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Biomedical subjects

C C Lang

Publications and source records attributed to C C Lang.

At least 19 recordsLinked to original sources
PubMed2006

The influence of CYP3A gene polymorphisms on cyclosporine dose requirement in renal allograft recipients.

Cyclosporine is a substrate of cytochrome P-450 3A (CYP3A) subfamily of enzymes and characterized by a narrow therapeutic range with wide interindividual variation in pharmacokinetics. A few single-nucleotide polymorphisms detected in CYP3A genes have been shown to correlate significantly with the CYP3A protein expression and activity. We therefore postulated that these polymorphisms could be responsible for some of the interindividual variation in cyclosporine pharmacokinetics. The objective of our study is to determine correlation if any between single-nucleotide polymorphisms of CYP3A5 and CYP3AP1 on cyclosporine dose requirement and concentration-to-dose ratio in renal allograft recipients. Cyclosporine-dependent renal allograft recipients were genotyped for CYP3A5 A6986G and CYP3AP1 G-44A. The cyclosporine dosages prescribed and the corresponding cyclosporine trough levels for each patient were recorded so that cyclosporine dose per weight (mg/kg/day) and concentration-to-dose ratio (C(0)/D, whereby C(0) is trough level and D is daily dose per weight) could be calculated. A total of 67 patients were recruited for our study. The dose requirement for 1, 3, and 6 months post-transplantation ranged 2.3-11.4, 1.0-9.0, and 1.4-7.2 mg/kg/day, respectively. Patients with *1*1*1*1 (n=5) CYP3A5- and CYP3AP1-linked genotypes needed higher dose of cyclosporine compared to patients with *1*3*1*3 (n = 27) and *3*3*3*3 (n = 33) linked genotypes in months 3 and 6 post-transplantation (P < 0.016). The identification of patients with *1*1*1*1 by CYP3A5 and CYP3AP1 genotyping may have a clinically significant and positive impact on patient outcome with reduced rejection rate by providing pretransplant pharmacogenetic information for optimization of cyclosporine A dosing.

Adult↗
PubMed2005

Attitudes of medical students towards euthanasia in a multicultural setting.

A cross-sectional survey of 400 medical students of multicultural backgrounds at the University of Malaya was conducted to understand their attitudes towards euthanasia and factors related to medical decisions and ethical reasoning concerning the prolongation of life, the right to die and euthanasia. The student respondents completed self-administered questionnaires that comprised of twelve questions with multiple stems addressing personal perceptions, knowledge, attitudes, and decisions about euthanasia and the relief of suffering. The majority of respondents (52%) were for the withdrawal of active therapy in a patient suffering from a terminal painful disease while 48% of them were against it. Seventy-one percent of the students involved in the study were against the idea of active euthanasia i.e. the administration of a lethal injection. However, 27% of the respondents felt that there was a moral justification to assist patients to die. Thirty-two percent of the respondents favoured the legalization of euthanasia in Malaysia while 67% of them were strongly against it. The majority (61%) of respondents would not practice euthanasia as a doctor nor would they have performed on themselves if or when it became legal. The main issue surrounding euthanasia that concerned the respondents was the misuse of it by unethical practitioners and they felt that further debate on the matter was essential, both within the local and international communities.

Attitude of Health Personnel↗
PubMed2003

Evidence of an interaction between nifedipine and nafcillin in humans.

AIMS: Nafcillin (Wyeth Laboratories, Philadelphia, PA, USA) has been reported to induce the metabolism of cyclosporin and warfarin, which are known substrates of cytochrome P-450 (CYP). However, there has not been any report to date on its possible interaction with nifedipine, an index substrate of the enzyme, CYP3A4. METHODS: Nine healthy normotensive subjects participated in this randomized placebo-controlled two-way crossover study examining the effects of 5 days' pretreatment of nafcillin 500 mg or placebo four times daily on the pharmacokinetics of an oral dose of nifedipine 10 mg. Plasma nifedipine concentrations were measured by gas chromatography-mass spectro. RESULTS: The area under the plasma nifedipine concentration-time curve (AUC0-alpha) in nafcillin-pretreated subjects (80.9 +/- 32.9 micro g l-1 h-1) was significantly decreased compared with subjects who received only nifedipine (216.4 +/- 93.2 micro g l-1 h-1) (P < 0.001). Total plasma clearance of nifedipine (CL/F) was significantly increased with nafcillin pretreatment (138.5 +/- 42.0 l h-1 vs 56.5 +/- 32.0 l h-1) (P < 0.002). CONCLUSIONS: The results show that nafcillin pretreatment markedly increased the clearance of nifedipine and suggest that nafcillin is a potent inducer of CYP enzyme.

Adult↗
PubMed2003

Prevalence of peripheral artery disease in urban high-risk Malaysian patients.

Atherosclerosis is a progressive, disseminated condition that affects all the vascular beds. Peripheral arterial disease (PAD), a manifestation of atherosclerosis, measured non-invasively in the legs by ankle-brachial index (ABI) is associated with increased cardiovascular morbidity and mortality. Though several studies in the western industrialised countries have shown that PAD is widely prevalent in the general older population at risk, not much data are available in the South East Asian developing countries. We have conducted an epidemiological survey on the prevalence of PAD in high-risk patients at an urban hospital in Malaysia. A total of 301 consecutive patients aged 32-90 years were recruited during their follow-up clinic visits for established cardiovascular disease, ischaemic stroke or diabetes mellitus > or = 5 years. All participants underwent ABI measurement and were subjected to the Edinburgh claudication questionnaire to assess leg symptoms. The prevalence of PAD in our high-risk population was 23%, of which only 27% were symptomatic with the classical intermittent claudication. All the patients with PAD were diagnosed at the time of the study. PAD was found in 33% of patients with pre-existent cardiovascular disease, 28% in patients with ischaemic stroke and 24% in diabetic patients. PAD was also highly prevalent among the younger patients. Our study has shown that PAD is highly prevalent among high-risk Malaysian patients and is not necessarily a disease of older age. Only 27% of these patients were symptomatic. All the subjects with PAD were diagnosed at the time of the study, which would suggest it is an unrecognised and underdiagnosed condition, even in patients with atherosclerotic risk factors.

Adult↗
PubMed2002

A faint discrete source origin for the highly ionized iron emission from the Galactic Centre region.

The origin of the X-ray emission for the central region of our Galaxy has remained a mystery. In particular, the relative spectral contributions of the diffuse emission and discrete sources, which are critical to understanding the high-energy phenomena in this environment, have been unclear because of the lack of sufficient spatial resolution. Here we report the results of a large-scale imaging survey of the Galactic Centre that resolves these components. We find that the Kalpha emission from iron that has been highly ionized (so that it has only two electrons left), which has previously been attributed to the diffuse component, actually arises mainly from discrete sources. This suggests that the presence of a large amount of hot gas (T approximately 108 K) is no longer required to explain the iron line emission. The spectra of the discrete sources indicate the presence of numerous accreting white dwarfs, neutron stars, and/or black holes in the region. The diffuse emission dominates over the contribution from the faint point sources, and is shown to be associated globally with interstellar features that have been observed at radio and mid-infrared wavelengths, suggesting that it is the product of recent massive star formation.

Journal Article↗
PubMed2001

The impact of QT lag compensation on dynamic assessment of ventricular repolarization: reproducibility and the impact of lead selection.

In cardiac disease, abnormalities exist in the rate-corrected QT interval and the relationship between QT and heart rate. The QT/RR relationship is known to be dynamic and show circadian variation. The availability of automated methods for measurement of QT and RR intervals allows monitoring of the QT/RR relationship and may provide insights into arrhythmia onset. Using a method for analyzing 24-hour recordings that incorporates beat-by-beat QT and RR measurement and an automated mechanism for compensating for lag in adaptation of QT to changes in RR, the authors evaluated the impact of lag compensation on assessment of the QT/RR relationship, reproducibility, and the effect of lead selection in 15 normal subjects. The QT/RR relationship is continuously estimated from the lag compensated data over a 5-minute scrolling time frame. The relationship is expressed as an exponential formula, QT = QTo.RRJ where QTo is the QT interval at a standardized RR interval of 1 second and J is a variable exponent. We found that the use of lag compensation significantly improves the mean 24-hour correlation between QT and RR data (r = 0.87 vs 0.65). The 24-hour mean of QTo and J were highly reproducible (coefficients of variation 2% and 8%, respectively). The mean 24-hour QT/RR relationship for the population was QT = 0.415.(RR)0.32. There was a small difference between leads in QTo and J. Compensating for QT adaptation lag provides a means of assessing the QT/RR relationship over long and short periods. This method allows investigation of the effect of acute interventions on the dynamic QT/RR relationship, which has previously been restricted by the presence of QT hysteresis.

Adult↗
PubMed2001

Hypertension in black people: study of specific genotypes and phenotypes will provide a greater understanding of interindividual and interethnic variability in blood pressure regulation than studies based on race.

Hypertension is more frequent and more severe in some Black populations. Although many studies have focused on hypertension in black people in an attempt to understand the genetic and environmental factors that regulate blood pressure, this approach has not been productive. Study of the relationship between specific phenotypes and genotypes, both within and across ethnic groups, is more likely to advance our understanding of the regulation of blood pressure than studies focused on race and blood pressure.

Black People↗
PubMed2000

Increased vascular adrenergic vasoconstriction and decreased vasodilation in blacks. Additive mechanisms leading to enhanced vascular reactivity.

Blood pressure reactivity is enhanced in young black subjects through mechanisms that are poorly understood. We compared alpha-adrenergic-mediated vasoconstrictor and ss-adrenergic vasodilator sensitivity and their relation to sympathetic activity in blacks and whites. Ten healthy black (age, 29.9+/-2.4 years) and 10 white (age, 28.3+/-1.9 years) men were studied. Forearm blood flow was measured with strain-gauge plethysmography after the intrabrachial artery administration of phenylephrine (1.25 to 20 microgram/min) and isoproterenol (60 and 400 ng/min) after application of lower-body negative pressure and after a cold pressor test. Forearm and systemic norepinephrine spillover were measured with a radioisotope dilution technique. alpha-Adrenergic vasoconstriction was markedly increased (ANOVA P=0.008) and ss-adrenergic vasodilation decreased (ANOVA P=0.02) in blacks. Phenylephrine (10 microgram/min) decreased forearm blood flow by 58.0+/-2.5% in blacks but only by 26.6+/-6.0% in whites (P<0.001). Vasoconstrictor response to endogenous norepinephrine, stimulated by a cold pressor test, resulted in a higher forearm vascular resistance in blacks than in whites (107.3+/-13 versus 64.8+/-13 mm Hg. mL(-)(1). 100 mL(-)(1), P=0.03). There were no significant ethnic differences in basal or stimulated forearm or systemic norepinephrine spillover. Increased vasoconstrictor and decreased vasodilator responses in blacks were not correlated. Increased sympathetically mediated vascular tone caused by enhanced vasoconstriction and attenuated vasodilation, effects that would be additive, and not increased sympathetic activity could enhance vascular reactivity and may play a role in the pathogenesis of hypertension in blacks.

Adrenergic alpha-Agonists↗
PubMed1998

Abnormalities of the QT interval in primary disorders of autonomic failure.

BACKGROUND: Experimental evidence shows that activation of the autonomic nervous system influences ventricular repolarization and, therefore, the QT interval on the ECG. To test the hypothesis that the QT interval is abnormal in autonomic dysfunction, we examined ECGs in patients with severe primary autonomic failure and in patients with congenital dopamine beta-hydroxylase (DbetaH) deficiency who are unable to synthesize norepinephrine and epinephrine. SUBJECTS AND METHODS: Maximal QT and rate-corrected QT (QTc) intervals and adjusted QTc dispersion [(maximal QTc - minimum QTc on 12 lead ECG)/square root of the number of leads measured] were determined in blinded fashion from ECGs of 67 patients with primary autonomic failure (36 patients with multiple system atrophy [MSA], and 31 patients with pure autonomic failure [PAF]) and 17 age- and sex-matched healthy controls. ECGs of 5 patients with congenital DbetaH deficiency and 6 age- and sex-matched controls were also analyzed. RESULTS: Patients with MSA and PAF had significantly prolonged maximum QTc intervals (492+/-58 ms(1/2) and 502+/-61 ms(1/2) [mean +/- SD]), respectively, compared with controls (450+/-18 ms(1/2), P < .05 and P < .01, respectively). A similar but not significant trend was observed for QT. QTc dispersion was also increased in MSA (40+/-20 ms(1/2), P < .05 vs controls) and PAF patients (32+/-19 ms(1/2), NS) compared with controls (21+/-5 ms(1/2)). In contrast, patients with congenital DbetaH deficiency did not have significantly different RR, QT, QTc intervals, or QTc dispersion when compared with controls. CONCLUSIONS: Patients with primary autonomic failure who have combined parasympathetic and sympathetic failure have abnormally prolonged QT interval and increased QT dispersion. However, QT interval in patients with congenital DbetaH deficiency was not significantly different from controls. It is possible, therefore, that QT abnormalities in patients with primary autonomic failure are not solely caused by lesions of the sympathetic nervous system, and that the parasympathetic nervous system is likely to have a modulatory role in ventricular repolarization.

Aged↗
PubMed1998

Effect of CYP3A inhibition on vesnarinone metabolism in humans.

OBJECTIVE: To identify the cytochrome P450 (CYP) enzymes involved in the conversion of vesnarinone to it main primary metabolite OPC-18692 and to investigate the effect of CYP3A inhibition on the pharmacokinetics of vesnarinone in vivo. METHODS: Formation of the primary vesnarinone metabolite OPC-18692 was measured in microsomes from AHH-1 TK +/- cells heterologously expressing CYP1A1, CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, or CYP3A4. The pharmacokinetics of vesnarinone and OPC-18692 were defined for 12 health white men after oral administration of 60 mg vesnarinone before and after CYP3A inhibition, which was produced by pretreatment with erythromycin. CYP3A inhibition was verified with erythromycin breath test. RESULTS: In vitro, expressed CYP2E1 and CYP3A4 produced significant amounts of OPC-18692 with the higher formation rate observed by CYP3A4 (12.3 pmol/pmol VYP3A4 per 2 hours versus 1 pmol/pmol CYP2E1 per 2 hours). In vivo, the area under the concentration-time curve extrapolated to infinity (AUC[infinity]) of vesnarinone after pretreatment with erythromycin increased from 133 +/- 26 micrograms.hr/ml to 202 +/- 47 micrograms.hr/ml (p < 0.001), and the half-life increased from 36.5 +/- 9.6 hours to 46.2 +/- 9.2 hours (p < 0.01). Clearance decreased from 372 +/- 68 ml/min to 256 +/- 49 ml/min (p < 0.001). These changes in the disposition of vesnarinone were accompanied by a decrease in plasma concentration of the metabolite OPC-18692 so that the AUC(0-48) was reduced from 1311 +/- 513 micrograms.hr/ml to 850 +/- 148 micrograms.hr/ml (p < 0.001). The total amount of vesnarinone excreted in the urine up to 168 hours after administration increased after erythromycin pretreatment (p < 0.001). Although renal clearance did not change, OPC-18692 was not detectable in the urine. The erythromycin breath test showed significant inhibition after pretreatment with erythromycin (p < 0.001). CONCLUSIONS: CYP2E1 and CYP3A4 are involved in the phase I metabolism of vesnarinone. Inhibition of CYP3A activity in vivo increases the plasma concentration of vesnarinone and delays its elimination in humans so that monitoring of its plasma levels may be helpful in preventing concentration-related toxicity when CYP3A activity is impaired. Whether CYP3A induction and altered CYP2E1 activity may also change the in vivo disposition of vesnarinone remains to be determined.

Administration, Oral↗
PubMed1998

Regulation of local tissue-type plasminogen activator release by endothelium-dependent and endothelium-independent agonists in human vasculature.

OBJECTIVES: This study sought to define the local regulation of vascular tissue-type plasminogen activator (t-PA) release. BACKGROUND: The vascular endothelium, through the production of t-PA and plasminogen activator inhibitor (PAI-1), is an important regulator of fibrinolysis. Plasma t-PA levels increase in response to adrenergic stimulation; however, it is unclear whether this increase is the result of systemic reflex responses or direct effects on the vascular endothelium. METHODS: Forearm blood flow dose responses were generated to low doses of agonist infused directly into the brachial artery in 15 normotensive men (mean [+/-SE] age 28.9 +/- 2.2 years). Simultaneous arterial and venous blood samples were drawn at baseline and in response to the intraarterial administration of isoproterenol (400 ng/min), methacholine (8 microg/min) and sodium nitroprusside (SNP) (8 microg/min). PAI-1 and t-PA antigen levels were measured by enzyme-linked immunosorbent assay, and the net release across the forearm was calculated. RESULTS: Forearm plasma flow increased significantly from baseline (1.4 +/- 0.2 ml/100 ml per min) after administration of isoproterenol, methacholine and SNP (9.7 +/- 1.9, 8.7 +/- 1.9 and 6.7 +/- 1.1 ml/100 ml per min, respectively) (p < 0.001 by analysis of variance). Baseline net t-PA release (0.7 +/- 0.3 ng/100 ml per min) increased significantly after administration of isoproterenol (26.2 +/- 11.6 ng/100 ml per min, p = 0.005) and methacholine (15.3 +/- 5.5 ng/100 ml per min, p = 0.001) but not after administration of SNP (1.8 +/- 2.2 ng/100 ml per min, p = 0.84). There was no net release of PAI-1 across the vascular bed. CONCLUSIONS: Marked, rapid local t-PA release occurred in response to isoproterenol, a beta-adrenoceptor agonist, and methacholine, an endothelium-dependent nitric oxide agonist, in the human forearm. This effect was selective and independent of the effects of shear stress due to increased flow because SNP induced similar increases in forearm blood flow without affecting t-PA release. Vascular t-PA release may be a potentially valuable tool for evaluating endothelial function in diseases associated with increased risk of thrombosis.

Adult↗
PubMed1998

The effect of mivacurium pretreatment on intra-ocular pressure changes induced by suxamethonium.

Forty patients without eye disease, undergoing elective nonophthalmic surgery, were studied in a double-blind, randomised, placebo-controlled study evaluating the efficacy of mivacurium pretreatment in attenuating the rise in intra-ocular pressure in response to suxamethonium administration, laryngoscopy and intubation. The patients were randomly allocated to receive either mivacurium 0.02 mg.kg-1 or normal saline as pretreatment 3 min before a rapid sequence induction technique using alfentanil, propofol and suxamethonium. Suxamethonium induced a significant increase in intra-ocular pressure in the control group but not in the mivacurium pretreatment group (mean (SEM) increase = 3.5 (1.2) mmHg vs. 0.4 (0.8) mmHg, p < 0.05). There was a decrease in intra-ocular pressure in both groups after laryngoscopy and intubation with no significant difference between the two groups. These results show that mivacurium pretreatment is effective in preventing the increase in intra-ocular pressure after suxamethonium administration.

Adolescent↗
PubMed1997

Normalization of acquired QT prolongation in humans by intravenous potassium.

BACKGROUND: QT interval prolongation and dispersion have been implicated in serious arrhythmias in congestive heart failure (CHF) and the congenital and drug-induced long-QT syndromes (LQTS). In a subset of the congenital LQTS, infusion of potassium can correct QT abnormalities, consistent with in vitro increases in outward currents such as I(Kr) or I(Kl) when extracellular potassium concentration ([K+]o) is increased. Furthermore, increasing [K+]o decreases the potency of I(Kr)-blocking drugs in vitro. The purpose of this study was to test the hypothesis that increasing [K+]o corrects QT abnormalities in CHF and in subjects treated with quinidine. METHODS AND RESULTS: KCl (maximum, 40 mEq) was infused into (1) 12 healthy subjects treated with quinidine sulfate (5 doses of 300 mg/5 h) or placebo and (2) 8 CHF patients and age-matched normal control subjects. Mean [K+] increased from 4 to 4.2 mEq/L to 4.7 to 5.2 mEq/L. Potassium infusion significantly reversed QTUc prolongation, especially in the precordial leads (quinidine, 590+/-79 to 479+/-35 [+/-SD] ms(1/2), P<.001; CHF, 521+/-110 to 431+/-47 ms(1/2), P<.05). There was no effect in either control group. Similarly, potassium decreased QTUc dispersion (quinidine, 210+/-62 to 130+/-75 ms(1/2), P<.01; CHF, 132+/-68 to 84+/-35 ms(1/2), P=.07) and was without effect in the control subjects. QT morphological abnormalities, including U waves and bifid T waves, were reversed by potassium. CONCLUSIONS: Potentially arrhythmogenic QT abnormalities during quinidine treatment and in CHF can be nearly normalized by modest elevation of serum potassium.

Adult↗
PubMed1997

Effect of sympathoinhibition on exercise performance in patients with heart failure.

BACKGROUND: In patients with heart failure, excessive sympathetic activation during exercise could interfere with exercise performance by impairing arteriolar dilation in working muscle and by adversely altering skeletal muscle metabolic behavior. To test this hypothesis, we examined the effect of sympathoinhibition with clonidine, a central sympatholytic agent, on skeletal muscle blood flow and metabolism in patients with heart failure. METHODS AND RESULTS: Swan-Ganz and femoral venous catheters were inserted in 20 patients with chronic heart failure and exercise intolerance (peak exercise VO2 = 9.3 +/- 1.4 [SEM] mL.min-1.kg-1). Central hemodynamic measurements, leg blood flow determined by thermodilution, and systemic and leg metabolic parameters were measured during maximal treadmill exercise before and 2 hours after clonidine 2 micrograms/kg IV (n = 15) or 0.9% normal saline (n = 5). During-control exercise before the administration of clonidine, leg blood flow increased from 0.3 +/- 0.1 to 1.8 +/- 0.2 L/min and plasma norepinephrine increased from 485 +/- 61 to 2155 +/- 186 pg/mL (both P < .01). Treatment with clonidine markedly suppressed norepinephrine levels during exercise (matched peak exercise workload: control, 2137 +/- 187 versus clonidine, 1430 +/- 161 pg/mL), increased leg blood flow (control, 1.8 +/- 0.2 versus clonidine, 2.3 +/- 0.4 L/min), reduced systemic oxygen consumption (control, 1002 +/- 70 versus clonidine, 966 +/- 68 mL/min), reduced pulmonary artery lactate concentration (control, 3.2 +/- 0.3 versus clonidine, 2.6 +/- 0.2 mEq/L), and decreased minute ventilation (control, 39.7 +/- 2.1 versus clonidine, 34.9 +/- 2.4 L/min) (all P < .05). CONCLUSIONS: These findings suggest that sympathetic activation during exercise reduces leg blood flow, increases muscle glycolysis, and decreases muscle efficiency in patients with heart failure.

Cardiomyopathy, Dilated↗