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Biomedical subjects

T M Ludden

Publications and source records attributed to T M Ludden.

At least 91 records · Page 5Linked to original sources
PubMed1982

N-Acetylprocainamide kinetics after single and repeated oral doses.

The kinetic behavior of N-acetylprocainamide (NAPA) was studied after single and repeated oral doses in six healthy subjects and five patients with cardiomyopathy. Renal clearance (CLR) of NAPA was lower in patients than in normal subjects after an initial 1-gm dose (1.3 +/- 0.4 [x +1- SD] and 2.7 +/- 0.4 ml . min-1 . kg-1, P less than or equal to 0.001) and a final 2 gm dose (1.6 +/- 0.4 and 2.6 +/- 0.5 ml . min-1 . kg-1, P less than or equal to 0.01) even though there was no difference between measured creatinine clearance (ClCR) 80.8 +/- 23.6 and 93.2 +/- 19.3 ml . min-1 [1.73 M2]-1). The decrease in the ratio of NAPA ClR to ClCR (R) could not be accounted for by age alone. A published regression formula overestimated the R ratio for patients (1.65 +/- 0.09 and 1.25 +/- 0.17, P less then 0.025), but accurately predicted the R ratio for healthy subjects (2.10 +/- 0.04 and 1.99 +/- 0.54). Mean steady-state concentration (normalized for daily dose per unit of body mass) after 2 gm every 8 hr for at least 3 days was higher for patients (P less than or equal to 0.05). Comparing the parameters for all subjects after the initial 1-gm dose to those after the last 2-gm dose with paired data, oral clearance was somewhat lower after the last dose (3.7 +/- 1.0 and 3.1 +/- 1.0 ml . min-1 . kg-1, P less than or equal to 0.01). In spite of this, before and 2 hr after dose steady-state NAPA serum concentration were generally proportional to dose over the concentration range studied. Net deacetylation of NAPA to procainamide in both groups was minimal.

Acecainide↗
PubMed1982

Hemodynamic effects of N-acetylprocainamide in heart disease.

In six normal subjects and 6 patients with primary cardiomyopathy, left ventricular performance was evaluated at rest and during isometric handgrip exercise after 4 days of oral N-acetylprocainamide (NAPA) at each of the three dosage levels (3, 4, 5, and 6 gm/day). Changes in heart rate, blood pressure, and echocardiographic performance indices were noted during isometric exercise, but no effect of NAPA could be demonstrated. In five additional patients with ventricular dysrhythmias due to cardiac diseases, NAPA was given by vein until dysrhythmias were controlled and then a maintenance infusion was continued for 48 hr. Continuous ECG recordings showed excellent dysrhythmia control in four of the five patients, but no effect of NAPA on heart rate, blood pressure, mean pulmonary artery pressure, mean pulmonary artery wedge pressure, or cardiac output was demonstrated, either at the peak of initial infusion (serm NAPA 27 +/- 6.7 microgramsm/ml) or at steady state during the maintenance infusion (16 +/- 4.5 microgramm/ml). We conclude that NAPA by vein and mouth in clinically appropriate doses should be safe in patients with the reduced left ventricular performance due to cardiac disease.

Acecainide↗
PubMed1982

Endogenous generation of hydralazine from labile hydralazine hydrazones.

The hypothesis that the pharmacologically active hydralazine hydrazones (HH) are endogenously hydrolyzed to parent hydralazine (H) was tested in a series of in vitro and in vivo systems. The stable hydrazones H alpha-ketoglutaric acid hydrazone and H pyruvic acid hydrazone did not hydrolyze to H in vitro (buffer or plasma), were inactive in vivo and did not generate urinary metabolites of parent H. By contrast, the labile HH, H acetaldehyde hydrazone and acetone hydrazone (HAH) generated H in vitro. H acetaldehyde hydrazone produced in vitro effects that were equipotent to the H concentration measured in the dose solutions. When administered to conscious rats and rabbits, the labile hydrazones reduced blood pressure. This effect was more gradual in onset than that of H. The hypotensive effects of HH were significantly greater than predicted by the amount of H contained in the dose solutions. Metabolic studies were conducted with the labile HH, HAH. After administration of HAH to rabbits, the proportional excretion of the urinary H metabolite, H pyruric acid hydrazone, was equal to that observed after the administration of H. We conclude that HH are inactive, except when hydrolyzed to H. The hydrolysis of certain HH, including HAH and H acetaldehyde hydrazone, in vivo may be nearly complete. Differences in the pharmacodynamic properties between labile HH and H may be related to the time course of generation of H, sequestration of hydrolysis in physiologically inactive sites or other unrecognized mechanisms.

Animals↗
PubMed1981

Variability of plasma hydralazine concentrations in male hypertensive patients.

The efficacy and toxicity of hydralazine differ widely among individual patients, possibly because of different sensitivities to drug effect or as a reflection of pharmacokinetic differences. Therefore, the variability in plasma hydralazine concentrations after single intravenous and single and multiple oral doses was studied in 9 male hypertensive patients. After an intravenous dose of 0.3 mg/kg the area under the plasma concentration time curve (AUC) varied over less than a twofold range 17.5-29.5 muM-minute. However, after a single oral dose, 1 mg/kg, and after at least the fifth dose of a regimen consisting of 1 mg/kg given every 12 hours, there were much wider variations in AUC values: 4.0-30.4 and 3.2-38.5 muM-minute, respectively. Similar ranges in peak hydralazine concentration, Cp, were also noted, 0.12-1.31 muM after single oral dose and 0.10-1.39 muM after the multiple dose regimen. A significant portion of the observed interpatient variability could be explained by differences in acetylation ability. The AUC and Cp values for both the single and multiple oral doses were significantly lower (P less than 0.001) in rapid than in slow acetylators. Therefore, determining the acetylation ability of patients requiring hydralazine may help to optimize therapeutic benefit and minimize toxicity.

Acetylation↗
PubMed1981

Factors influencing procainamide total body clearance in the immediate postmyocardial infarction period.

Fifteen acute myocardial infarction patients (only one of whom had evidence of significant renal dysfunction) received a constant-rate intravenous infusion of procainamide at one rate for a least 24 hours. Steady-state plasma levels achieved during these infusions were used to calculate total body clearance (C/B). Linear regression analysis of C/B versus a variety of clinical and laboratory patient characteristics yielded only body weight (or parameters derived from it) as a significant covariant (r = 0.713, P less than or equal to 0.005). Interestingly, the data from these 15 patients suggest that the presence of a significant degree of heart failure at the start of therapy did not result in a significant decrease in C/B (C/B = 5.9 ml/min/kg when class 0-I failure was present at the start of therapy and C/B = 5.5 ml/min/kg when class III-IV failure was present). If the data from five other patients who were studied previously are added to the group reported here, the conclusions reached would be the same. These data suggest that in patients with good renal and hepatic function, initial procainamide infusion rate could be selected on the basis of body weight and need not consider the initial presence of moderate heart failure. However, intense clinical monitoring for signs of impeding serious toxicity is strongly recommended since the observed regression line did not predict total body clearance accurately in 10-15 per cent of the patients studied.

Adult↗
PubMed1981

Continuous infusion of lidocaine in patients with cardiac arrhythmias. Unpredictability of plasma concentrations.

Recent studies suggest that lidocaine hydrochloride continues to accumulate during prolonged infusions. Plasma levels of lidocaine and monoethylglycinexylidide (MEGX) were measured in 26 patients with cardiac arrhythmias during lidocaine infusions of 15 to 69 hours' duration. Clearance varied, ranging from 3.2 to 14.7 mL/min/kg, and was significantly less in the ten patients with heart failure (5.8 +/- 1.7 mL/min/kg) as compared with the remaining 16 (8.4 +/- 2.6 mL/min/kg; P < .05). The MEGX levels were < 1 microgram/mL. In four patients, steady states were achieved at two different infusion rates, and changes in lidocaine plasma levels were generally proportional to changes in infusion rates. Lidocaine elimination half-lives ranged from 3.2 to 8.7 hours, and no accumulation continued beyond four half-lives. Clearance values, elimination half-lives, apparent volumes of distribution, and, consequently, steady-state levels were widely variable, which can be partly explained by the inclusion of patients with congestive heart failure. Monitoring of serum lidocaine levels may aid in individualization of therapy.

Aged↗
PubMed1980

Hydralazine kinetics in hypertensive patients after intravenous administration.

Previous studies on intravenous hydralazine kinetics have been performed using nonselective analytical techniques that measure not only hydralazine but also certain hydralazine metabolites such as hydralazine pyruvic acid hydrazone (HPH). We studied the time course of hydralazine and HPH in eight hypertensive patients after 0.3 mg/kg intravenous with selective high-pressure liquid chromatographic assays. "Apparent" hydralazine concentrations were also determined using a nonselective gas-liquid chromatographic procedure. Total plasma clearance, CLT[72.9 +/- 4.9 (SEM) ml . min-1 . kg-1], apparent volume of distribution, Vd area (5.83 +/- 0.30 1 . kg-1), steady-state volume of distribution, Vd ss (1.83 +/- 0.17 . kg-1), and terminal half-life, t1/2 (53.7 min, harmonic mean) were independent of acetylator phenotype. The high ClT is compatible with rapid intravascular conversion of hydralazine to HPH and a high hepatic extraction ratio. Peak HPH concentrations occurred 10 to 60 min after dose; mean HPH t1/2 was 239 min. "Apparent" hydralazine concentrations were usually highest in the 2-min plasma sample and declined with a mean t1/2 of 296 min. Reports based on nonselective assay methods have underestimated CLT, Vd ss, and Vd area and have overestimated the t1/2 of hydralazine.

Half-Life↗
PubMed1980

Hydralazine kinetics after single and repeated oral doses.

In reports on hydralazine kinetics plasma hydralazine levels have been measured with nonspecific assay techniques. The techniques used also include acid-labile hydralazine metabolites and therefore markedly overestimate hydralazine levels. We have developed specific, sensitive assay methods for the measurement of hydralazine and its major plasma metabolite, hydralazine pyruvic acid hydrazone (HPH). By these methods, we determined hydralazine and HPH kinetics after single and repeated oral doses of hydralazine in eight hypertensive patients. Hydralazine bioavailability in the fast acetylator group (9.5% single dose, 6.6% repeated doses) and in the slow acetylator group (31.3% single dose, 39.3% repeated doses) was phenotype dependent. Peak plasma levels were lower than those reported with nonspecific assays: 0.32 microM for the single dose and 0.14 microM for repeated doses in the fast acetylator group and 1.03 microM for the single dose and 0.96 microM repeated doses in the slow acetylator group. There was no alteration in kinetics and no cumulation in plasma on repeated administration. HPH plasma levels were proportional to those of hydralazine in both acetylator groups and were 2.5 to 4 times as high as those of hydralazine. Elimination half-lifes were phenotype independent, ranging from 4 to 6 hr. HPH cumulated in the rapid but not in the slow acetylator group after repeated doses of hydralazine.

Acetylation↗
PubMed1980

Displacement of phenytoin from plasma binding sites by salicylate.

Six healthy male subjects received phenytoin sodium as 9 100-mg capsules alone or with aspirin in a randomized, crossover fashion. Aspirin, 975 mg every 6 hr, was started 22 hr before a phenytoin dose and continued for an additional 48 hr during blood sampling. Mean 4-hr plasma salicylate levels ranged from 104 to 157 micrograms/ml during the sampling period. Individual mean values for the free fraction of salicylate varied from 0.107 to 0.167. The fraction of free phenytoin in plasma rose from 0.128 +/- 0.004 to 0.163 +/- 0.009 when aspirin was given (p less than 0.001). Subjects had lower total phenytoin 48-hr area under the curve (AUC) values when on aspirin (323 +/- 36 without and 261 +/- 49 micrograms . hr . ml-1 with aspirin; p less than 0.001) but free phenytoin AUC values were unchanged (41.4 +/- 4.5 and 42.4 +/- 9.0 micrograms . hr . ml-1; p less than 0.5). Thus, more rapid clearance of total phenytoin probably compensated for salicylate displacement of phenytoin from plasma protein binding sites. Total phenytoin levels for therapeutic monitoring must be interpreted cautiously when patients also receive salicylate.

Adult↗
PubMed1980

Phenytoin toxicity and blood levels after a large oral dose.

The pharmacokinetics and side effects of a single oral 900-mg dose of phenytoin sodium were studied in six healthy men. Nine 100-mg phenytoin sodium capsules were administered with water to six fasting healthy men. Phenytoin plasma levels were measured by gas chromatography for up to 48 hours after dosing. Patients were observed and tested for gastrointestinal, cardiovascular, and neurologic side effects. Peak total (bound and free) plasma phenytoin levels were within the therapeutic range (10--20 microgram/ml) for two subjects and close (not less than 8.39 microgram/ml) for the remaining four. Peak free drug levels were 1.01--1.60 microgram/ml. Time to reach total and free peak plasma levels was long and variable (6--14 hours and 2--10 hours, respectively). Phenytoin protein binding (11.9--13.6%) was relatively stable among patients and at various plasma levels. A few mild transient side effects were noted; most occurred within two to four hours after dosing. Sinus bradycardia and a shortened PR interval were noted in two patients but did not correlate with peak plasma phenytoin levels. It appears that an oral loading dose of phenytoin sodium may be useful in ambulatory patients but further study of its side effects is recommended.

Adult↗
PubMed1980

Dose-dependence of the apparent half-life of phenytoin in the rat.

The effect of dose on phenytoin pharmacokinetics was examined in the rat. In a randomized study on nine animals (not crossed over) it was observed that the apparent half-life ((t 1/2) of this drug increased four-fold as dose was increased from 10 to 50 mg/kg (6 1/2 - 64 +/- 42 min vs. 267 +/- 118 min, respectively; mean +/- S.D.). In a crossover study on three animals, an even larger dose-dependent increase in t 1/2 was observed (37.8 vs. 271 min). Finally, six animals received the 10 and 50 mg/kg doses in a randomized crossover fashion and urine was collected for 72 hours. A dose-dependent decrease in the fraction of the dose excreted as conjugates of 5-(p-hydroxyphenyl)-5-phenylhydantoin (59 +/- 20 vs. 39 +/- 12%) was found. It is concluded that phenytoin pharmacokinetics in the rat are non-linear but that a simple one compartment Michaelis-Menten model cannot account for the observed behavior.

Anesthesia↗
PubMed1979

Rapid metabolism of phenytoin: a method of calculating proper dosage.

The optimal dosage of phenytoin can be accurately determined by a pharmacokinetic method. By plotting the rate of administration of phenytoin acid against the apparent plasma clearance rate, we estimated the maximum rate of metabolism and the serum concentration at which the rate of metabolism was one half the maximum rate for phenytoin and then applied the Michaelis-Menten equation to optimize the dosage of phenytoin in a 48-year-old man with uncontrolled idiopathic generalized seizures and increased metabolism of phenytoin. The patient became seizure free on a regimen of 650 mg of phenytoin daily and experienced no side effects of phenytoin over-dosage. The pharmacokinetic technique described is simple to use and can be applied in an outpatient clinic.

Dose-Response Relationship, Drug↗
PubMed1979

Phenytoin cumulation kinetics.

Four male subjects were given phenytoin orally in single or twice-daily doses. Subjects were on 2 or 3 different dosing rates from 260 to 600 mg phenytoin sodium daily. Predose blood samples were obtained almost daily. The resulting serum levels, measured by gas-liquid chromatography, ranged from 1 to 18 micrograms/ml. Serum phenytoin concentration-time data were fit to a 1-compartment open model with zero-order input and Michaelis-Menten elimination. The resulting computer-generated parameter estimates (Vmax, 5.28 to 8.41 mg/kg/day; Km, 0.83 to 4.18 mg/1; Vd, 0.74 to 0.97 1/kg) are in agreement with the ranges of values in the literature. The time course of phenytoin cumulation is compatible with the presence of a major elimination pathway exhibiting Michaelis-Menten kinetic behavior.

Administration, Oral↗
PubMed1979

Plasma naltrexone kinetics after intravenous bolus administration in dogs and monkeys.

This investigation generated data characterize a specific electron-capture GLC assay reported previously for naltrexone and applied the method to a determination of naltrexone pharmacokinetics. Extraction efficiencies are reported for the assay, and mass spectral evidence indicates that naltrexone forms a triester when derivatized for electron-capture GLC with pentafluoropropionic anhydride and a base catalyst. Plasma level-time data for intravenous naltrexone at two dose levels in monkeys yielded no evidence of dose-dependent kinetics. A two-compartment open pharmacokinetic model was fitted to plasma level-time data for naltrexone in two dogs and yielded a total body clearance of 51-55 ml/min/kg. Urine collected for 0-24 hr contained 36% of the dose as naltrexone conjugates with less than 1% as unchanged naltrexone. Plasma level-time data for intravenous naltrexone in six monkeys yielded an average terminal half-life of 7.8 hr and a total body clearance of 64 ml/min/kg. The total body clearance for naltrexone was greater than the hepatic plasma or blood flow in both dogs and monkeys. This finding, together with the extremely low renal excretion of naltrexone, suggests the existence of elimination mechanisms besides liver metabolism and renal excretion.

Animals↗
PubMed1979

High-pressure liquid chromatographic assay for hydralazine in human plasma.

A specific high-performance liquid chromatographic assay for hydralazine in human plasma was developed. Plasma hydralazine is reacted with 10 microliter of p-anisaldehyde for 7 min at room temperature to form hydralazine p-anisaldehyde hydrazone. This derivative is extracted into ethyl acetate, and the solvent is removed by evaporation. The residue is reconstituted in 100 microliter of methanol, and 90 microliter is injected onto a reversed-phase column. The mobile phase is 32% acetonitrile in 0.75 M acetate buffer, pH 3.4, at a flow rate of 2 ml/min. The retention time of hydralazine p-anisaldehyde hydrazone is 6.5 min. The average coefficient of variation over 10-200 ng/ml is 5.5%, and the sensitivity limit is 5 ng/ml. Under the assay conditions, hydralazine pyruvic acid hydrazone, a known plasma metabolite of hydralazine, yields less than 0.1% hydralazine. Detectable plasma hydralazine levels of 5-20 ng/ml were found 10-30 min after a 0.5-mg/kg oral dose of hydralazine hydrochloride was given to a male volunteer.

Adult↗