John M. Strong

Northwestern University, Evanston, Illinois, United States

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Publications (19)100.3 Total impact

  • Izet M. Kapetanovic · John S. Dutcher · John M. Strong

    No preview · Article · Nov 1977 · Analytical Chemistry
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    ABSTRACT: The pharmacokinetics of procainamide (PA) and N-acetylprocainamide (NAPA) were compared in 3 normal subjects after simultaneous intraveous injection of PA and NAPA-13C. The distribution kinetics of both compounds were modeled with a 3-compartment mamillary system, and it was found that their steady-state distribution volumes were not significantly different, averaging 1.41 L/kg for PA and 1.46 L/kg for NAPA. However, the intercompartmental clearances of NAPA were slower than those of PA. In these normal subjects, the average elimination t1/2 and total elimination clearance for PA were 2.5 hr and 589.8 ml/min, and for NAPA were 6.2 hr and 233.7 ml/min. Mean renal clearances of PA (346.7 ml/min) and of NAPA (199.5 ml/min) exceeded the usual rate of glomerular filtration, which suggests that both compounds are eliminated in part by renal tubular secretion. All subjects were phenotypic rapid acetylators of isoniazid and converted approximately one fourth of the administered PA dose to NAPA-12C. The fate of 15.4% of the administered PA and 14.5% of the administered NAPA-13C was not determined.
    No preview · Article · Nov 1977 · Clinical Pharmacology &#38 Therapeutics
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    ABSTRACT: Ten patients with chronic premature ventricular contractions (PVCs) received short-term oral therapy with N-acetylprocainamide (NAPA) to determine its antiarrhythmic efficacy and side effects under the conditions of a placebo-controlled, dose-ranging trial. NAPA was effective in suppressing PVCs in 8 patients but caused a paradoxical increase in PVC frequency in one. Results were equivocal in the remaining patient because PVCs did not recur when NAPA therapy was withdrawn. Mean NAPA plasma levels as high as 41.1 microng/ml did not have untoward hypotensive or myocardial depressant effects, as judged by electrocardiographic and systolic time intervals. There was, in fact, a consistent reduction in PEP/LVET ratio, indicating that NAPA increases the force of myocardial contraction. The mean NAPA elimination half-life of 10.9 hr was longer than the 6.2 hr half-life reported for normal subjects, but its prolongation was predictably correlated with reductions in creatinine clearance. Gastrointestinal side effects experienced by 3 patients and insomnia noted by 2 patients are similar to known adverse reactions to procainamide.
    No preview · Article · Jun 1977 · Clinical Pharmacology &#38 Therapeutics
  • Arthur J. Atkinson · John M. Strong
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    ABSTRACT: Application of pharmacokinetic principles to patient therapy requires prior elucidation of the relationship between the plasma concentration of a drug and its pharmacological effects. This relationship is complicated by the fact that many drugs are converted to active metabolites so that observed effects represent a composite of the pharmacological activity of a drug and its metabolites. In fact, discrepancies between the observed duration of drug action and the biological half-life of a given drug should suggest that an active drug metabolite may have been formed. As is illustrated by the anticonvulsant drug methsuximide, drug metabolite levels may be so much higher than those of the parent drug that only the metabolite levels are of routine clinical significance. In other cases, levels of both the parent drug and one or more metabolites must be considered together and combined according to their relative potency to give an index of total pharmacological activity. This situation poses obvious difficulties with respect to the ease and safety of drug therapy with these agents. It generally would seem preferable to treat patients with drugs that are converted to inactive metabolites or are excreted largely unchanged.
    No preview · Article · May 1977 · Journal of Pharmacokinetics and Biopharmaceutics
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    ABSTRACT: Oral administration of a 1.5-gm dose of N-acetylprocainamide (NAPA) to 9 patients with premature ventricular contractions (PVCs) confirmed previous indirect evidence that this metabolite of procainamide has antiarrhythmic efficacy and potency comparable to those of procainamide. Although the mechanism by which NAPA acts as an antiarrhythmic drug is not known, it was found that the 6 patients with coupled PVCs responded to NAPA therapy and that the 3 patients without coupled PVCs failed to respond. Coupling interval prolongation also occurred during NAPA therapy in 4 of the 6 responding patients. These observations suggest that NAPA may terminate coupled PVCs by slowing and then interrupting conduction of re-entrant impulses, as has been proposed for procainamide. NAPA plasma concentrations of 7.4-17.2 mug/ml were well tolerated by the patients and produced an average fall of 3 mm Hg in mean arterial pressure and a 7.6% mean increase in corrected QT interval.
    No preview · Article · Jun 1976 · Clinical Pharmacology &#38 Therapeutics
  • John M. Strong · John S. Dutcher · W K Lee · A. J. Jr. Atkinson
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    ABSTRACT: Absorption of a single oral dose of N-acetylprocainamide (NAPA) was studied in 3 normal subjects. Approximately 85% of the oral dose was absorbed and peak plasma NAPA concentrations were reached in 45 to 90 min. In 2 subjects, NAPA was absorbed at a fast initial rate, then more slowly, prolonging the apparent elimination phase half-life. Absolute bioavailability was determined by a new stable isotope method that entailed intravenous injection of NAPA 13C at the same time that an unlabeled NAPA capsule was given orally. Plasma levels and urine excretion of both compounds were determined by mass fragmentography. Bioavailability was assessed by deconvoluting the plasma level vs time curves resulting from intravenous and oral drug administration, and also by comparing the relative percentage of NAPA and NAPA-13C excreted unchanged in the 24 hr after simultaneous administration.
    No preview · Article · Dec 1975 · Clinical Pharmacology &#38 Therapeutics
  • John M. Strong · John S. Dutcher · W K Lee · Arthur J. Atkinson
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    ABSTRACT: The pharmacokinetics of N-acetylprocainamide (NAPA) have been studied in three normal subjects who received 500 mg of this compound by timed intravenous injection. Plasma N APA concentrations and urine excretion were measured by quadrupole mass fragmentography, and a three- compartment pharmacokinetic model was used for data analysis. NAPA elimination half-life and total distribution volume averaged 6.0 hr and 1.38 liters/kg, respectively. Renal excretion of unchanged NAPA accounted for 81% of its elimination, and the mean renal NAPA clearance was 179 ml/min. Approximately 2% of the injected NAPA was deacetylated to procainamide. The fate was not determined of 17% of the NAPA that was estimated to have been eliminated during the 16- hr study period.
    No preview · Article · Sep 1975 · Journal of Pharmacokinetics and Biopharmaceutics
  • John M. Strong · Arthur J. Atkinson · Robert J. Ferguson

    No preview · Article · Aug 1975 · Analytical Chemistry
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    ABSTRACT: The kinetics of distribution and elimination of lidocaine and two of its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), were studied in 4 uremic patients on chronic hemodialysis. Each patient received a loading dose of 75 mg of lidocaine, followed by a 30 mug/kh/min lidocaine infusion. No toxic side effects from lidocaine were seen during the study. Average values for lidocaine steady-state plasma levels (2.3 mug/ml) clearance (12.3 ml/min/kg), terminal half-life (148 min), and total volume of distribution (1.9 L/kg) were found, and are similar to those values reported for normal subjects MFGX and after lidocaine infusion averaged 1/5-2/3 of the corresponding lidocaine level, as in nonuremic subjects, and plateaued by 6-8 hr. GX levels did not reach plateau by 12 hr and remained relatively unchanged after infusion. It is concluded that lidocaine infusion in uremic patients is safe, with no abnormal cumulation of lidocaine or MEGX. GX levels, however, may increase progressively, even after 12 hr.
    No preview · Article · Aug 1975 · Clinical Pharmacology &#38 Therapeutics
  • James Elson · John M. Strong · W K Lee · A.J. Jr. ATKINSON
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    ABSTRACT: Compared to procainamide in an animal arrhythmic model, the antiarrhythmic potency of the N-acetylated metabolite of procainamide (NAPA) was 92% with respect to dose and 70% with respect to plasma level. The antiarrhythmic effects of combinations of the drugs were additive. Measurements of procainamide and NAPA plasma levels needed to suppress ventricular extrasystoles suggested that both compounds are nearly equipotent in patients as well. The average plasma level required for arrhythmia control in these patients was equivalent to 5.1 mcg/ml procainamide. Since patients on long-term procainamide therapy have plasma concentrations of NAPA that are usually comparable to, and occasionally greater than, their procainamide levels, dose regiments based on procainamide levels alone need revision to include consideration of the levels of this metabolite.
    No preview · Article · Mar 1975 · Clinical Pharmacology &#38 Therapeutics
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    ABSTRACT: Glycinexylidide (GX) is a metabolite of lidocaine that is frequently present in mug/ml concentrations in the plasma of patients treated with lidocaine infusions for 24 hr or more. Plasma levels of GX have 26% the antiarrhythmic activity of lidocaine in an animal model, and GX adversely affects the mental performance of normal subjects at plasma concentrations comparable to those found in patients. The total volume of GX distribution in man is similar to that of lidocaine but the plasma clearance is less, so that the 10-hr elimination phase half-life of GX is much longer than the 1 1/2 hr half-life reported in normal subjects for lidocaine. About half of an administered dose of GX is excreted unchanged in urine, roughly 15% appears in urine as conjugates of xylidine and p-OH xylidine, and the fate of the rest is unknown.
    No preview · Article · Mar 1975 · Clinical Pharmacology &#38 Therapeutics
  • A J Atkinson · J M Strong

    No preview · Article · Jan 1975 · Acta pharmaceutica Suecica
  • J M Strong · T Abe · E L Gibbs · AJ Jr. Atkinson
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    ABSTRACT: The plasma concentration of N desmethylmethsuximide in patients receiving chronic methsuximide therapy averages about 700 times the concentration of the parent drug. Both compounds were measured simultaneously by quadrupole mass fragmentography in the plasma of 17 patients receiving methsuximide for various types of epilepsy. Because methsuximide is only slightly more effective than N desmethylmethsuximide in anticonvulsant tests on laboratory animals, it is likely that N desmethylmethsuximide is primarily responsible for seizure control in these patients. Although more study is needed to define the precise range of therapeutically effective plasma concentrations, plasma levels of N desmethylmethsuximide below 10 mcg/milliliter appear to be ineffective while those above 40 mcg/milliliter are toxic.
    No preview · Article · Apr 1974 · Neurology
  • J Blumer · J M Strong · A.J. jr Atkinson
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    ABSTRACT: The convulsant potencies of lidocaine, monoethylglycinexylidide (MEGX) and glycinexylidide (GX) were compared by standard dose response studies in rats. The median convulsant dose (CD50) was 52 mg/kg for lidocaine and 67 mg/kg for MEGX. Convulsions were not observed even when lethal doses of GX were given alone, but in combination GX appeared to potentiate lidocaine and MEGX seizures. The extent of this potentiation suggested that GX might have 1/10 the convulsant activity of lidocaine and MEGX, which places the hypothetical CD50 for this metabolite well above its LD50 of 183 mg/kg. Blood concentrations of lidocaine, MEGX and GX were determined at the onset of convulsions by quadrupole mass fragmentography. The blood level studies showed that lidocaine and MEGX were equally potent and suggested that metabolism of MEGX to less active GX caused the dose response studies to underestimate MEGX potency. The sum of plasma lidocaine and MEGX levels ranged from 18.7 to 21.7 μg/ml in agreement with threshold lidocaine levels found when seizures have resulted from the rapid administration of this drug to monkeys or man. These findings may be directly applicable to the interpretation of the results of blood level measurements in patients treated with lidocaine.
    No preview · Article · Aug 1973 · Journal of Pharmacology and Experimental Therapeutics
  • John M. Strong · Michele Parker · Arthur J. Atkinson
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    ABSTRACT: Glycinexylidide (GX) has been identified in the urine of 8 patients treated with intravenous infusions of lidocaine. The concentration o f GX ranged from 1.0 to 2.7 μg per milliliter in the plasma of 3 of these patients. This di-desethylated product of lidocaine metabolism, like the mono-desethylated metabolite, monoethylglycinexylidide (MEGX) also has local anesthetic activity. Both compounds may contribute to central nervous system (CNS) toxicity in some patients treated with lidocaine.
    No preview · Article · Jan 1973 · Clinical Pharmacology &#38 Therapeutics
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    ABSTRACT: >From first international conference on stable isotopes in chemistry, biology, and medicine; Argonne, Illinois, USA (9 May 1973). In proceedings of the first international conference on stable isotopes in chemistry, biology, and medicine. Quantitative mass fragmentography has made it possible to solve analytical problems in animal and human pharmacology that are important in drug research. We have developed an approach to mass fragmentography which uses a quadrupole gas chromatograph-mass spectrometer. This instrument has adequate sensitivity and precision for mass fragmentography and offers advantages over magnetic sector instruments with respect to ease of operation, wide range of ion monitoring and cost. The utility of this approach in pharmacology has been shown through studies in man and rats in which plasma levels of lidocaine and its active N-dealkylated metabolites were measured with a high degree of specificiiy. These plasma level studies helped lead to important clinical conclusions and demonstrated certain pitfalls in conventional dose-response studies of drug potency. The technique of quadrupole mass fragmentography also should have a ready application to work with stable isotopes. (auth)
    No preview · Conference Paper · Dec 1972
  • John M. Strong · Arthur J. Atkinson
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    ABSTRACT: Lidocaine and its pharmacologically active metabolite, monoethylglycinexylidide (MEGX), have been measured in samples of blood plasma by the technique of quadrupole mass fragmentography. The standard deviation of the method was 3.1% for lidocaine and 7.4% for MEGX over the range of concentrations usually encountered in clinical practice. The technique of mass fragmentography was extended to include rigorous criteria for compound identification based on statistical analysis of the ratio of two fragment ions present in each of these compounds and in the trimecaine added to the plasma samples as an internal standard. These ratios were reproducible with a standard deviation of less than 10%. The quadrupole mass spectrometer was found to be a suitable instrument for quantitative mass fragmentography, and offered an important advantage over presently available magnetic instruments with respect to the range of m/e of the fragment ions that could be recorded.
    No preview · Article · Dec 1972 · Analytical Chemistry
  • Source

    Preview · Article · Aug 1972 · Clinical Chemistry
  • J. Dutcher · J. Strong · W. Lee · Atkinson, A., Jr

    No preview · Article ·

Publication Stats

737 Citations
100.30 Total Impact Points

Institutions

  • 1977
    • Northwestern University
      Evanston, Illinois, United States
  • 1975
    • Stanford Medicine
      Stanford, California, United States
    • Northwest University
      Chicago, Illinois, United States