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Biomedical subjects

B Tomlinson

Publications and source records attributed to B Tomlinson.

At least 73 records · Page 4Linked to original sources
PubMed1999

Superoxide dismutase gene expression and activity in the brain of spontaneously hypertensive rats and normotensive rats.

OBJECTIVE: To determine if changes in superoxide dismutase (SOD) in the brain occur in the hypertensive state. METHODS: We compared the levels of the two main subtypes of this enzyme in spontaneously hypertensive rats (SHR) with age-matched normotensive Wistar Kyoto (WKY) rats using enzyme activity estimation, Western blotting for enzyme contents, and Northern blotting of mRNA level. Five discrete brain regions, cerebrocortex, hypothalamus, hippocampus, the remaining non-cortex cerebrum (NCC area), and cerebellum, were employed for comparison in 30-31 weeks old rats. RESULTS: A lower level of both Mn-SOD activity and Mn-SOD mRNA expression was found in all areas of the brain of SHR as compared with WKY rats. Also, the mRNA levels of Cu, Zn-SOD in the brain of SHR differed from WKY rats in parallel to the enzyme activities. The activity and mRNA expression of Cu, Zn-SOD were lower in the hypothalamus and cerebellum of SHR but the mRNA level and the activity in hippocampus were significantly higher in the SHR compared to WKY rats. No differences for Cu, Zn-SOD were observed in cerebrocortex or NCC area in the two species. However, the amount of SOD enzyme subtypes, determined by Western blotting analysis, was not different between SHR and WKY rats. CONCLUSIONS: The results indicate a lower gene expression and less activity of Mn-SOD in SHR brain. This alternation of SOD may be one of the important factors for the vulnerability of the brain from oxygen free radicals or may be related to the pathogenesis of hypertension in this species.

Animals↗
PubMed1999

Effect of beta-blockade on baroreceptor and autonomic function in heart failure.

Although beta-adrenoreceptor antagonists appear to be beneficial in chronic heart failure there is little information on their effects on autonomic and baroreceptor function which may have important prognostic implications. We sought to determine first whether beta-adrenoreceptor blockade will improve baroreceptor function and vagal tone in chronic heart failure, and second whether there were any differences between standard therapy with metoprolol and the second-generation vasodilating beta-blocker celiprolol. In this double-blind randomized placebo-controlled study 50 patients with stable chronic heart failure received either celiprolol 200 mg daily, metoprolol 50 mg twice daily or placebo for 12 weeks after a 4-week dose titration period. Thirty-five healthy normal subjects were also studied. Baroreceptor gain was assessed non-invasively by cross-spectral analysis of R-R and systolic blood pressure low- and high-frequency components (the alpha angle) during controlled respiration. High-frequency power was used as a measure of vagal modulation. Satisfactory recordings for analysis were obtained in 31 patients with heart failure. The results showed that at baseline baroreceptor gain (alphaHF) was significantly depressed in patients with heart failure compared with the normal control group (4.95+/-0. 55 versus 11.73+/-1.32 ms/mmHg, P<0.0001). After 12 weeks of treatment with metoprolol baroreceptor gain improved significantly whether measured while supine (P=0.03) or standing (P=0.009), and this was associated with a significant increase in R-R HF power (P=0. 008). There were no significant changes after treatment with celiprolol or placebo. We conclude that metoprolol but not celiprolol therapy restores baroreceptor gain towards normal and increases vagal tone in chronic heart failure. The ancillary properties of celiprolol do not appear to provide any advantages over metoprolol for the restoration of autonomic and baroreceptor function in heart failure.

Adrenergic beta-Antagonists↗
PubMed1998

The effect of stevioside on blood pressure and plasma catecholamines in spontaneously hypertensive rats.

Stevioside is a sweet-tasting glycoside, composed of stevia, a diterpenic carboxylic alcohol with three glucose molecules, mainly used as a substitute for non-alcoholic sweetener. It has previously been shown to reduce blood pressure in studies in animals and human. The effect of intravenous stevioside on the blood pressure was studied in spontaneously hypertensive rats (SHR). The hypotensive effect on both systolic and diastolic blood pressure was dose-dependent for intravenous doses of 50, 100 and 200 mg/kg in conscious SHR. The maximum reductions in systolic and diastolic blood pressure were 31.4 +/- 4.2% and 40.8 +/- 5.6% (mean +/- SEM) respectively and the hypotensive effect lasted for more than 60 min with a dose of 200 mg/kg. Serum dopamine, norepinephrine and epinephrine levels were not changed significantly 60 min after intravenous injection of stevioside 100 mg/kg in anesthetized SHR. The present data show that stevioside given intravenously to conscious SHR was effective in blood pressure reduction and there was no change in serum catecholamines in anaesthetized animals with this natural compound.

Animals↗
PubMed1998

Caco-2 cell permeability of a new (hydroxybenzyl)ethylenediamine oral iron chelator: correlation with physicochemical properties and oral activity.

This study describes the transport of CGP 75254A, a novel oral iron chelator, across Caco-2 cells in an attempt to model intestinal epithelial cell permeability in man. CGP 75254A was dosed to the apical side of Caco-2 cell monolayers, together with [14C]mannitol as an internal permeability standard. The apparent permeability (Papp) was calculated from the cumulative appearance of drug in the basolateral fluid with time. The [14C]mannitol Papp indicated that the Caco-2 monolayers remained intact and that the iron chelator was not toxic to the cells. Permeabilities of CGP 75254A were compared with the Caco-2 permeabilities of compounds of known absorption in man. The results predict that absorption of CGP 75254A is likely to be virtually complete at pH values between 5.5 and 7.0. However, at pH 8.0 permeability is predicted as negligible. Cell permeability data are in full accordance with key physicochemical properties of CGP 75254A and suggest that the drug is passively absorbed. The results, which suggest likely quantitative absorption in vivo, are supported by preliminary pharmacological experiments in marmosets.

Administration, Oral↗
PubMed1998

Antioxidant power of angiotensin-converting enzyme inhibitors in vitro.

AIMS: There is controversy regarding the potential antioxidant effect of captopril, therefore this study was performed to compare the in vitro antioxidant power of captopril with other angiotensin-converting enzyme (ACE) inhibitors. METHODS: Antioxidant power of captopril, enalapril, fosinopril, perindopril, quinapril and ramipril in aqueous solution was measured using the ferric reducing (antioxidant) power (FRAP) assay; captopril was also measured in ethanolic solution. RESULTS: Only captopril showed significant antioxidant power, demonstrating a stoichiometric factor of 1.0 in this assay. Concentration-related antioxidant power was seen in both aqueous and ethanolic solutions. CONCLUSIONS: Captopril shows antioxidant activity in vitro. This property could be relevant in vivo if captopril is concentrated in membranes, lipoproteins or at other important sites.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Mutations in the low-density lipoprotein receptor gene in Chinese familial hypercholesterolemia patients.

It has been reported that in China, patients with heterozygous familial hypercholesterolemia (FH) may go unrecognized because they do not have xanthomata or premature coronary heart disease and their LDL cholesterol levels are lower than those in their Western counterparts. However, in the Chinese patients in Hong Kong, heterozygous FH appears to manifest in a way similar to that seen in Western countries or Japan. We studied sequence variations in the promoter and coding regions of the 18 exons of the LDL receptor gene in 30 Chinese FH patients. Eighteen mutations were identified in 21 patients scattered in the promoter and 10 exons. Eleven of them were first found in this study. We also found 6 polymorphisms with allelic frequencies different from those in whites but similar to the Japanese, indicating some isolation between white and Oriental populations. A total of 29 mutations in the LDL receptor gene are now known in the Chinese. There is no definite common mutation due to a founder effect. Meanwhile, there were no detectable LDL receptor gene mutations in 9 clinically diagnosed FH patients in whom the R3500Q mutation in apolipoprotein B had also been excluded. The gene defects leading to the FH phenotype in these patients may occur somewhere else in the apolipoprotein B or other related genes, or even in the noncoding sequences of the LDL receptor gene.

Adolescent↗
PubMed1998

Acute effects of a surgical menopause on serum concentrations of lipoprotein(a).

OBJECTIVE: The aim of this study was to investigate acute changes in serum concentrations of lipoprotein(a) and other atherogenic lipids and lipoproteins after a surgical menopause. METHODS: A total of 100 premenopausal Chinese women who were booked for hysterectomy for benign gynecological disorders were recruited. They study group comprised 40 subjects undergoing hysterectomy as well as bilateral oophorectomy. The control group consisted of 60 subjects undergoing hysterectomy with conservation of the ovaries. Complete data were available from 30 of the 40 subjects in the study group and from 44 of the 60 controls. Serum concentrations of lipoprotein(a) and other atherogenic lipids and lipoproteins were measured before surgery and these measurements were repeated 3 days, 8 weeks and 6 months postoperatively. Those study patients who received hormone replacement therapy and control patients who became menopausal, according to biochemical criteria, during the study period were excluded from analysis. RESULTS: Three days after surgery, there was a significant increase in the mean lipoprotein(a) concentration in the control group from 19.1 to 23.0 mg/dl (p < 0.01), but there was no significant change in the study group. There were no significant changes from baseline in the mean lipoprotein(a) concentration in either group 8 weeks or 6 months after surgery. There was a significant increase in the mean concentration of total cholesterol in the study group 8 weeks after surgery from 5.08 to 5.45 mmol/l (p < 0.01), in low density lipoprotein cholesterol from 3.22 to 3.49 mmol/l (p < 0.01), and in apolipoprotein B from 95.6 to 103.0 mg/dl (p < 0.05). However, the mean concentrations 6 months after surgery were not significantly different from baseline levels. The mean concentrations of high density lipoprotein cholesterol, apolipoprotein A-1 and triglycerides also did not differ significantly from baseline in the study group, either 8 weeks or 6 months after surgery. CONCLUSIONS: These results suggest that any increase in concentrations of lipoprotein(a), and other atherogenic lipids and lipoproteins which occur after the menopause, develops relatively slowly. The changes in concentrations which occurred within 8 weeks of surgery were probably an acute-phase reaction after surgery rather than a response to a decreasing estradiol concentration.

Adult↗
PubMed1998

Hyperlipidaemia in Chinese populations.

Chinese populations have been protected from coronary heart disease by a low fat diet and low plasma lipids. Fat intake has increased in more affluent populations but coronary heart disease mortality has remained relatively low. Further increases in dietary fat in young people and rising rates of diabetes in the older population may increase the prevalence of hyperlipidaemia and vascular disease.

Adult↗
PubMed1997

Efficient high-performance liquid chromatographic assay for the simultaneous determination of metoprolol and two main metabolites in human urine by solid-phase extraction and fluorescence detection.

An improved, more efficient method for the determination of metoprolol and its two metabolites in human urine is reported. The simultaneous analysis of the zwitterionic metoprolol acidic metabolite (III, H117/04) with the basic metabolites alpha-hydroxymetoprolol (II, H119/66), metoprolol (I) and guanoxan (IV, internal standard) was achieved employing solid-phase extraction and isocratic reversed-phase HPLC. The analytes were extracted from urine (100 microliters) using C18 solid-phase extraction cartridges (100 mg), and eluted with aqueous acetic acid (0.1%, v/v)-methanol mixture (40:60, v/v, 1.2 ml). The eluents were concentrated (250 microliters) under vacuum, and aliquots (100 microliters) were analysed by HPLC with fluorescence detection at 229 nm (excitation) and 309 nm (emission) using simple isocratic reversed-phase HPLC (Novapak C18 radial compression cartridge, 4 microns, 100 x 5 mm I.D.). Acetonitrile-methanol-TEA/phosphate buffer pH 3.0 (9:1:90, v/v) was employed as the eluent (1.4 ml/min). All components were fully resolved within 18 min, and the calibration curves for the individual analytes were linear (r2 > or = 0.996) within the concentration range of 0.25-40.0 mg/ml. Recoveries for all four analytes were greater than 76% (n = 4). The assay method was validated with intra-day and inter-day variations less than 2.5%.

Administration, Oral↗
PubMed1997

Short-term safety and efficacy of low-dose simvastatin in elderly patients with hypertensive hypercholesterolemia and fasting hyperinsulinemia.

To evaluate the short-term safety and efficacy of low-dose (10 mg) simvastatin in hypercholesterolemic, hypertensive elderly Chinese patients receiving antihypertensive treatment, a randomized, double-blind, placebo-controlled, 3-month trial was conducted. The patients had a total plasma cholesterol level of at least 250 mg/dL and had been, for at least 3 months, consuming a standard lipid-lowering diet (American Heart Association Step 1 Diet). Elderly hypertensive patients (n = 76) were randomized to receive treatment with either placebo (n = 38) or simvastatin (n = 38). The dosage consisted of 10 mg simvastatin daily during the 3-month trial. During that period, in the simvastatin group, plasma levels of total cholesterol and low-density lipoprotein cholesterol decreased significantly (27% and 33%, respectively) compared with those levels in plasma in the placebo group. The plasma levels of high-density lipoprotein cholesterol increased (7%), whereas triglyceride levels slightly decreased (8%). There were no serious side effects, and simvastatin was generally well tolerated. Fasting hyperinsulinemia also improved (-21%) after 3 months of simvastatin therapy. Results of this study confirmed that a low dose (10 mg) of simvastatin daily is a safe and effective method of reducing plasma levels of total and low-density lipoprotein cholesterol in hypercholesterolemic, hypertensive elderly patients receiving concurrent antihypertensive drug therapy, and that it has the additional potential benefit of reducing plasma levels of insulin.

Aged↗
PubMed1997

Double-blind comparison of losartan, lisinopril, and metolazone in elderly hypertensive patients with previous angiotensin-converting enzyme inhibitor-induced cough.

This study compared the incidence of cough with the angiotensin-converting enzyme (ACE) inhibitor lisinopril and the diuretic metolazone with angiotensin II receptor antagonist losartan in elderly hypertensive patients with previous histories of ACE inhibitor-induced cough. A randomized, double-blind, stratified, parallel-group comparison of lisinopril at 10 mg, losartan at 50 mg, and metolazone at 1 mg, each given once daily for a maximum of 10 weeks, was performed in four hypertension clinics in four centers in two countries. Cough was detected by a questionnaire (the primary end point) given to elderly patients with hypertension, and the cough frequency was quantified by a visual analog scale (a secondary end point). A total of 84 elderly patients with hypertension, all who were nonsmokers with ACe inhibitor-induced cough and were confirmed by lisinopril rechallenge then placebo dechallenge, were randomized to the three treatment groups. The incidence of cough with losartan (18%) was significantly lower than with lisinopril (97%) and similar to that for metolazone (21%). Cough frequency evaluated by the visual analog scale was significantly lower for losartan than for lisinopril and similar to that for metolazone. The specific, selective angiotensin II receptor antagonist losartan is associated with a decrease in the incidence of cough in patients with previous ACE inhibitor-induced cough.

Aged↗
PubMed1997

Non-invasive continuous arterial pressure, heart rate and stroke volume measurements during graded head-up tilt in normal man.

The haemodynamic effects of head-up tilt (HUT) at different tilt angles were investigated non-invasively in eight normal male subjects. Mean arterial pressure (MAP; by Ohmeda Finapres 2300), stroke volume (SV) and heart rate (HR; by BoMed NCCOM3-R7S) were continuously recorded whilst performing a series of HUTs (55 degrees, 10 degrees, 20 degrees, 30 degrees and 55 degrees) lasting 3 min each. The response to HUT was proportional to the sinc of the tilt angle. The magnitude of the response varied between subjects. HUT to 55 degrees resulted in mean (95% confidence limits) increases in MAP by 16 (+/-16)% and HR by 11 (+/-24)% and a decrease in SV by -25 (+/-22)%. These results were repeatable after 30 min. At small tilt angles, i.e. < or = 20 degrees, MAP did not change and HR decreased by -3 (+/-4)%. A detailed analysis revealed immediate dynamic (0-30 s), late dynamic (30-90 s) and plateau (after 90 s) phases in the response to HUT. In conclusion, HUT produces reproducible haemodynamic effects, although differences exist among subjects. A detailed analysis of these effects can be successfully performed using non-invasive methods.

Adult↗
PubMed1997

Myocardial protective effect of trilinolein: an antioxidant isolated from the medicinal plant Panax pseudoginseng.

In a previous study we demonstrated that trilinolein, a natural plant triacylglycerol, is a novel myocardial protective agent in vivo. The mechanism probably involves an antioxidant effect. This work investigated the mechanism of myocardial protection of trilinolein to determine if inhibition of calcium influx and alteration of activity of superoxide dismutase are involved. In isolated cardiomyocytes, pretreatment with trilinolein at a low concentration of 10(-9) M effectively reduced 45Ca2+ influx stimulated by hypoxia/normoxia by 34%. In isolated perfused rat heart subjected to 60 min global hypoxemia without reperfusion, pretreatment with 10(-7) M trilinolein for 15 min reduced infarct size by 37%. Assay of superoxide dismutase-mRNA by Northern blot analysis in in vivo rat heart subjected to 30 min ischaemia and 10 min reperfusion showed pretreatment with 10(-7) M trilinolein had a synergistic action with antioxidant systems preventing the rise in superoxide dismutase-mRNA. These results reconfirm the myocardial protection of trilinolein and suggest it may be related to antioxidant activity and inhibition of 45Ca2+ influx.

Animals↗
PubMed1997

Additive effects of diltiazem and lisinopril in the treatment of elderly patients with mild-to-moderate hypertension.

A multicenter, double-blind, placebo-controlled trial with multifactorial design was conducted to evaluate the safety and efficacy of the calcium-channel blocker diltiazem, in a sustained release preparation, and the angiotensin converting enzyme inhibitor, lisinopril, in the treatment of elderly Chinese patients with mild-to-moderate hypertension. In addition to the hypotensive effects of combinations of both drugs compared with monotherapy, all given once daily, the effect on quality of life was also evaluated. This study consisted of a 3 x 2 multifactorial design in which 156 women and men with a sitting diastolic pressure of between 95 mm Hg and 114 mm Hg, after a 4-week placebo washout phase, were randomized to one of six treatment groups for 12 weeks of active treatment. Monotherapy with diltiazem 120 or 240 mg produced increasing reductions of systolic and diastolic blood pressure. Compared with placebo, lisinopril 10 mg had an effect intermediate between the diltiazem doses. The combinations of diltiazem 240 mg + lisinopril 10 mg and diltiazem 120 mg + lisinopril 10 mg showed increased efficacy in reducing systolic and diastolic blood pressure compared to these drug doses used in monotherapy, but the effect of the combinations was less than predicted by an additive model. Although the total number of other adverse events reported was similar for all active treatment groups compared to placebo, lisinopril-induced cough was common with an incidence of 31% after rechallenge. Premature drug withdrawal was necessary in four of 78 patients receiving lisinopril, due to intractable cough. The combination of diltiazem 240 mg and lisinopril 10 mg was significantly more effective at reducing blood pressure than either drug alone; this additive effect did not result in a higher rate of adverse effects or impairment of quality of life. Thus, combination therapy with these agents was well tolerated and resulted in increased efficacy in these elderly patients.

Aged↗
PubMed1997

A prescription survey in a hospital hypertension outpatient clinic.

AIMS: The objective of this study was to investigate drug utilization in the management of hypertension in Hong Kong. METHODS: We conducted a prescription survey to examine the use of antihypertensive drugs in a hypertension clinic in a regional hospital and the resulting expenditure incurred. The use of concurrent medications such as antidiabetic drugs and lipid-lowering agents was also examined. RESULTS: During a 7-week study period, 530 prescriptions were collected. All except 14 patients received antihypertensive drugs with 262 (50.8%) on monotherapy and 254 (49.2%) on combination therapy. Calcium channel blocking agents and beta-adrenoceptor blocking agents were the two most popular antihypertensive drugs used in both monotherapy (38% and 31%, respectively) and combination therapy (27% and 33%, respectively). Forty-nine patients (19%) received three antihypertensive drugs or more. The number of antihypertensive drugs showed a significant positive correlation with the duration of attendance at the clinic (r=0.88, P < 0.001). Of the total 530 prescriptions, 5.6% and 10% contained antidiabetic drugs and lipid-lowering agents, respectively. Calcium channel blocking agents, angiotensin converting enzyme (ACE) inhibitors and lipid lowering agents, accounted for 82% (HK$211,654; pounds sterling 1 approximately HK$12) of the total drug expenditure (HK$258,115). Seventy-nine percent of the lipid lowering agents prescribed were hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors. Amlodipine accounted for 26% of usage but contributed to 41% of the overall costs of calcium channel blocking agents. Alpha1-adrenoceptor blocking agents were only used infrequently and were the most expensive class of drugs, due to the preferred use of doxazosin rather than prazosin which is far cheaper than the former. CONCLUSIONS: In view of the use of these often costly drugs for long-term therapy, monitoring of their use and its correlation with clinical outcomes and quality of life is essential to ensure the optimal use of health care resources.

Antihypertensive Agents↗
PubMed1997

New insights into the treatment of hypertension.

1. The choice of initial pharmacological therapy is one area where the different hypertension management guidelines vary in recommending either the use of diuretics and beta-blockers as preferred drugs or choosing from any of the five major classes of antihypertensives. 2. Improvement in cardiovascular morbidity and mortality may have been shown most conclusively with diuretics and beta-blockers, but the effects on coronary events with these drugs were less than predicted and the other agents have a number of theoretical advantages. 3. Recent worries regarding the possible adverse effects of calcium antagonists have led to a reappraisal of the risks and benefits of these drugs and antihypertensives in general. 4. Many patients, particularly the elderly, have other conditions that influence the choice of first-line therapy and ethnic variations in the effects of hypertension or the efficacy or side effects of drugs should also be taken into account. 5. There is considerable heterogeneity within the major categories of antihypertensive drugs, so it is important to distinguish the different subgroups, dosages and formulations that may be used.

Adrenergic beta-Antagonists↗
PubMed1997

Effect of trilinolein on superoxide dismutase activity and left ventricular pressure in isolated rat hearts subjected to hypoxia and normoxic perfusion.

Oxygen-derived free radicals have been implicated in the development of myocardial injury during hypoxia/reperfusion. Antioxidants can effectively inhibit the formation of free radicals and ameliorate the myocardial damage which may occur during hypoxia/reperfusion. Trilinolein is a triacylglycerol recently purified from the traditional Chinese medicinal plant Panax pseudo-ginseng. It has linoleic-acid residues as the only type of fatty acid residue in all three esterified positions of the triacyglycerol. It has been proposed that decreased endogenous superoxide dismutase (SOD) activity may contribute to free radical-mediated reperfusion injury of the ischemic myocardium. In the present study, when isolated rat hearts were subjected to hypoxia for 10, 30, 60 and 90 min without normoxic perfusion, a significant decrease in Mn-SOD activity was shown throughout the period of hypoxia, whereas the Cu.Zn-SOD activity was increased at 10 and 30 min but was not different from the baseline at 60 and 90 min of hypoxia. In rat hearts pretreated with 10(-7) mol/l trilinolein and subjected to 60 min of hypoxia without normoxic perfusion, Cu.Zn-SOD was augmented compared with baseline and compared with hearts subjected to 60 min of hypoxia without trilinolein, whereas Mn-SOD activity was still reduced compared with baseline, although less so than after 60 min of hypoxia without trilinolein. Pretreatment with trilinolein was associated with better preservation of left ventricular function during hypoxia and more rapid return to recovery during normoxic perfusion. This myocardial protective effect may be related to an antioxidant effect through potentiation of SOD, particularly Cu.Zn-SOD during hypoxia.

Animals↗