John J. Ambre

Kinetics of cocaine distribution, elimination, and chronotropic effects

The pharmacokinetics of cocaine were studied in five subjects with histories of drug abuse who were otherwise healthy. A two‐compartment system was used to model the distribution kinetics of the drug. The steady‐state volume of distribution averaged 131.8 L or 1.96 L/kg, elimination clearance was 2.10 L/min, and the t½ was 48 minutes. Cocaine concentrations in a hypothetic biophase were estimated to correlate the chronotropic effects of this drug with its pharmacokinetics. The experimentally determined kinetic parameters indicate that the peak chronotropic effect would occur 7.3 minutes after intravenous bolus injection of cocaine, and that biophase cocaine concentrations would initially accelerate the heart rate by 0.3 bpm for each 1 ng/ml. The kinetic analysis also demonstrated that the chronotropic effects of cocaine decline more rapidly than either plasma levels or biophase concentrations. This progressive attenuation in intensity of the chronotropic effect of a given biophase cocaine concentration could be modeled as a first‐order process and is compatible with either the intervention of homeostatic reflex mechanisms or the phenomenon of acute tolerance.

Acute tolerance to cocaine in humans

There is controversy as to whether acute tolerance develops to the principal effects of cocaine in humans. The studies described here demonstrate the phenomenon of acute tolerance to cocaine chronotropic and subjective effects and the rate and extent of tolerance development. Stable plasma cocaine concentrations were produced and then maintained in volunteer cocaine users by administering an intravenous cocaine injection followed by a cocaine infusion designed to compensate for the plasma clearance of cocaine. The euphoric effect (high) intensified to a peak at about 1 hour and then declined toward baseline at 4 hours despite the presence of constant plasma cocaine levels. The chronotropic effect reached a peak within 10 minutes and then declined, with a half‐life of 31 ± 13 (mean ± SD) minutes toward a plateau at 33% ± 21% of its peak intensity. Tolerance development was quantified as an exponential process, with a rate constant (tolerance factor) accounting for the progressive alteration of the cocaine concentration‐effect relationship.

Intravenous Elemental Mercury Injection: Blood Levels and Excretion of Mercury

The blood level and excretion of mercury was measured in a patient who injected 1 ml (13.6 g) of elemental mercury intravenously. The chest radiograph showed metallic densities delineating small pulmonary vessels. The patient had no signs or symptoms of mercury intoxication in the year after injection. Mercury blood levels were essentially constant, averaging 62 ng/ml. Although exhalation of mercury vapor was a major route of excretion and urinary mercury rose fivefold with administration of penicillamine, excretion by all routes, estimated for the year after injection, represented only 1% of the dose. Total body clearance of mercury wasonly 5 ml/min. Penicillamine therefore appeared to be of little value in reducing the body burden of mercury. The data also suggest that acute systemic mercury intoxication is unlikely after intravascular elemental mercury injection because blood mercury levels are low.

Comparison of prednisolone kinetics in patients receiving daily or alternate‐day prednisone for asthma

Prednisolone pharmacokinetics were compared in seven patients with asthma managed by alternate‐day prednisone therapy and in seven patients with asthma requiring daily doses of prednisone. Steroid requirements of these patients were carefully characterized and had been stable for at least 12 months. Prednisolone volume of distribution, elimination clearance, and elimination t½averaged 0.606 ± 0.061 and 0.553 ± 0.162 L/kg, 2.28 ± 0.43 and 1.93 ± 0.54 ml/min/kg, and 204 ± 44 and 214 ± 19 minutes in patients receiving alternate‐day or daily prednisone therapy, respectively. These results indicate that differences in these pharmacokinetic parameters do not account for the well‐established clinical observation that some patients require daily prednisone doses and that their disease cannot be managed with alternate‐day steroid therapy.

Mothball composition: three simple tests for distinguishing paradichlorobenzene from naphthalene

We describe three analytical procedures that can be used to distinguish naphthalene from the less toxic mothball component paradichlorobenzene. An initial presumptive identification can be made by noting the characteristic aroma of the two substances. This can be followed by one of the three analytical tests, each of which is simple to perform, gives an answer in seconds to minutes, and is definitive enough to eliminate the need for costly additional testing at an analytical reference laboratory. These tests have as additional advantages that the endpoints are dramatic and the reagents are commonly available.

A technique for producing constant plasma drug concentrations.

Excerpt To the editor: It is well known that the ideal intravenous drug regimen designed to achieve immediately and then maintain a constant plasma drug concentration is a loading dose injection fo...