Biomedical subjects

J F Brien

Publications and source records attributed to J F Brien.

At least 19 recordsLinked to original sources

PubMed1992

Carbon monoxide does not inhibit glyceryl trinitrate biotransformation by or relaxation of aorta.

Carbon monoxide (CO) was employed to assess the role of ferrous hemoproteins in the vasodilation and biotransformation of glyceryl trinitrate (GTN) in rabbit aortic strips. These tissues were contracted submaximally with phenylephrine, exposed to CO for 5 min, and then incubated with 0.5 microM [1,3(14) C]GTN in the presence of CO for 2 min or 30 s. The [14C]GTN-induced relaxation of the strips was recorded, and [14C]GTN biotransformation to [14C]glyceryl dinitrate metabolites by the tissues was determined by thin-layer chromatographic-liquid scintillation spectrometric analysis. CO treatment inhibited neither GTN-induced relaxation nor GTN biotransformation to glycerol dinitrate metabolites. These results indicate that ferrous hemoproteins are probably not involved in the biotransformation of GTN that is associated with relaxation of the rabbit aortic strips.

Animals↗

PubMed1992

Plasma disposition and hemodynamic effects of a single oral dose of isosorbide dinitrate in human males and females.

The goal of the present work was to determine the plasma disposition and hemodynamic effects of isosorbide dinitrate (ISDN) in human males and females. Fourteen healthy human volunteers took part in the study; seven males, 21.7 +/- 2.5 y (SD), and seven females, 20.7 +/- 3.4 y. Measurements of forearm blood flow (FBF), vascular conductance (FVC), and venous capacitance (Cv) were obtained by venous occlusion plethysmography, whereas blood pressure was measured by automatic sphygmomanometry. Blood samples were taken through a catheter placed in the antecubital vein at 0, 15, 30, 45, 60, 90, 120, 360, 480, 720, and 1440 min following a single 10 mg oral dose of ISDN. Plasma concentrations of ISDN and its mononitrate metabolites, isosorbide-2-mononitrate (2-ISMN) and isosorbide-5-mononitrate (5-ISMN), were determined by large bore capillary column gas-liquid chromatography. Hemodynamic measurements were made at corresponding experimental times up to 480 min. No differences were observed in the disposition of ISDN, 2-ISMN or 5-ISMN between the male and female volunteers. In addition, the plasma concentrations of ISDN and its mononitrate metabolites did not consistently correlate with the hemodynamic changes of the individual subjects. Diastolic blood pressure was significantly decreased for a 0.5 h period starting at 30 min, which was the time at which plasma ISDN concentrations peaked, and which preceded the time when the plasma concentrations of 2-ISMN and 5-ISMN were maximal. These observations indicate that, for a single 10 mg oral dose of ISDN, there were no gender-dependent differences in the plasma disposition of the parent drug or its mononitrate metabolites, and the vascular changes responsible for the decrease in diastolic blood pressure in these volunteers occurred in vascular beds other than those of skeletal muscle as represented by forearm blood flow.

Administration, Oral↗

PubMed1992

Effect of ethanol on the release of prostaglandins from ovine fetal brain stem during gestation.

Prostaglandins (PGs) have been implicated as mediators of the ethanol-induced suppression of ovine fetal breathing movements (FBM). The objectives of the present study were to determine the ontogeny of the in vitro efflux of PGE2 and 6-keto PGF1 alpha in ovine fetal brain stem during the second half of gestation and to determine the effect of in vitro ethanol exposure on the efflux of these PGs. Ovine fetal brain stem tissue was obtained at mean gestational ages of 80 days (n = 6), 105 days (n = 10), and 135 days (n = 16) by rapid excision following maternal euthanization. Tissue slices (400 microM thickness) were prepared from the lower pons-medulla region of the brain stem. After a 1-hr equilibration period in artificial cerebrospinal fluid, efflux of PGE2 and 6-keto PGF1 alpha in the brain stem was determined using the brain slice-superfusion method, and the PGE2 and 6-keto PGF1 alpha concentrations in the superfusate were determined by specific radioimmunoassay. The mean spontaneous efflux of PGE2 and 6-keto PGF1 alpha expressed as pmol PG/gram wet weight of tissue/5-min collection period was, respectively, 31.9 +/- 4.2 and 26.6 +/- 2.4 at 80 days, 38.3 +/- 5.2 and 29.6 +/- 2.2 at 105 days, and 57.4 +/- 3.1 and 27.1 +/- 1.1 at 135 days of gestation. In vitro exposure to 20, 40, and 80 mM ethanol did not affect PG efflux in the brain stem at 80 and 105 days of gestation. In vitro ethanol exposure decreased PGE2 and 6-keto PGF1 alpha efflux at 135 days of gestation to 36.8 +/- 5.3% and 41.6 +/- 4.3% of spontaneous efflux within 15 min, respectively; this effect of ethanol was not dose-dependent. The data do not support the hypothesis that ethanol increases PG efflux in the ovine fetal brain stem. In view of these findings and the data implicating PGs in the mechanism of ethanol-induced suppression of FBM, it is possible that ethanol acts at either central sites rostral to the brain stem (i.e., upstream CSF) or peripheral sites to increase the synthesis of PGs and their efflux into the systemic circulation, with subsequent transfer to the respiratory control region(s) of the brain stem.

6-Ketoprostaglandin F1 alpha↗

PubMed1992

Direct evidence for nitric oxide formation from glyceryl trinitrate during incubation with intact bovine pulmonary artery.

It has been proposed that the mechanism of the vasodilator action of glyceryl trinitrate (GTN) involves biotransformation to nitric oxide. A sensitive chemiluminescence method for nitric oxide determination was used to test this hypothesis. In four experiments, bovine pulmonary artery (BPA) was incubated with GTN (0.1 mM) in Krebs' solution (2 mL) containing 30 mM KCl, and in anaerobic conditions using 95% Ar - 5% CO2, in a sealed micro-Fernbach flask (6.2-mL volume). After incubation for 2, 5, 10, or 20 min at 37 degrees C, 400-microL aliquots of headspace gas were removed and injected into a redox chemiluminescence detector. Nitric oxide formation was first measurable at 5 min (76 +/- 53 pmol/g wet wt. BPA), and increased with incubation time (174 +/- 46 pmol/g wet wt. BPA after 10 min and 310 +/- 67 pmol/g wet wt. BPA after 20 min). This is the first direct chemical measurement of nitric oxide formation during interaction of GTN with vascular smooth muscle. These data support the concept that GTN is a nitrovasodilator prodrug acting via the formation of nitric oxide.

Animals↗

PubMed1992

Biotransformation of glyceryl trinitrate by rat brain homogenate.

Incubation of glyceryl trinitrate (GTN) with 5% (w/v) rat brain homogenate (RBH) resulted in biotransformation of the organic nitrate vasodilator drug to a mixture of glyceryl-1,2-dinitrate (1,2-GDN) and glyceryl-1,3-dinitrate (1,3-GDN). Heating of the RBH at 100 degrees C for 5 min and (or) pretreatment with 5 mM N-ethylmaleimide at 37 degrees C for 10 min demonstrated that about two-thirds of the GTN biotransformation activity was due to a sulfhydryl-dependent enzymatic process resulting in the predominant formation of 1,2-GDN, and that the remaining biotransformation activity was due to a sulfhydryl-dependent nonenzymatic process resulting in the selective formation of 1,3-GDN. In a preliminary experiment, nitric oxide formation was observed during the incubation of GTN with RBH under anaerobic conditions. These data support the idea that some of the therapeutic and adverse effects of GTN are mediated through its action in the central nervous system.

Animals↗

PubMed1992

Ontogeny of glutamate and gamma-aminobutyric acid release in the hippocampus of the guinea pig.

The ontogeny of the L-glutamate (GLU) and gamma-aminobutyric acid (GABA) neuronal systems in the guinea pig hippocampus was investigated with respect to tissue amino acid content, and spontaneous and K(+)-stimulated release of GLU and GABA. Transverse hippocampal slices were prepared from the guinea pig fetus at day 45 (brain growth spurt), 55 and 63 of gestation (term, about 68 days), from the 5-days-old neonate, and from the young adult. GLU and GABA release was determined as efflux from hippocampal slices into Krebs'-bicarbonate medium using a dynamic, submerged, superfusion apparatus. Hippocampal GLU content decreased during development, whereas GABA content was constant for all the ages investigated. The magnitude of spontaneous GLU efflux decreased during development; there was no measurable spontaneous GABA efflux. The K+ concentration-GLU efflux response curve was bell-shaped for the fetus at the three selected gestational ages, and was curvilinear for the neonate and adult. The apparent EC75 of K(+)-stimulated GLU efflux was higher for the neonate and adult compared with the fetus. In contrast, the K+ concentration-GABA efflux response curve was curvilinear, and the apparent EC75 of K+ was similar for all the ages investigated. K(+)-stimulated efflux of GLU and GABA was Ca++ dependent, but this was not the case for spontaneous GLU efflux. These data indicate that, in the guinea pig hippocampus, the GLU neuronal system is developing throughout gestation, whereas the GABA neuronal system appears to mature before the brain growth spurt.

Animals↗

PubMed1991

Quantitation of nitric oxide formation from nitrovasodilator drugs by chemiluminescence analysis of headspace gas.

A rapid and reliable method has been developed for the quantitation of nitric oxide by chemiluminescence analysis of headspace gas. Aqueous nitric oxide standards are used to calibrate the method. There is a linear relationship between the amount of nitric oxide and the redox chemiluminescence detector response over the range of 52-2445 pmol of nitric oxide in 2.0 mL of deionized water contained in a sealed 6.2-mL flask. The intra-day and inter-day coefficient of variation values of the method do not exceed 4% and 9%, respectively. The lower limit of quantitative sensitivity and the lower limit of qualitative detection are 52 pmol and 26 pmol of nitric oxide, respectively. This method has been used to measure nitric oxide formation during the incubation of glyceryl trinitrate or sodium nitroprusside in the presence of cysteine. This method has two major advantages over the currently available procedures for the quantitation of nitric oxide, viz., no artifactual formation of nitric oxide during sample preparation and decreased instrumental contamination.

Cysteine↗

PubMed1991

Does carbon monoxide have a physiological function?

Recently endothelium-derived relaxing factor (EDRF) has been identified as nitric oxide. The source of the nitric oxide is L-arginine, and the L-arginine-nitric oxide pathway has been proposed to function as a widespread transduction mechanism for the regulation of cell function and communication. Gerald Marks and colleagues suggest that carbon monoxide, which is formed endogenously from heme catabolism and which shares some of the chemical and biological properties of nitric oxide, may play a similar role. This would be achieved by carbon monoxide binding to the iron atom of the heme moiety of soluble guanylyl cyclase and to the iron-sulfur centers of macrophage enzymes.

Animals↗

PubMed1991

Effects of ethanol exposure on the embryo-fetus: experimental considerations, mechanisms, and the role of prostaglandins.

The purpose of this review is to critically examine the effects of ethanol on the embryo-fetus. There has been a tremendous amount of human epidemiological and experimental animal research on the characterization of the anomalies produced by chronic prenatal ethanol exposure and the identification of critical periods of vulnerability and critical amounts of ethanol necessary to produce fetal effects and (or) abnormal development. Few studies have examined the underlying mechanism(s) of the action of ethanol, and even fewer studies have examined the effects of single-dose ethanol exposure on the embryo-fetus. In this review, the current state of knowledge of the effects of chronic use of ethanol on the embryo-fetus is summarized. The primary focus of the review is on the embryonic-fetal effects of acute ethanol exposure, with particular emphasis on the ethanol-induced suppression of fetal breathing movements, as this effect appears to be a very sensitive index of acute exposure of the near-term fetus to ethanol. Factors to be considered in the selection of experimental animals to investigate the mechanism of action of ethanol and to study the acute effects of ethanol are discussed. Postulated mechanisms of action of ethanol on the embryo-fetus are evaluated with a focus on the role of prostaglandins. Finally, future directions in this field of research are proposed.

Animals↗

PubMed1991

Adrenoceptors of the human internal thoracic artery.

Adrenoceptor function in the human internal thoracic artery (ITA) was characterized in vitro using segments of the artery obtained during coronary bypass operations. Specimens were prepared as isolated arterial rings mounted in a tissue bath, and mechanical activity (isometric tension) was measured in response to drugs. The ITA responded to phenylephrine (PE), epinephrine, and norepinephrine with concentration-dependent contractions. The PE-induced contractions were antagonized by phenoxybenzamine, prazosin, and high concentrations of yohimbine. The ITA was not effectively contracted by clonidine in the concentration range normally associated with alpha 2-adrenoceptor stimulation. The beta-adrenoceptor agonist, isoproterenol, had a weak and variable effect on the ITA; samples from 9 out of 12 subjects did not respond to isoproterenol, whereas samples from 3 subjects responded with relaxations of between 33 and 42%. These in vitro studies indicate that the most important adrenoceptors of the human ITA are alpha-adrenoceptors; this may be relevant for the pharmacologic management of patients undergoing coronary bypass surgery using the ITA.

Adrenergic alpha-Antagonists↗

PubMed1991

Relationship between myocardial amiodarone concentration and antiarrhythmic effect in dogs with myocardial infarction and electrically induced ventricular arrhythmias.

The relationship between the antiarrhythmic effect of amiodarone and its myocardial concentration was studied in dogs with 1-week-old myocardial infarction and reproducibly inducible sustained ventricular tachycardia or ventricular fibrillation. Three groups of animals (n = 10/group) received amiodarone, 40 mg.kg-1.day-1 (low-dose amiodarone), amiodarone 60 mg.kg-1.day-1 (high-dose amiodarone), or no amiodarone (control group). After 1 week of treatment, programmed electrical stimulation was repeated, and plasma and myocardial amiodarone and desethylamiodarone concentrations were measured. In the control group, sustained ventricular tachycardia or ventricular fibrillation was induced in six dogs (p = NS) when compared with baseline data. In the low-dose amiodarone group, sustained ventricular tachycardia or ventricular fibrillation was induced only in two dogs after 1 week of treatment (p less than 0.01 vs. baseline data). Sustained ventricular tachycardia or ventricular fibrillation was induced in seven dogs after treatment with high-dose amiodarone (p = NS vs. baseline data). Plasma amiodarone concentration in the low-dose amiodarone group (2.54 +/- 1.95 micrograms/mL) was significantly less (p less than 0.01) than that in the high-dose amiodarone group (4.64 +/- 1.66 micrograms/mL). Similarly, the plasma desethylamiodarone in the low-dose amiodarone group (0.32 +/- 0.16 microgram/mL) was significantly less (p less than 0.001) than that in the high-amiodarone dose group (0.56 +/- 0.23 microgram/mL). The myocardial amiodarone concentration in the low-dose amiodarone group (49.7 +/- 23.1 micrograms/g) was significantly lower (p less than 0.001) than that in the high-dose group (98.4 +/- 32.1 micrograms/g).(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone↗

PubMed1991

Interaction of glyceryl trinitrate and sodium nitroprusside with bovine pulmonary vein homogenate and 10,000 x g supernatant: biotransformation and nitric oxide formation.

The current proposed mechanism of action of nitrovasodilator drugs involves biotransformation to nitric oxide, which is postulated to be the active vasodilator substance. Our objective was to determine whether nitric oxide was formed from two prototype nitrovasodilator drugs, glyceryl trinitrate (GTN) and sodium nitroprusside (SNP), after incubation with bovine pulmonary vein (BPV) preparations. GTN or SNP was incubated in an argon atmosphere with phosphate buffer, BPV homogenate, or the 10,000 x g supernatant fraction of the homogenate. Nitric oxide formation, as determined by a chemiluminescence-headspace gas method, was measurable following the incubation of SNP with BPV homogenate and 10,000 x g supernatant. There was no detectable formation of nitric oxide from the incubation of GTN with the two BPV preparations, although GTN was biotransformed to glyceryl dinitrate, as determined by gas-liquid chromatography. There was decreased recovery of nitric oxide during the incubation of authentic nitric oxide with the two BPV preparations as compared with buffer. In conclusion, formation of nitric oxide was measured for the interaction of SNP, but not GTN, with BPV preparations. However, the data do not exclude the possible formation of nitric oxide from GTN, as nitric oxide was shown to be sequestered or transformed by the BPV preparations.

Animals↗

PubMed1991

Sequestration of glyceryl trinitrate (nitroglycerin) by cardiopulmonary bypass oxygenators.

The effectiveness of glyceryl trinitrate (nitroglycerin) in controlling myocardial ischemia and blood pressure during coronary artery bypass graft surgery is frequently lost during surgery, possibly as a result of drug sequestration by the cardiopulmonary bypass circuit. The objective of this study was to utilize a gas-liquid chromatographic assay to determine the extent of removal of glyceryl trinitrate from the priming fluid by the bubble and membrane oxygenators. The apparatus was maintained at either 25 or 37 degrees C, the two extreme temperatures experienced by the patient during bypass surgery. At apparent steady state, the circulating glyceryl trinitrate concentration was decreased by 20.6%, 46.6%, and 67.3% with the Maxima membrane oxygenator, Cobe membrane oxygenator, and Bentley bubble oxygenator, respectively. The three-layer defoaming filters that are used in the Bentley bubble oxygenator were studied by immersing each of the three filters in fluid containing 60 nM glyceryl trinitrate and monitoring the drug concentration in Plasmalyte. The filters sequestered approximately 90% of the glyceryl trinitrate from the bathing solution of which 31% was recovered with a single methanol wash of the polyurethane filter. These data demonstrate that the different oxygenators used in the cardiopulmonary bypass circuit remove glyceryl trinitrate to varying degrees from the circulating fluid.

Cardiopulmonary Bypass↗

PubMed1991

Release of glutamate and gamma-aminobutyric acid in the ovine fetal hippocampus: ontogeny and effect of hypoxia.

The effects of increased potassium ion concentration (50 mM) and hypoxia on the efflux of glutamate and gamma-aminobutyric acid (GABA) were studied in ovine fetal hippocampal slices using the static-pool-interface superfusion method at three selected gestational ages (85 days, 105 days, 135 days; term, about 147 days). There was no difference in spontaneous efflux of either amino acid across the three gestational ages. Potassium ion stimulated the efflux of glutamate in the hippocampus of the 85-days-old fetus only, and this efflux of glutamate was not calcium-ion dependent. Potassium ion stimulated the efflux of GABA in the ovine fetal hippocampus at days 85 and 105 only; this efflux was calcium-ion dependent. A ten-minute period of hypoxia did not enhance the efflux of either glutamate or GABA. The data indicate that both glutamate and GABA are present in the ovine fetal hippocampus, and can be released by depolarizing concentrations of potassium ion in the immature fetus. The lack of potassium ion-evoked efflux of glutamate and GABA in the mature fetal hippocampus may reflect a toxic response to this stimulus. The lack of calcium ion regulation of glutamate efflux compared with GABA efflux indicates either a difference in maturation of glutamatergic synaptic mechanisms compared with GABAergic mechanisms, or is indicative of glial release of glutamate. Prolonged, severe hypoxia (greater than 10 min) may be required to evoke efflux of glutamate in the developing fetal hippocampus.

Animals↗

PubMed1991

The effects of indomethacin and prostaglandin E2 on the ethanol-induced suppression of ovine fetal breathing movements.

A study was performed to examine the role of prostaglandins (PGs) in the mechanism of the ethanol-induced suppression of FBM, in which the objective was to test the hypothesis that fetal administration of PGE2 can suppress the incidence of FBM following reversal of ethanol-induced suppression of FBM by indomethacin, a fatty acid cyclooxygenase inhibitor. Instrumented near-term pregnant ewes received 1-h maternal infusion of ethanol (1 g/kg maternal body weight) followed 0.5 h later by a 3-h fetal infusion of indomethacin (1 mg/kg fetal body weight/h), and then a 2-h fetal infusion of PGE2 (400 ng/kg fetal body weight/min). Prior to drug administration, FBM occurred approximately 36.1 +/- 2.6% of the time. FBM were suppressed during the period of ethanol infusion (9.6 +/- 1.7%); the ethanol-induced suppression of FBM was reversed by fetal indomethacin treatment (77.5 +/- 14.1%); shortly after the onset of fetal PGE2 infusion, the incidence of FBM decreased to a 2-h mean incidence of 14.1 +/- 4.2%, which was similar in magnitude to that observed after maternal ethanol infusion. After the completion of PGE2 infusion, the incidence of FBM rapidly increased to a peak incidence of 83.4 +/- 19.2%, which was indicative of a prolonged effect of indomethacin on FBM. The data indicate that PGs mediate the ethanol-induced suppression of ovine FBM and that the action of indomethacin to antagonize ethanol-induced suppression of FBM is primarily due to its inhibition of PG synthesis.

Animals↗

PubMed1991

Effects of alcohol (ethanol) on the fetus.

Alcohol (ethanol) use during pregnancy can produce a wide spectrum of effects in the developing embryo/fetus that are dependent on the maternal drinking pattern. The effects of chronic ethanol exposure on the developing conceptus are reviewed with primary focus on ethanol teratogenesis, manifesting in the human as the fetal alcohol syndrome or fetal alcohol effects. The effects of acute ethanol exposure on the near-term fetus are described, including suppressed fetal breathing movements, electrocorticographic (ECoG) activity and electrooculographic (EOG) activity. The ethanol-induced suppression of fetal breathing movements is a very sensitive index of acute exposure of the near-term fetus to ethanol, and appears to involve a direct mechanism of action rather than an indirect mechanism involving suppression of electrocortical activity. The disposition of ethanol and its pharmacologically active proximate metabolite, acetaldehyde, and the activity of alcohol dehydrogenase and aldehyde dehydrogenase in the near-term maternal-fetal unit are described, and a pharmacokinetic model is proposed. The effects of short-term ethanol exposure on the near-term fetus include the development of tolerance to the ethanol-induced suppression of fetal breathing movements, low-voltage ECoG activity and EOG activity. The development of tolerance occurs more rapidly to the latter two fetal biophysical activities. The mechanism of tolerance development appears to be pharmacodynamic (functional) in nature, as there is no increase in the rate of ethanol elimination from the maternal-fetal unit. The role of prostaglandins (PGs) in the mechanism of the ethanol-induced suppression of fetal breathing movements is described. In the near-term fetus, there is a direct relationship between fetal blood ethanol concentration and fetal plasma PGE2 concentration, and an inverse relationship between the incidence of fetal breathing movements and each of fetal plasma and fetal cerebrospinal fluid (CSF) PGE2 concentrations. Indomethacin, a PG synthetase inhibitor, selectively blocks and reverses the ethanol-induced suppression of fetal breathing movements. These data support the postulates that the ethanol-induced suppression of fetal breathing movements is mediated by increased PGE2 concentration in the near-term fetus and that the ability of indomethacin to antagonize the ethanol-induced suppression of fetal breathing movements is due to its biochemical action to decrease fetal PGE2 concentration.(ABSTRACT TRUNCATED AT 400 WORDS)

Alcohol Drinking↗

PubMed1991

Effect of ethanol on 15-hydroxyprostaglandin dehydrogenase activity in the brain stem of the near-term fetal sheep.

The effect of in vitro incubation with ethanol (10-80 mM) on 15-hydroxyprostaglandin dehydrogenase (15-OH-PGDH) activity was determined in the brain stem (pons and medulla) of the fetal sheep at a mean gestational age of 126 days (term: about 147 days). Enzyme activity was determined by measuring the rate of oxidation of PGE2 to 15-keto-PGE2 using a radiometric assay. There was no statistically significant ethanol-induced inhibition of 15-OH-PGDH activity. The data apparently do not support the hypothesis that acute in vitro exposure to ethanol directly inhibits 15-OH-PGDH activity in the near-term fetal brain stem.

Animals↗

PubMed1991

Plasma concentration time course and pharmacological effects of a standardized oral amiodarone dosing regimen in humans.

This study was undertaken to clarify the relationships among dose, plasma concentration time course, therapeutic efficacy, electrocardiographic effects, and toxicity of amiodarone during the initiation and maintenance of oral therapy. A standardized dosing regimen (cumulative dose 10.4 g in the initial two weeks, maintenance dose 400 mg/day, five days per week) was used in eight patients with ventricular arrhythmias. Plasma amiodarone and desethylamiodarone concentrations, electrocardiographic parameters, and selected clinical and laboratory markers of toxicity were monitored at frequent intervals. Arrhythmia control was satisfactory in seven patients. Steady-state plasma amiodarone and desethylamiodarone concentrations (1.7 +/- 1.3 and 1.1 +/- 0.5 microgram/mL, respectively) occurred only after the first month of therapy. In most patients the amiodarone level then remained between 0.5 and 1.0 microgram/mL, but in two it consistently exceeded 2.0 microgram/mL. These were the only patients whose liver function tests became abnormal. Keratopathy and cutaneous photosensitivity were common. No other toxic effects occurred. The heart rate decreased by 20% while the PR interval, QRS duration and QTc interval did not change. The conservative dosing regimen used in this study is therapeutically effective, results in considerable interpatient variation in plasma drug and metabolite concentrations, slows the heart rate without significantly affecting other electrocardiographic parameters, and does not prevent keratopathy, cutaneous photosensitivity or hepatic dysfunction.

Administration, Oral↗