Serum Cocaine Concentrations Research Articles

Is cocaine a safe topical agent for use during endoscopic sinus surgery?

Is cocaine a safe topical agent for use during endoscopic sinus surgery?

Mechanisms of acute cocaine toxicity.

Patients with acute cocaine poisoning present with life-threatening symptoms involving several organ systems. While the effects of cocaine are myriad, they are the result of a limited number of cocaine-protein interactions, including monoamine transporters, neurotransmitter receptors and voltage-gated ion channels. These primary interactions trigger a cascade of events that ultimately produce the clinical effects. The purpose of this article is to review the primary interactions of cocaine and the effects that these interactions trigger. We also describe the progression of symptoms observed in cocaine poisoning as they relate to serum cocaine concentrations.

The pharmacokinetic determinants of the frequency and pattern of intravenous cocaine self-administration in rats by pharmacokinetic modeling.

We investigated the pharmacokinetic determinants of the frequency of intravenous cocaine self-administration in 2.5-h sessions. Two groups of rats were implanted with dual catheters that permitted cocaine infusion and blood sampling via the femoral and jugular vein catheters, respectively. Half of the animals in each group self-administered one of the two cocaine unit doses (0.5 and 1 mg/kg/infusion) by pressing a lever under a continuous schedule of reinforcement. To monitor serum cocaine concentrations, the remaining animals received concurrent, response-independent infusions whenever the matched animals self-administered cocaine infusions. Multiple concentration-time data in two successive self-administrations were determined to monitor the extent of fluctuation in concentrations by pharmacokinetic modeling. Behavioral analyses revealed the higher unit dose (1 mg/kg) resulted in less frequent cocaine self-administration, and a longer interinfusion interval, whereas the total doses were similar for the two groups (24.5-27.0 mg/kg/2.5 h). Cocaine decayed biexponentially. Both the values of clearance and terminal elimination rate constant for the self-administration paradigm were significantly greater than those after the bolus cocaine dosing series (0.5 and 1 mg/kg, separated by 3 days). The regularity in cocaine self-administration produced relatively stable serum cocaine concentrations that oscillated between maximum (C(max)) and minimum (C(min)) values regardless of dose size and interinfusion interval. Although the C(max) for the 1-mg/kg unit dose (1.47 microg/ml) was significantly higher than that for the 0.5-mg/kg dose (0.82 microg/ml), the C(min) values between the groups approximated each other (0.28, and 0.34 microg/ml, respectively). Hence, the C(min) is the determinant of the initiation of the next drug-taking behavior.

Arteriovenous serum cocaine concentration difference after intravenous bolus injection and constant-rate infusions: relation to pharmacodynamic estimates in rats

We characterized the pharmacokinetics of cocaine using both arterial and venous serum data after a bolus dose (2 mg/kg) and two constant-rate infusions (12.24 and 24.48 μg/min) for 2 h in rats. A published behavioral effect was used to investigate the effects of arteriovenous serum concentration differences on pharmacodynamic estimates for the 2 mg/kg dose. Significant temporal arteriovenous serum cocaine and benzoylecgonine (the major metabolite) concentration differences existed after cocaine administrations. The AUCs for arterial serum data were greater than the AUCs for venous data, indicating that cocaine was metabolized more extensively in the venous sampling site. Cocaine’s behavioral effect could be directly related to serum concentrations with no hysteresis observed between the effects and arterial or venous serum concentrations. The pharmacodynamic estimates derived from arterial serum data approximated those from the venous data due to the most decline of cocaine’s effect occurred in the elimination phase during which serum cocaine concentrations were not significantly different between the two sampling sites.

Tolerance develops to the sympathomimetic but not the local anesthetic effects of cocaine.

The cardiovascular effects of cocaine are complex and include sympathomimetic as well as local anesthetic effects. The aim of the present study was to delineate cocaine toxicity in a model simulating cocaine binging patterns. Prospective laboratory investigation. Twelve dogs were randomized to receive 6 intravenous boluses of cocaine 5.25 mg/kg (high dose, n = 5), 3.5 mg/kg (low dose, n = 4), or placebo (n = 3) at 15-minute intervals. Arterial pressure, electrocardiogram, and serum cocaine were measured at control, then at fixed time intervals after each bolus of cocaine or placebo. Statistical significance was determined by ANOVA. Peak serum cocaine concentrations were 3500 ng/mL and 2167 ng/mL in the high- and low-dose groups. There were progressive decreases in mean arterial pressure in the high-dose cocaine group by as much as 32% (p = .003) after each cocaine bolus. However, in the low-dose group, increases in mean arterial pressure were observed after the initial cocaine boluses by as much as 31% (p = .013). Significant QRS prolongation was observed in both the high- and low-dose cocaine groups by as much as 65% (p < .001) and 10% (p < .03), respectively. However, the prolongation observed in the high-dose group was more pronounced and cumulative, while in the low-dose group the prolongation was transient. At low doses, cocaine's sympathomimetic properties predominate but tolerance develops. At high doses, cocaine's local anesthetic properties predominate, become more pronounced with repeated administration, and may have implications for cocaine-related dysrhythmias, cardiovascular collapse, and sudden death.

Anti-Cocaine Catalytic Antibodies—A Novel Approach to the Problem of Addiction

ABSTRACT Cocaine reinforces its self-administration in relation to the magnitude of and rate of rise to the peak serum concentration of the drug. Catalytic antibodies are artificial enzymes which could reduce serum cocaine concentrations, deprive the abuser of cocaine's reinforcing effect and thus favor extinction of the addiction. Catalytic antibodies are elicited by immunization with a stable analog of a transition-state for a chemical reaction. Through our new method for synthesizing phosphonate monoesters, we constructed several phos-phonate-based transition-state analogs of cocaine hydrolysis. Using these analogs, monoclonal antibodies were elicited and, thus far, nine anti-analog antibodies with hydrolytic activity against cocaine have been identified, cloned and studied. The activity of one of these antibodies, 15A10, is sufficient to commence preclinical studies.

Intravenous Cocaine Induces Platelet Activation in the Conscious Dog

Cocaine consumption has been associated with thrombosis of coronary and peripheral arteries. Since cocaine has been found to induce platelet activation in vitro, we sought to establish whether cocaine induced platelet activation in vivo. Chronically instrumented, conscious dogs were infused with cocaine (1 mg/kg), norepinephrine (0.2 to 0.4 mg/kg), or saline intravenously over 1 minute. Activated canine platelets were identified in whole blood collected from an indwelling aortic catheter by flow cytometric detection of the binding of a monoclonal antibody directed against the activation-dependent antigen P-selectin. Infusion of cocaine resulted in an elevation of mean arterial pressure (91 +/- 3 to 128 +/- 7 mm Hg [P < .01]) and heart rate (87 +/- 9 to 125 +/- 11 beats per minute [P < .01]). A similar change (P = NS) in mean arterial pressure followed norepinephrine infusion (100 +/- 5 to 137 +/- 13 mm Hg [P < .04]), whereas saline infusion had no effect. Cocaine resulted in a substantial but delayed increase in platelet P-selectin expression (14 +/- 7% [P < .08], 31 +/- 12% [P < .04], and 55 +/- 22% [P < .04] at 17, 22, and 27 minutes after drug infusion, respectively). The magnitude of this increase was similar to that found in blood treated ex vivo with the agonists ADP or PAF (23 +/- 7% and 53 +/- 15%, respectively). No significant increase in P-selectin expression was detected in the blood of animals that received norepinephrine or saline. Serum cocaine concentrations were highest immediately after infusion (538 +/- 55 ng/mL at 2 minutes) but declined rapidly (185 +/- 22 and 110 +/- 25 ng/mL at 17 and 32 minutes after infusion); in contrast, the increase in benzoylecgonine concentrations was delayed (from < 25 ng/mL in all but one animal [34 ng/mL] at 2 minutes to 46 +/- 4 and 71 +/- 11 ng/mL at 17 and 32 minutes, respectively, after infusion). Intravenous cocaine induces activation of individual circulating platelets; this effect is not reproduced by infusion of norepinephrine at doses sufficient to exert similar hemodynamic effects. The delay in detection of activated platelets after treatment with cocaine may result from the adhesion and subsequent detachment of activated platelets; alternatively, cocaine metabolites, rather than the drug itself, may induce platelet activation.

Cocaine stimulant effects vary with cocaine levels in medial prefrontal cortex.

Rats treated with 10 mg kg-1 cocaine exhibited hyperlocomotion. Individual variation in the magnitude of this response was not correlated with serum cocaine concentration. Brain cocaine concentration, particularly in the medial prefrontal cortex, was highly correlated with the cocaine-induced locomotor stimulant effect. These findings indicate that variation in the uptake of cocaine into the brain is a critical variable in determining individual variation in its stimulant effects.

Cocaine LD 50 in long-evans rats is not altered by pregnancy or progesterone

Progesterone increases cocaine's cardiovascular toxicity in sheep and rats. To determine whether progesterone enhances the lethality of cocaine, nonpregnant female rats were treated with either IM progesterone (P4) or vehicle, and pregnant rats (Preg) were untreated. The rats received one IP injection of cocaine at a dose between 25–75 mg/kg and were observed for seizures and/or death. All 62 rats that died did so within 17 min, preceded by seizures in 90.3%. Mean times-to-seizure and times-to-death, and mean lethal serum cocaine concentrations did not differ among groups. Serum progesterone levels (ng/ml ± SEM) at the time of death were different among groups: 24 ± 1.7 (C), 102 ± 6.4 (P4), and 139 ± 5.2 (Preg). Logistic regression dose/fatality curves, LD 50s, and LD 10s for the pregnant, progeste and control groups were not significantly different from one another. Though progesterone has enhanced cocaine's cardiac toxicity in some studies, it does not increase the risk of death from acute cocaine exposure in rats.

Differential temporal dynamics of serum and brain cocaine: Relationship to behavioral, neuroendocrine and neurochemical cocaine induced responses

Rats administered cocaine 10 mg/kg i.p. exhibited hyperlocomotion which occured within 5 min post injection. Subsequently, rats were injected with 10 mg/kg cocaine and brain and serum concentrations of cocaine were measured at 5, 10, and 20 min post injection. Within this time frame, cocaine concentration in limbic brain tissue was maximal at 5 min post injection and then declined substantially by 20 min post injection. In contrast, serum cocaine concentration increased from 5 to 20 min. post injection. Neurochemical effects of cocaine upon limbic dopamine turnover and plasma corticosterone had a time course similar to serum cocaine. Brain cocaine concentrations paralleled the locomotor stimulant cocaine response whereas cocaine neuroendocrine effects paralleled serum cocaine concentrations. These findings point to the importance of brain cocaine concentration ddeterminations in neurobehavioral studies of cocaine.

Oral cocaine self-administration: Relation of locomotor activity to pharmacokinetics

Rats were exposed to daily schedule-induced polydipsia sessions in which solutions of cocaine HCl were available. Both cocaine solution concentration (0.08–0.32 mg/ml) and session duration (0.25–3 h) were varied to determine their effects on locomotor activity rate. Additional animals were used to determine the effect of session length on serum cocaine and metabolite levels when drinking 0.32 mg/ml cocaine solution. Changes in locomotor activity rate were related to serum cocaine concentration by a linear concentration-effect model. By estimation from the linear model, the serum cocaine concentration threshold for increasing locomotor activity was about 0.01 μg/ml. Under these schedule-induction conditions, there was no evidence for the development of acute tolerance to the locomotor-stimulating activity of cocaine.

Collection and handling of clinical blood samples to assure the accurate measurement of cocaine concentration.

The measurement of serum cocaine concentration is difficult because it is rapidly metabolized in vivo and in vitro. Previous investigators have used sodium fluoride (0.5-3.0%) in an attempt to stabilize its concentration in samples of whole blood, but these concentrations of sodium fluoride are not readily available outside the analytical laboratory. This study was performed to assess the stability of cocaine in whole blood when stabilized in a commonly available concentration of sodium fluoride (0.25%), with or without concomitant refrigeration. Whole blood was enriched with cocaine to a final concentration of 900 ng/mL and added to flasks containing sodium fluoride (0, 0.25, 0.5, and 1.0%) or 0.25% sodium fluoride plus potassium oxalate (gray-top Vacutainer tubes), after which it was stored at 4 degrees C or at room temperature. Whole blood cocaine concentrations were measured at 0, 24, and 48 h by gas chromatography. Sodium fluoride at all concentrations, with or without refrigeration and potassium oxalate, effectively inhibited cocaine degradation, with 86-91% of the drug present after 48 h. In contrast, substantial degradation of cocaine occurred in the samples stored without sodium fluoride, regardless of temperature. Thus, the use of commercial gray-top Vacutainer tubes effectively stabilizes cocaine in blood during procurement, transport, and short-term storage.