol.

Paraoxonase (PON) is an enzyme carried by high-density lipoprotein cholesterol (HDL-C). Two gene polymorphisms leading to amino acid substitutions of methionine for leucine at position 55 (M/L55) and arginine for glutamine at position 192 (R/Q192) modulate the activity of the enzyme and possibly also lipid and apolipoprotein concentrations. Our purpose was to examine the effect of the PON genotype on HDL-C and apolipoprotein AI (apo AI) responses to pravastatin treatment. Fifty-one mildly hypercholesterolemic male subjects (mean age 35 +/- 4 years) were enrolled by this prospective, randomized, double-blind study. Lipid concentrations were measured at baseline and after 6 months of pravastatin (n = 25) or placebo (n = 26) therapy. Low active (MM, ML or QQ) and high active (LL or RQ, RR) PON genotype groups were related to lipid and apolipoprotein concentration changes. Pravastatin increased the apo AI concentration 12% (P = 0.017, RANOVA) and tended to increase the HDL-C concentration (P = 0.095, RANOVA) in R allele carriers but not in QQ homozygotes. Significant predictors of the change in apo AI concentration during pravastatin treatment were R/Q192 genotype (P = 0.002), apo AI concentration at baseline (P = 0.002) and M/L55 genotype (P = 0.042). Correspondingly, R/Q192 (P = 0.009) and M/L55 (P = 0.050) genotypes were the statistically significant determinants of HDL-C concentration change. The PON genotype thus modifies the effect of pravastatin on serum HDL-C and apo AI concentrations. This could partly explain the contradictory results obtained from previous studies on the effects of statins on the serum HDL-C concentration.

Adult↗
PubMed1999

Pharmacokinetics of intravenous N-acetylcysteine in pre-term new-born infants.

BACKGROUND: Reactive oxygen species have been considered to play a role in several clinical complications in pre-term infants. The aim of this study was to determine the pharmacokinetics of intravenous N-acetylcysteine in pre-term neonates. This information is needed to evaluate the use of N-acetylcysteine as an antioxidant in this patient group. METHODS: N-acetylcysteine was infused intravenously in ten patients (gestational age 24.9-31.0 weeks, weight 500-1384 g) for 24 h (3.4-4.6 mg/kg/h), starting 2.0-11.2 h from birth (study I) and in six patients (gestational age 25.9-29.7 weeks, weight 520-1335 g) for 6 days (0.3-1.3 mg/kg/h), starting at the age of 24 h (study II). Arterial plasma N-acetylcysteine and cyst(e)ine concentrations were determined from timed samples taken during (study I and II) and after (study I) the N-acetylcysteine infusion. RESULTS: In study I, the mean elimination half-life of N-acetylcysteine was 11 h (range 7.8-15.2 h). The mean plasma clearance of N-acetylcysteine was 37 ml/kg/h (range 13-62 ml/kg/h) and the mean volume of distribution was 573 ml/kg (range 167-1010 ml/kg). The plasma clearance and volume of distribution correlated with weight (r = 0.81, P < 0.01, and r = 0.78, P < 0.01, respectively) and with gestational age (r = 0.71, P < 0.05, and r = 0.64, P < 0.05, respectively). In study II, the steady-state concentration of N-acetylcysteine was reached in 2-3 days in five of six patients during a constant infusion. CONCLUSIONS: The pharmacokinetics of N-acetylcysteine in pre-term infants depend markedly on weight and gestational age. The elimination of N-acetylcysteine is much slower in pre-term new-borns than in adults.

Acetylcysteine↗
PubMed1999

Low-density lipoprotein-independent effects of statins.

Statins have pleiotropic properties that complement their cholesterol-lowering effects. These properties may partly account for their established benefit in the prevention of coronary artery disease beyond the reduction of LDL-cholesterol levels. The most widely recognized properties are reviewed here. They include: (i) nitric oxide-mediated improvement of endothelial dysfunction and upregulation of endothelin-1 expression; (ii) antioxidant effects; (iii) anti-inflammatory properties; (iv) inhibition of cell proliferation with anticarcinogenic actions in animals; (v) stabilization of atherosclerotic plaques; (vi) anticoagulant effects; and (vii) inhibition of graft rejection after heart and kidney transplantation. As advances are made in our knowledge, new properties are steadily being uncovered. Pleiotropic effects are currently being given consideration when instituting combination therapy for patients at high cardiovascular risk. Some pleiotropic effects are negative, and may account for occasional untoward drug interactions. For many of these new properties, the clinical relevance has not been established. The challenge for the future will be to design and carry out appropriate clinical trials to establish their relative importance in the prevention of coronary artery disease.

Animals↗
PubMed1998

Modification of neuromagnetic cortical signals by thalamic infarctions.

Auditory evoked responses and spontaneous cortical activity were recorded with a whole-scalp 122-channel neuromagnetometer from 7 patients, who had small thalamic infarctions in the region of the left anterior tuberothalamic artery and associated memory defects. In contrast to healthy control subjects, with dominant rhythmic activity at 10.6 +/- 0.6 Hz in the parieto-occipital region, the spectral maximum in the patients was at 8.9 +/- 0.4 Hz. Abnormal acceleration of rhythmic activity was also observed bilaterally in rolandic areas. Our findings imply that lesions of non-specific thalamic nuclei may disturb human brain rhythms in widespread cortical areas. 'Mismatch responses' to deviant tones (1.1 kHz) among standards (1.0 kHz), suggested to reflect sensory auditory memory in healthy subjects, were absent in 2 patients, markedly decreased in 3, and normal in 2, implying that pathways passing through the anteromedial thalamus contribute to modulation of these responses. We conclude that local unilateral lesions in the anteromedial thalamus may cause extensive, bilateral alterations in the brain's electric activity.

Adult↗
PubMed1996

The effect of simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and ubiquinone in skeletal muscle.

It has been hypothesized that treating hypercholesterolemic patients with statins will lead not only to a reduction in cholesterol, but also to inhibited synthesis of other compounds which derive from the synthetic pathway of cholesterol. In theory, this could further lead to ubiquinone deficiency in muscle cell mitochondria, disturbing normal cellular respiration and causing adverse effects such as rhabdomyolysis. Furthermore, ubiquinone is one of the lipophilic antioxidants in low-density lipoprotein (LDL), and therefore it has also been hypothesized that statin treatment will reduce the antioxidant capacity of LDL. We investigated the effect of 6 months of simvastatin treatment (20 mg/day) on skeletal muscle concentrations of high-energy phosphates and ubiquinone by performing biopsies in 19 hypercholesterolemic patients. Parallel assays were performed in untreated control subjects. The muscle high-energy phosphate and ubiquinone concentrations assayed after simvastatin treatment were similar to those observed at baseline and did not differ from the values obtained in control subjects at the beginning and end of follow-up. These results do not support the hypothesis of diminished isoprenoid synthesis or energy generation in muscle cells during simvastatin treatment. Furthermore, the results of analysis of antioxidant concentrations in LDL before and after simvastatin treatment indicate that the antioxidant capacity of LDL is maintained in simvastatin-treated patients.

Adenosine Triphosphate↗
PubMed1996

The effects of anabolic androgenic steroids on serum ubiquinone and dolichol levels among steroid abusers.

We measured serum ubiquinone and dolichol concentrations in 13 men while they abused anabolic androgenic steroids (AAS) and during the following withdrawal period. Serum total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol and triglycerides were also determined. AAS administration increased serum ubiquinone by 68% (P < .001) and decreased serum dolichol by 30% (P < .002). Both nonsterol isoprenoid levels in plasma correlated with the AAS dose, ubiquinone positively (P < .001) and dolichol negatively (P < .002). When the subjects were taking steroids, the ubiquinone to LDL ratio was 42% higher than during the withdrawal period. In conclusion, our study suggests that AAS have an influence on the by-products of the mevalonate pathway.

Adult↗
PubMed1995

Ubiquinone supplementation and exercise capacity in trained young and older men.

It has been suggested that ubiquinone improves exercise performance and antioxidant capacity. We studied the effects of ubiquinone supplementation (120 mg.day-1 for 6 weeks) on aerobic capacity and lipid peroxidation during exercise in 11 young (aged 22-38 years) and 8 older (aged 60-74 years), trained men. The cross-over study was double-blind and placebo-controlled. Serum ubiquinone concentration increased after supplementation (P < 0.0001 for treatment) in both age groups. The maximal oxygen uptake (VO2max) was measured using a direct incremental ergometer test. In the young subjects, the VO2max after placebo and ubiquinone treatment was 58.5 (95% confidence interval: 53.0-64.0) and 59.0 ml.min-1.kg-1 (52.2-66.8), respectively. The corresponding results in the older subjects were: 37.2 (31.7-42.7) and 33.7 ml.min-1.kg-1 (26.2-41.7) (P < 0.0001 for age group, P > 0.05 for treatment). In a prolonged test (60-min submaximal, then incremental load until exhaustion) time to exhaustion was longer after the placebo [young men: 85.7 (82.4-89.0), older men: 82.9 min (75.8-89.9)] than after ubiquinone [young men: 82.1 (78.5-85.8), older men: 77.2 min (70.1-83.7); P = 0.0003 for treatment]. Neither ubiquinone supplementation nor exercise affected serum malondialdehyde concentration. Oral ubiquinone was ineffective as an ergogenic aid in both the young and older, trained men.

Adult↗
PubMed1995

Decreases in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatment in humans.

Statins, which are commonly used drugs for hypercholesterolemia, inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. Important nonsterol compounds, such as ubiquinone, are also derived from the same synthetic pathway. Therefore it has been hypothesized that statin treatment causes ubiquinone deficiency in muscle cells, which could interfere with cellular respiration causing severe adverse effects. In this study we observed decreased serum levels but an enhancement in muscle tissue ubiquinone levels in patients with hypercholesterolemia after 4 weeks of simvastatin treatment. These results indicate that ubiquinone supply is not reduced during short-term statin treatment in the muscle tissue of subjects in whom myopathy did not develop.

Acyl Coenzyme A↗
PubMed1995

Serum and muscle tissue ubiquinone levels in healthy subjects.

Ubiquinone, or coenzyme Q, is a mitochondrial component with antioxidant properties. It has been suggested that ubiquinone therapy may have clinical benefits in some diseases with mitochondrial dysfunction and that the antioxidant effects could be useful, for example, in the prevention of atherosclerosis. Based on this clinical interest, guidelines for the interpretation of ubiquinone analyses are needed. Our results show that serum and muscle ubiquinone levels vary over a wide range in healthy subjects. The serum levels of ubiquinone depend mostly on the amount of ubiquinone-containing lipoproteins in circulation. Physical activity markedly affects muscle tissue levels of ubiquinone. We observed that serum and muscle tissue ubiquinone levels do not correlate with each other, suggesting that they are independently regulated.

Adult↗
PubMed1994

Serum ubiquinone concentrations after short- and long-term treatment with HMG-CoA reductase inhibitors.

Serum ubiquinone levels were studied during long- and short-term treatment with 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors in 17 men with primary non-familial hypercholesterolaemia. The serum ubiquinone levels were determined after the patients had received simvastatin (20-40 mg per day) for 4.7 years, after a 4 week treatment pause and again after they had resumed treatment with lovastatin (20-40 mg per day) for 12 weeks. During the treatment pause the average serum ubiquinone levels increased by 32%; resumption of treatment caused a reduction of 25%. The changes in the levels of ubiquinone and serum total cholesterol as well as those of ubiquinone and low-density lipoprotein cholesterol were closely parallel. This suggested that changes in serum ubiquinone reflected changes in cholesterol-containing serum lipoproteins which could serve as carrier vehicles for ubiquinone. After long-term simvastatin treatment and after short-term lovastatin treatment, average serum ubiquinone levels (1.16 and 1.22 mg.l-1, respectively) were similar to that observed in a group of apparently healthy middle-aged men (1.16 mg.l-1).

Adult↗