Acute tolerance to pressor effects of cocaine in humans.

We have suggested previously that acute tolerance to the chronotropic effect of cocaine develops and that tolerance is incomplete, such that the heart-rate decline in the presence of stable plasma cocaine concentrations approaches a plateau that exceeds the baseline heart rate. One possible mechanism for heart-rate decline could be pressor-induced reflex slowing. We have investigated this phenomenon in intravenous (i.v.) cocaine users given prolonged steady-state i.v. cocaine infusions, as described previously. We have found that the contour of the pressor response, under conditions of the study, is identical to that of the chronotropic response. We also analyzed data presented in a report at variance with our conclusion (Drug and Alcohol Dep 22:169, 1988). In that study, heart-rate, pressor, and subjective effect data were collected after repeated intranasal doses of cocaine in a "naturalistic" setting. We found that the data are describable by our model and, in fact, provide further evidence to support our view. Application of our kinetic-dynamic model gave a tolerance factor of 19 min, suggesting that the adaptation process far exceeds the expected time course of cardiovascular reflexes or baroreceptor resetting. We conclude that tolerance does indeed develop to the pressor effects of cocaine, that the response is similar to the tolerance to heart-rate effect, and that our mathematical model of tolerance can also be used to describe the effects of cocaine taken intranasally in a naturalistic setting.

A kinetic model of benzoylecgonine disposition after cocaine administration in humans.

Cocaine (C) and benzoylecgonine (BZ) plasma levels and urinary excretion rate data from a series of intravenous cocaine studies were used to develop a kinetic model for C and BZ, with the main objective of characterizing BZ disposition. Kinetic analyses were made with the CONSAM 30 computer program. Under assumptions of the model, calculated parameters indicated a BZ distribution volume of 50 L, a half-time for BZ formation of 1.9 h and a BZ excretion half-time of 4.7 h. The model may eventually provide a basis for interpretation of analytical data on isolated samples of plasma or urine.

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.

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 t1/2 averaged 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.

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 t 1/2 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.

Ecgonine methyl ester, a major metabolite of cocaine.

Most assays for the identification of cocaine use are aimed at detection of benzoylecgonine, a major urinary metabolite. Gas chromatography assays require derivatization of benzoylecgonine. Recently, ecgonine methyl ester (methylecgonine) has been shown to be major urinary metabolite of cocaine in man after oral administration. These results indicate that ecgonine methyl ester is a prominent urinary metabolite after street use of cocaine, which primarily involves intranasal application and intravenous injection rather than ingestion. Advantages of GC/MS analysis for ecgonine methyl ester in identifying cocaine use include the ability to chromatograph it on common stationary phases without derivatization and its early elution.

Methanol poisoning in human subjects. Role for formic acid accumulation in the metabolic acidosis.

Whereas a great deal of information is available on the etiology of methanol poisoning in the monkey, very little study has been made in human subjects. The role of formic acid in methanol toxicity in human subjects has not been established. Two patients have been studied who have presented with the characteristics of methanol poisoning--metabolic acidosis and ocular toxicity. This has made possible a confirmation of the role of formate in the toxic syndrome. Acidosis was very severe in both cases with arterial pH values of about 6.9 and plasma bicarbonate concentrations of 3 meq/liter. A sensitive and specific assay was used to measure formic acid levels in blood and other fluids. Formate accumulation was marked with initial blood levels ranging from 11.1 to 26.0 meq/liter. Decreases in blood bicarbonate concentrations of similar magnitude coincided with the increase in formate. Thus, accumulation of formic acid plays a major part in the acidosis observed in human subjects poisoned with methanol, as has been demonstrated in monkeys. Treatment involving bicarbonate administration, ethanol infusion and hemodialysis, rapidly decreased formate levels in the blood to control values. Methanol concentrations were reduced but to lesser extent than that of formate. Despite the reduction in formate and methanol concentrations in both cases, the treatment was successful in only one of the two patients.

Therapeutic use of albumin.

Increasing use of normal human serum albumin may be contributing to the rising cost of medical care. To investigate whether albumin is extensively overused or abused, a study of the quality of albumin use was conducted in a Veterans Administration Hospital. Specific criteria for appropriate use were developed using guidelines defined at a national symposium. A review of use during a three-month period showed that surgery patients received 91% of the albumin administered during that period; of the total amount administered, 41% was used inappropriately; the decision to administer albumin to patients undergoing surgery appeared to be correct only 29% of the time; and an estimated $40,000 was spent on inappropriately used albumin at this hospital in 1977.

A selected ion monitoring method for glutethimide and six metabolites: application to blood and urine from humans intoxicated with glutethimide.

A method employing selected ion monitoring for the analysis of glutethimide and six of its metabolites has been developed. Hydroxylated metabolites analyzed as trifluoroacetates, included 4-hydroxyglutethimide, (1-hydroxyethyl)glutethimide and p-hydroxyglutethimide. The unchanged drug, 3-dehydroglutethimide, desethylglutethimide and the internal standard, [2H5]glutethimide, were chromatographed underivatized on OV-225. The assay was used to measure drug and metabolites in the plasma and urine of patients intoxicated with glutethimide. High levels (e.g. 20--35 microgram ml-1) of unconjugated 4-hydroxyglutethimide, an active metabolite, were found in all patients at a time when levels of unchanged drug were lower and declining. Other unconjugated and conjugated metabolites were found in relatively low concentrations in the plasma (i.e. less than 4 microgram ml-1). The major urinary metabolites were conjugates of 4-hydroxyglutethimide and (1-hydroxyethyl)glutethimide. The unchanged drug and other conjugated and unconjugated metabolites were found in lower amounts in the urine. Normal plasma half-lives of glutethimide and the relatively small amounts in urine of unchanged drug and unconjugated metabolites indicated that drug elimination was not markedly impaired in the intoxicated patients.

Pharmacokinetics of etomidate, a new intravenous anesthetic.

Etomidate sulfate, 0.3 mg/kg, was administered intravenously to eight patients and venous blood samples were drawn at intervals for the subsequent 10 hours. Plasma etomidate was determined by mass fragmentography. Plasma concentrations were fitted to a triexponential equation consistent with a three-compartment open pharmacokinetic model. Mean (+/-SD) variables were: initial t1/2, 2.6 +/- 1.3 min; intermediate t1/2, 28.7 +/- 14.0 min; apparent elimination t1/2, 4.6 +/- 2.6 hours; volume of the central compartment, 23.2 +/- 11.41; total apparent volume of distribution, 4.5 +/- 2.21/kg; fraction of drug in the central compartment, 7 per cent; total plasma clearance, 860 +/- 230 ml/min. Total blood clearance was estimated to be 754 ml/min and hepatic clearance, 739 ml/min. The large apparent volume of distribution indicates considerable tissue uptake. The hepatic clearance, being about 50 per cent of hepatic blood flow, indicates that changes in hepatic blood flow or hepatic metabolism will have only moderate effects on etomidate disposition.

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.

Mass fragmentographic determination of plasma etomidate concentrations.

The intravenous anesthetic etomidate was measured in human plasma by mass fragmentography. The method is accurate, sensitive, and specific. Results of the analyses indicate that after a single 0.3-mg/kg iv dose of etomidate, there are at least three phases in its disappearance from human plasma. Detectable plasma concentrations exist for more than 6 hr after injection.