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Biomedical subjects

A J Atkinson

Publications and source records attributed to A J Atkinson.

At least 55 records · Page 3Linked to original sources
PubMed1985

Reduction in slow intercompartmental clearance of urea during dialysis.

The kinetics of urea and inulin were analyzed in five anesthetized dogs during sequential 2-hour periods before, during, and after hemodialysis. The distribution of both compounds after simultaneous intravenous injection was characterized by three-compartment models, and the total volumes of urea (0.66 +/- 0.05 L/kg) and inulin (0.19 +/- 0.01 L/kg) distribution were similar to expected values for total body water and extravascular space, respectively. Intercompartmental clearances calculated before dialysis were used to estimate blood flows to the fast and slow equilibrating compartments. In agreement with previous results, the sum of these flows was similar to cardiac output, averaging 101% of cardiac output measured before dialysis (range 72% to 135%). Dialysis was accompanied by reductions in the slow intercompartmental clearances of urea (81%) and inulin (47%), which reflected a 90% attenuation in blood flow supplying the slow equilibrating compartments. This was estimated to result in a 10% average reduction in the efficiency with which urea was removed by dialysis (range 2.0% to 16.4%). Mean arterial pressure fell by less than 5% during dialysis, but total peripheral resistance increased by 47% and cardiac output fell by 35%. In the postdialysis period, total peripheral resistance and cardiac output returned toward predialysis values, but blood flow to the slow equilibrating peripheral compartment was still reduced by 80%. These changes parallel activation of the renin-angiotensin system, but further studies are required to establish causality.

Animals↗
PubMed1984

Torsade de pointes induced by N-acetylprocainamide.

N-Acetylprocainamide (NAPA), a class III antiarrhythmic drug, caused torsade de pointes in a 72 year old woman who had this arrhythmia on two previous occasions while being treated with quinidine and disopyramide. Initial evaluation with an intravenous infusion of NAPA indicated a favorable antiarrhythmic response. The QTC interval was prolonged, but the 2.4 ms/microgram per ml incremental QTC interval lengthening caused by NAPA was not greater than usual. During subsequent oral therapy with NAPA, torsade de pointes developed at plasma levels of this drug that appeared to be well tolerated during the initial evaluation.

Acecainide↗
PubMed1984

Kinetics of epsilon-aminocaproic acid distribution, elimination, and antifibrinolytic effects in normal subjects.

The kinetics of epsilon-aminocaproic acid (EACA) distribution and elimination were studied in six normal subjects after a single 10-gm iv dose. Steady-state distribution volume averaged 30.01 or 0.39 l/kg. Mean elimination t 1/2 was 294 min and the elimination clearance was 0.19 l/min. Renal excretion of unchanged EACA accounted for 68% of its elimination and renal EACA clearance averaged 115% of creatinine clearance. EACA antifibrinolytic effect kinetics were also characterized in five of the subjects by the monitoring of clot lysis times in whole blood and platelet-rich plasma. Peak antifibrinolytic effects were observed 15 to 60 min after peak EACA plasma concentrations were attained. A model of maximal fibrinolysis inhibition (Emax) was used to estimate a half-maximal inhibition (IC50) of 63 +/- 19.7 microgram/ml. This agrees with the value of 0.55 mM or 72 microgram/ml that has been reported for the dissociation constant of the EACA-plasminogen complex and is consistent with the proposed biochemical mechanism of EACA action.

Adult↗
PubMed1984

Urea distribution kinetics analyzed by simultaneous injection of urea and inulin: demonstration that transcapillary exchange is rate limiting.

The kinetics of urea and inulin were studied after simultaneous i.v. injection in six anesthetized dogs. The distribution of both compounds was characterized by a three-compartment model. The initial volume of urea distribution averaged 2.21 +/- 0.39 liters (+/- S.D.) and was similar to the expected volume of intravascular space. Although the 0.66 +/- 0.05 liters/kg of total volume of urea distribution corresponds to total body water, transcapillary exchange between intravascular space and rapid and slow equilibrating interstitial fluid spaces is the rate-limiting step in urea distribution and accounts for the three-compartmental structure of the system used to model the distribution kinetics of both urea and inulin. The free-water diffusion coefficient ratio of urea and inulin and the intercompartment clearances calculated after the simultaneous injection of these compounds were used to estimate blood flows to the fast and slow equilibrating interstitial fluid compartments. The sum of these flows averaged 97% of measured cardiac output (range, 83-113%) and was not significantly different from cardiac output. These studies suggest that the rate of urea removal during dialysis may be affected by hemodynamic factors, as we have shown previously for drugs.

Animals↗
PubMed1983

Efficacy and safety of N-acetylprocainamide in long-term treatment of ventricular arrhythmias.

Four patients with chronic ventricular arrhythmias, shown to respond over the short term to N-acetylprocainamide (NAPA), were treated for between 3 and 4 yr with NAPA, and 24-hr ambulatory ECGs were obtained monthly to monitor their responses. When the patients were ambulatory and receiving NAPA, the mean frequency of premature ventricular complexes averaged 70% (range 60% to 82%) below that recorded at 6-mo intervals when the patients were hospitalized and receiving placebo. Analysis of variance showed that NAPA exerted an antiarrhythmic effect in these patients and that tolerance to this effect did not develop with long-term therapy. Plasma NAPA concentrations required to achieve this level of response averaged 21 micrograms/ml (12 to 35 micrograms/ml) and were roughly twice as high as those which appeared to be maximally effective when the patients were hospitalized for their initial evaluation. NAPA therapy was associated with positive antibody titers in only one patient and seems less prone to cause drug-induced lupus erythematosus than procainamide, but NAPA shares the gastrointestinal and other side effects of procainamide.

Acecainide↗
PubMed1983

Kinetic analysis of D-xylose absorption in normal subjects and in patients with chronic renal failure.

D-Xylose kinetics were studied in 12 normal subjects and in nine patients with chronic renal failure requiring dialysis (five hemodialysis and four peritoneal dialysis). None of the study subjects had demonstrable gastrointestinal disease. Doses of D-xylose were given intravenously (10 gm) and orally (25 gm) on different nondialysis days in order to determine the distribution and elimination kinetics and the absolute bioavailability of this compound. Our findings were as follows. (1) The nonrenal clearance of D-xylose is markedly reduced in chronic renal failure patients (43.3 vs. 90.9 ml/min, p less than 0.002). (2) D-Xylose is less completely absorbed in patients with chronic renal failure than in normal subjects (48.6% vs. 69.4%, p less than 0.01). (3) The absorption rate of D-xylose is slower in these patients than in normal subjects (0.555 hr-1 vs. 1.03 hr-1, p less than 0.05). (4) The absorption rate is positively correlated with the extent of D-xylose absorption (r = 0.49, p = 0.03). (5) Although peak D-xylose concentrations measured 1 hr after oral administration are well correlated with the extent of D-xylose absorption in normal subjects and in functionally anephric patients (r = 0.59, p less than 0.01), formal kinetic study is required to determine D-xylose bioavailability precisely because of the large variability in peak serum D-xylose concentrations and in the time required to reach these peak concentrations.

Adult↗
PubMed1983

Pharmacokinetics of pentobarbital in the dog.

The pharmacokinetics of pentobarbital were studied after i.v. administration of a 30-mg/kg dose to five dogs. Pentobarbital plasma concentrations were measured with a new gas chromatographic method, utilizing on-column methylation of pentobarbital and as a butabarbital internal standard. The kinetics of pentobarbital distribution and elimination were analyzed with a three-compartment open mammillary model. The elimination-phase half-life of pentobarbital was 8.2 +/- 2.2 hr. The steady-state volume of pentobarbital distribution was 1.08 +/- 0.21 liters/kg and the elimination clearance was 0.0013 +/- 0.0004 liters/min X kg. Threshold pentobarbital concentrations required to suppress the corneal reflex and withdrawal response to pain were 26.4 +/- 4.6 and 23.0 +/- 2.9 micrograms/ml, respectively. These results should facilitate the design of i.v. anesthetic regimens with pentobarbital.

Anesthesia, Intravenous↗
PubMed1982

Excessive serum lidocaine levels during maintenance infusions: mechanisms and prevention.

Clinical and pharmacokinetic data were reviewed in 72 patients who developed excessive lidocaine serum levels during maintenance infusions. Fifty-one of the 72 (70%) were cardiac patients who had mean lidocaine excretory clearances less than one half of normal. Forty percent of these became toxic in spite of a reduced infusion rate (30 micrograms/kg/min). Seven patients with normal excretory mechanisms became toxic when they received large doses of lidocaine. The remaining 14 cases lacked an identifiable cause to explain the development of higher than therapeutic serum levels. Inordinately high serum levels of monoethylglycinexylidide (MEGX), an active lidocaine metabolite, were found in seven patients, but in only one was MEGX greater than lidocaine. Prolonged infusions (24 hours or greater) were not clearly associated with the worst lidocaine elimination clearances. Lidocaine toxicity was life-threatening or significantly complicated the management of 15 patients. Based on the data presented, guidelines are offered as an approach to the prevention of toxicity from maintenance lidocaine infusions.

Aged↗
PubMed1982

Heterogeneity of interstitial fluid space demonstrated by simultaneous kinetic analysis of the distribution and elimination of inulin and gallamine.

The kinetics of inulin and gallamine were studied after simultaneous i.v. injection in anesthetized dogs. The distribution of both compounds in extracellular fluid space was characterized by a three-compartment model in which the mean central compartment blood volume of 1.37 liters was identical with the expected value. The two peripheral compartments of the model appear to represent rapid and slow equilibrating interstitial fluid compartments. A mammillary model structure was selected in which intercompartmental clearance corresponds to transcapillary exchange. Previous studies indicate that inulin and smaller hydrophyllic molecules diffuse across capillary walls at rates proportional to their respective free water diffusion coefficients. For the ratio of the transcapillary permeability coefficients of inulin and gallamine to equal their free water diffusion coefficient ratio of 5.34 +/- 0.02 (+/- S.D)., it appears that the sum of blood flow to the fast and slow interstitial fluid compartments is less than cardiac output. When this assumption is made, blood flow to fast equilibrating interstitial fluid is estimated to be 39% of cardiac output, in agreement with previous measurements of splanchnic blood flow. This supports the hypothesis that the fast equilibrating interstitial fluid space is supplied by porous splanchnic capillaries that lack a continuous investment of basement membrane.

Animals↗
PubMed1981

Analysis of the contributions of permeability and flow of intercompartmental clearance.

Recent pharmacokinetic studies indicate that both flow and permeability contribute to intercompartmental clearance. A previous analysis of flow and permeability components of transcapillary exchange has been adapted to a three-compartment model of PA and NAPA pharmacokinetics. Data from a study that simultaneously determined the pharmacokinetic parameters of these two compounds made it possible to estimate permeability coefficients for the fast equilibrating compartment averaging 3.32 liters/min for PA and 1.35 liters/min for NAPA, and for the slow equilibrating compartment averaging 2.05 liters/min for PA and 0.78 liters/min for NAPA. These results were then used to estimated flow-intercompartmental clearance relationships for PA and NAPA and to predict the extent of hemodynamic changes causing the slow intercompartmental clearance of NAPA to decrease by 77% during hemodialysis without an apparent alteration in fast intercompartmental clearance.

Capillary Permeability↗
PubMed1981

On-column propylation method for measuring plasma valproate concentration by gas chromatography.

A gas-chromatographic method is described for measuring plasma valproate concentrations. This method incorporates double-solvent extraction of the plasma sample and on-column propylation of valproic acid and 2-propylhexanoic acid, used as the internal standard. The identity of the propyl ester derivatives of these compounds was confirmed by gas chromatography-mass spectrometry. The accuracy and simplicity of the method make it suitable for routine laboratory use. The assay is sufficiently rapid that a plasma sample can be analyzed in duplicate within 30 min.

Alkylation↗
PubMed1981

Plasma concentrations of desethyl N-acetylprocainamide in patients treated with procainamide and N-acetylprocainamide.

We describe a method for routinely measuring plasma concentrations of procainamide (PA), N-acetylprocainamide (NAPA) and desethyl N-acetylprocainamide (NAPADE) by high-performance liquid chromatography (HPLC). The method has been used together with mass spectrometry of the appropriate chromatographic fraction to demonstrate that NAPADE is a metabolite of NAPA. In addition, comparison of NAPADE concentrations in the plasma of patients receiving PA and NAPA indicates that NAPA is not an intermediate for most of the NAPADE formed from PA. We propose that the principal route of NAPADE formation from PA occurs by initial dealkylation to form rho-amino-N-[2-(ethylamino)ethyl]benzamide (PADE), a hypothetical PA metabolite that has yet to be identified.U

Acecainide↗
PubMed1981

Identification of desethyl procainamide in patients: a new metabolite of procainamide.

Desethyl procainamide (PADE) was identified in the urine of a patient treated with procainamide (PA) by high-performance liquid chromatography followed by solid-probe mass spectrometry. PADE prevented ventricular fibrillation in chloroform-asphyxiated mice but PA was 1.5 times more potent than PADE with respect to dose and 1.7 times more potent with respect to plasma concentration measured after administration of antiarrhythmic ED50 doses of the two compounds. N-acetylprocainamide was found to be 1.8 times more potent than desethyl N-acetylprocainamide with respect to dose and 2.9 times more potent with respect to plasma concentration. Measurements of PA, PADE, N-acetylprocainamide and desethyl-N-acetylprocainamide concentrations in 10 patients receiving long-term PA therapy suggest that only PA and N-acetylprocainamide concentrations make important contributions to observed therapeutic responses.

Acecainide↗
PubMed1980

Kinetics of theophylline transfer to breast milk.

Investigation of three nursIng women given theophylline intravenously defined the kinetics of theophylline transfer into breast milk. In each subject, R was constant, with no significant delay between the attainment of peak plasma and peak milk concentrations. The amount of theophylline eliminated into milk was equal to the product of R, milk volume, and the simultaneous maternal plasma concentration. The data indicate that theophylline cumulation to toxic concentrations should not occur in most breast-fed infants of asthmatic women treated with appropriate doses of theophylline.

Adult↗
PubMed1980

Kinetics of N-acetylprocainamide deacetylation.

The kinetics of N-acetylprocainamide (NAPA) deacetylation to procainamide (PA) were determined in a normal subject using NAPA-13C, labeled in the acetyl group. The deacetylation clearance of NAPA (ClD) was found to be 6.5 ml/min whereas total NAPA elimination clearance was 231 ml/min, so that 2.8% of the administered NAPA-13C was metabolized by deacetylation. This estimated of ClD was shown to be representative of the rate of NAPA deacetylation in four patients on long-term NAPA therapy. Steady-state [PA]/[NAPA] ratios averaged 0.024, but would be expected to rise to 0.057 if functionally anephric patients were treated with NAPA. Despite reports that patients with the PA-induced systemic lupus erythematosus-like reaction have had symptomatic and immunologic remission when switched to NAPA, the demonstration that NAPA is deacetylated to PA indicates that the apparently greater immunologic safety of NAPA may be relative rather than absolute.

Acecainide↗
PubMed1980

Impact of active metabolites on monitoring plasma concentrations of therapeutic drugs.

Monitoring plasma concentrations of therapeutic drugs presents special problems when these drugs are metabolized to compounds that have pharmacologic activity. This presentation reviews several methods for evaluating the pharmacologic activity of drug metabolites and describes the impact of active drug metabolites on the pharmacokinetic design of dose regimens and on the formulation of guidelines for plasma level interpretation. Lidocaine and monoethylglycinexylidide illustrate the considerations that pertain when both a drug and its active metabolite have similar therapeutic and toxic actions. Procainamide and N-acetylprocainamide exemplify the much more complex situation that arises when a drug and its active metabolite have different pharmacologic activity.

Animals↗
PubMed1979

Long-term antiarrhythmic therapy with N-acetylprocainamide.

The effects of long-term NAPA therapy were evaluated in 6 patients with chronic PVCs known to respond to this drug during a previous placebo-controlled, dose-ranging trial. Underlying cardiac status was evaluated every six months by switching each patient from NAPA to placebo. Placebo period PVC frequency after one year of NAPA therapy was reduced, compared to baseline placebo values. Mean PEP/LVET, measured while the patients received placebo, was elevated at the beginning of the study but was normal after one year of NAPA therapy. Comparison of NAPA and placebo period observations indicated a reduction in PEP/LVET when NAPA therapy was begun. This effect, however, could not be demonstrated one year later when mean placebo period PEP/LVET was normal. The apparent dependence of this effect on underlying status of left ventricular function suggests that the initial reduction in PEP/LVET represents an an indirect effect of NAPA rather than a direct inotropic action. NAPA therapy was well tolerated by the 6 patients and ANA titers became abnormal in only one, in marked contrast to reported experience with procainamide.

Aged↗