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A procedure is described for the extraction of cocaine and benzoylecognine from whole blood using a modified JETUBE procedure in which only one-fourth of the JETUBE is used for the extraction. The benzoylecognine is derivitized using 0.025 mol/l tetrabutylammonium hydrogen sulfate (TBAHS) in 0.2 mol/L trimethylanalinium hydroxide (TMAH) and ethyl iodide at 100 degrees C for 8 minutes to given its corresponding ethyl ester. Cocaine and ethylbenzoylecognine are then quantitated on a gas chromatograph, equipped with a nitrogen-phosphorous detector (NPD), using the propyl ester of benzoylecognine as the internal standard. Twenty forensic toxicology cases are presented that were quantitated for cocaine and benzoylecognine. In the cases where the cause of death was not directly attributable to cocaine, only benzoylecognine was found.

It has been shown that there is a dose-response relationship between blood levels of intravenously injected cocaine and magnitude of evoked heat rate (Javaid et al. 1978). This relationship also holds for inhaled cocaine while plasma levels are increasing, but the cardiovascular effects of the drug dissipate more rapidly than cocaine disappears from the plasma. This suggests that the repeated administration or sustained blood level of cocaine might produce an acute tolerance. Using an intranasal route of administration it is possible to maintain cocaine blood levels for a substantial period of time after heart rate begins to decrease from its peak levels. If an intravenous dose is then administered on top of this preexisting blood level, the effects of this second dose can be compared to the same dose administered to subjects with no preexisting blood level.

The effects of cocaine hydrochloride infusion on left ventricular function in the anesthetized dog were observed under controlled heart rate and blood pressure conditions. In every case an immediate decrease in performance, as evidenced by maximal + rate of change of ventricular pressure (dP/dt), occurred and was a linear function of cumulative dose. Maximal (-) dP/dt also declined, indicating a decreased rate of ventricular relaxation. Right atrial and left ventricular end diastolic pressure increased, with no change in cardiac output or cardiac work, whereas coronary flow decreased slightly. This small decrease in coronary flow was probably related to the decrease in contractile vigor rather than a direct effect of cocaine on vascular tone. Although plasma norepinephrine concentration initially increased, ventricular function did not increase and continued to decline with cumulative cocaine dose. Tissue norepinephrine levels measured in isolated heart-lung preparations were not depleted. These findings indicate a direct toxic action of cocaine on the myocardium, decreasing both contractile performance and relaxation state. Plasma cocaine levels were constant during continuous infusion of the drug, indicating that the progressive toxicity observed did not result from increased circulating cocaine.

A method is described for extraction of the cocaine metabolite benzoylecgonine, conversion to the butyl ester derivative and gas chromatographic analysis using packed or capillary columns. Using a capillary column, cocaine and benzoylecgonine may be determined simultaneously. The extraction scheme has been designed to facilitate processing of large numbers of samples generated in pharmacokinetic studies. Structural analogues, m-toluylecgonine and m-toluylecgonine methyl ester, are used as internal standards. Concentrations as low as 10 ng/ml in 1-ml samples of plasma or urine are readily determined. Between-run coefficients of variation were 1.01% for cocaine and 4.18% for benzoylecgonine for concentrations of 75 and 350 ng/ml, respectively.

Comparative experiments were performed on female rats given pregnenolone-16 alpha-carbonitrile (PCN), spironolactone, triamcinolone, estradiol or diethylstilbestrol to study correlations between the toxic effect of cocaine, its blood clearance and its urinary excretion. PCN and estradiol significantly reduced the toxicity of the drug as well as its plasma levels and urinary excretion. Diethylstilbestrol and spironolactone, unlike triamcinolone, also diminished cocaine toxicity and plasma concentrations.

After applying 5% or 10% cocaine to the nasal mucosa, blood concentration were measured in 9 patients undergoing rhinoplasty and in 6 unoperated controls. The concentrations in the unoperated persons were lower than in those undergoing rhinoplasty, and lower concentrations were found after 5% solutions in both groups than in those exposed to 10% solutions. There was no correlation between the strength of the solution used and the degree of bleeding or the success of the anesthesia. One patient developed symptoms of toxicity within two minutes of a 5% cocaine application to his nasal mucosa. The cocaine concentrations in his blood were the highest seen in our studies, and we cannot explain this.

Studies are described in which normal healthy volunteers were tested with a wide range of intravenous doses of cocaine of d-amphetamine. Physiological measurements included heart rate, electrocardiogram, blood pressure, respiration rate, and temperature. Behavioral measures included the use of the Profile of Mood States to assess drug-related mood changes, the Addiction Research Center Inventory to assess drug-related changes in verbal reports of their effects, and ratings comparing drug effects of experimentally administered and "street" drugs. In addition, plasma levels of cocaine were monitored to correlate with physiological and behavioral effects. Subjects were also allowed to choose between intravenous injections of cocaine or saline. As with nonhuman research subjects, cocaine was consistently chosen over saline by all subjects tested. The self-administration data and data describing the subjective and cardiovascular spectrum of action were combined to yield a more complete profile of cocaine's action in humans.

This article describes 15 cocaine associated deaths in Utah in a 3 1/2-month period in early 1984, compared to 6 cocaine associated deaths for all of 1983. Brief case histories of the 15 cases are presented along with data on age, sex, county of death, cause of death, association of the cocaine with the death, cocaine analytical methodology, and a summary of cocaine concentrations in blood and urine. In four of the cases, cocaine by injection was the cause of death, whereas the other cases had cocaine or metabolite detected incidentally. The epidemiology of a single, well-defined cocaine source is described and related to this transient, remarkable increase in cocaine associated deaths.

Cocaine hydrochloride was administered to experienced users as an intravenous (IV) loading dose of 40 to 80 mg, followed by four-hour continuous IV infusions of either cocaine or placebo. Rates of cocaine infusion were individualized to maintain steady-state cocaine concentrations for the duration of the infusion. During the infusions, subjects rated themselves on questions that assessed their suspiciousness and paranoia, and nurse-observers took descriptive notes on the subjects' behavior; these notes were later scored on a scale for guarded, suspicious, and paranoid behavior. Nurses observed and rated moderately suspicious behavior when cocaine IV bolus loading doses were followed by cocaine infusions, but not when loading doses were followed by saline solution infusions; subjects did not rate themselves as suspicious during any of the study conditions. Suspiciousness during low-dose cocaine infusions significantly correlated with the amount of cocaine previously administered to the subjects. Suspiciousness during infusions was not related to plasma cocaine concentrations, preadmission drug use, or psychiatric symptoms and history. Cocaine infusions may be a useful tool to pursue the biology of stimulant psychoses.

Cocaine plasma concentration-response-time data obtained from the literature were analyzed by pharmacokinetic methods. The plasma concentration-time data yield an elimination half-life of approximately 1 hour and the data suggest that only about 20% of an oral dose of cocaine is absorbed intact into the systemic circulation. Response, as assessed by means of a relative "high" rating scale, declined linearly with time as predicted by theory. The rate of decline of response was found to be 0.0221 "high"/min. The rate of decline of response is a function of the apparent first-order elimination rate constant (K) of the drug and the slope of the response-log plasma concentration curve (m). A value for m of 4.2 "high" was calculated from the response-time data which agreed well with a value of 3.9 "high" for m determined from the slope of the response-log plasma concentration curve.

A method for the detection of benzoylecgonine (cocaine metabolite) and opiates in whole blood is described. This method employs the Abbott TDx fluorescence polarization immunoassay technique, which was designed for urine analysis. Drug-free whole blood was spiked with varying concentrations of benzoylecgonine, morphine, and codeine. Samples were prepared for analysis by adding 300 microL of 10% trichloroacetic acid to 300 microL of blood. Specimens were vortexed and centrifuged with 50 microL of supernatant required per assay. Precision studies of six replicate samples spiked with benzoylecgonine at 0.5 mg/L gave a within-run CV of 4.7% and a between-run CV of 4.7% with a detection limit of 0.1 mg/L. Within-run CVs for morphine at 0.5 mg/L and 0.1 mg/L were 1.7% and 7.9% respectively. The detection limits for morphine and codeine were 0.05 mg/L. Correlation coefficients for spiked whole blood calibration curves of benzoylecgonine, morphine, and codeine were 0.984, 0.999, and 0.997 respectively. This preliminary evaluation demonstrates a potential application of the TDx fluorescence polarization immunoassay technique to the analysis of drugs in whole blood.

Fatal cocaine intoxication presenting as an excited delirium is described in seven recreational cocaine users. Symptoms began with the acute onset of an intense paranoia, followed by bizarre and violent behavior necessitating forcible restraint. The symptoms were frequently accompanied by unexpected strength and hyperthermia. Fatal respiratory collapse occurred suddenly and without warning, generally within a few minutes to an hour after the victim was restrained. Five of the seven died while in police custody. Blood concentration of cocaine averaged 0.6 mg/L, about ten times lower than that seen in fatal cocaine overdoses. Police, rescue personnel, and emergency room physicians should be aware that excited delirium may be the result of a potentially fatal cocaine intoxication; its appearance should prompt immediate transport of the victim to a medical facility. Continuous monitoring, administration of appropriate cocaine antagonists, and respiratory support will hopefully avert a fatal outcome.

The absorption of cocaine from the nasal mucosa was measured by serial plasma analysis in patients who received nasal cocaine for routine nasal surgery using the modified Moffett's method. Two groups were compared: one received cocaine alone and one with adrenaline 1:1000 added. Changes in pulse rate and blood pressure were recorded in each group. The group that received intranasal cocaine and adrenaline solution had significantly lower plasma cocaine levels. There was no significant difference in cardiovascular parameters between the two groups.

This paper describes a procedure for the quantitative determination of methadone, meperidine, normeperidine, pentazocine, propoxyphene, norpropoxyphene, and dextromoramide in serum down to levels of 10 micrograms/L and of cocaine down to 25 micrograms/L. The procedure involves a simple extraction technique and high-performance liquid chromatography and is suitable for use in overdose drug screening, forensic toxicology, therapeutic drug monitoring, and pharmacokinetic studies.

Cocaine hydrochloride (30, 15, or 0 mg/kg) was administered daily subcutaneously to male rats for a minimum of 72 days. Animals receiving the 15-mg/kg and 0-mg/kg doses were pair-fed with animals receiving the higher dose. A fourth group served as a nontreated ad libitum-fed control to assess the role of cocaine-associated decreases in food and water intake. Administration of cocaine resulted in dose-related decreases in body weights, increases in locomotor activity, and decreases in estradiol levels. The high dose of cocaine was also associated with an increase in the percentage of spermatozoa with heads separated from tails. Cocaine did not affect sexual behavior, relative weights of the testis or accessory organs, histology of the testis, number of implantations, resorptions, fetal or newborn weight of offspring, or offspring weight at 21 days of age but did result in hyperactivity and increased perseverance in a T maze.

Eight normal adult volunteer subjects received an intranasal pretreatment of either 4 (placebo) or 96 mg of cocaine. Sixty minutes later 16, 32 or 48 mg of cocaine was injected i.v. Cocaine plasma levels were determined periodically over a 2-hr period and both cardiovascular effects and verbal report of drug effects were monitored for 8 hr daily. The plasma concentrations of cocaine were always related to the dose administered. When i.v. cocaine was given after a 96-mg intranasal pretreatment, the increase in heart rate was not as great as when an i.v. injection followed a 4-mg inhalation. Comparable changes were obtained in subjective effects as measured on the Addiction Research Center Inventory, the Profile of Mood States and a subjective effects questionnaire. These results suggest that there is a decrease in physiological and subjective effects of cocaine when administered repeatedly in humans. This acute tolerance appeared to have dissipated within 24 hr.

The total amount of cocaine used by ENT departments in the United Kingdom is about 960 kg. per year and this costs the Health Service in this country over 100,000 pounds. The majority of this cocaine is used intranasally prior to or during surgical procedures to provide mucosal vasoconstriction and analgesia. The techniques of applying cocaine vary from hospital to hospital. A comparison is made between two common methods of use, Moffett's solution and method, and 25 per cent cocaine paste applied on a wire and cotton wool probe. Cocaine serum levels were monitored and compared to known toxic dose levels.

Transplacental passage of cocaine in response to maternal administration of intravenous (IV) cocaine in doses of 1.0 and 2.0 mg/kg was studied in 6 pregnant ewes and fetuses and correlated with maximum changes in maternal and fetal blood pressures (BP), heart rates (HR) and fetal arterial blood gas values. Certain animals were given larger doses (3.0 and 5.0 mg/kg) of cocaine to examine cocaine-related cardiopulmonary and neurologic sequelae. Cocaine was extracted on C-18 sorbent columns and analyzed by gas chromatography. At 1.0 and 2.0 mg/kg, cocaine produced dose-dependent increases in maternal HR and BP which were maximum by 1 minute. The fetal response was characterized by maximum increases in BP and decreases in PO2 by 3 minutes and increases in HR by 15 minutes. Cocaine rapidly appeared in the fetal circulation, was approximately 15% of maternal concentrations by 5 minutes, and was undetectable in both circulations by 60 minutes. At cocaine doses of 3.0 and 5.0 mg/kg significant maternal cardiopulmonary and neurologic complications were encountered including bradyarrhythmias, respiratory distress, seizure and death. These data indicate that cocaine exerts direct drug actions upon maternal cardiovascular and neurologic function. In addition, cocaine affects fetal cardiovascular function directly via transplacental passage and indirectly by fetal hypoxemia from cocaine-induced uterine artery vasoconstriction. (NIDA 04415)

In vitro and in vivo studies in rats indicate cocaine to be metabolized primarily in the liver to form benzoylecgonine and norcocaine. The formation of these metabolites was significantly hindered by SKF-525A, a microsomal enzyme inhibitor. In in vivo studies, pretreatment of rats with SKF-525A prior to receiving cocaine resulted in increased amounts of unchanged cocaine in the brain. No accompanying increase in spontaneous motor activity was observed for these animals, indicating a possible role for metabolites in the stimulant action of cocaine.

Data are presented on 694 criminal homicide victims killed in the city of New Orleans during four years; 1979, 1982, 1985, and 1986. The homicide rate for black males was 6.5 times higher than that for white males for the years studied. Over 70% of victims were killed by handguns. When victims were assigned to one of five socioeconomic strata, homicide rates for blacks exceeded those for whites by a factor of at least 2.5 times for each socioeconomic stratum. White victims were more likely than were black victims to be legally intoxicated at the time of death, but black victims were nearly four times more likely to have illicit drugs other than alcohol detected. During the time period investigated, there was a marked decrease in the number of victims with pentazocine and tripelennamine ("Ts and blues") detected and an abrupt increase in the number of victims with detectable phencyclidine and cocaine levels. Further studies are needed to investigate risk factors for homicide victimization so that effective intervention strategies can be employed.

A procedure is described for the determination of as little as 20 ng of cocaine from 1 ml of whole blood or plasma. Methods are also given for the storage of whole blood or plasma containing cocaine as well as for whole blood or plasma extracts. Blood levels in patients receiving intranasal cocaine for topical anesthesia while undergoing rhinoplasty are also presented.

We compared the psychological effects of three doses of intranasal cocaine hydrochloride (.2, .75, and 1.5 mg/kg) with cocaine plasma concentrations in four volunteers. Intranasal lidocaine hydrochloride (.2 mg/kg) was used as a topically active placebo. Peak "high" ratings were related to both dose and peak plasma concentrations. At a given plasma concentration, "high" ratings were greater when plasma levels were increasing than when they were decreasing. This indicates that acute tolerance by tachphylaxis occurred after single doses. The cocaine "high" was a pleasant feeling but was without distinctive sensations. The dramatic effects of intranasal cocaine on the street may be related to larger or repeated doses as well as the setting.

Twenty patients presenting for submucous resection of the nasal septum under general anaesthesia were randomly allocated to four groups to receive either 1.0 ml 25% cocaine HCl in paraffin paste, 1.0 ml 25% cocaine HCl combined with 0.1% adrenaline in paraffin paste, 4.0 ml aqueous 4% cocaine HCl combined with 0.05% adrenaline or 4.0 ml aqueous 4% cocaine HCl on ribbon gauze applied to the nasal mucosa. Mean intraoperative blood loss was significantly decreased when the 25% cocaine 0.1% adrenaline combination in paraffin paste was used (11 (SD 8) ml, 60 (SD 30) ml, P less than 0.05, for adrenaline and plain paste respectively). Combination of adrenaline with cocaine in the aqueous formulation was not associated with a significant decrease in blood loss compared with aqueous cocaine alone (75 (SD 51), 96 (SD 66) ml respectively). Cocaine adrenaline paste and plain cocaine paste were associated with higher mean maximum cocaine blood concentrations (1.6 (SD 1.4), 2.0 (SD 1.5) micrograms/ml respectively) when compared with aqueous cocaine adrenaline and aqueous cocaine alone (0.03 (SD 0.003), 0.5 (SD 0.3) microgram/ml respectively). Heart rate and blood pressure changes were similar in all four groups and cardiovascular toxicity was not observed. One ml of topical intranasal 25% cocaine HCl with 0.1% adrenaline in paraffin paste provided the best haemostasis for nasal septal surgery.

A study was undertaken to assess the stability and the radioimmunoassay (RIA) detection of cocaine, benzoylecgonine (BZE), and 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) in whole blood while stored in 4 different kinds of blood collection tubes for up to 30 days at refrigeration and room temperatures. At various intervals, the tubes were sampled and analyzed using Abuscreen RIA. Also, semi-quantitative data derived from RIA analysis of forensic blood specimens were compared with quantitative data acquired using gas chromatography (GC) or GC/mass spectrometry (GC/MS) on the same specimens. RIA and chromatographic studies revealed that BZE and THC-COOH were stable in blood under all conditions studied. Cocaine, however, was found not to be stable in blood, especially when stored at room temperatures. Despite cocaine's instability in blood, RIA was able to detect the presence of cocaine and its breakdown products in blood under all conditions studied.

Cocaine hydrochloride (0 to 30 mg/kg, s.c.) was administered daily for a minimum of 72 days to Long Evans rats. Animals receiving the lower doses were pair fed to animals receiving the higher dose. Males were bred to untreated females. Paternal cocaine administration did not affect litter size, birth weight, or weight at weaning, but did result in offspring hyperactivity. A similar study was conducted for paternal alcohol consumption in Long Evans rats. Males consumed alcohol (35%, 17.5% or 0% ethanol derived calories) for 8 to 9 weeks and were then bred to untreated females. Males consuming the lower concentrations were pair fed to 35% EDC animals. Paternal alcohol consumption did not affect birth weight or weight at weaning but resulted in offspring hypoactivity. Mice sired by alcohol-consuming males were also hypoactive.

A 27-year-old male died as the result of swallowing a bag of cocaine. Using gas chromatography and ultraviolet spectrophotometry, the concentration of cocaine was determined on all specimens submitted for analysis. These analyses revealed what may possibly be the highest concentrations of cocaine ever reported in the toxicology literature. These values were confirmed by another medical examiner toxicology laboratory.

The effects of the intravenous administration of cocaine (0.05-5.0 mg/kg) on body temperature, heart rate, respiration rate and several unconditioned behavioral categories were ascertained in unanesthetized male rhesus monkeys. Statistically significant increases in body temperature, respiration rate and heart rate occurred only after the largest dosage tested. Subjective increases in pupil size, activity, reactivity and vocalization as well as the occurrence of stereotyped behaviors, mydriasis and refusal to ingest fruit, were observed following injection with 0.2, 0.5 mg/kg and 5.0 mg/kg. A large degree of consistent intersubject variability in the magnitude of these responses was present. There was no consistent correlation across subjects between the magnitude of these responses and the plasma level of cocaine. However, within a given subject a direct correlation existed between these parameters.

The epidemiologic, pathological, and toxicological findings of 60 cocaine-related overdose deaths from middle 1978 through 1982 were studied and compared with a previous publication by this office. In addition, 180 deaths where cocaine was an incidental toxicological finding are also discussed. Currently, the average street cocaine fatality victim is 29 years old, and 42% of the victims are female. Blacks comprise 39% of the cases. The blood cocaine concentration in "street cocaine" fatality victims averaged 6.2 mg/L with a wide range, necessitating careful interpretation of the toxicological results in conjunction with terminal events. Although autopsy findings were generally nonspecific, multiple needle-puncture marks with surrounding ecchymoses are typical of IV cocaine abuse. An increase in cocaine-related overdose deaths is anticipated because of its popularity, increasing availability, and, currently, the increased purity of street cocaine.

A method for the simultaneous analysis of cocaine (COC), derivatized benzoylecgonine (BE), and derivatized ecgonine methyl ester (EME) has been developed. Blood or urine containing deuterated analogs of the three analytes is extracted by pouring over a Chem-Elut column and eluting with chloroform/isopropanol (9:1). The eluent is collected, split into two equal aliquots, and evaporated to dryness. In one aliquot, dimethylformamide and dimethylformamide dipropyl acetal are allowed to react and to derivatize BE to n-propyl COC. In the other aliquot, 4-fluorobenzoyl chloride, pyridine, and benzene are used to derivatize EME to p-fluoro-COC. COC is not affected by these reactions and may be found in either aliquot. Separation was performed on an HP 5890 GC using an HP-1 capillary column. The oven temperature was initially 100 degrees C for 1 minute, then programmed at 30 degrees/minute to a final temperature of 260 degrees C. The GC/MS was operated in the SIM mode, and the masses monitored were 303, 321, and 331 respectively for COC and derivatized EME and BE, and 308, 324, and 334 for the respective deuterated internal standards. The assay showed a minimum linear range of 0.05-2.0 mg/L for COC and 0.10-4.0 mg/L for each of the metabolites.

1. Beagle dogs were chronically treated with cocaine, 5 mg/kg subcutaneously twice daily for 6 weeks, followed by same dose of [3H]cocaine given intravenously. 2. The t1/2 values of cocaine in plasma, liver, spleen and heart, in acutely and chronically treated dogs, were: 1-2, 1-1; 2-2, 1-8; 1-8, 1-3; 2-0, 1-2 h, respectively. In both groups, cocaine disappeared from all areas of the central nervous system 12-24 h after injection but significant amounts of radioactivity due to benzoylnorecgonine and benzoylecgonine persisted in the CNS even 1 week after administration of cocaine. Brain-to-plasma ratios of cocaine were lower in chronically-treated than in acutely-treated dogs 2 and 4 h after injection. 3. Norcocaine, benzoylnorecgonine, benzoylecgonine and ecgonine were metabolites of cocaine in dog brain in both groups. Norcocaine and benzoylnorecgonine were present in higher amounts in brains of chronically treated dogs. Rate of disappearance of norcocaine was similar to cocaine in both groups. 4. The amounts of cocaine excreted in urine and faeces as percentage of dose were 0-9-5-0, 1-1-6 in the acute and 2-2-3-3 and 0-2-0-3 in the chronically treated dogs. Major excretion of radiactivity occurred in urine within 24 h in both groups. Total radioactivity (65% of dose) in urine plus faeces was similar in both groups. 5. Norcocaine, benzoylnorecgonine, benzoylecgonine, ecgonine, norecgonine, ecgonine methyl ester and unidentified compounds were urinary metabolites of cocaine in both groups. Benzoylnorecgonine and ecgonine were excreted in higher amounts and benzoylecgonine and norecgonine in lower amounts in the acute than in the chronically treated dogs. 6. The possible role of persistence of benzoylnorecgonine and benzoylecgonine (which possessed potent stimulant activity intracisternally) in the CNS is discussed.

Cocaine is a potent vasoconstrictive agent that is currently the subject of widespread drug abuse. Because little is known of the physiologic responses to cocaine in pregnancy, the effects of intravenous cocaine on uterine blood flow and other maternal and fetal cardiovascular parameters were studied. Eight ewes in late pregnancy were equipped with electromagnetic flow probes around both uterine arteries and catheters were placed in the maternal and fetal inferior vena cavae and aortas. Bolus intravenous infusion of 0.5 and 1.0 mg/kg of maternal body weight achieved peak plasma cocaine levels similar to those observed in human subjects after abuse of the drug (mean level = 229 to 400 ng/ml, n = 8). After bolus infusion of 0.5 or 1.0 mg/kg of cocaine, mean maternal arterial pressure increased 32% and 37%, respectively (p less than 0.005). Fetal blood pressure rose 12.6% after a dosage of 0.5 mg/kg of cocaine. These cocaine infusions significantly decreased uterine blood flow by 36% and 42% for a duration of 15 minutes (p less than 0.005). Analysis of maternal catecholamine responses demonstrated a significant (210%) rise in plasma norepinephrine levels after cocaine infusion. These studies demonstrate that cocaine, when administered in doses that produce plasma levels observed in humans, significantly decreases uterine blood flow for a duration of greater than or equal to 15 minutes while inducing a hypertensive response in the pregnant ewe and fetus.

Serum, plasma, and postmortem blood treated with two volumes of N,N-dimethylformamide (DMF) and centrifuged, were directly analyzable by means of the EMIT d.a.u. reagents on the Syva Autocarousel in the same manner as urine. Cutoff values in milligrams (immunochemically cross-reactive analyte equivalents)/L are 0.05 for morphine (MOR), 0.15 for benzoylecgonine (BZE), 0.20 for oxazepam (OX), and 0.02 for 11-nor-delta 9-tetrahydrocannabinol carboxylic acid (THCC). The relationship of concentrations (micrograms/mL serum) to absorbance changes (delta A) were S-shaped up to greater than 3.0 for MOR, 4.0 for BZE, greater than 5.0 for OX, and 0.2 for THCC. Beyond these maximal concentrations, delta A values declined. Thus, negatives should be repeated on substantially diluted aliquots to avoid missing extraordinarily high positives. "False" quantitative negative/positive noncongruence between total EMIT cross-reactives and free-drug analyses by gas chromatography/mass spectrometry (GC/MS) were 0/17 (N = 75) for opiates, 8/0 (N = 119) for cocaine products, and 19/5 (N = 103) for cannabinoids. For benzodiazepines (N = 58) the "false" negative/"false" positive ratio of EMIT (total)/high performance liquid chromatography (HPLC) (free) was 4/4. Within-day precision as coefficient of variation (CV) of quantitative estimates was 8-18%. For between-day precision, quantitative estimates varied by 8% for MOR, 15% for BZE, 18% for OX, and 34% for THCC.

Plasma cocaine levels were determined in 7 subjects after intranasal and oral cocaine. Intranasal doses of 0.19, 0.38, 0.75, 1.5, and 2.0 mg/kg were given as a 10% aqueous solution; 0.38 mg/kg was given as crystalline cocaine HCl. Oral cocaine was administered in doses of 2.0 and 3.0 mg/kg. Intranasal cocaine kinetics were described by a 1-compartment open model with 2 consecutive first-order input steps and first-order elimination. Oral cocaine disposition was described by a 1-compartment open model with a lag time followed by a single first-order input phase and first-order elimination. The mean elimination half-life (t 1/2) for cocaine by the intranasal route to 7 subjects was 75 +/- 5 min (mean +/- SE). The mean t 1/2 after oral administration to 4 subjects was 48 +/- 3 min. The relative bioavailability [as determined by the area under the concentration-time curve (AUC)] for the 2.0-mg/kg dose by the intranasal and oral routes was not different. There was a linear increase in AUC with increasing intranasal dose.

Cocaine was stable (93.6 +/- 5.0 (SD)% remaining after 120 minutes) when incubated in plasma from six patients with histories of succinylcholine sensitivity and low dibucaine numbers (phenotype A), but was rapidly hydrolyzed (40.6 +/- 6.6% remaining after 120 minutes) when incubated in plasma obtained from normal subjects (phenotype U). Intermediate decay (69.4 +/- 9.0% remaining) occurred in three heterozygous offspring of the succinylcholine-sensitive patients. Since serum cholinesterase has recently been implicated in the human metabolism of cocaine, patients who are homozygous for the atypical enzyme may be at greater risk for a toxic reaction when administered this drug. We recommend caution in using cocaine for topical anesthesia in patients with histories of succinylcholine sensitivity or low dibucaine numbers.

A simple and economical radioimmunoassay for benzoylecgonine in blood or urine is described. Haemolysis, decomposition, common anticoagulants and sodium fluoride do not affect the results. A commercially available antiserum is used at a dilution of 1:600. The tracer is radioiodinated p-hydroxybenzoylecgonine. It is prepared by reacting p-acetoxybenzoic anhydride with methyl ecgonine followed by mild hydrolysis and radioiodination by the Iodo-gen method. The product is purified on a disposable silica cartridge and has a specific activity of about 30 TBq mmol-1. Polyethylene glycol is used to separate the bound and free fractions in the assay. The range of the dose-response curve is 0-400 ng ml-1 benzoylecgonine. The assay is largely specific for benzoylecgonine. Cocaine, ecgonine, methylecgonine and cinnamoyl cocaine have slight or negligible cross-reactivities. The inter-assay coefficient of variation is 7.5% and the recovery of benzoylecgonine from 'spiked' blood is 103%. The 'cut-off' is 20 ng ml-1 benzoylecgonine for both blood and urine. Radioimmunoassay and high-performance liquid chromatography results agree well.

The distribution of cocaine and the cocaine metabolite benzoylecgonine (BE) in brain and plasma of Sprague-Dawley rat dams and their near-term fetuses was assessed 0.5 and 2 h post-injection on gestational day 20 following chronic daily subcutaneous injections of 10, 20, or 40 mg/kg/3 ml cocaine hydrochloride beginning on gestational day 8. Plasma concentrations of cocaine reached in the dams were found to be in the range of, or to exceed, those reported in human cocaine users. Dose-related increases in plasma and brain levels of cocaine in the dams and the fetuses were observed, particularly at 2 h post-injection. Fetal concentrations of cocaine in brain and plasma were approximately 2-3-fold less than those of the dams, suggesting that the placenta may somewhat restrict cocaine entry into fetal circulation. Brain/plasma cocaine ratios, however, were generally equivalent in the dams and fetuses, suggesting that once cocaine enters the circulation, its affinity for brain tissue is similar in the fetus and dam. Whereas plasma levels of BE, like cocaine levels per se, were greater in the dams than fetuses, BE concentrations in fetal brain were greater than those observed in maternal brain. These high levels of BE may contribute to the production of neurobehavioral alterations in cocaine-exposed offspring, given that this active cocaine metabolite has been shown to form molecular complexes with calcium ions (Misra and Mule 1975), thereby having the potential to influence a multiplicity of calcium-regulated developmental events.(ABSTRACT TRUNCATED AT 250 WORDS)

Cocaine (1.5 milligrams per kilogram) was applied to the nasal mucosa of human subjects. The cocaine persisted in the plasma for 4 to 6 hours and reached peak concentrations of 120 to 474 nanograms per milliliter at 15 to 60 minutes. In that residual cocaine was detectable on the nasal mucosa for 3 hours, continuous absorption secondary to its vasoconstrictive action might explain its persistence in the plasma.