Biomedical subjects

Edward J Cone

Publications and source records attributed to Edward J Cone.

At least 19 recordsLinked to original sources

PubMed2006

Opioid disposition in human sweat after controlled oral codeine administration.

BACKGROUND: Characterization of opioid excretion in sweat is important for accurate interpretation of sweat tests in drug treatment, criminal justice, and workplace drug testing programs. METHODS: Participants (n=20) received placebo, 3 low (60 mg/70 kg) or 3 high (120 mg/70 kg) codeine sulfate doses (used as a model for opioid excretion) within 1 week. Codeine and metabolites in sweat were collected with PharmChek Sweat Patches; hourly patches were applied for 1 to 15 h (n=775) and weekly patches for 7 days (n=118). Patches were analyzed by solid-phase extraction and gas chromatography-mass spectrometry for codeine, norcodeine, morphine, normorphine, and 6-acetylmorphine. Limits of quantification were 2.5 ng/patch (codeine and morphine) and 5 ng/patch (other analytes). RESULTS: Codeine was the only analyte identified in 12.6% of hourly patches and 83.3% of weekly sweat patches worn during dosing. Weekly patch concentrations (SD) were 38.6 (59.9) ng/patch [median (range), 15.9 (0-225.1) ng/patch] for low and 34.1 (32.7) ng/patch [24.0 (0-96.2) ng/patch] for high codeine doses. Codeine detected 1 week after dosing was 4.6 (5.3) ng/patch [median (range), 4.0 (0-17.1) ng/patch; n=11] after low and 7.7 (7.1) ng/patch [6.9 (0-20.5) ng/patch; n=10] after high doses. In total, 2.6% of hourly, 38.5% of low-dose, and 45.5% of high-dose weekly patches contained codeine at the proposed Substance Abuse and Mental Health Services Administration cutoff. CONCLUSIONS: Codeine was the only analyte detected, at highly variable concentrations, up to 2 weeks after dosing. These results are consistent, considering the complex processes of codeine deposition in sweat. Sweat testing is a useful alternative technique for qualitative monitoring of opioid use.

Administration, Oral↗

PubMed2006

Simultaneous quantification of methamphetamine, cocaine, codeine, and metabolites in skin by positive chemical ionization gas chromatography-mass spectrometry.

A positive chemical ionization gas chromatography-mass spectrometric method was validated to simultaneously quantify drugs and metabolites in skin collected after controlled administration of methamphetamine, cocaine, and codeine. Calibration curves (2.5-100 ng/skin biopsy) for methamphetamine, amphetamine, cocaine, norcocaine, benzoylecgonine, cocaethylene, norcocaethylene, anhydroecgonine methyl ester, morphine, codeine, and 6-acetylmorphine (5-100 ng/skin biopsy for ecgonine methyl ester and ecgonine ethyl ester) exhibited correlation coefficients >0.999 and concentrations +/-20% of target. Intra- and inter-run precisions were <10%. This procedure should be useful for postmortem analysis; data are included on drug concentrations in skin after controlled drug administration.

Calibration↗

PubMed2006

Ephemeral profiles of prescription drug and formulation tampering: evolving pseudoscience on the Internet.

The magnitude of non-therapeutic use, or misuse of prescription pharmaceuticals now rivals that of illicit drug abuse. Drug and formulation tampering enables misusers to administer higher doses by intended and non-intended routes. Perceived motives appear to be a combination of interests in achieving a faster onset and enhancing psychoactive effects. Narcotic analgesics, stimulants, and depressants are widely sought, examined, and tampered with for recreational use. This review examines tampering methods reported on the Internet for selected pharmaceutical products. The Internet provides broad and varied guidance on tampering methods that are specific to drug classes and unique formulations. Instructions are available on crushing, separating, purifying and chemically altering specific formulations to allow changes in dosage, route of administration, and time course of effects. Many pharmaceutical formulations contain features that serve as "barriers" to tampering. The nature and effectiveness of formulation barriers vary widely with many being overcome by adventurous misusers. Examples of successes and failures in tampering attempts are frequently described on Internet sites that support recreational drug use. Successful tampering methods that have widespread appeal evolve into recipes and become archived on multiple websites. Examples of tampering methods include: (1) how to separate narcotic drugs (codeine, hydrocodone, oxycodone) from excipients and non-desirable actives (aspirin, acetaminophen, ibuprofen); (2) overcoming time-release formulations (beads, layers, matrices); (3) removal of active drug from high-dose formulations (patches, pills); (4) alteration of dosage forms for alternate routes of administration. The development of successful formulations that inhibit or prevent drug/formulation tampering with drugs of abuse should take into consideration the scope and practice of tampering methods available to recreational drug users on the Internet.

Chemistry, Pharmaceutical↗

PubMed2006

Caffeine content of energy drinks, carbonated sodas, and other beverages.

The caffeine content of 10 energy drinks, 19 carbonated sodas, and 7 other beverages was determined. In addition, the variability of the caffeine content of Coca-Cola fountain soda was evaluated. Caffeine was isolated from the samples by liquid-liquid extraction and analyzed by gas chromatography with nitrogen-phosphorus detection. The caffeine concentration of the caffeinated energy drinks ranged from none detected to 141.1 mg/serving. The caffeine content of the carbonated sodas ranged from none detected to 48.2 mg/serving, and the content of the other beverages ranged from < 2.7 to 105.7 mg/serving. The intra-assay mean, standard deviation, and % coefficient of variation for the Coca-Cola fountain samples were 44.5, 2.95, and 6.64 mg/serving, respectively.

Caffeine↗

PubMed2006

Effect of repeated cocaine administration on detection times in oral fluid and urine.

Detection times reported for single-dose studies may not predict detection times following repeated cocaine dosing. Although repeated cocaine administration can result in drug accumulation and extended excretion time, there is a paucity of data from controlled dosing studies with repeated drug administration. We compared detection times for cocaine and benzoylecgonine (BZE) in oral fluid and BZE in urine following single and repeated cocaine dosing. Two groups of cocaine-experienced subjects participated in these studies. The single-dose group received cocaine by intravenous, intranasal, and smoked administration. The repeated dose group received daily escalating oral cocaine doses culminating in a total of 1,250-2,000 mg. Oral fluid and urine specimens following the last dosing were analyzed by gas chromatography-mass spectrometry. Detection times were determined as the time to the last positive specimen. The effect of repeated dosing was to extend oral fluid detection times for cocaine approximately fourfold and BZE detection times sevenfold, whereas urine BZE detection times were extended twofold. Because cocaine abusers frequently self-administer higher and repeated doses, we conclude that the short detection times observed in single-dose studies underestimate the utility of oral fluid for detection of cocaine abuse in realistic settings.

Adult↗

PubMed2006

Major and minor metabolites of cocaine in human plasma following controlled subcutaneous cocaine administration.

Cocaine is rapidly metabolized to major metabolites, benzoylecgonine (BE) and ecgonine methyl ester (EME), and minor metabolites, norcocaine, p-hydroxycocaine, m-hydroxycocaine, p-hydroxybenzoylecgonine (pOHBE), and m-hydroxybenzoylecgonine. This IRB-approved study examined cocaine and metabolite plasma concentrations in 18 healthy humans who provided written informed consent to receive low (75 mg/70 kg) and high (150 mg/70 kg) subcutaneous cocaine hydrochloride doses. Plasma specimens, collected prior to and up to 48 h after dosing, were analyzed by gas chromatography-mass spectrometry (2.5 ng/mL limits of quantification). Cocaine was detected within 5 min, with mean+/-SE peak concentrations of 300.4+/-24.6 ng/mL (low) and 639.1+/-56.8 ng/mL (high) 30-40 min after dosing. BE and EME generally were first detected in plasma 5-15 min post-dose; 2-4 h after dosing, BE and EME reached mean maximum concentrations of 321.3+/-18.4 (low) and 614.7+/-46.0 ng/mL (high) and 47.4+/-3.0 (low) and 124.4+/-18.2 ng/mL (high), respectively. Times of last detection were BE>EME>cocaine. Minor metabolites were detected much less frequently for up to 32 h, with peak concentrations<or=18 ng/mL for all analytes except pOHBE (up to 57.7 ng/mL). These data improve our knowledge of the pharmacokinetics of cocaine and its major and minor metabolites in plasma following controlled subcutaneous cocaine administration.

Adult↗

PubMed2006

Caffeine content of decaffeinated coffee.

Caffeine is the most widely consumed drug in the world with coffee representing a major source of intake. Despite widespread availability, various medical conditions necessitate caffeine-restricted diets. Patients on certain prescription medications are advised to discontinue caffeine intake. Such admonition has implications for certain psychiatric patients because of pharmacokinetic interactions between caffeine and certain anti-anxiety drugs. In an effort to abstain from caffeine, patients may substitute decaffeinated for caffeinated coffee. However, decaffeinated beverages are known to contain caffeine in varying amounts. The present study determined the caffeine content in a variety of decaffeinated coffee drinks. In phase 1 of the study, 10 decaffeinated samples were collected from different coffee establishments. In phase 2 of the study, Starbucks espresso decaffeinated (N=6) and Starbucks brewed decaffeinated coffee (N=6) samples were collected from the same outlet to evaluate variability of caffeine content of the same drink. The 10 decaffeinated coffee samples from different outlets contained caffeine in the range of 0-13.9 mg/16-oz serving. The caffeine content for the Starbucks espresso and the Starbucks brewed samples collected from the same outlet were 3.0-15.8 mg/shot and 12.0-13.4 mg/16-oz serving, respectively. Patients vulnerable to caffeine effects should be advised that caffeine may be present in coffees purported to be decaffeinated. Further research is warranted on the potential deleterious effects of consumption of "decaffeinated" coffee that contains caffeine on caffeine-restricted patients. Additionally, further exploration is merited for the possible physical dependence potential of low doses of caffeine such as those concentrations found in decaffeinated coffee.

Caffeine↗

PubMed2006

Oral fluid testing: new technology enables drug testing without embarrassment.

Drug abuse is a widespread problem across society, and its negative impact on performance and safety in the workplace cannot be overstated. Even as abuse of older, illicit drugs such as heroin, cocaine, marijuana, and amphetamines persists, new mind-altering chemicals continue to emerge, contributing to an ever-changing landscape of drug abuse and its physical and psychological consequences. Abuse of multiple drugs, and the combined use of alcohol and illicit and prescription drugs, have become increasingly common. The growing and continually evolving problem of drug abuse demands novel strategies for drug testing that reliably and reproducibly detect drugs of abuse, offer an effective solution to persistent problems related to test accuracy and the potential for sample adulteration and substitution, and speak to the growing concerns over issues of individual privacy. Oral fluid testing is a reliable, new technology that overcomes many of the problems of older methods for drug detection.

Cocaine↗

PubMed2005

Disposition of cocaine and its metabolites in human sweat after controlled cocaine administration.

BACKGROUND: Sweat testing is a noninvasive technique for monitoring drug exposure in treatment, criminal justice, and employment settings. METHODS: We evaluated cocaine excretion in 9 participants' sweat after they received 3 low doses (75 mg/70 kg) of cocaine HCl subcutaneously within 1 week and, 3 weeks later, 3 high doses (150 mg/70 kg). Six additional participants completed portions of the study. PharmChek sweat patches (n = 1390) were collected throughout a 3-week washout period, reflecting previously self-administered drugs, and during and after controlled dosing. RESULTS: Cocaine was the primary analyte detected with 24% of patches positive at the gas chromatography-mass spectrometry limit of quantification of 2.5 ng/patch and 7% of patches at the proposed Substance Abuse and Mental Health Services Administration cutoff of 25 ng/patch. Ecgonine methyl ester (EME) was detected more often and at generally higher concentrations than benzoylecgonine. In patches containing both metabolites, there was no statistically significant difference in the benzoylecgonine/EME ratio based on length of patch wear. During washout, 2 participants' weekly patches tested positive (> or =25 ng/patch) during the first week; one remained positive during week 2; and none were positive during week 3. Cocaine and EME were detectable within 2 h; benzoylecgonine was not detected until 4-8 h after low doses and slightly sooner after high doses. The majority of drug was excreted within 24 h. Over 70% of weekly patches worn during low doses were positive for cocaine (> or =25 ng/patch), increasing to 100% during high doses. CONCLUSION: Sweat testing is an effective and reliable method of monitoring cocaine exposure.

Adult↗

PubMed2005

Intravenous butyrylcholinesterase administration and plasma and brain levels of cocaine and metabolites in rats.

Butyrylcholinesterase is a major cocaine-metabolizing enzyme in humans and other primates, catalyzing hydrolysis to ecgonine methylester. Increasing butyrylcholinesterase activity may be a treatment for cocaine addiction. We evaluated the effect of 30-min pretreatment with horse-derived butyrylcholinesterase (5-15,000 U i.v.) or with the selective butyrylcholinesterase inhibitor cymserine (10 mg/kg i.v.) on the metabolism of cocaine (17 mg/kg i.p.) in anesthetized rats. Venous blood samples were collected for two hours after cocaine administration and later assayed for cocaine and metabolites by gas chromatography/mass spectroscopy. Whole brains were collected after the last blood sample and similarly assayed. Butyrylcholinesterase significantly increased plasma and brain ecgonine methylester levels and decreased cocaine plasma half-life from 26.2 min (saline) to 16.4 min (15,000 U). Butyrylcholinesterase had no significant effect on plasma or brain cocaine or benzoylecgonine levels. Cymserine had no effect on any variable. These findings suggest that butyrylcholinesterase treatment may have benefits in enhancing cocaine metabolism and in increasing levels of ecgonine methylester, which may have a protective action against cocaine.

Animals↗

PubMed2005

Dose-related distribution of codeine, cocaine, and metabolites into human hair following controlled oral codeine and subcutaneous cocaine administration.

Hair testing for the determination of drug exposure has many useful applications. Drug incorporated into hair can be found for extended periods following drug exposure. There are few controlled drug administration studies investigating drug distribution into human hair. Ten volunteers participated in a 10-week controlled cocaine and codeine administration study while residing in the secure research ward. Weekly hair samples were collected by electric razor. During the low-dose week (week 4), volunteers received 75 mg/70 kg cocaine subcutaneously and 60 mg/70 kg codeine orally on alternating days, a total of three doses for each drug. Similarly, during week 7, volunteers received three doses 150 mg/70 kg cocaine and 120 mg/70 kg codeine. Maximum hair concentrations (C(max)) were found 1 to 3 weeks after low and high doses. Dose-related C(max) values of cocaine, benzoylecgonine, ecgonine methyl ester, norcocaine, cocaethylene, and codeine were found following low and high doses. Hair analysis was performed using liquid chromatography tandem mass spectrometry. A positive linear relationship was found between total melanin content of hair and C(max) of codeine, cocaine, and metabolites following high dosing. This study demonstrated dose-related concentrations of cocaine and metabolites in human hair following controlled cocaine administration. These data are the first demonstrating melanin-related incorporation of cocaine and metabolites into human hair following controlled cocaine administration.

Administration, Oral↗

PubMed2005

Passive cannabis smoke exposure and oral fluid testing. II. Two studies of extreme cannabis smoke exposure in a motor vehicle.

Two studies were conducted to determine if extreme passive exposure to cannabis smoke in a motor vehicle would produce positive results for delta-tetrahydrocannabinol (THC) in oral fluid. Passive exposure to cannabis smoke in an unventilated room has been shown to produce a transient appearance of THC in oral fluid for up to 30 min. However, it is well known that such factors as room size and extent of smoke exposure can affect results. Questions have also been raised concerning the effects of tobacco when mixed with marijuana and THC content. We conducted two passive cannabis studies under severe passive smoke exposure conditions in an unventilated eight-passenger van. Four passive subjects sat alongside four active cannabis smokers who each smoked a single cannabis cigarette containing either 5.4%, 39.5 mg THC (Study 1) or 10.4%, 83.2 mg THC (Study 2). The cigarettes in Study 1 contained tobacco mixed with cannabis; cigarettes in Study 2 contained only cannabis. Oral fluid specimens were collected from passive and active subjects with the Intercept Oral Specimen Collection Device for 1 h after smoking cessation while inside the van (Study 1) and up to 72 h (passive) or 8 h (active) outside the van. Additionally in Study 1, Intercept collectors were exposed to smoke in the van to assess environmental contamination during collection procedures. For Study 2, all oral fluid collections were outside the van following smoking cessation to minimize environmental contamination. Oral samples were analyzed with the Cannabinoids Intercept MICRO-PLATE EIA and quantitatively by gas chromatography-tandem mass spectrometry (GC-MS-MS). THC concentrations were adjusted for dilution (x 3). The screening and confirmation cutoff concentrations for THC in neat oral fluid were 3 ng/mL and 1.5 ng/mL, respectively. The limits of detection (LOD) and quantitation (LOQ) for THC in the GC-MS-MS assay were 0.3 and 0.75 ng/mL, respectively. Urine specimens were collected, screened (EMIT, 50 ng/mL cutoff), and analyzed by GC-MS-MS for THCCOOH (LOD/LOQ = 1.0 ng/mL). Peak oral fluid THC concentrations in passive subjects recorded at the end of cannabis smoke exposure were up to 7.5 ng/mL (Study 1) and 1.2 ng/mL (Study 2). Thereafter, THC concentrations quickly declined to negative levels within 30-45 min in Study 1. It was found that environmentally exposed Collectors contained 3-14 ng/mL in Study 1. When potential contamination during collection was eliminated in Study 2, all passive subjects were negative at screening/confirmation cutoff concentrations throughout the study. Oral fluid specimens from active smokers had peak concentrations of THC approximately 100-fold greater than passive subjects in both studies. Positive oral fluid results were observed for active smokers 0-8 h. Urine analysis confirmed oral fluid results. These studies clarify earlier findings on the effects of passive cannabis smoke on oral fluid results. Oral fluid specimens collected in the presence of cannabis smoke appear to have been contaminated, thereby falsely elevating THC concentrations in oral fluid. The risk of a positive test for THC was virtually eliminated when specimens were collected in the absence of THC smoke.

Adolescent↗

PubMed2005

Relationship between plasma and oral fluid nicotine concentrations in humans: a pilot study.

The relationship between plasma and oral fluid concentrations of nicotine after infusion at varying times was investigated. Five healthy human volunteers were administered 0, 0.75, and 1.5 mg nicotine as 0.5-, 1.0-, 2.5-, and 5-minute infusions. Blood and oral fluid were collected before drug administration and for 4 hours thereafter. Nicotine concentrations were determined by HPLC using a limit of quantification of 1 ng/mL. Plasma nicotine concentrations were dose related. Peak plasma concentrations (mean+/-SD) at the 4 infusion times were 14.1+/-5.5, 11.8+/-5.3, 12.8+/-1.9, and 11.5+/-4.0 ng/mL (N=5) after the 0.75-mg dose and 26.3+/-11.7, 19.3+/-12.8, 24.54+/-10.4, and 19.02+/-6.5 ng/mL after the 1.5-mg dose. In general, the highest peak concentration occurred at the shortest infusion time at each dose. Peak nicotine oral fluid concentrations (mean+/-SD) at the 4 infusion times of 22.4+/-29.1, 22.64+/-29.9, 19.1+/-13.5, and 49.1+/-31.7 ng/mL (n=5) after the low dose and 35.8+/-21.1, 26.0+/-7.7, 33.3+/-28.8, and 104.0+/-68.9 ng/mL, after the 1.5 mg dose. The highest oral fluid concentration of nicotine occurred at the longest infusion time at each dose. Oral fluid/plasma were >1 for up to 60 minutes after the low dose and 120 minutes after the high dose. There was no correlation between plasma and oral fluid nicotine concentrations.

Adult↗

PubMed2004

Relationship of Delta 9-tetrahydrocannabinol concentrations in oral fluid and plasma after controlled administration of smoked cannabis.

Understanding the relationship of Delta(9)-tetrahydrocannabinol (THC) concentrations in oral fluid and plasma is important in interpretation of oral fluid test results. Current evidence suggests that THC is deposited in the oral cavity during cannabis smoking. This "depot" represents the primary or sole source of THC found when oral fluid is collected and analyzed. In this research, oral fluid and plasma specimens were collected from six subjects following smoking of cannabis cigarettes containing 1.75% and 3.55% THC. There was at least one week between each cannabis administration. Plasma specimens were analyzed by gas chromatography-mass spectrometry (GC-MS) and paired oral fluid specimens were analyzed by radioimmunoassay (RIA). In addition, one individual's oral fluid specimens were also analyzed by GC-MS. These data are unique in that they represent simultaneous or near simultaneous collection of oral fluid and plasma specimens in subjects following controlled cannabis dosing. The first oral fluid specimen, collected from one subject at 0.2 h following initiation of smoking, contained a THC concentration of 5800 ng/mL (GC-MS). By 0.33 h, the THC concentration in oral fluid had fallen to 81 ng/mL. From approximately 0.3 h through 4.0 h, the mean (+/- SD) THC ratio of oral fluid to plasma THC concentrations was 1.18 (0.62) with a range of 0.5 to 2.2. Within 12 h, both oral fluid and plasma THC concentrations generally declined below 1 ng/mL. RIA analyses of oral fluid specimens for six subjects demonstrated the same pattern of initial high levels of contamination immediately after smoking, followed by rapid clearing, and a slower decline over 12 h. Mean THC oral fluid concentrations by RIA at 0.2 h were 864 ng/mL and 4167 ng/mL compared to plasma concentrations of 52 ng/mL and 230 ng/mL at 0.27 h following the low- and high-dose cannabis cigarettes, respectively. The similarity in oral fluid and plasma THC concentrations following the dissipation of the initial "contamination" indicates the likelihood of a physiological link between these specimens. Recent studies have shown that sublingual or transmucosal administration of pure THC results in direct absorption of intact THC into the bloodstream, thereby bypassing the gastrointestinal tract. The current study demonstrates that THC is deposited in the oral cavity and remains for up to 24 h following cannabis smoking. The decline in THC oral fluid concentration over this time suggests that there may be absorption of THC into blood as previously shown with pure THC. Passive cannabis exposure studies appear to indicate that positive oral fluid tests for THC can occur shortly after cannabis smoke exposure, but results were negative within 1 h. Consequently, when very recent passive exposure to cannabis smoke can be ruled out, it is concluded that a positive oral fluid test provides credible evidence of active cannabis use.

Adult↗

PubMed2004

Passive cannabis smoke exposure and oral fluid testing.

Oral fluid testing for Delta(9)-tetrahydrocannabinol (THC) provides a convenient means of detection of recent cannabis usage. In this study, the risk of positive oral fluid tests from passive cannabis smoke exposure was investigated by housing four cannabis-free volunteers in a small, unventilated, and sealed room with an approximate volume of 36 m(3). Five active cannabis smokers were also present in the room, and each smoked a single cannabis cigarette (1.75% THC). Cannabis smoking occurred over the first 20 min of the study session. All subjects remained in the room for approximately 4 h. Oral fluid specimens were collected with the Intercept DOA Oral Specimen Collection Device. Three urine specimens were collected (0, 20, and 245 min). In addition, three air samples were collected for measurement of THC content. All oral fluid specimens were screened by enzyme immunoassay (EIA) for cannabinoids (cutoff concentration = 3 ng/mL) and tested by gas chromatography-tandem mass spectrometry (GC-MS-MS) for THC (LOQ/LOD = 0.75 ng/mL). All urine specimens were screened by EIA for cannabinoids (cutoff concentration = 50 ng/mL) and tested by GC-MS-MS for THCCOOH (LOQ/LOD = 1 ng/mL). Air samples were measured for THC by GC-MS (LOD = 1 ng/L). A total of eight oral fluid specimens (collected 20 to 50 min following initiation of smoking) from the four passive subjects screened and confirmed positive for THC at concentrations ranging from 3.6 to 26.4 ng/mL. Two additional specimens from one passive subject, collected at 50 and 65 min, screened negative but contained THC in concentrations of 4.2 and 1.1 ng/mL, respectively. All subsequent specimens for passive participants tested negative by EIA and GC-MS-MS for the remainder of the 4-h session. In contrast, oral fluid specimens collected from the five cannabis smokers generally screened and confirmed positive for THC throughout the session at concentrations substantially higher than observed for passive subjects. Urine specimens from active cannabis smokers also screened and confirmed positive at conventional cutoff concentrations. A biphasic pattern of decline for THC was observed in oral fluid specimens collected from cannabis smokers, whereas a linear decline was seen for passive subjects suggesting that initial oral fluid contamination is cleared rapidly and is followed by THC sequestration in the oral mucosa. It is concluded that the risk of positive oral fluid tests from passive cannabis smoke inhalation is limited to a period of approximately 30 min following exposure.

Adult↗

PubMed2004

Oxycodone involvement in drug abuse deaths. II. Evidence for toxic multiple drug-drug interactions.

Recent surveys suggest that the abuse of drugs, often in combination, is pervasive throughout society. Adverse consequences of drug abuse tend to be attributed to the single drug "most likely" to be responsible. This is frequently seen in fatality cases, particularly those involving opioids. However, it is difficult to determine the specific cause of death when multiple drugs are involved. Although enhanced toxicity of alcohol and other centrally acting drugs with opioids has been well established in animal studies, there is a paucity of data in well-controlled human studies. We evaluated 1014 fatality cases involving oxycodone (OXC) for evidence of enhanced toxicity associated with multiple drug-drug interactions. We previously reported on these cases, and we classified them by a standardized method into groups that distinguished cases unrelated to drug abuse from those related to drug abuse, cases that involved only OXC from cases involving multiple drugs, drug-induced fatalities from drug-related fatalities, and cases in which the specific drug product OxyContin (oxycodone HCl controlled-release) Tablets were identified from cases where OxyContin was not identified. Our working hypothesis was that OXC in combination with other centrally acting drugs is more toxic than OXC alone, evidenced by the finding of lower mean blood concentrations of OXC in multiple-drug-induced deaths compared to single (OXC only)-drug-induced deaths. Assessment of blood levels determined by specific assay methodology (primarily gas chromatography-mass spectrometry) in these cases provided the following mean postmortem concentrations of OXC: multiple-drug-induced deaths, OxyContin identified, 0.93 microg/mL (N = 167); multiple-drug-induced deaths, OxyContin not identified, 0.73 microg/mL (N = 579); single (OXC)-drug-induced deaths, OxyContin identified, 1.55 microg/mL (N = 12); and single (OXC)-drug-induced deaths, OxyContin not identified, 1.70 microg/mL (N = 15). Overall, mean OXC concentration trends were as follows: single (OXC)-drug-induced, drug-abuse deaths > multiple-drug-induced drug-abuse deaths > drug-related drug-abuse deaths approximately deaths unrelated to drug abuse; and deaths in which OxyContin was identified approximately deaths in which OxyContin was not identified, whether the deaths involved oxycodone alone or multiple drugs. Drug abuse patterns in the multiple-drug-induced cases were complex. Over 135 drugs that were considered to be plausibly contributory to enhanced toxicity were identified in body fluids and tissues. Evaluation of mean OXC blood concentrations in cases that contained one, two, three, four, five, and six or more contributory drugs in combination demonstrated consistently lower mean OXC concentrations than those cases in which OXC was the only drug identified. A smaller number of cases were evaluated in the multiple-drug-induced groups in which OXC was paired with a single other contributory drug. The overall mean OXC concentration for these cases was 0.71 microg/mL (N = 90) as compared to 1.64 microg/mL (N = 27) for the cases in the single drug-induced groups. The consistent finding of lower mean OXC blood levels associated with multiple-drug-induced fatalities supports the stated hypothesis that OXC in combination with other centrally active drugs is more toxic than when OXC was the only drug involved. It was concluded that in cases of multiple-drug fatalities, cause of death (COD) should not be attributed to any single drug. Rather, the unique combination of drugs, the pattern of drug use/abuse, and individual factors, such as tolerance to the respiratory depressant effects of opioids, must be taken into account in arriving at a valid COD statement.

Cause of Death↗

PubMed2004

Urinary pharmacokinetics of methamphetamine and its metabolite, amphetamine following controlled oral administration to humans.

Methamphetamine is widely abused for its euphoric effects. Our objectives were to characterize the urinary pharmacokinetics of methamphetamine and amphetamine after controlled methamphetamine administration to humans and to improve the interpretation of urine drug test results. Participants (n = 8) received 4 daily 10-mg (low) oral doses of sustained-release (d)-methamphetamine hydrochloride within 7 days. After 4 weeks, 5 participants received 4 daily 20-mg (high) oral doses. All urine specimens were collected during the study. Methamphetamine and amphetamine were measured by GC-MS/PCI. Maximum excretion rates ranged from 403 to 4919 microg/h for methamphetamine and 59 to 735 microg/h for amphetamine with no relationship between dose and excretion rate. The mean molar percentage of dose in the urine as total methamphetamine and amphetamine were 57.5 +/- 21.7% (low dose) and 40.9 +/- 8.5% (high dose). Mean urinary terminal elimination half-lives across doses were 23.6 +/- 6.6 hours for methamphetamine and 20.7 +/- 7.3 hours for amphetamine. Methamphetamine renal clearance across doses was 175 +/- 102 mL/min. The mean amphetamine/methamphetamine percentage ratio based on the area under the urinary excretion-time curve increased over time from 13.4 +/- 6.5% to 35.7 +/- 26.6%. Slow urinary excretion results in drug accumulation and increases in detection time windows. Our findings also support the presence of an active renal excretion mechanism for methamphetamine.

Administration, Oral↗

PubMed2004

Effects of high-dose intravenous buprenorphine in experienced opioid abusers.

Sublingual buprenorphine, a long-acting, partial mu-opioid agonist, is as effective as methadone in the treatment of heroin dependence, with a better safety profile due to its antagonist activity. However, the safety of therapeutic doses (8 to 16 mg) that might be diverted for intravenous (i.v.) use has not been demonstrated. To evaluate the safety and possible ceiling effects of buprenorphine administered i.v. to experienced opioid users, buprenorphine was administered to 6 nondependent opioid abusers residing on a research unit; the doses tested, in separate sessions, were 12 mg buprenorphine sublingual, i.v./sublingual placebo, and escalating i.v. buprenorphine (2, 4, 8, 12, and 16 mg). Physiologic and subjective measures were collected for 72 hours post-drug administration. Buprenorphine minimally but significantly increased systolic blood pressure. Changes in heart rate or oxygen saturation among the 7 drug conditions were not statistically significant. The mean maximum decrease in oxygen saturation from baseline was greatest for the 8-mg i.v. dose. Buprenorphine produced positive mood effects, although with substantial variability among participants. Onset and peak effects occurred earlier following i.v. administration: peak i.v. effects occurred between 0.25 and 3 hours; peak sublingual effects occurred at 3 to 7 hours. Duration of effects varied among the outcome measures. The dose-response curves were flat for most parameters, particularly subjective measures. Side effects were mild except in one participant who experienced severe nausea and vomiting after the 12-mg i.v. dose. Buprenorphine appears to have a ceiling for cardiorespiratory and subjective effects and a high safety margin even when taken by the i.v. route.

Administration, Sublingual↗