Biomedical subjects

S T Chiang

Publications and source records attributed to S T Chiang.

At least 19 recordsLinked to original sources

PubMed1995

The pharmacokinetics of venlafaxine when given in a twice-daily regimen.

The comparative bioavailability of the novel antidepressant venlafaxine and its pharmacologically active metabolite O-desmethylvenlafaxine was assessed when venlafaxine was given orally twice daily (75 mg bid) or 3 times daily (50 mg tid). Eighteen healthy subjects participated in an open-label, randomized, two-period, crossover study lasting 12 days. Each subject was randomly assigned to take venlafaxine according to a bid or a tid regimen through day 8 and was crossed over to the other regimen on days 9 to 12. The daily dose was titrated up to 150 mg/d and was held constant on days 5 to 12. Plasma samples for quantitation of venlafaxine and O-desmethylvenlafaxine were obtained during a 24-hour steady-state interval on days 8 and 12. Analysis of variance showed no significant differences between the two venlafaxine regimens for peak concentration (Cmax), area under the curve during 24 hours (AUC0-24), trough concentration, or fluctuation ratio for venlafaxine or O-desmethylvenlafaxine in plasma. The bioequivalence ratios for Cmax and AUC0-24 of both compounds were calculated to compare the bid regimen and the tid regimen. The mean value for each of the 4 ratios was between 96 and 100%, and the 90% confidence limits around each ratio were within 90 to 110%. These results indicate that dividing a daily 150-mg venlafaxine dose into 2 or 3 doses provides equivalent total exposure and peak plasma concentrations of venlafaxine and O-desmethylvenlafaxine, its active metabolite. Therefore, based on pharmacokinetic considerations, it appears that the same daily dose of venlafaxine can be given in either two or three divided doses without compromising efficacy.

Adult↗

PubMed1995

Pharmacokinetic and pharmacodynamic evaluation of the potential drug interaction between venlafaxine and diazepam.

To assess possible pharmacokinetic and pharmacodynamic interactions between the antidepressant venlafaxine and diazepam, a randomized, two-period, crossover study was conducted in 18 men. Multiple-dose venlafaxine (50 mg every 8 hours) or placebo (double-blind) was given for 10 days; on day 4 a single placebo dose (same appearance as diazepam capsule, single-blind) was given; and on day 5 a single dose of diazepam (10 mg) was given. Pharmacokinetic data indicated that diazepam had no significant effect on venlafaxine or O-desmethylvenlafaxine disposition. Diazepam pharmacokinetics were minimally changed in the presence of venlafaxine. Diazepam oral clearance (CL/f) increased slightly (24 +/- 8 versus 26 +/- 6 mL/h/kg; P = .007), volume of distribution (Vz/f) increased (0.85 +/- 0.28 versus 0.99 +/- 0.34 L/kg; P = .02), and AUC decreased (5973 +/- 2304 versus 5008 +/- 1354 ng.h/mL; P = .02). Venlafaxine did not alter desmethyldiazepam pharmacokinetics. Pharmacodynamic data showed a statistically significant diazepam-venlafaxine interaction for only one of the eight psychometric tests given. Critical flicker fusion slightly decreased (P = .01) between placebo-diazepam (37.85 +/- 3.28 Hz) and venlafaxine-diazepam (37.09 +/- 4.13 Hz) treatments. The observed pharmacokinetic and pharmacodynamic interactions between diazepam and venlafaxine were small and probably clinically insignificant.

Adult↗

PubMed1994

The effect of renal disease on the disposition of venlafaxine.

The pharmacokinetics of venlafaxine and its active metabolite O-desmethylvenlafaxine were studied in subjects with various degrees of renal dysfunction, including subjects requiring maintenance hemodialysis. Venlafaxine was administered as a single 50 mg dose, with blood and urine samples obtained at intervals up to 48 hours after administration for the subjects receiving dialysis or 72 hours for the subjects not receiving dialysis. Six subjects receiving dialysis also completed an intradialysis evaluation to estimate dialysis clearance. Concentrations of venlafaxine and O-desmethylvenlafaxine in plasma, urine, and dialysate fluid were determined by high-performance liquid chromatography. Apparent total clearance of venlafaxine and O-desmethylvenlafaxine were both significantly decreased by approximately 55% in the subjects receiving dialysis, and terminal disposition half-life was significantly prolonged for both compounds. Venlafaxine and O-desmethylvenlafaxine are poorly dialyzable. In conclusion, the disposition of venlafaxine and O-desmethylvenlafaxine is markedly altered in renal disease; therefore dosage adjustment is warranted for patients with creatinine clearance values below 30 ml/min.

Analysis of Variance↗

PubMed1993

Increased concentrations of atrial and plasma atrial natriuretic peptide in castrated male rats.

The effects of orchiectomy and testosterone replacement on the plasma concentration and the atrial stores of atrial natriuretic peptide (ANP) were studied in the rats. Male rats were orchiectomized (Orc) three weeks before replacement with testosterone propionate (TP, 20 mg/ml/kg body weight) or sesame oil for five days. Immunoreactive ANP (IR-ANP) in the extracted right atria and plasma of experimental rats was measured. Plasma ANP concentrations were 206 +/- 22, 927 +/- 151, and 264 +/- 61 pg/ml in normal control, Orc, and Orc + TP rats, respectively. ANP contents in right atria were higher in Orc (108 +/- 9 ng/mg tissue) and TP-treated Orc rats (123 +/- 9 ng/mg tissue) than in normal animals (32 +/- 7 ng/mg tissue). These results indicate an increased plasma concentration and atrial stores in the castrated male rats. Replacement of testosterone in the castrated male rats does not decrease the atrial ANP stores, but decreases the plasma ANP concentration.

Animals↗

PubMed1993

Effect of hypothyroidism on the in vitro release of atrial natriuretic peptide in response to sodium challenge in rats.

The release of atrial natriuretic peptide (ANP) in vitro in response to the challenge of sodium chloride was investigated in hypothyroid rats. Male rats were injected with propylthiouracil (PTU, 20mg/kg BW, intraperitoneally), or PTU and thyroxine (T4, 20 micrograms/kg BW, subcutaneously) once daily for 14 days before decapitation. Rats injected with saline were used as control. The plasma samples were collected and extracted by Sep-Pak C18 cartridge. The concentrations of ANP in extracted plasma were measured by a radioimmunoassay (RIA). PTU-induced hypothyroidism resulted in decreased concentrations of plasma ANP. Replacement of T4 in PTU-treated hypothyroid rats restored the plasma concentrations of ANP to normal levels. Furthermore, we examined the right atrial ANP contents and the in vitro release of ANP in PTU-treated rats and control animals. The right atrium was excised and divided into 5 equal pieces, one was homogenized with 0.1 N HCl and extracted by Sep-Pak C18 immediately, and the others were incubated with Locke's solution at 37 degrees C. After basal incubation for 30 min, rat atrial tissues were then incubated with 154, 160, or 165 mM NaCl for 30 min. The concentrations of ANP in extracted atrial tissue and medium samples were also measured by RIA. Decreased atrial contents of ANP were noted in hypothyroid rats. The in vitro release of ANP in response to 165 mM sodium ion was significantly lower in PTU than in saline-injected animals. These results suggest that lower concentration of plasma ANP in hypothyroid rats is at least in part due to impairment of stimulation-secretion responses of right atria during thyroid hypofunction in rats.

Animals↗

PubMed1992

Introduction of a composite parameter to the pharmacokinetics of venlafaxine and its active O-desmethyl metabolite.

Venlafaxine is a structurally novel, nontricyclic compound that is being evaluated for the treatment of various depressive disorders. A randomized three-period crossover study was conducted to obtain pharmacokinetic and dose proportionality data on the drug and its active metabolite, O-desmethylvenlafaxine. Eighteen healthy young men received single doses of venlafaxine 25, 75, and 150 mg followed by 3 days of administration every 8 hours (q8h). Steady-state elimination half-life was 3 to 4 hours for venlafaxine and 10 hours for O-desmethylvenlafaxine; both were independent of dose. Venlafaxine had a high oral-dose clearance, ranging from 0.58 to 2.63 L/hr/kg across doses with the lowest mean clearance, 0.98 L/hr/kg, at the highest dose. The apparent clearance of O-desmethylvenlafaxine was lower than venlafaxine, ranging from 0.21 to 0.66 L/hr/kg, and the lowest mean clearance, 0.33 L/hr/kg, occurred at the lowest dose. The area under the metabolite curve was two to three times greater than that for venlafaxine. Each compound had linear dose proportionality up to 75 mg q8h. A composite parameter incorporating venlafaxine plus O-desmethylvenlafaxine was introduced (i.e., AUC [area under the curve] + activity factor.AUCm), which extended linearity to 150 mg q8h. In summary, venlafaxine is a high-clearance drug that forms a metabolite with almost equal activity and demonstrates linear dose-proportionality.

Adult↗

PubMed1992

The effect of renal disease on tolrestat pharmacokinetics.

Many patients with diabetes who may benefit from treatment with tolrestat, a new aldose reductase inhibitor, will have nephropathy. Therefore the effect of renal dysfunction on the pharmacokinetics of tolrestat was evaluated in eight subjects maintained on hemodialysis, 11 subjects with partial renal impairment (creatinine clearance values ranging from 14 to 80 ml/min/1.73 m2), and eight normal subjects. Each subject received a single oral dose of 200 mg tolrestat. Blood and urine samples were collected during a 48-hour period, and tolrestat concentrations were measured by HPLC. Renal dysfunction had no apparent effect on the rate of absorption or volume of distribution of tolrestat. However, tolrestat clearance was significantly reduced from 30 +/- 3 (SD) ml/hr/kg in the normal subjects to 15 +/- 5 ml/hr/kg in the subjects receiving dialysis, and tolrestat half-life was prolonged from 11 to 16 hours. Therefore a reduction in tolrestat dose is suggested for patients with severe renal impairment.

Adult↗

PubMed1991

The absolute bioavailability and dose proportionality of intravenous and oral dosage regimens of recainam.

Recainam is a novel class I antiarrhythmic agent with electrophysiologic characteristics of all three subclasses. The authors evaluated the absolute bioavailability and dose proportionality of three oral doses and two 2-stage intravenous (IV) infusion doses. Single oral doses of 200, 400, and 800 mg and IV infusions consisting of 0.8 mg/kg/5 min + 1.2 mg/kg/hr (3.75 mg/kg) and 1.6 mg/kg/5 min + 1.2 mg/kg/hr for 4 hours and 55 minutes (7.50 mg/kg) were administered to 15 healthy men. Plasma and urine samples were collected during the 36-hour period after drug administration and analyzed for recainam concentrations by HPLC. No significant differences were found in any of the pharmacokinetic parameters between the two IV dosage regimens. The absolute bioavailability of orally administered recainam increased from 73% for the 200 mg dose to 81% and 84% for the 400 and 800 mg doses, respectively. Dose proportionality deviated from linearity by 13% for the 200 vs. 400 mg doses, and 10% for the 400 vs. 800 mg doses. The slight deviation from linearity was apparently caused by increased absorption at the higher oral doses. The slight disproportionality in the disposition of recainam is not expected to be clinically significant.

Administration, Oral↗

PubMed1990

Improved computation of respiratory resistance as measured by transiently increased resistance.

The authors have previously described an automated system for measuring total respiratory resistance. The technique used by this system involves a transient, externally applied increase in resistance to breathing. The utility of this technique is limited by a number of assumptions and to free it from the constraints imposed by one of these assumptions a new method for analysing the data was developed. The paper describes the new method of analysis and presents data comparing the resulting Rrss with those computed using the old method.

Humans↗

PubMed1990

Pharmacokinetic comparison of two triphasic oral contraceptive formulations containing levonorgestrel and ethinylestradiol.

The pharmacokinetics of levonorgestrel (LNG) and ethinylestradiol (EE2) were determined in 24 women (aged 21 to 35 years), following the administration of a single tablet from the second phase of two different triphasic preparations (Triphasil and Trinordiol. Each tablet contained 0.075 mg of LNG and 0.040 mg of EE2. The data were compared to the pharmacokinetics of LNG and EE2 obtained following the oral administration of a hydroalcoholic solution (standard) containing the same steroids and dose. The study consisted of a randomized design in which the three formulations were administered to each of the 24 subjects in a three-period crossover pattern. Blood samples were taken at frequent intervals after dosing. Serum levels of LNG and EE2 were measured by specific radioimmunoassays. The results show that both LNG and EE2 in the Triphasil and Trinordiol tablets are bioequivalent with respect to rate and extent of absorption. Furthermore, LNG, but not EE2, in both tablet formulations was bioequivalent to the solution dose. The serum concentration-time profiles for the three formulations showed that the range of mean peak levels was 2.3-2.8 ng/ml for LNG and 116-159 pg/ml for EE2. These levels were achieved within 2 hours in the majority of subjects. The ranges of mean values calculated for the areas under the curves were 15-16 ng.hr/ml for LNG and 1053-1390 pg.hr/ml for EE2. The ranges of mean values calculated for other pharmacokinetic parameters were: volume of distribution: LNG--1.6-1.8 L/kg, EE2--7.7-9.1 L/kg; clearance: LNG--84-88 ml/hr/kg, EE2--0.67-0.99 ml/hr/kg; half-life: LNG--13-15 hr, EE2--7-12 hrs.

Adult↗

PubMed1990

Electrophysiological effects of dermorphin on locus coeruleus neurons of rat.

Intracellular recording was used to study the effects of dermorphin on neurons of the locus coeruleus in the rat, in a totally submerged brain slice preparation. Dermorphin caused the inhibition of spontaneous firing of all neurons of the locus coeruleus tested, with an IC50 of 7 nM. Based on the inhibition of spontaneous firing rate, dermorphin was 16.5 times more potent than morphine. Larger concentrations of dermorphin (30-100 nM) further hyperpolarized the neurons of the locus coeruleus and simultaneously caused a reduction in input resistance. These effects were antagonized by naloxone, with a dissociation equilibrium constant of 0.8 nM. The hyperpolarization of neurons of the locus coeruleus, caused by dermorphin, was reversed at a membrane potential of -112 mV in this preparation. Furthermore, this hyperpolarization was blocked by cesium chloride and barium chloride. Thus, these data suggest that dermorphin binds to mu-opioid receptors on the cell membrane of neurons of the locus coeruleus. This leads to opening of the inward-going rectification potassium channels, resulting in the observed hyperpolarization of the membrane.

Analgesics, Opioid↗

PubMed1990

Responses of single phrenic motoneurons to altered ventilatory drives in anesthetized dogs.

We studied the effects of altered ventilatory drives on the activity of the whole phrenic nerve and single phrenic motoneurons in dogs anesthetized with alpha-chloralose and paralyzed with gallamine triethiodide. Single phrenic motoneurons were classified as either late-onset or early-onset motoneurons (LOM and EOM, respectively), depending on the time of onset of their activity during inspiration. Increase in ventilatory drive was induced by altering chemical drive with changes in arterial blood gases and also by altering the vagal afferent contribution to ventilatory drive. The latter was accomplished by inducing pulmonary gas embolism (PGE) during hyperoxia. Whole phrenic nerve activity was increased by both types of increase in ventilatory drive. In both cases, changes in the firing pattern of LOMs and EOMs were responsible for the increased phrenic output. The changes in post-PGE firing pattern of the LOMs generally consisted of a shift in the time of onset to an earlier point in inspiration and an increase in the number of spikes per inspiratory cycle. Vagotomy abolished the difference between the contributions of LOMs and EOMs to the phrenic response to PGE. Data from dogs studied while they were breathing spontaneously were qualitatively the same as those from the paralyzed animals, indicating no major role for phasic volume feedback in these responses. Our data regarding altered chemical drive are similar to those reported earlier in other species, whereas those regarding PGE demonstrate that vagally mediated increases in ventilatory drive affect both LOMs and EOMs, although LOMs are affected to a greater degree.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗

PubMed1990

Right ventricular pressure and ventilatory responses to pulmonary gas embolism.

This study was designed to test the hypothesis that changes in right ventricular pressure (PRV) are responsible in part for the altered breathing frequency (f) during pulmonary gas embolism (PGE). PGE was induced by infusing air into the femoral vein of alpha-chloralose anesthetized dogs. Respiratory flow pattern was recorded and analyzed in relation to PRV changes induced resulting from PGE. The rise of PRV, whether induced by PGE, by pulmonary artery occlusion, or by acute elevation of pulmonary arterial blood flow, was consistently associated with increased f. Breathing frequency rose principally through reduction of expiratory duration (TE). The inspiratory duration (TI) was shortened somewhat and the fractional inspiratory cycle, TI/(TE + TI), increased. The relationships between PRV and f were altered by changes of PRV resulting from the administration of histamine antagonist, by beta-adrenergic blockade, beta-adrenergic stimulation, and by changing pulmonary arterial blood flow. The responses did not occur after bilateral cervical vagotomy. These results demonstrate that f during PGE is partially regulated in response to changes in PRV and is mediated through the vagal afferent.

Adrenergic beta-Antagonists↗

PubMed1989

Total respiratory resistance in chronic obstructive pulmonary disease.

Using a recently described automated system, we measured total respiratory resistance (Rrs) of 59 patients with obstructive lung disease during spontaneous tidal breathing. We also measured airway resistance (Raw) and various other indices of pulmonary function. The results demonstrate that this system gives values of Rrs which correlate well with other objective measures of the severity of obstructive lung disease. It can also be used to detect changes in resistance after inhalation of a bronchodilator. In 10 patients we measured Raw during tidal breathing and computed the total non-airway resistance (Rnaw) as the difference between Rrs and Raw. Rnaw made up a larger portion of Rrs than would be expected in these patients. These results could not be accounted for by differences in breathing frequency, and may instead have been caused by differences between the times in the ventilatory cycle at which Rrs and Raw were measured. We cannot exclude the possibility that Rnaw was abnormally elevated in these patients.

Adult↗

PubMed1989

Measurements of components of resistance to breathing.

Total respiratory resistance (Rrs), pulmonary resistance (RL), and airway resistance (Raw) of 12 male patients with chronic obstructive lung disease were measured by the partial occlusion method, intraesophageal balloon technique, and body plethysmography, respectively. Chest wall resistance (Rew) and lung tissue resistance (Rti) were computed. Percentages of Rew/Rrs, RL/Rrs, Raw/Rrs, Rti/Rrs, Raw/RL, and Rti/RL were calculated. The magnitude of the components of resistance to breathing of this study and the data appearing in the literature are compared. Wide variation between the data reported by various authors was observed. The possible causes of these variations are discussed.

Aged↗

PubMed1989

Activities of uterine muscles from rats in late pregnancy.

Although it has been reported that, in the uterine wall of rats at term, gap junctions between fibers of the same muscle layer are responsible for synchronized strong contractions, much less attention has been paid to the interaction between muscle layers. To learn about the relationship between the two uterine muscles of rats in late pregnancy, we developed a technique to do simultaneous monitoring of activities in two muscle layers. Using rectangular muscle strips, the electrical activity in one layer was measured with an intracellular microelectrode while the mechanical activity of the other layer was recorded through a force transducer. In some of the uterine wall strips prepared from animals on gestation day 15 and 16, interaction between longitudinal and circular muscle layers was observed. However, well coordinated activities of these two muscles did not occur until the morning of gestation day 21 and continued toward delivery. Usually, coordination presented as paired contractions, one in the circular muscle and the other in the longitudinal muscle. While these pairs of contractions appeared regularly, they also kept similar intervals. Sometimes, coordination presented as a continuous appearance of groups of three contractions, one in one layer and two in the other. Coordinating contractions of uterine muscles is considered to be beneficiary to the propelling of fetuses toward the cervix during parturition.

Action Potentials↗

PubMed1988

Volume and pressure during transient added resistance.

Total respiratory resistance (Rrs) can be computed from measurements of flow before and during a brief period of added resistance. This "added resistance' method does not require measurement of total driving pressure (Pt). One of the assumptions of this method is that the change in Pt (delta Pt) is negligible during the time of increased resistance. To evaluate this assumption we measured both the volume exhaled during a brief imposition of an external resistor, and the total respiratory compliance (Crs) of 7 healthy volunteers. The mean volume exhaled was 18.6 ml, and the mean Crs was 88 ml/cm H2O. The volume exhaled divided by Crs gives the change in total static elastic recoil pressure (delta Pel, rs), which is one component of delta Pt. The mean delta Pel, rs was 0.22 cm H2O. Since the pressure exerted by contraction of inspiratory muscles (Pmus,I) opposes Pel, rs, we also estimated delta Pmus,I and subtracted it from delta Pel, rs to obtain delta Pt. The computed mean delta Pt during the time of added resistance was 0.045 cm H2O. This value is quite small in relation to Pt during a spontaneous expiration at rest. We also studied 13 subjects with Chronic Obstructive Pulmonary Disease and found no significant effect of transient added resistance on intraesophageal pressure. We conclude that the assumption of negligible delta Pt should not prevent the added resistance method from being very useful, particularly when simplicity of equipment and testing procedure are important.

Adult↗

PubMed1988

Determination of total respiratory resistance in health and disease by added external resistance.

Previous studies have indicated that total respiratory resistance (Rrs) can be measured by addition of an external resistor. In an earlier study, the apparatus used to accomplish this included a multiperforated steel plate. In this study, we sought to improve the device. Details of this are given in this article. With this device, resistance was found to be reproducible over five consecutive days, and was sensitive to the increase in airway resistance induced by head and neck flexion. We also report on a comparison between this method and a commercially available device that works on the "interruptor" principle. There was no significant difference in either mean or variance of resistance between the two methods. The instrumentation required for the newly designed method is minimal, and its operation is simple. Furthermore, the measurement can be performed without invasive procedures during tidal breathing.

Adult↗