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Biomedical subjects

D M Roden

Publications and source records attributed to D M Roden.

At least 55 records · Page 3Linked to original sources
PubMed1999

Inherited long QT syndromes: a paradigm for understanding arrhythmogenesis.

The inherited long QT syndrome (LQTS) is a familial disease characterized by QT interval changes that often are labile, syncope, and sudden death due to arrhythmias, predominantly in young people. Multiple mutations in five genes encoding structural subunits of cardiac ion channels now have been identified in families with LQTS. Correlations are being described between genotype and specific clinical features in LQTS. However, increasing screening of affected families and sporadic cases has identified incomplete penetrance with highly variable clinical manifestations, even among individuals carrying the same mutations. The identification of LQTS disease genes represents a crucial first step in developing an understanding of the molecular basis for normal cardiac repolarization. This information will be important not only for identifying new therapies in LQTS, but also in further understanding arrhythmias, and their potential therapies, in situations such as heart failure, cardiac hypertrophy, myocardial infarction, or sudden infant death syndrome, where abnormal repolarization has been linked to sudden death. LQTS thus presents a new paradigm to cardiac electrophysiology, in which new molecular information is being brought to bear both on clinical management of patients and on development of a new framework to study the fundamental causes of arrhythmias and new approaches to therapy.

Anti-Arrhythmia Agents↗
PubMed1999

An overview of contemporary approaches to antiarrhythmic therapy.

This review discusses the evolution in the approach to the therapy of cardiac arrhythmias that has occurred during the past 2 decades. The major changes have been driven by advances in understanding arrhythmia mechanisms, in bioengineering, and in clinical trials. It seems likely that progress in understanding the cellular and molecular basis of arrhythmias and their response to drug therapy may allow further identification of patient subsets in which specific therapies are indicated or contraindicated.

Anti-Arrhythmia Agents↗
PubMed1999

Modulation of effect of dietary salt on prehepatic first-pass metabolism: effects of beta-blockade and intravenous salt loading.

We previously demonstrated that increased dietary salt markedly decreases plasma quinidine concentrations shortly after p.o. dosing, without an effect on the drug's terminal elimination half-life or concentrations after i.v. administration. These findings suggest an effect of dietary salt on intestinal metabolism or transport of the drug. Because one effect of salt loading is sympathetic inhibition, we examined the effect of beta-adrenoceptor blockade on salt-related changes in quinidine disposition. Furthermore, we examined whether the action of salt is local or systemic by determining the effect of salt loading by the i.v. route. To assess the effect of beta-blockade, quinidine disposition was studied in eight normal volunteers after a single p.o. dose of quinidine; data were obtained after 1 week on a high-salt diet (400 mEq/day) and 1 week on a low-salt diet (10 mEq/day) during chronic nadolol and compared with those previously obtained in the same subjects without the beta-blocker. beta-Blockade had no effect on oral clearance during the high-salt diet [0.28 +/- 0.1 (quinidine + nadolol) versus 0.30 +/- 0.2 liters/h/kg (quinidine alone)] but increased clearance on the low-salt diet from 0.23 +/- 0.1 to 0.29 +/- 0.1 liters/h/kg (p <. 05). For the i.v. salt study, the disposition of single p.o. and single i.v. doses of quinidine was determined on two occasions in eight subjects: once during a low-salt diet (10 mEq/day) and once during the same diet, supplemented by 400 mEq/day NaCl i.v. for 8 days. In contrast to our findings after p.o. salt loading, i.v. salt loading did not alter the pharmacokinetics of p.o. quinidine. Taken together, these data implicate a local alteration of drug-metabolizing activity and/or drug transport in the intestinal mucosa as the major effect of dietary salt on the disposition of p.o. quinidine and further suggest that beta-adrenergic activation by a low-salt diet is one component of a signaling pathway whereby intestinal drug disposition is suppressed, resulting in increased oral bioavailability.

Administration, Oral↗
PubMed1998

Modulation by dietary salt of verapamil disposition in humans.

BACKGROUND: The intestine is an increasingly well-recognized site of first-pass drug metabolism. In this study, we determined the influence of dietary salt on the steady-state disposition of verapamil, a drug that undergoes extensive first-pass metabolism. METHODS AND RESULTS: Eight normal volunteers received 120 mg of racemic verapamil orally twice a day for 21 days. The disposition kinetics of verapamil enantiomers were determined after coadministration of intravenous deuterated verapamil with the morning oral dose on days 7, 14, and 21. Each study day was preceded by 7 days on a fixed-salt diet: in 5 subjects, the initial study was conducted during a low-salt (10 mEq/d) diet, the second study during a high-salt (400 mEq/d) diet, and the third during a low-salt diet, whereas in the other 3 subjects, the sequence of diets was reversed. Plasma concentrations of both unlabeled enantiomers (ie, from oral therapy) were significantly (P<0.05) lower during the high-salt phase (eg, mean area under the time-concentration curve [0 to 12 hours] for S-verapamil: 7765+/-2591 ng. min. mL-1 [high salt] versus 12 514+/-3527 ng. min. mL-1 [low salt], P<0.05). Peak plasma concentrations were significantly lower and the extent of PR interval prolongation significantly blunted with the high-salt diet. In contrast, data with labeled drug (ie, reflecting the intravenous route) were nearly identical for the 2 diets. CONCLUSIONS: These data indicate that a clinically important component of presystemic drug disposition occurs at the prehepatic (presumably intestinal) level and is sensitive to dietary salt.

Administration, Oral↗
PubMed1998

A K+ channel splice variant common in human heart lacks a C-terminal domain required for expression of rapidly activating delayed rectifier current.

We have cloned HERG USO, a C-terminal splice variant of the human ether-à-go-go-related gene (HERG), the gene encoding the rapid component of the delayed rectifier (IKr), from human heart, and we find that its mRNA is approximately 2-fold more abundant than that for HERG1 (the originally described cDNA). After transfection of HERG USO in Ltk- cells, no current was observed. However, coexpression of HERG USO with HERG1 modified IKr by decreasing its amplitude, accelerating its activation, and shifting the voltage dependence of activation 8.8 mV negative. As with HERG USO, HERGDeltaC (a HERG1 construct lacking the C-terminal 462 amino acids) also produced no current in transfected cells. However, IKr was rescued by ligation of 104 amino acids from the C terminus of HERG1 to the C terminus of HERGDeltaC, indicating that the C terminus of HERG1 includes a domain (</=104 amino acids) that is critical for faithful recapitulation of IKr. The lack of this C-terminal domain not only explains the finding that HERG USO does not generate IKr but also indicates a similar mechanism for hitherto-uncharacterized long QT syndrome HERG mutations that disrupt the splice site or the C-terminal. We suggest that the amplitude and gating of cardiac IKr depends on expression of both HERG1 and HERG USO.

Alternative Splicing↗
PubMed1998

Modulation of cardiac Na+ current phenotype by beta1-subunit expression.

Na+ current (INa) is smaller, activates and inactivates more slowly, and displays less negative voltage dependence of inactivation in the neonatal rat than in the adult rat. We have observed very similar changes when INa is recorded as a function of time in culture in mouse atrial tumor (AT-1) cells. The differences between mature and immature INa are reminiscent of those observed when skeletal muscle Na+ channel alpha subunits are expressed alone (immature) or with the beta1 subunit (mature). In the present experiments, we tested the hypothesis that suppression of beta1-subunit expression by antisense oligonucleotides would prevent the development of a mature INa. The mouse beta1 subunit was cloned from an AT-1 cDNA library and found to be identical to that in the rat at 216/218 amino acids. AT-1 cells exposed to anti-beta1 antisense oligonucleotides displayed an immature INa at day 8 in culture, whereas untreated cells or cells exposed to sense oligonucleotides displayed a mature INa. This result was observed with 2 different oligonucleotides, and neither affected the rapidly activating component of the delayed rectifier K+ current, another current recorded in AT-1 cells. These findings indicate that in these cells, the gating of INa is modulated by beta1 expression and that alpha-beta1 coexpression is required for the development of a mature cardiac INa phenotype.

Animals↗
PubMed1998

Mechanisms and management of proarrhythmia.

It is now well recognized that therapy with antiarrhythmic drugs can not only suppress cardiac arrhythmias, but also may increase their frequency or provoke new ones. Specific proarrhythmia syndromes, each with a distinct underlying mechanism and approach to therapy, have been described. The best-recognized examples are digitalis intoxication, proarrhythmia associated with sodium-channel block, and torsade de pointes occurring during QT-prolonging therapies. In the case of sodium-channel blockers, 2 forms of proarrhythmia are commonly recognized: slow atrial flutter with 1:1 atrioventricular conduction, and frequent ventricular tachycardia ([VT], most often found in patients with pre-existing VT reentrant circuits). In all cases, the best approach to therapy is to identify patients at risk (and thereby avoid therapy entirely), to recognize proarrhythmia when it occurs, to withdraw offending agent(s), and to use specific corrective therapies when available. Although most recognized episodes of proarrhythmia are thought to occur early in drug therapy, the increased mortality during chronic antiarrhythmic therapy demonstrated in large randomized trials suggests this phenomenon can also develop during long-term drug treatment. The recognition of proarrhythmia and the delineation of its underlying mechanisms should not only improve therapy with available drugs, but may also direct development of newer agents devoid of this potential.

Anti-Arrhythmia Agents↗
PubMed1998

The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors.

Currently available HIV-1 protease inhibitors are potent agents in the therapy of HIV-1 infection. However, limited oral absorption and variable tissue distribution, both of which are largely unexplained, complicate their use. We tested the hypothesis that P-glycoprotein is an important transporter for these agents. We studied the vectorial transport characteristics of indinavir, nelfinavir, and saquinavir in vitro using the model P-glycoprotein expressing cell lines L-MDR1 and Caco-2 cells, and in vivo after intravenous and oral administration of these agents to mice with a disrupted mdr1a gene. All three compounds were found to be transported by P-glycoprotein in vitro. After oral administration, plasma concentrations were elevated 2-5-fold in mdr1a (-/-) mice and with intravenous administration, brain concentrations were elevated 7-36-fold. These data demonstrate that P-glycoprotein limits the oral bioavailability and penetration of these agents into the brain. This raises the possibility that higher HIV-1 protease inhibitor concentrations may be obtained by targeted pharmacologic inhibition of P-glycoprotein transport activity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
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

Cisapride-induced torsades de pointes.

Two cases of torsades de pointes associated with cisapride are presented, both in association with concomitant drug therapy that inhibits cisapride biotransformation. In one case, plasma cisapride was elevated days after the event, strongly supporting a role for accumulation of the drug in causing the arrhythmia. It is emphasized that these adverse drug reactions are not idiosyncratic, but rather are predictable based on an understanding of the underlying mechanisms.

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

A practical approach to torsade de pointes.

The term torsade de pointes refers to polymorphic ventricular tachycardia that occurs in the setting of an abnormally long QT interval. While the most common cause is treatment with QT prolonging drugs, torsade de pointes also occurs in the congenital long QT syndromes and in the setting of acquired heart block or severe electrolyte disturbance, notably hypokalemia. Among QT prolonging drugs that cause torsade de pointes, both antiarrhythmics and "noncardioactive" drugs have been recognized. The electrocardiographic features of torsade de pointes include labile QT intervals, prominent U waves, and a "pause-dependent" onset of the arrhythmia. Treatment consists of recognition of the syndrome, correction of underlying electrolyte abnormalities, and withdrawal of any offending drugs. Magnesium, isoproterenol, or cardiac pacing provides specific antiarrhythmic therapy in torsade de pointes.

Electrocardiography↗
PubMed1997

Dietary salt increases first-pass elimination of oral quinidine.

BACKGROUND: Some cytochrome P450 (CYP) enzymes, including CYP3A, are expressed not only in the liver but also in the intestine; the latter may therefore be an important site of drug disposition. Animal data suggests that dietary salt modulates expression of renal CYPs. We therefore hypothesized that intestinal CYP3A may be similarly modulated by dietary salt. METHODS: The effect of changes in dietary salt on the disposition of two CYP3A substrates, quinidine (administered orally and intravenously) and 14C-erythromycin (administered intravenously) were determined after normal volunteers were given high-salt (400 mEq/day) and low-salt (10 mEq/day) diets for 7 to 10 days each. RESULTS: Plasma concentrations after oral quinidine were significantly lower during the high-salt phase, with the difference between the two treatments attributable to changes within the first 1 to 4 hours after administration. For example, the area under the plasma concentration-time curve for the first hour after drug administration was 0.56 +/- 0.38 microgram.hr/ml for the high-salt diet compared with 1.57 +/- 0.60 micrograms.hr/ml for the low-salt diet (p < 0.05). Similarly, the peak plasma concentration (Cmax) achieved was lower and the time to reach Cmax was later for the high-salt diet (p < 0.05). In contrast, the terminal phase elimination half-lives were similar for the two diets, and no differences in disposition were found with the intravenous drug. The erythromycin breath test was unaffected by the dietary treatments. CONCLUSIONS: These results indicate an effect of dietary salt on the presystemic disposition of orally administered quinidine. Although the mechanism(s) of CYP3A activity modulation is unknown, this finding may be important in determining drug availability in conditions associated with abnormal salt homeostasis.

Administration, Oral↗
PubMed1997

Structure and function of cardiac sodium and potassium channels.

The application of patch-clamp and molecular approaches has resulted in an increasingly refined understanding of the molecular entities underlying cardiac sodium and potassium currents. The sodium current results from expression of a single large alpha-subunit, whereas multiple potassium currents and potassium channel alpha-subunits have been identified. Recapitulation of some ion currents in heterologous expression systems requires not only expression of alpha-subunits but also ancillary (beta) subunits. Domains common to functions such as activation, inactivation, and drug block are now being identified in alpha- and beta-gene products. Variability in the expression or function of individual ion-channel genes is an increasingly recognized source of variability in the ion currents recorded in heart cells under physiological conditions (e.g. during development) as well as in disease.

Animals↗