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CORK Bibliography: Absorption, Drugs

64 citations. January 1997 to present

Prepared: March 2011

Adams WL. Interactions between alcohol and other drugs. IN: Gurnack AM, ed. Older Adults' Misuse of Alcohol, Medicines, and Other Drugs. New York: Springer Publishing Co., 1997. pp. 185-205. (80 refs.)

This chapter begins with the epidemiological findings in respect to the use of alcohol among the elderly. It also discuss the mechanisms which can cause significant alcohol-drug interactions, including the process of metabolism, and aging related changes in pharmacology and absorption. The chapter also focuses upon the major adverse outcomes of alcohol-drug interactions including, altered blood levels of prescribed medications, lowered toxicity, GI system problems, and interference with the desired effects of prescribed drugs.

Benowitz NL; Herrera B; Jacob P. Mentholated cigarette smoking inhibits nicotine metabolism. Journal of Pharmacology and Experimental Therapeutics 310(3): 1208-1215, 2004. (33 refs.)

Smoking mentholated cigarettes has been suggested to convey a greater cancer risk compared with smoking nonmentholated cigarettes. Two of the possible mechanisms by which mentholated cigarette smoking could increase risk are by increasing systemic exposure to tobacco smoke toxins and by affecting the metabolism of nicotine or tobacco smoke carcinogens. To examine these possibilities, we performed a crossover study in 14 healthy smokers, one-half of whom were African-Americans and one-half whites. Subjects were randomly assigned to smoke mentholated or nonmentholated cigarettes for 1 week, then to cross over to the other type of cigarettes for another week. Subjects were confined to a Clinical Research Center for 3 days of each week, during which time blood levels of nicotine and carbon monoxide were measured throughout the day and an intravenous infusion of deuterium-labeled nicotine and cotinine was administered to determine the rate and pathways of nicotine metabolism. The systemic intake of nicotine and carbon monoxide was, on average, not affected by mentholation of cigarettes. Mentholated cigarette smoking did significantly inhibit the metabolism of nicotine ( clearance: 1289 versus 1431 ml/min, two sided, p = 0.02). Inhibition of nicotine metabolism occurred both by slower oxidative metabolism to cotinine and by slower glucuronide conjugation. Our data do not support the hypothesis that mentholated cigarette smoking results in a greater absorption of tobacco smoke toxins. Our finding of impaired metabolism of nicotine while mentholated cigarette smoking suggests that mentholated cigarette smoking enhances systemic nicotine exposure.

Bernstein DM. A review of the influence of particle size, puff volume, and inhalation pattern on the deposition of cigarette smoke particles in the respiratory tract. (review). Inhalation Toxicology 16(10): 675-689, 2004. (78 refs.)

Ventilation of the cigarette was designed to allow dilution of the cigarette smoke and thereby reduce the dose delivered to the smoker. Following the toxicological principle of dose response, a lower concentration of cigarette smoke should be associated with a lower toxicological response. However, there have been many studies reporting on the phenomenon of compensation whereby the smoker increases puff volume and/or frequency in order to obtain higher volumes of smoke. This article reviews studies of the particle size of cigarette smoke and examines, based on available literature, the associated differences in the tobacco smoke and smoking behavior and their relationship to deposition patterns in the lung. The data available indicate that particle size of the cigarette smoke does not significantly change as a function of cigarette type or smoking behavior. The cigarette smoke particle size is in the same range as the minimum deposition particle size in the lung. While varying concentrations of particles are taken into the mouth, the subsequent inhalation pattern has been reported as remaining constant and also does not appear to change significantly under different smoking types and conditions. The dynamics of what happens to the smoke in the short time it is retained in the mouth have not been studied, and this perhaps should be the subject of future investigations. The current data therefore suggest that the particle deposition pattern of the smoke within the lung would not change significantly if compensation occurs.

Bolinder G. Smokeless tobacco. A less harmful alternative? IN: Bolliger CT; Fagerstrom KO, eds. The Tobacco Epidemic. Basel: Karger, 1997. pp. 199-212. (80 refs.)

This chapter begins with an historical overview of the use of smokeless tobacco, whether snuff or chewing tobacco. While cigarette smoking has declined the use of smokeless products has risen significantly. While previously use was more common among the elderly, however, use among younger persons, especially teenagers and young adults has risen significantly. This chapter deals with the dominant products manufactured and used in the US and Europe, as opposed to the various products using in developing countries. The author reviews the types of products, nicotine absorption, dependence, and mucosal effects in the mouth. It also reviews carcinogenesis and cancer epidemiology, effects on the GI system, cardiovascular effects both acute and chronic. In conclusions it is noted that the adverse health effects are less serious than those for smokers. Nonetheless the mortality rates are higher than for non-users. Dependence is quite common and cessation is seen as being as difficult for smokeless tobacco users as is cessation among smokers.

Compton P; Ling W; Chiang NC; Moody DE; Huber A; Ling D et al. Pharmacokinetics of buprenorphine: A comparison of sublingual tablet versus liquid after chronic dosing. Journal of Addiction Medicine 1(2): 88-95, 2007. (29 refs.)

Although buprenorphine is approved for use in the outpatient treatment of opioid addiction in 2 tablet formulations, a monoproduct containing buprenorphine only (Subutex) and a buprenorphine/naloxone combination product (Suboxone), much of the clinical data that support the approval by the U.S. Food and Drug Administration were generated by using a sublingual liquid. To interpret the literature in prescribing parameters for tablet buprenorphine, this study was designed to determine steady state buprenorphine plasma levels for the 2 formulations and to assess the relative bioavailability of each. A randomized, double-blind, crossover study with dose increases was conducted during a 12-week period at an outpatient treatment clinic. Of the 184 subjects initially randomized to treatment, 133 (72.3%) were evaluated for the steady-state trough plasma concentration, 16 (8.7%) for relative bioavailability, and 31 (16.8%) for dose proportionality. At steady state, differences in the trough plasma concentrations of buprenorphine between the 2 formulations were found across all the dose levels. Average plasma concentration (Cavg) of the tablet at twice the milligram dose of the liquid was twice that of the liquid; intersubject variability was greater for the tablet. At double the dose of tablet, there is no difference in steady state plasma concentrations. The bioavailability seems equivalent for the 2 formulations across all the dose levels.

Cone EJ. Recent discoveries in pharmacokinetics of drugs of abuse. Toxicology Letters 103: 97-101, 1998. (8 refs.)

Controlled human dosing studies with drugs of abuse have revealed the importance of the chosen route of administration on the delivery of drugs to the bloodstream and to their site of action. Recently, the intranasal and smoked routes have become favored by some populations for the administration of illicit drugs. Research studies with experienced heroin and cocaine users indicated that an intranasally administered drug generally provided lower blood concentrations of drug and a slower onset of action compared to the intravenous route; however, intranasal doses are easily manipulated by the user and adequate bioavailability and desired drug effects can be achieved. In addition, the trauma of needle use is avoided and disease exposure is reduced by this route. For marijuana, the smoked route of administration has always been the preferred route. In recent studies with smoked marijuana, it was revealed that single puffs of marijuana smoke produced detectable blood concentrations of tetrahydrocannabinol, the active ingredient of marijuana. Continued smoking produced rapid increases in blood concentrations with peak concentrations and effects occurring before or near the end of smoking, demonstrating the rapidity and efficacy of the smoking route for marijuana. The smoked route has also become popular with cocaine and heroin users. This route provided equivalent peak blood concentrations and time of onset of drug effects as the intravenous route. In addition, arterial boli drug concentrations reaching the brain are likely to be higher following the smoked route compared to the intravenous route. Overall, these studies demonstrated that the smoked and intranasal routes are highly efficacious for the delivery of illicit drugs and produce a similar profile of drug action to the intravenous route of administration.

Dale O; Hoffer C; Sheffels P; Kharasch ED. Disposition of nasal, intravenous, and oral methadone in healthy volunteers. Clinical Pharmacology & Therapeutics 72(5): 536-545, 2002. (58 refs.)

Objective: Nasal administration of many opioids demonstrates rapid uptake and fast onset of action. Nasal administration may be an alternative to intravenous and oral administration of methadone and was therefore studied in human volunteers. Methods: The study was approved by the Institutional Review Board of the University of Washington, Seattle. Eight healthy volunteers (6 men and 2 women) aged 19 to 33 years were enrolled after informed written consent was obtained. Subjects received 10 mg methadone hydrochloride nasally, orally, or intravenously on 3 separate occasions in a crossover design. Nasal methadone (50 mg/mL in aqueous solution) was given as a 100-muL spray in each nostril (Pfeiffer BiDose sprayer). Blood samples for liquid chromatography-mass spectrometry analyses of methadone and the metabolite 2-ethyl-1,5- dimethyl-3,3-diphenylpyrrolinium were drawn for up to 96 hours. The methadone effect was measured by noninvasive infrared pupilometry coincident with blood sampling. Results: Nasal uptake of methadone was rapid, with maximum plasma concentrations occurring within 7 minutes. The maximum effects of intravenous, nasal, and oral methadone, on the basis of dark-adapted pupil diameter, were reached in about 15 minutes, 30 minutes, and 2 hours, respectively. The respective durations were 24, 10, and 8 hours. Both nasal and oral bioavailabilities were 0.85. Subjects reported that nasal methadone caused a burning sensation. Conclusions: Nasal administration of methadone results in rapid absorption and onset of effect and high bioavailability, which was greater than that reported for other nasal opioids, with a similar duration of effect. Nasal administration may be an alternative route of methadone administration; however, improved formulations are desirable to reduce nasal irritation.

D'Alessandro A; Benowitz NL; Muzi G; Eisner MD; Filiberto S; Fantozzi P; Montanari L; Abbritti G. Systemic nicotine exposure in tobacco harvesters. Archives of Environmental Health 56(3): 257-263, 2001. (30 refs.)

Several epidemics of nicotine intoxication have been described among tobacco harvesters; however, little is known about nicotine absorption under typical working conditions. To assess systemic nicotine absorption during a regular working shift, the authors performed an observational field study. Included in the study were 10 healthy, nonsmoking, female tobacco harvesters and a control group of 5 healthy, nonsmoking, female hospital workers. Nicotine and cotinine were measured in sequential samples of blood and urine during a regular workshift. Blood nicotine levels rose from a nadir value of 0.79 +/- 0.12 ng/ml to a peak value of 3.45 +/- 0.84 ng/ml (p <.05 [Tukey's modified t test]) in the exposed group. In the control group, levels were stable at 0.1 +/- 0.1 ng/ml (p <.01). Moreover, the mean blood nicotine level measured 3 mo following the end of exposure in 6 of 10 exposed subjects was 0.24 +/- 0.12 ng/ml (p <.01). Corresponding higher values of urine nicotine and urine cotinine were observed in the exposed versus control group (comparative p values were <.01 and <.05, respectively). Overall, tobacco harvesters absorbed approximately 0.8 mg of nicotine daily. Given that nicotine can induce adverse health effects, the authors believe that prevention of nicotine absorption in tobacco harvesters should be sought and that workers should be informed about occupational risks.

De Letter EA; Lambert WE; Bouche MPLA; Cordonnier JACM; Van Bocxlaer JF; Piette MHA. Postmortem distribution of 3,4-methylenedioxy-N,N-dimethyl-amphetamine (MDDM or MDDA) in a fatal MDMA overdose. International Journal of Legal Medicine 121(4): 303-307, 2007. (27 refs.)

In this manuscript, a newly identified compound, 3,4-methylenedioxy-N,N-dimethylamphetamine (MDDM or also called MDDA), was quantified. The substance was identified in the biological specimens of a 31-year-old man who died following a massive 3,4-methylenedioxymethamphetamine (MDMA) overdose. In addition, the postmortem distribution of the identified substance in various body fluids and tissues was evaluated. For MDDM quantitation, a formerly reported and validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method was adapted. The following quantitative results of the MDDM quantitation were obtained: Femoral blood, aorta ascendens, and right atrial blood contained 2.5, 21.7, and 11.6 ng MDDM/ml, respectively. In left and right pleural fluid and pericardial fluid, concentrations of 47.0, 21.7, and 31.9 ng/ml, respectively, were found. MDDM levels in urine, bile, and stomach contents were 42.4, 1,101, and 1,113 ng/ml, respectively. MDDM concentrations in lungs, liver, kidney, and left cardiac muscle ranged from 12.8 to 39.8 ng/g, whereas these levels were below the limit of quantitation (< LOQ) in right cardiac and iliopsoas muscle. In conclusion, for the first time, MDDM was unambiguously identified in a fatal MDMA overdose. MDDM was probably present as a synthesis by-product or impurity in the MDMA tablets, which were taken in a huge amount by the victim, or MDDM was ingested separately and prior to the MDMA overdose. A third option, i.e., the eventual formation of MDDM as a result of postmortem methylation of MDMA by formaldehyde, produced by putrefaction processes or during storage under frozen conditions, is also discussed. The MDDM levels, substantiated in various body fluids and tissues, are in line with the distribution established for other amphetamine derivatives and confirm that peripheral blood sampling, such as that of femoral blood, remains the "golden standard".

DeVeaugh-Geiss AM; Chen LH; Kotler ML; Ramsay LR; Durcan MJ. Pharmacokinetic comparison of two nicotine transdermal systems, a 21-mg/24-Hour Patch and a 25-mg/16-Hour Patch: A randomized, open-label, single-dose, two-way crossover study in adult smokers. Clinical Therapeutics 32(6): 1140-1148, 2010. (26 refs.)

Background: A comparison of the 21-mg NiQuitin patch with other marketed nicotine patches reported significant differences in pharmacokinetic profiles, even among patches of the identical labeled dose strength. The 25-mg Nicorette Invisi patch became available in the United Kingdom at the end of 2008. No published studies have directly compared the pharmacokinetic profile of this new patch with that of the 21-mg NiQuitin patch. Objectives: This study was conducted to compare the single-dose pharmacokinetics of the 21-mg/24-hour patch and the 25-mg/16-hour patch. To determine whether any pharmacokinetic differences might be related to differences in wear time, a post hoc exploratory analysis evaluated the nicotine delivery profiles of the patches under the assumption that the 21-mg patch was removed after 16 rather than 24 hours. Methods: This was a single-center, randomized, open-label, single-dose, 2-way crossover study in healthy adults who smoked >10 cigarettes per day in the 6 months before the study. Eligible subjects were housed at the study center for 2 baseline and 2 treatment sessions; no smoking was permitted during the baseline or treatment sessions. Subjects were allocated to receive either the 21-mg patch (removed after 24 hours) or the 25-mg patch (removed after 16 hours) during the first treatment session, after which they crossed over to the alternative sequence in the second treatment session. Blood samples were obtained at predetermined time points before and after patch application. The primary pharmacokinetic parameter was the AUC(0-infinity), an indication of total nicotine exposure. Secondary pharmacokinetic parameters included AUC(0-t), C-max, and T-max. Post hoc exploratory parameters were the AUC(0-16) and the AUC(0-infinity) assuming a 16-hour application time for the 21-mg patch. The differences in AUC(0-infinity), AUC(0-t), C-max, AUC(0-16), and AUC(0-infinity) assuming a 16-hour application time for the 21-mg patch were considered significant if the lower limit of the 90% CI for the geometric mean ratio (21 mg:25 mg) was >100%. Ti-max values were compared using a signed-rank test. Adverse events were elicited using a standard open-ended question on each day of confinement; spontaneously reported events were also captured. The topical effects of the patch (erythema; edema; extent of erythema/papules/pustules; self-reported pruritus) were assessed by study staff before patch application and 1 and 8 hours after patch application using a 4-point rating scale; any topical effects were recorded as adverse events. Results: Fifty otherwise healthy smokers (29 men, 21 women) were enrolled; 47 (94%) were white. Their mean (SD) age was 31.5 (9.57) years (range, 20-53 years), mean weight was 70.24 (9.56) kg (range, 51.0-95.9 kg), and mean height was 173.0 (8.02) cm (range, 156 194 cm). Subjects reported smoking between 11 and 40 cigarettes per day before the study. The AUC(0-infinity) was significantly higher for the 21-mg patch worn for 24 hours than for the 25-mg patch worn for 16 hours (382.36 vs 243.69 ng/mL.h, respectively; geometric mean ratio: 156.90%; 90% CI, 148.10%-166.23%; P < 0.001). T-max was reached significantly sooner with the 21-mg patch than with the 25-mg patch (6.0 vs 12.0 hours; P < 0.001). C-max was significantly higher for the 21-mg patch compared with the 25-mg patch (18.34 vs 16.56 ng/mL; geometric mean ratio: 110.72%; 90% CI, 104.82%-116.94%; P < 0.01). The exploratory analyses suggested that the 21-mg patch applied for 16 hours may provide greater total nicotine exposure than the 25-mg patch applied for 16 hours. Although most subjects reported adverse events (75.0% with the 21-mg patch, 89.8% with the 25-mg patch), the majority of these events were mild. Conclusions: In this single-dose study in adult smokers, the 21-mg patch was associated with significantly greater nicotine exposure compared with the 25-mg patch. The 21-mg patch provided a maximal nicotine concentration faster than did the 25-mg patch.

Evans EB. Pharmacology of inhalants. IN: Tarter RE; Ammerman RT; Ott PJ, eds. Handbook of Substance Abuse. New York: Plenum Publishing Co., 1998. pp. 255-262. (58 refs.)

This chapter considers the pharmacology of inhalants. It traces the use of inhalants back to the Greeks. Inhalants are typically categorized into four classes: volatile or organic solvents, aerosols, anesthetics, and volatile nitrites. These groups represent many chemical families and even a few therapeutic classes. A table is incorporated that sets forth the chemical constituents of 11 different types of inhalants. The pharmacological actions are considered, i.e. absorption, distribution, and metabolism, along with central nervous system effects, and the phenomena of tolerance and dependence. Although the acute depressant actions may be rapid and complete, specific organ toxicities can emerge in the face of prolonged abuse. Many inhalants and their metabolites are prototypic toxins, of the renal system, peripheral nervous system, liver. the particular organ affected depends on the particular compound used. The chapter concludes with a discussion of the mechanisms of action in the central nervous system.

Fant RV; Henningfield JE; Nelson RA; Pickworth WB. Pharmacokinetics and pharmacodynamics of moist snuff in humans. Tobacco Control 8(4): 387-392, 1999. (17 refs.)

Objective-To examine the effects of four brands of commercially available moist snuff and non-tobacco mint "snuff" on plasma nicotine concentration, heart rate, blood pressure, and subjective measures. Intervention-Four brands of moist snuff and a non-tobacco mint snuff were tested. Subjects reported to the laboratory for five experimental sessions. After baseline measurement of dependent variables, each subject placed 2 g of one of the brands of snuff (or one Skoal Bandits pouch) between the cheek and gum for 30 minutes. The subjects remained in the experimental laboratory for an additional 60 minutes. Subjects-Ten volunteers who were daily users of smokeless tobacco. Main outcome measures-Plasma nicotine concentration, cardiovascular effects, and subjective effects. Results-Large amounts of nicotine were delivered rapidly to the bloodstream. The amount of nicotine absorbed and the rate of absorption were related to the pH of the snuff product in aqueous suspension. Cardiovascular and subjective effects were related to me amount of nicotine absorbed. Conclusions-Snuff products are capable of rapidly delivering high doses of nicotine, which can lead to dependence. Long-term use of snuff can lead to a number of adverse health effects including oral cancers, cardiovascular diseases, and gingival diseases. For these reasons, it is important that the public health community considers oral snuff use as a burden on public health in the same way that cigarette smoking is recognised.

Foulds J; Russell MAH; Jarvis MJ; Feyerabend C. Nicotine absorption and dependence in unlicensed lozenges available over the counter. Addiction 93(9): 1427-1431, 1998. (6 refs.)

Aim. To demonstrate the nicotine absorption and dependence potential from unlicensed nicotine containing lozenges. Design. A single case report of dependence on nicotine lozenges, plus measurements of nicotine levels before and after consumption of eight nicotine lozenges over 2 hours in volunteers. Setting. Hospital Smokers' Clinic. Participants. One male patient suffering from schizophrenia who had consumed 150 "Stoppers" lozenges per day for the previous 5 years, plus seven non-smoker volunteers. Measurements. Blood nicotine concentration. Findings. The patient's low expired carbon monoxide level (5 p.p.m.) and high plasma nicotine (32 ng/ml) and cotinine levels (947 ng/ml) were consistent with very heavy lozenge consumption. The non-smoker volunteers obtained nicotine concentrations of around II ng/ml by consuming eight Stoppers lozenges over 2 hours. Other brands of nicotine lozenges produced lower initial levels, but also produced delayed intestinal absorption and vomiting after food consumption. Conclusion. Nicotine lozenges are a potential aid to smoking cessation but their safety, efficacy and abuse potential remain to be properly evaluated.

Frolich M; Giannotti A; Modell JH. Opioid overdose in a patient using a fentanyl patch during treatment with a warming blanket. Anesthesia and Analgesia 93(3): 647-648, 2001. (5 refs.)

Fentanyl transdermal systems (FTS) are being used effectively for treating chronic pain for which prolonged opioid use is often required. Transdermal drug delivery is marketed to be safe and to maintain plasma concentrations at a steady state. However, there is evidence that these drug delivery systems, when exposed to heat, may result in increased fentanyl release causing hypoventilation. The authors report a patient who showed classic symptoms of excessive opioids when using a FTS while an upper-body-warming blanket was used. Her medications were transdermal fentanyl (75 �g/hr), gabapentin 600 mg once daily, baclofen 5 mg three times a day, sertraline 50 mg, once daily, zolpidem as needed for insomnia, and acetaminophen/oxycodone 325 mg/5 mg, for breakthrough pain. The patient had a lumbar epidural catheter placed at L3-4 for intra- and postoperative analgesia. This case illustrates a potentially serious side effect of FTS. The sequence of events and the absence of other factors that could have resulted in the clinical scenario presented here strongly point toward the systemic effects of a fentanyl overdose. There are few case reports of adverse reactions related to the use of a fentanyl patch. This case is the first account of an actual overdose related to FTS, which occurred in the operating room in a patient whose vital signs were continuously monitored. The pharmacology of transdermal delivery systems has been studied carefully. Based on pharmacokinetic observations, the fentanyl absorption is dependent on diffusion characteristics of the patch as well as the skin. The patient's core temperature had decreased to 34.9�C with the associated skin temperature probably being lower. On exposure of the skin to the heating blanket, a significant increase in skin perfusion can be expected. The increased cutaneous perfusion is likely to result in increased systemic absorption of fentanyl from the intracutaneous fentanyl depot. Although we did not measure fentanyl plasma concentrations, we believe that this mechanism was responsible for increased systemic fentanyl levels and the observed symptoms of opioid overdose in this patient. On the basis of our experience, we recommend close perioperative monitoring of patients medicated with a FTS, particularly if external heat is applied.

Furst RT. The re-engineering of heroin: An emerging heroin "cutting" trend in New York City. Addiction Research 8(4): 357-379, 2000. (33 refs.)

The objective of this paper is to identify and to make sense out of changes in the use of adulterants and diluents found in samples of street bags of heroin collected in New York City. An analysis of the ratio of adulterants to diluents was conducted. Findings indicate that a change in the ratio of adulterants to diluents has occurred, notably, an increase in the use of adulterants from 1991-1996. This suggests that foreign producer/distributor and retail sellers are cutting heroin to psychaoctively enhance its' effect. One of the adulterants used (theophylline) has the capability of enhancing the intranasal absorption of heroin into the bloodstream; thereby enhancing the "high" of heroin and possibly hastening dependency. These findings are based on an analysis of 406 chemical assays of street bags of heroin purchased by informants for the Drug Enforcement Administration (DEA), Domestic Monitor Purities (DMP) program. In addition, ethnographic observations of injecting drug users (IDUs) and interviews with street dealers are utilized to augment forensic analysis. Change in the ratio of adulterants to diluents has implications for the marketing of heroin and may have medical and health consequences for heroin users.

Gaulier JM; Merle G; Lacassie E; Courtiade B; Haglund P; Marquet P et al. Fatal intoxications with chloral hydrate. Journal of Forensic Sciences 46(6): 1507-1509, 2001. (23 refs.)

This article reports toxicological findings in two fatalities after voluntary ingestion of chloral hydrate, a sedative-hypnotic drug. The first case, an alcohol-dependent man treated with chloral hydrate syrup to which he was dependent, was discovered comatose and in respiratory arrest. Death occurred on the 9th day of hospitalization following cerebral edema. The second case, an alcohol-dependent woman who was depressed and epileptic, was admitted to the intensive care unit with heart and respiratory failure following chloral hydrate absorption. She died 3 days later after a deep coma. In these two cases, chloral hydrate intoxication was confirmed by toxicological analysis: chloral hydrate and its major metabolite trichloroethanol were identified and determined in serum and urine using headspace capillary gas chromatography-mass spectrometry. The concentrations measured were compared with those found in previously published fatalities. The analytical method used can be proposed for both clinical and forensic cases.

Gold MS; Tabrah H; Frost-Pineda K. Psychopharmacology of MDMA (Ecstasy). Psychiatric Annals 31(11): 675-681, 2001. (29 refs.)

Greaves I; Goodacre S; Grout P. Management of drug overdoses in accident and emergency departments in the United Kingdom. Journal of Accident & Emergency Medicine 13(1): 46-48, 1996. (12 refs.)

A questionnaire consisting of 10 overdose scenarios was sent to 190 career accident and emergency staff in the United Kingdom, asking in each case how the respondents would treat a patient to prevent drug absorption. The responses showed lack of consensus in treatment methods. There was extensive use of both ipecacuanha induced emesis and gastric lavage despite a lack of experimental evidence to support these techniques.

Green JT; Evans BK; Rhodes J; Thomas GAO; Ranshaw C; Feyerabend C et al. An oral formulation of nicotine for release and absorption in the colon: Its development and pharmacokinetics. (review). British Journal of Clinical Pharmacology 48(4): 485-493, 1999. (33 refs.)

Aims: Ulcerative colitis is predominantly a disease of nonsmokers and transdermal nicotine has therapeutic value in active disease; however side-effects are troublesome. The aim of this study was to develop an oral formulation of nicotine which would be slowly released in the colon over 6 h, and to examine its pharmacokinetic profile in 12 healthy volunteers, with measurements of serum nicotine and cotinine, its principal metabolite. Methods: Nicotine was combined with a polyacrylic carbomer, Carbopol 974P which was incorporated into 13 different vehicles and their release profiles examined in vitro. The polyglycolized glyceride, Gelucire 50/13, was chosen for subsequent kinetic studies because it consistently produced a suitable release pattern which was linear. Capsules containing 3 mg nicotine, combined with carbomer in Gelucire 50/13, were coated with an acrylic resin Eudragit L; this ensured the capsule would remain intact until the ileum. On 2 separate days, 6 and 15 mg nicotine, contained in 2 and 5 capsules, respectively, were administered to 12 subjects, all nonsmokers, mean age 28 years. Serial blood measurements were taken for 36 h, serum nicotine and cotinine concentrations were measured by gas liquid chromatography. Results: There was considerable intersubject variability in the nicotine and cotinine values. Plasma nicotine levels began to rise about 4 h after ingestion of the capsules, corresponding with the oro- caecal transit time. C-max nicotine values were 2.2 and 5 ng ml(-1), obtained 7 h after the ingestion of 6 and 15 mg, respectively, of the formulation. The corresponding C-max values for cotinine were 37 and 94.4 ng ml(-1) occurring after 9-10 h. The mean for elimination half- lives in the 24 studies, including the 6 and 15 mg doses, for nicotine were 4.3+/-2.7 h and for cotinine 16.8+/-7.5 h. With 6 mg nicotine-carbomer, only 1 of 12 volunteers had possible side-effects, but with the 15 mg dose 11 out of the 12 reported adverse effects which were systemic or gastrointestinal in nature-their timing corresponded with peak serum concentrations of nicotine. Conclusions: An oral formulation of nicotine has been developed; in the ileum and colon, this becomes available for slow linear release over 6 h and delivers high concentrations of nicotine for topical effect on the colon. 6 mg Nicotine was well tolerated, whilst 15 mg gave both systemic and gastrointestinal side-effects. High concentrations of topical nicotine in the colon are achieved with relatively low systemic bioavailablity-reflected by the C-max and AUC values for nicotine. This, or comparable formulations, may be of therapeutic value in ulcerative colitis.

Harris DS; Boxenbaum H; Everhart ET; Sequeira G; Mendelson JE; Jones RT. The bioavailability of intranasal and smoked methamphetamine. Clinical Pharmacology and Therapeutics 74(5): 475-486, 2003. (33 refs.)

Background. Patients in harm-reduction treatment programs are switching from intravenous to other routes of methamphetamine (INN, metamfetamine) administration to avoid risks associated with needle use. Relatively little has been reported about the bioavailability of methamphetamine when smoked or used intranasally. Methods. Eight experienced methamphetamine users were administered smoked or intranasal methamphetamine concurrently with an intravenous dose of deuterium-labeled methamphetamine. Plasma and urine concentrations were measured for calculation of bioavailability and other pharmacokinetic parameters by noncompartmental methods. Results. Methamphetamine was well absorbed after smoking or intranasal administration, with bioavailabilities of 79% after intranasal administration and 67% of the estimated delivered dose or 37.4% of the absolute (pipe) dose after smoking. Maximum methamphetamine concentrations occurred at 2.7 and 2.5 hours after intranasal and smoked doses. The elimination half-life was similar for intravenous (11.4 hours), intranasal (10.7 hours), and smoked (10.7 hours) methamphetamine. Clearance (272 mL . h(-1) . kg(-1)), steady-state volume of distribution (4.2 L/kg), and mean residence time (16 hours) of the intravenous dose were similar to previously reported values. Dextroamphetamine (INN, dexamfetamine) half-life (all routes) was 16.2 hours. Methamphetamine and dextroamphetamine renal clearances (all routes) were about 100 and 1100 mL . h(-1) . kg(-1), respectively. Conclusions. Intranasal and smoked methamphetamine are well absorbed. Although intranasal or smoked routes may decrease the risk of transmission of blood-borne diseases, exposure to methamphetamine and the possibility of drug-related complications remain substantial.

Hart CL; Gunderson EW; Perez A; Kirkpatrick MG; Thurmond A; Comer SD et al. Acute physiological and behavioral effects of intranasal methamphetamine in humans. Neuropsychopharmacology 33(8): 1847-1855, 2008. (39 refs.)

Intranasal methamphetamine abuse has increased dramatically in the past decade, yet only one published study has investigated its acute effects under controlled laboratory conditions. Thus, the current study examined the effects of single-dose intranasal methamphetamine administration on a broad range of behavioral and physiological measures. Eleven nontreatment-seeking methamphetamine abusers (two females, nine males) completed this four-session, in-patient, within-participant, double-blind study. During each session, one of four intranasal methamphetamine doses (0, 12, 25, and 50 mg/70 kg) was administered and methamphetamine plasma concentrations, cardiovascular, subjective, and psychomotor/cognitive performance effects were assessed before drug administration and repeatedly thereafter. Following drug administration, methamphetamine plasma concentrations systematically increased for 4 h postdrug administration then declined. Methamphetamine dose dependently increased cardiovascular measures and 'positive' subjective effects, with peaks occurring approximately 5-15 min after drug administration, when plasma levels were still ascending. In addition, cognitive performance on less complicated tasks was improved by all active methamphetamine doses, whereas performance on more complicated tasks was improved only by the intermediate doses (12 and 25 mg). These results show that intranasal methamphetamine produced predictable effects on multiple behavioral and physiological measures before peak plasma levels were observed. Of interest is the dissociation between methamphetamine plasma concentrations with cardiovascular measures and positive subjective effects, which might have important implications for potential toxicity after repeated doses.

Harvey DJ. Absorption, distribution, and biotransformation of the cannabinoids. IN: Nahas GG; Sutin KM; Harvey DJ; Agurell S; Pace N; Cancro R, eds. Marihuana and Medicine. Totowa: Humana Press, Inc., 1999. pp. 91-104. (137 refs.)

This paper describes the occurrence, properties, distribution, metabolism, and excretion of the cannabinoids. Over 60 of these compounds have been identified in the plant Cannabis sativa, the major ones being the pharmacologically active -tetrahydrocannabinol (THC), its biosynthetic precursor, cannabidiol (CBD), and the degradation product, cannabinol (CBN). Once absorbed, usually by smoking, these lipophilic compounds partition into the fatty tissues of the body where they can remain for a considerable time. The half-life of the drug is measured in days or even weeks. Various estimates of the half-life in humans are discussed in the paper. All cannabinoids are good substrates for the cytochrome P450 mixed function oxidases. Biotransformation of A9-THC and its synthetic isomer, A'-THC, give mono-, di-, and tri-hydroxy metabolites and further oxidation leads to a series of acids, carbonyl compounds, and their hydroxy derivatives. Primary sites of hydroxylation in both isomers are the side-chain and the allylic carbon atoms of the alicyclic ring leading to A9-THC- 11 -oic acid as the major human metabolite from A9-THC. Lower homologues yield greater proportions of acidic metabolites, whereas higher homologs are metabolized mainly to hydroxy compounds. P-Oxidation and related oxidations of the aliphatic chain lead to a series of chain-shortened metabolites, most of which are additionally hydroxylated in the alicyclic ring or at G 11. Large species-related differences in biotransformation are seen, particularly in the sites of initial hydroxylation. Several of the monohydroxy metabolites, particularly the 11- and 3'-hydroxy THCs show comparable pharmacological activity to that of the parent drug whereas polysubstituted metabolites are inactive. Phase 11 metabolism is mainly by conjugation with glucuronic acid. Other cannabinoids are metabolised similarly. CBD yields additional metabolites as the result of hydroxylation and epoxidation of the isopropene group but CBN yields fewer metabolites as the aromatic rings do not appear to be hydroxylated. Cannabichromene and cannabigerol again show extensive, species-related hydroxylation of their alkyl chains.

Hassan TB; Pickett JA; Durham S; Barker P. Diagnostic indicators in the early recognition of severe cocaine intoxication. Journal of Accident & Emergency Medicine 13(4): 261-263, 1996. (25 refs.)

Acute cocaine intoxication is an ever increasing problem in the United Kingdom. Aggressive resuscitation linked to early diagnosis is essential in preventing death. Three cases of severe cocaine toxicity are presented to highlight certain diagnostic indicators in recognising the condition in patients presenting in a collapsed state to the accident and emergency department. Acidosis was a striking feature. The acute management of such patients is supportive and should involve methods to minimise continuing absorption.

Hendriks VM; van den Brink W; Blanken P; Bosman IJ; van Ree JM. Heroin self-administration by means of 'chasing the dragon': Pharmacodynamics and bioavailability of inhaled heroin. European Neuropsychopharmacology 11(3): 241-252, 2001. (35 refs.)

In this controlled clinical study, the bioavailability and pharmacodynamics of inhaled heroin are evaluated and compared between 'chasing the dragon' and inhalation from a heating device, and at three dose levels, 25, 50 and 100 mg heroin, in two separate study phases. In study phase I, no differences between the inhalation methods were detected on any of the physiological or behavioral measures, nor in bioavailability. Subjectively, the participants had a strong preference for the method of chasing. which was therefore used in study phase 2. In phase 2, heroin produced a dose-related increase in subjective drug-liking, body temperature and heart rate, and a clear, dose-related decline in reaction time. Linearly dose- related differences were found in the amount of total morphine in urine, amounting to an average of 45% of the parent heroin base received. Based on these findings, it is concluded that chasing is quite an effective route of heroin administration, producing rapid, dose-related subjective and objective effects and a sufficiently high and reproducible bioavailability.

Huestis M. Pharmacokinetics of THC in inhaled and oral preparations. IN: Nahas GG; Sutin KM; Harvey DJ; Agurell S; Pace N; Cancro R, eds. Marihuana and Medicine. Totowa: Humana Press, Inc., 1999. pp. 105-116. (11 refs.)

This chapter considers the absorption, distribution,, and elimination of marijuana. These are a function of a number of factors -- route of administration, for, dosage, THC is very rapidly distributed, binds to almost everything. Concentrations in blood and plasma are low due to its extensive metabolism. It is rapidly absorbed, and excretion is difficult to capture because it extends over a very long time period. Availability ranges between 18-50%, due to route of administration and the pattern of smoking if inhaled (e.g. number of puffs, time between puffs). There are 12 figures and 5 tables that summarize the information.

Huestis MA; Cone EJ. Methamphetamine disposition in oral fluid, plasma, and urine. Annals of the New York Academy of Sciences. Oral-based Diagnostics 1098(104-121), 2007. (8 refs.)

This review of the disposition of methamphetamine in oral fluid, plasma, and urine is based on a comprehensive controlled dosing study involving five healthy, drug-free research volunteers who resided on a closed clinical ward for 12 weeks. Subjects were administered four low (10 mg) and high (20 mg) daily oral doses of methamphetamine in two separate sessions. Near-simultaneous collections of oral fluid and plasma were performed on the first day of each low- and high-dose session. Thereafter, oral fluid was provided on each day of dosing by different oral fluid collection methods. All urine specimens were collected on an ad libitum basis throughout the study. Specimens were analyzed by gas-chromatography mass spectrometry for methamphetamine and the metabolite, amphetamine, with a limit of quantification of 2.5 ng/mL for each analyte. Methamphetamine and metabolite concentrations in oral fluid appeared to follow a similar time course in oral fluid as in plasma and were dose-proportional, but oral fluid concentrations exceeded plasma concentrations. Urine drug concentrations were substantially higher than those in oral fluid. Some drug accumulation was noted with daily dosing, but generally did not markedly influence detection times or detection rates of oral fluid tests. Detection times and detection rates for oral fluid and urine were determined at cessation of 4 days of dosing. Generally, detection times and rates for urine were longer than those observed for oral fluid at conventional cutoff concentrations. When contemplating selection of oral fluid as a test matrix, the advantages of oral fluid collection should be weighed against its shorter time of detection compared to that of urine.

Hunault CC; van Eijkeren JCH; Mensinga TT; de Vries I; Leenders MEC; Meulenbelt J. Disposition of smoked cannabis with high Delta(9)-tetrahydrocannabinol content: A kinetic model. Toxicology and Applied Pharmacology 246(3): 148-153, 2010. (26 refs.)

Introduction: No model exists to describe the disposition and kinetics of Inhaled cannabis containing a high THC dose. We aimed to develop a kinetic model providing estimates of the THC serum concentrations after smoking cannabis cigarettes containing high THC doses (up to 69 mg THC). Methods. Twenty-four male non-daily cannabis users smoked cannabis cigarettes containing 293 mg, 49 1 fig, and 69 4 mg THC Blood samples were collected over a period of 0-8 h and serum THC concentrations were measured. A two-compartment open model was fitted on the individual observed data. Results: Large inter-individual variability was observed in the pharmacokinetic parameters. The median pharmacokinetic parameters generated by the model were C-max = 175 ng/mL, T-max = 14 min, and AUC(0-8h) = 8150 ng x min/mL for the 69 4 mg THC dose Median model results show an almost linear dose response relation for C-max/Dose = 2.8 x 10(-6)/mL and AUC(0-8h)/Dose = 136 x 10(-6) min/mL. However, for increasing dose level, there was a clear decreasing trend C-max/Dose = 3 4, 2.6 and 2 5 x 10(-6)/mL and AUC(0-8h)/Dose = 157, 133 and 117 x 10(-6) min/mL for the 29 3, 49.1 and 69 4 mg dose, respectively. Within the restriction of 8 h of observation, the apparent terminal half life of THC was 150 min. Conclusion: The model offers insight into the pharmacokinetics of THC in recreational cannabis users smoking cannabis containing high doses of THC mixed with tobacco. The model is an objective method for providing serum THC concentrations up to 8 h after smoking cannabis with a high THC content (up to 23%).

Jenkins AJ; Cone EJ. Pharmacokinetics, drug absorption, distribution, and elimination. IN: Karch SB, ed. Drug Abuse Handbook. Boca Raton FL: CRC Press, 1998. pp. 151-202. (141 refs.)

This chapter considers the pharmacokinetics of the major drug classes. It begins with a review of basic concepts and models, including transfer across biological membrane, biotransformation, elimination, and pharmacokinetic parameters, dosage regimens and therapeutic drug monitoring, and factors affecting pharmacokinetics parameters. The remainder of the chapter reviews the pharmacokinetics of specific drugs: amphetamines, methamphetamines, barbiturates, benzodiazepines, cocaine, LSD, opiates, marijuana, morphine and phencyclidine, reviewing the pharmacology, absorption, distribution, and the metabolism and excretion of each.

Jones AW; Karlsson L. Relation between blood- and urine-amphetamine concentrations in impaired drivers as influenced by urinary pH and creatinine. Human and Experimental Toxicology 24(12): 615-622, 2005. (15 refs.)

Amphetamine undergoes extensive renal excretion and significant amounts are present in urine as the unchanged parent drug. This prompted us to investigate whether a quantitative relationship existed between blood and urine concentrations of amphetamine in the body fluids of drug-impaired drivers apprehended in Sweden, where this stimulant is the major drug of abuse. The relationship between blood and urine concentrations of amphetamine was determined by multivariate analysis with urinary pH and creatinine as predictor variables. Amphetamine was determined in blood and urine by gas chromatography-mass spectrometry with deuterium-labelled internal standards. The concentration of amphetamine in urine was about 200 times greater than the concentration in blood; the mean and median urine/blood ratios were 214 and 160, respectively, with large individual variations. The Pearson correlation coefficient between urine (y) and blood (x) amphetamine was r = 0.53, n = 48, which was statistically highly significant (P < 0.001), although the residual standard deviation (SD) was large (+/- 181 mg/L). The correlation coefficient increased (r = 0.60) when the concentration of amphetamine in urine was normalized for dilution by dividing with the creatinine content. When urinary pH and creatinine were both included as predictor variables, the correlation coefficient was even higher (r = 0.69), now explaining 48% (r(2) = 0.48) of the variation in urine-amphetamine concentration. However, the partial regression coefficient for creatinine (53 +/- 28.7) was not statistically significant (t = 1.85, P > 0.05), whereas the corresponding regression coefficient for pH was highly significant and had a negative sign (-102 +/- 32.6, t = -3.12, P < 0.005). Other factors could impact on the urine-blood amphetamine relationship, such as route of administration, pattern of voiding and time elapsed after use of the drug.

Kalasinsky KS. Drug distribution in human hair by infrared microscopy. Cellular and Molecular Biology 44(1): 81-87, 1998

Localization of drug metabolites within human hair is important in determining the pharmacokinetics of drug incorporation in hair. This information is critical to validate drug testing data from hair. Microspectroscopic probing of small areas within longitudinally microtomed hair sections provides a profile of the deposition of drug along a growth line and thus indicates localization as a function of time. Probing across individual hairs may reveal the hydrophobic/hydrophilic characteristics of the substance. Hydrophobic drugs tend to bind to the central core or medulla of the hair while hydrophilic drugs tend to be spread throughout the cortex of the hair and appear, generally, in lower concentrations per dose. Profiles of distribution with high spatial resolutions of the regions of the hair are necessary for these determinations. This information is available to a certain extent in normal infrared microscopy and enhanced in synchrotron powered infrared microscopy.

Kashuba ADM; Nafzinger AN. Physiological changes during the menstral cycle and their effects on the pharmacokinetics and pharmacodynamics of drugs. (review). Clinical Pharmacokinetics 34(2): 203-218, 1998. (131 refs.)

There is an increasing awareness that the exclusion of women from clinical trials may lead to inaccurate application of drug therapy in women. Gender and estrus cycle differences in the pharamacokinetics and pharamacodynamics of drugs in animals have been appreciated for over 60 years, but investigation into these differences in humans has only recently occurred. It is postulated that the hormonal fluctuations within the menstrual cycle phase may be a primary cause of documents gender differences in the pharmacokinetics and pharmacodynamics of drugs. Existing data suggests that menstrual cycle variations do occur in renal, cardiovascular, haematological and immune systems. These physiological changes could potentially impact on the pharmacokinetics of pharmacodynamics of drugs by altering properties, such as protein binding of the volume of distribution, and thereby causing significant effects at various times during the menstrual cycle. However, systematic investigations of physiological variability throughout the menstrual cycle are limited. Fluctuations in symptom severity and clinical course coinciding with the menstrual cycle phase have been seen in some diseases. Hormonal fluctuations within the menstrual cycle have been postulated to cause disease exacerbation. They may also worsen disease severity by impacting on the pharamcokinetics or pharamcodynamics of the medication. Menstrual cycle hormonal changes may influence drug absorption, distribution, metabolism or excretion. In vivo data to demonstrate an effect of endogenous estrogen or progesterone on pharamcokinetics are limited and contradictory. Systematic investigations of specific pharmacokinetic and pharmarcodynamic changes within the menstrual cycle are lacking. Most published studies have been conducted with small numbers of women and a limited numbers of menstrual cycle phases within 1 menstrual cycle. These design problems have resulted in incomplete data for assessing the effects of the menstrual cycle. To date, there are no demonstrated clinically significant changes that occur in the absorption, distribution or elimination of drugs. With respect to drug metabolism, data are exceedingly sparse and have been collected in suboptimal fashion. Standardisation of study design and analyses in systematic investigations of the influence of the menstrual cycle on drug pharamcokinetics and pharamcodynamics are needed.

Liao BS; Hilsinger RL Jr; Rasgon BM; Matsuoka K; Adour KK. A preliminary study of cocaine absorption from the nasal mucosa. Laryngoscope 109(1): 98-102, 1999. (11 refs.)

Objective/Hypothesis: To determine factors affecting the safe use of topical cocaine for anesthesia and vasoconstriction during rhinologic surgery. Study Design: Prospective, randomized study of the kinetics of cocaine absorption through human nasal mucosa in 12 consecutive patients without nasal mucosal disease who were having septoplasty or septorhinoplasty. Methods: With patients under general anesthesia, cocaine was applied topically to each nasal cavity by using cottonoid pledgets. Group I received 4 mL of a 4% solution (160 mg) of cocaine for 10 min, Group II received 4 mt of a 4% solution (160 mg) of cocaine for 20 min, and Group Ill received 4 mL of a 10% solution (400 mg) of cocaine for 20 min. Absorption rate was determined by measuring serum cocaine concentration at intervals of 5, 10, 15, and 20 min. Residual cocaine was extracted from the pledgets and was analyzed quantitatively by using gas chromatography and mass spectroscopy, Results: Of total cocaine applied, 35% was absorbed systemically: 17% was absorbed within 5 min, 25% within 10 min, and 32% within 15 min, Of the cocaine absorbed, 47% was absorbed within the first 5 min, 70% within 10 min, and 90% within 15 min. Two patients (16.6%), both in Group III, had intraoperative hypertension; one of these patients also had transient ventricular tachycardia Conclusions: Although a 4% solution of cocaine applied to the nasal mucosa on cottonoid pledgets for 20 min is safe, we observed an idiosyncratic absorption rate four times greater than expected; therefore, we advise against topical use of a 10% cocaine solution for anesthesia and vasoconstriction during rhinologic surgery.

Liguori A; Hughes JR; Grass JA. Absorption and subjective effects of caffeine from coffee, cola and capsules. Pharmacology, Biochemistry and Behavior 58(3): 721-726, 1997. (32 refs.)

Coffee is often perceived as producing greater pharmacological effects than cola. The present study compared the magnitude and rapidity of peak caffeine levels and subjective effects between coffee and cola. Thirteen users of both coffee and cola (mean daily caffeine consumption = 456 mg) ingested 400 mg caffeine via 12 oz unsweetened coffee, 24 oz sugar-free cola or 2 capsules in a random, double-blind, placebo-controlled, within-subjects design. Subjects provided a saliva sample and completed subjective effect scales 15 min before and 30, 60, 90, 120, 180 and 240 min after ingestion. Mean peak saliva caffeine levels did not differ between coffee (9.7 +/- 1.2 mu g/ml) and cola (9.8 +/- 0.9 mu g/ml) and appeared to be greater with these beverages than with the capsule (7.8 +/- 0.6 mu g/ml; p = NS). Saliva caffeine levels peaked at similar times for coffee (42 +/- 5 min) and cola (39 +/- 5 min) but later for capsule (67 +/- 7 min; p = 0.004). There was no main effect of vehicle or interaction of vehicle and drug on magnitude of peak effect or time to peak increase on self-report scale's. In summary, peak caffeine absorption, time to peak absorption, and subjective effects do not appear to be influenced by cola vs. coffee vehicle. Perceived differences in the effects of coffee vs. cola may be due to differences in dose, time of day, added sweetener, environmental setting or contingencies.

Littleton J; Little H. Interactions between alcohol and nicotine dependence: A summary of potential mechanisms and implications for treatment. Alcoholism: Clinical and Experimental Research 26(12): 1922-1924, 2002. (8 refs.)

This article summarizes the potential mechanisms which underlie the interactions between alcohol and nicotine dependence. There is discussion of pharmacokinetic interactions that influence metabolism, absorption, and distribution. Also liver metabolism of both drugs may be altered through cytochrome induction after long-term exposure to both. There are also factors at the molecular level that need be considered, the impact on various neurotransmitters, and alcohol's effects on nicotinic receptors. It is also noted that, in contradistinction to the view that specific mechanisms are causal to the use of both drugs, there is the view that the phenomenon may be more indicative of a functional interaction. For example, possibly the cognitive enhancing effects of nicotine may offset the cognitive inhibition resulting from alcohol use. The role of conditioning in this phenomenon is reviewed. The author notes in conclusion, that whatever the basis the strength of dependence is greater among co-abusers.

Liu RH; Liu HC; Lin DL. Distribution of methylenedioxymethamphetamine (MDMA) and methylenedioxyamphetamine (MDA) in postmortem and antemortem specimens. Journal of Analytical Toxicology 30(8): 545-550, 2006. (15 refs.)

With increasing requests for the analysis of various specimens related to fatal and non-fatal abuse of methylenedioxymethamphetamine (ecstasy, MDMA), the toxicology laboratory of the Institute of Forensic Medicine has established protocols for the analysis of MDMA and related compounds in hair, urine, and various postmortem specimens. Analytical protocols include extraction, derivatization, and gas chromatographic-mass spectrometric analysis adapting deuterated analogs of the analytes as internal standards. Data resulting from these analyses and hereby reported include postmortem distribution of MDMA and methylenedioxyamphetamine (MDA) in heart blood, gastric content, urine, and bile specimens from 20 fatal cases; other drugs found in the heart blood from these 20 cases; and the distribution of MDMA and MDA in 25 antemortem urine and 6 hair specimens. The MDA/MDMA concentration ratio observed in a limited number of hair specimens (n=6) are consistent and appear to be higher than those found in other specimens. Compared to other commonly abused drugs (e.g., cocaine and heroin), the "drug/metabolite" concentration ratio (MDMA/MDA) in hair is not significantly different from the ratios derived from other specimens, such as urine and blood. This observation is consistent with the relative drug/metabolite incorporation rates reported for cocaine/benzoylecgonine, tetrahydrocannabinol/tetrahydrocannabinoic acid, and MDMA/MDA.

McDonald T; Berkowitz R; Hoffman WE. Plasma naltrexone during opioid detoxification. Journal of Addictive Diseases 19(4): 59-64, 2000. (6 refs.)

Orogastric naltrexone is used for opioid detoxification, but it is not known how gastric absorption affects plasma concentrations of the drug. We measured plasma naltrexone during orogastric naltrexone, given in repeated doses of 12.5 mg, 25 mg, 50 mg and 50 mg. Plasma naltrexone was measured after each naltrexone dose. The increase in plasma naltrexone was highly variable between patients during orogastric administration. Adequate detoxification was, questioned in 4 of 10 patients because plasma naltrexone did not increase above 5 ng/ml. There was a negative correlation between plasma naltrexone and the presence of withdrawal symptoms on the day after the procedure (r = - 0.78, P < 0.05). These results show that the increase in plasma naltrexone is variable during orogastric administration and this may impair successful detoxification.

Metz CN; Gregersen PK; Malhotra AK. Metabolism and biochemical effects of nicotine for primary care providers. (review). Medical Clinics of North America 88(6): 1399+, 2004. (109 refs.)

Nicotine is a colorless and volatile liquid alkaloid naturally occurring in the leaves and stems of Nicotiana tabacum and Nicotiana rustica. Nicotine, the primary component of tobacco, is responsible for both tobacco product addiction (with chronic exposure) and the odor associated with tobacco. In addition to cigarettes, nicotine is found in chewing gum, transdermal patches, nasal spray, and sublingual tablets. Following its inhalation and absorption, nicotine and its metabolic products exert diverse physiologic and pharmacologic effects. This article covers the absorption and metabolism of nicotine, nicotine toxicity, pharmacologic effects of nicotine, nicotine-drug interactions, and the use of nicotine for the treatment of disease.

Miller NS; Klamen DL; Costa E. Medications of abuse and addiction: Benzodiazepines and other sedatives/hypnotics. IN: Tarter RE; Ammerman RT; Ott PJ, eds. Handbook of Substance Abuse. New York New York: Plenum Publishing Co., 1998. pp. 485-498. (72 refs.)

This chapter is devoted to the sedative-hypnotic class, featuring benzodiazepines and other sedative-hypnotic medications. In 1826, after alcohol, bromides were the first sedatives to be marketed specifically for their sedative-hypnotic properties. Barbituric acid was introduced at the turn of the 20th century, followed by chloral hydrate. These drugs affect many aspect of mental function, including mood cognition, and behavior, and pharmacological and behavioral tolerance is to be expected. For this discussion the sedative-hypnotics are divided into three categories based on their chemical structure: benzodiazepines, barbiturates, and others with sedative-hypnotic actions. While the most attention is directed to the benzodiazepines, for each of these groups there is discussion of patterns of use, mechanisms of action, absorption and metabolism, addiction, tolerance and dependence syndromes, withdrawal syndromes and medical management, and therapeutic uses.

Molander L; Lunell E. Pharmacokinetic investigation of a nicotine sublingual tablet. European Journal of Clinical Pharmacology 56(11): 813-819, 2001. (22 refs.)

Objective: To evaluate the pharmacokinetics of a new 2-mg nicotine sublingual tablet under varying conditions of use. Methods: The pharmacokinetics of the 2-mg nicotine sublingual tablet were investigated in four separate studies involving healthy adult volunteer smokers: (1) a multiple-dose comparison with 2-mg nicotine chewing gum (n=24; 13 males, 11 females), (2) a dose-proportionality study comparing single doses of 2, 4 and 6 mg (n=21, 10 males, 11 females), (3) an evaluation of the effect of incorrect tablet use, i.e. chewing the tablet followed by either immediate or delayed swallowing (n = 19, 10 males, 9 females), and (4) the effect of oral and gastric pH on nicotine absorption from the tablet (n=20; 11 males, 9 females). Study parameters were maximal plasma concentration (C-max), time to C-max (t(max)), and area under the plasma concentration-time curve (AUC). Results: The plasma nicotine profiles were similar following repeated administration of the sublingual tablet and the 2-mg nicotine chewing gum (mean C-max 13.2 versus 14.4 ng/ml, median t(max) 20 versus 20 min, mean AUC(11-12) 12.4 versus 13.5 ng/ml per hour) with no statistically significant difference between the two treatments. The pharmacokinetics of the 4- and 6-mg doses were non-linear compared to the 2-mg dose, probably as a result of more of the dose being swallowed and undergoing first-pass metabolism in the liver. The mean C-max for the 2-, 4- and 6-mg dose was 3.8 +/- 1.0, 6.8 +/- 2.1, and 9.0 +/- 3.3 ng/ml, respectively, and in terms of dose proportionality the relative bioavailability of the 4- and 6-mg dose was 0.82 and 0.71, respectively. Incorrect tablet use, i.e. chewing the tablet and immediate swallowing decreased nicotine bioavailability both in terms of rate and extent. Mean C-max was 12.1 ng/ml (correct use), 10.3 ng/ml (chewing and immediate swallowing), and 12.1 ng/ml (chewing and delayed swallowing). Corresponding mean values for AUC(9-10) were 11.6, 9.6 and 11.2 ng/ml per hour. There were no significant differences between 'alkaline mouth' versus control,'acidic mouth' versus control or 'alkaline stomach' versus control, but the rate of nicotine absorption was increased at alkaline compared to acidic oral pH (mean C-max 6.1 versus 4.9 ng/ml, P = 0.003; median t(max) 60 versus 90 min, P = 0.0002). Conclusion: The pharmacokinetic profile of the nicotine 2-mg tablet was similar to that of the 2-mg nicotine chewing gum. Absorption of nicotine from the tablet was nonlinear at higher doses (two or three tablets). Chewing the tablet and keeping the remains in the mouth or concurrent use of acidic beverages or antacids are equivalent to recommended sublingual use during normal oral pH conditions.

Otberg N; Patzelt A; Rasulev U; Hagemeister T; Linscheid M; Sinkgraven R et al. The role of hair follicles in the percutaneous absorption of caffeine. British Journal of Clinical Pharmacology 65(4): 488-492, 2008. (30 refs.)

AIMS: The skin and its appendages are our protective shield against the environment and are necessary for the maintenance of homeostasis. Hypotheses concerning the penetration of substances into the skin have assumed diffusion through the lipid domains of the stratum corneum. It is believed that while hair follicles represent a weakness in the shield, they play a subordinate role in the percutaneous penetration processes. Previous investigation of follicular penetration has mostly addressed methodical and technical problems. Our study utilized a selective closure technique of hair follicle orifices in vivo, for the comparison of interfollicular and follicular absorption rates of caffeine in humans. METHODS: Every single hair follicle within a delimited area of skin was blocked with a microdrop of a special varnish-wax-mixture in vivo. Caffeine in solution was topically applied and transcutaneous absorption into the blood was measured by a new surface ionization mass spectrometry (SI/MS) technique, which enabled a clear distinction to be made between interfollicular and follicular penetration of a topically applied substance. RESULTS: Caffeine (3.75 ng ml(-1)) was detected in blood samples, 5 min after topical application, when the follicles remained open. When the follicles were blocked, caffeine was detectable after 20 min (2.45 ng ml(-1)). Highest values (11.75 ng caffeine ml(-1)) were found 1 h after application when the follicles were open. CONCLUSIONS: Our findings demonstrate that hair follicles are considerable weak spots in our protective sheath against certain hydrophilic drugs and may allow a fast delivery of topically applied substances.

Patten CA. A critical evaluation of nicotine replacement therapy for teenage smokers. (review). Journal of Child & Adolescent Substance Abuse 9(4): 51-75, 2000. (100 refs.)

The purpose of this review is to evaluate the appropriateness and feasibility of nicotine replacement therapy (NRT) in teenage smokers. In this paper, available forms of NRT, the theoretical rationale and efficacy of NRT, ethical considerations, and the feasibility of NRT in teenage smokers are addressed. Although there is a need to better understand the addiction process in adolescents, it is clear that teens have several characteristics similar to adult nicotine dependent smokers. These observations form the basis of the rationale for the use of NRT in teenagers. Only one report has examined the efficacy of NRT in teen smokers. This study observed a stop rate of 4.5% at six-months in 22 subjects using the nicotine patch. In addition to the potential benefits of NRT, ethical issues have been raised regarding the appropriate use of NRT in teenage smokers. Ethical considerations of NRT use in adult smokers, which need further study in adolescents, are nicotine absorption, long-term use, potential for side effects, concomitant smoking, use in pregnant smokers, and abuse liability in nonsmokers and light, intermittent smokers. The feasibility of NRT in adolescent smokers is also discussed, including its acceptability, convenience, social approval, cost, and availability. Many teens are nicotine dependent and additional clinical trials are warranted to evaluate whether NRT provides benefit to adolescent smokers. In addition, further research is needed to study adjunctive behavioral interventions tailored to the developmental and psychosocial needs of adolescents.

Pertwee RG. Cannabis and cannabinoids: Pharmacology and rationale for clinical use. Forschende Komplementarmedizin 6(Supplement): 12-15, 1999. (54 refs.)

It is now known that there are at least two types of cannabinoid receptors. These are CB1 receptors, present mainly on central and peripheral neurones, and CB2 receptors, present mainly on immune cells. Endogenous cannabinoid receptor agonists ('endocannabinoids') have also been identified. The discovery of this 'endogenous cannabinoid system' has led to the development of selective CB1 and CB2 receptor ligands and fuelled renewed interest in the clinical potential of cannabinoids. Two cannabinoid CB1 receptor agonists are already used clinically, as antiemetics or as appetite stimulants. These are Delta(9) tetrahydrocannabinol (THC) and nabilone. Other possible uses for CB1 receptor agonists include the suppression of muscle spasm/spasticity associated with multiple sclerosis or spinal cord injury, the relief of chronic pain and the management of glaucoma and bronchial asthma. CB1 receptor antagonists may also have clinical applications, e. g. as appetite suppressants and in the management of schizophrenia or disorders of cognition and memory. So too may CB2 receptor ligands and drugs that activate cannabinoid receptors indirectly by augmenting endocannabinoid levels at cannabinoid receptors. When taken orally, THC seems to undergo variable absorption and to have a narrow 'therapeutic window' (dose range in which it is effective without producing significant unwanted effects). This makes it difficult to predict an oral dose that will be both effective and tolerable to a patient and indicates a need for better cannabinoid formulations and modes of administration. For the therapeutic potential of cannabis or CB1 receptor agonists to be fully exploited, it will be important to establish objectively and conclusively (a) whether these agents have efficacy against selected symptoms that is of clinical significance and, if so, whether the benefits outweigh the risks, (b) whether cannabis has therapeutic advantages over individual cannabinoids, (c) whether there is a need for additional drug treatments to manage any of the disorders against which cannabinoids are effective, and (d) whether it will be possible to develop drugs that have reduced psychotropic activity and yet retain the ability to act through CB1 receptors to produce their sought-after effects.

Quinn DI; Wodak A; Day RO. Pharmacokinetic and pharmacodynamic principles of illicit drug-use and treatment of illicit drug-users. Clinical Pharmacokinetics 33(5): 344-400, 1997. (596 refs.)

Many clinicians are confronted by the use of illicit drugs on a daily basis. In dealing with problems related to drugs - opioids, psychostimulants, benzodiazepines, alcohol and nicotine- clinicians need a scientific understanding of their pharmacology, quantifiable effects, and potential adverse effects. Generally, rapid absorption, rapid entry into the central nervous system, high bioavailability, short-half-life, small volume of distribution, and high free drug clearance are pharmacokinetics characteristics which predict a high potential for harmful use, because these factors increase positive reinforcement. Drug users adapt the method and route of administration to optimize delivery of the drug to the brain and to maximize bioavailability. Inhalation and smoking are the routes of administration which allow the most rapid delivery while intravenous injection maximizes the bioavailability. Each route has attendant complication related to mucosal damage, carcinogenesis, and risk of infection. Negative reinforcement or withdrawal is a major drive to recurrent use. Many illicit drugs have pharmacological features that promote dependence, including long, half-life, low free drug clearance and sufficient drug exposure to allow the development of tolerance. The preventive or reductive pharmacotherapies make use of several subsets of agents, those which act on the same receptor or system as the illicit drug (methadone), those which produce an adverse reaction on consumption (disulfiram) and those which symptomatically attenuate illicit drug withdrawal (clonidine). The complications of illicit drug use present many therapeutic challenges. Illicit drug users are prone to developing drug interactions. The most common are pharmacodynamic in nature, most often due to additive effects. However, alcohol, cocaine, disulfiram, methadone, and tricyclic antidepressants may be involved in important pharmacokinetic interactions. Of these the effect of long term alcohol consumption in increasing the hepatotoxicity of paracetamol and of cytochrome P450 3A microsomal stimulating drugs are the most commonly encountered. Charts and tables help summarize the information. [Note. Cannabis is not included because there is not convincing evidence of significant contribution to morbidity and mortality. Similarly the hallucinogens are not covered because they account for little mortality or morbidity.]

Quraishi MS; Jones NS. The nasal delivery of drugs. (review). Clinical Otolaryngology 22(4): 289-301, 1997. (186 refs.)

This review focuses upon the increased use of nasal delivery of systemic drugs. It addresses anatomy and physiology; factors that affect the bioavailability; physical and chemical factors/ mechanisms for absorption; the effects of nasal and transnasal drugs on nasal mucosa; methods of delivery and distribution. [It does not deal with substances of abuse, per se.]

Rentsch KM; Kullak-Ublick GA; Reichel C; Meier PJ; Fattinger K. Arterial and venous pharmacokinetics of intravenous heroin in subjects who are addicted to narcotics. Clinical Pharmacology & Therapeutics 70(3): 237-246, 2001. (24 refs.)

Background: In Switzerland, medical prescription of heroin (diacetylmorphine) is currently being evaluated as a treatment option for heavily dependent addicts. Therefore the diacetylmorphine pharmacokinetics in opioid-addicted patients was studied. Methods: Three different diacetylmorphine doses (up to 210 mg) and 20 mg deuterium-labeled morphine (morphine-d3) were administered intravenously to 8 heroin-addicted patients. Arterial and venous plasma samples were collected, and diacetylmorphine, monoacetylmorphine, morphine, morphine-3-glucuronide, morphine-6- glucuronide, and morphine-d3 plasma concentrations were measured by liquid chromatography-mass spectrometry. Results: Maximal arterial concentrations of diacetylmorphine, monoacetylmorphine, and morphine were 2.4, 5.4, and 1.4 times higher and occurred 2 to 3 minutes earlier than maximal venous concentrations. Venous areas under the concentration-time curves (AUC) of diacetylmorphine and monoacetylmorphine were 35% and 26% lower than arterial AUC values, whereas for morphine the venous AUC was 15% higher. Morphine-3-glucuronide and morphine-6-glucuronide exhibited no arteriovenous differences. AUCs for diacetylmorphine, monoacetylmorphine, and morphine increased linearly with dose: Diacetylmorphine was completely metabolized to morphine. Substantial morphine input into the arterial circulation persisted for up to 90 minutes. The arterial clearances of diacetylmorphine, monoacetylmorphine, and morphine-d3 were 8.7 +/- 2.6, 6.7 +/- 1.6, and 2.3 +/- 0.3 L/min, respectively. The arterial half-lives of diacetylmorphine and morphine-d3 were 2.4 +/- 0.8 and 88 +/- 21 minutes, respectively. Conclusions: These data indicate that substantial arteriovenous differences exist for diacetylmorphine and metabolite kinetics, that the pharmacokinetics of diacetylmorphine and metabolites is linear even in the high dose range used by opioid addicts, and that not only diacetylmorphine but also monoacetylmorphine is substantially metabolized peripherally to morphine.

Rose ME; Grant JE. Alcohol-induced blackout phenomenology, biological basis, and gender differences. (review). Journal of Addiction Medicine 4(2): 61-73, 2010. (149 refs.)

Blackouts from acute alcohol ingestion are defined as the inability to recall events that occurred during a drinking episode and are highly prevalent in both alcoholic and nonalcoholic populations. This article reviews the clinical manifestations, epidemiology, risk factors, cognitive impairment, and neurobiology associated with alcohol-induced blackout, with special emphasis on the neurochemical and neurophysiological basis, and gender differences. Two types of blackout have been identified: en bloc, or complete inability to recall events during a time period, and fragmentary, where memory loss is incomplete. The rapidity of rise in blood alcohol concentration is the most robust predictor of blackout. Alcohol impairs different brain functions at different rates, and cognitive and memory performance are differentially impaired by ascending versus descending blood alcohol concentration. Cognitive and memory impairment occurs before motor impairment, possibly explaining how a drinker appearing fully functional can have little subsequent memory. Blackouts are caused by breakdown in the transfer of short-term memory into long-term storage and subsequent retrieval primarily through dose-dependent disruption of hippocampal CA1 pyramidal cell activity. The exact mechanism is believed to involve potentiation of gamma-aminobutyric acid-alpha-mediated inhibition and interference with excitatory hippocampal N-methyl-D-aspartate receptor activation, resulting in decreased long-term potentiation. Another possible mechanism involves disrupted septohippocampal theta rhythm activity because of enhanced medial septal area gamma-aminobutyric acid-ergic neurotransmission. Women are more susceptible to blackouts and undergo a slower recovery from cognitive impairment than men, due in part to the effect of gender differences in pharmacokinetics and body composition on alcohol bioavailability.

Roset PN; Farre M; de la Torre R; Mas M; Menoyo E; Hernandez C; Cami J. Modulation of rate of onset and intensity of drug effects reduces abuse potential in healthy males. Drug and Alcohol Dependence 64(3): 285-298, 2001. (40 refs.)

Low, medium, and high doses of flunitrazepam were tested in three independent randomized, double-blind, balanced cross-over, placebo- con trolled trials to study the influence of rate of onset of effects and dose administered on its acute effects. Three groups of 12 healthy male volunteers received six oral doses of placebo or flunitrazepam in slow and fast onset conditions as follows: six capsules of 0.16 mg (slow) and a single capsule of 0.8 mg (fast) in the low dose trial; six 0.25 mg (slow) and a single 1.25 mg (fast) capsules for medium dose; and six 0.4 mg (slow) and a single 2 mg (fast) capsule for high dose. At each dose level, slow or fast increasing flunitrazepam plasma concentrations lead to similar peak levels, but induced differential subjective and behavioral effects. In addition to objective and subjective sedation, flunitrazepam induced some pleasurable feelings, which were more intense in the fast than in the slow conditions. At the highest dose, unpleasant sedative effects surmounted positive effects, while at the lowest dose pleasurable effects were of low intensity. At the medium dose, the balance between pleasurable and unpleasant feelings resulted in euphorigenic effects, which were evident in the fast condition but were blunted in the slow condition.

Schneider NG; Olmstead RE; Franzon MA; Lunell E. The nicotine inhaler: Clinical pharmacokinetics and comparison with other nicotine treatments. Clinical Pharmacokinetics 40(9): 661-684, 2001. (118 refs.)

Nicotine inhaled in smoke is the most rapid form of delivery of the drug. With smoking, arterial boli and high venous blood nicotine concentrations are produced within seconds and minutes. respectively. The potency of nicotine as the primary reinforcement in tobacco addiction is attributed to this rapid rate of delivery. By design, nicotine treatments reduce the rate and extent of drug delivery for weaning from nicotine during smoking cessation. Theoretically, they prevent relapse by reducing withdrawal and craving associated with the abrupt cessation of cigarettes. The nicotine inhaler treats the complexity of smoking through weaning both from the drug and from the sensory/ritual components associated with smoking. The inhaler is 'puffed' but not lit and there is considerable 'puffing' required to achieve slower rising and lower nicotine concentrations. These factors allow it to be used as a nicotine reduction treatment. One inhaler contains 10mg of nicotine (and 1mg of menthol) of which 4mg of nicotine can be extracted and 2mg are systemically available. Shallow or deep 'puffing' results in similar nicotine absorption. Nicotine is delivered mainly to the oral cavity, throat and upper respiratory tract with a minor fraction reaching the lungs. This was confirmed with positron emission tomography and by assessment of arterial concentrations. A single inhaler can be used for one 20-minute period of continuous puffing or periodic use of up to 400 puffs per inhaler. With controlled puffing in laboratory testing, venous plasma nicotine concentrations from a single inhaler puffed 80 times over 20 minutes averaged 8.1 mug/L at 30 minutes. Lower concentrations of 6.4 to 6.9 mug/L have been reported for self-administration under clinical conditions. The time to peak plasma concentrations varies but is always significantly longer than with cigarette delivery. Estimates of nicotine intake from cotinine concentrations were higher than expected (60 to 70% of baseline smoking concentrations). This elevation may be due to the swallowing of nicotine and subsequent first-pass biotransformation to cotinine. In general, venous blood nicotine concentrations are considerably lower than with smoking and are within the range observed for other nicotine reduction therapies. Efficacy trials show consistent superiority of the inhaler over placebo. Despite the 'cigarette-like' appearance of the inhaler and the associated sensory/ritual elements, little treatment dependence or abuse has been reported. This is attributed to the slow rise time and low nicotine blood concentrations. The inhaler is a valuable addition to treatment of tobacco dependence and can be used alone or with other treatments.

Seeman JI. Possible role of ammonia on the deposition, retention, and absorption of nicotine in humans while smoking. (review). Chemical Research in Toxicology 20(3): 326-343, 2007. (155 refs.)

This perspective presents an overview of the properties of tobacco smoke aerosol and the possible effect of ammonia on the deposition location, retention and the amount and rate of nicotine absorption during cigarette smoking. Three main mechanisms describe the absorption of smoke constituents: (A) gas-phase constituents deposit directly; (B) particles deposit and the constituents then diffuse through the particle into the biological buffer and then into the tissue; and (C) particulate phase constituents evaporate from the particles and then deposit from the gas phase. Nicotine from smoking deposits and is absorbed predominately in the lungs. When particles deposit on the lung-blood interfaces, nicotine is absorbed rapidly, regardless of the acid-base nature of the particles. This is due to the buffering capacity of the lung-blood interfaces and the small mass of nicotine per puff distributed over a large number of particles depositing onto a huge lung surface. The composition of both tobacco smoke aerosol particles and the gas phase are time dependent. Ammonia in mainstream smoke evaporates faster from particles than nicotine. It is, therefore, unlikely that ammonia can significantly affect the volatility of MS smoke nicotine from particles in the smoke aerosol. It is certain that no single measurement of tobacco or of smoke, especially one made under equilibrium conditions, can adequately characterize the time-dependent properties of mainstream smoke aerosol. Thus, the fraction of nonprotonated freebase nicotine in trapped, aged smoke particulate matter has not been shown to be a useful predictor of the amount or total rate of nicotine uptake in human smokers. Similarly, "smoke pH" and "pH(eff)" are not useful practical parameters for providing understanding or predictability of tobacco smoke chemistry or nicotine bioavailability.

Smit HJ; Cotton JR; Hughes SC; Rogers PJ. Mood and cognitive performance effects of "energy" drink constituents: Caffeine, glucose and carbonation. Nutritional Neuroscience 7(3): 127 -139, 2004. (45 refs.)

Three studies using healthy volunteers (n = 271) investigated the effects of caffeine, carbohydrates and carbonation in functional "energy" drinks (EDs) with the aim of determining their benefit in every-day life. The results showed caffeine to be the main ED constituent responsible for the effects found, with possible minor, relatively weak effects of carbohydrates. EDs were found to improve and/or maintain mood and performance during fatiguing and cognitively demanding tasks relative to placebo. In terms of absolute values, EDs maintained levels of arousal compared to a deterioration in arousal where placebo was consumed. These effects were found in caffeine-deprived participants, and may be largely due to "withdrawal reversal". There were only minor differences in the effects of water vs. "sensory-matched" placebo, supporting previous findings indicating that the type of placebo does not alter the conclusions drawn about the effects of the full ED. Finally, carbonation had various effects on mood, some of which were present immediately following consumption, others were consistent with slower absorption of caffeine (and possibly carbohydrates) from carbonated drinks.

Smith SW; Topliff AR; Danigelis M; Zvosec DL; Schrag LL; Freiwald SA et al. Adverse events associates with ingestion of gamma-butyrolactone. Minnesota, New Mexico, and Texas, 1998-1999. MMWR. Morbidity and Mortality Weekly Report 48(7): 137-140, 1999. (10 refs.)

This report involves 41 cases reported in three states involving GBL-containing products. GBL is metabolized to GHB in the body, but because of better absorption GBL has greater bioavailability than GHB on an equimolar basis. Clinical effect of GHB, not approved for use except in clinical trials, appear to be dose related and include reports of vomiting, hypotonia, tremors, seizures, aggression, impairment of judgment, coma, respiratory depression, hypothermia and bradycardia. It is synergistic with alcohol to produce central nervous system depression. Symptoms usually resolve with supportive care within 2-96 hours. There is no antidote, treatment consists of supportive therapy. A withdrawal syndrome , which can include insomnia, tremor, and anxiety has been reported upon discontinuation by chronic high-dose users. GBL is marketed as a dietary supplement.

Public Domain

Sobue S; Sekiguchi K; Kikkawa H; Irie S. Effect of application sites and multiple doses on nicotine pharmacokinetics in healthy male Japanese smokers following application of the transdermal nicotine patch. Journal of Clinical Pharmacology 45(12): 1391-1399, 2005. (38 refs.)

The transdermal nicotine patch, which contains 25 mg nicotine per 30 cm(2), is designed to deliver approximately 15 nicotine to the blood circulation in 16 hours of application for the treatment of smoking cessation. It was applied to 3 different skin sites (upper arm, abdomen, and back) to examine regional variations in percutaneous nicotine absorption in a single-dose, 3-period, crossover study involving 9 healthy male Japanese smokers. Nicotine pharmacokinetics during once-daily application of the transdermal nicotine patch for 5 days was also investigated in 10 healthy smokers. There were statistically significant effects of application sites on percutaneous nicotine absorption. The ratios (90% confidence intervals) of AUC and C-max for comparison to the upper arm were 102% (88, 117%) and 106% (95, 119%) for the back and 75% (65, 87%) and 75% (66, 84%)for the abdomen, respectively. These suggest that systemic exposure after application to the upper arm was greater compared with the abdomen but equivalent to the back. Following multiple doses, linear pharmacokinetics and no significant accumulation of nicotine concentrations were observed, and steady state was reached by day 2. Only mild itching and erythema were observed at the application sites. The transdermal nicotine patch was well tolerated in both studies.

Strain EC. Pharmacology of buprenorphine. IN: Strain EC; Stitzer ML, eds. The Treatment of Opioid Dependence. Baltimore: Johns Hopkins University Press, 2006. pp. 213-229. (66 refs.)

Buprenorphine is a mixed agonist-antagonist opioid. The chapter reviews the pharmacology of buprenorphine, its actions at different opioid receptors, its absorption, metabolism, and excretion, half-life and duration of effects. The clinical features are summarized in terms of withdrawal suppression, analgesic effects, respiratory depression, cross tolerance, plus its subjective and cognitive/psychomotor effects. Also there is discussion of the pharmacologic rationale for combining buprenorphine and naloxone.

Thomas JA; Burns RA. Important drug-nutrient interactions in the elderly. (review). Drugs & Aging 13(3): 199-209, 1998. (60 refs.)

Several drug-nutrient interactions can occur, but their prevalence may be accentuated in the elderly. Geriatric patients may experience age-related changes in the pharmacokinetics of a drug - absorption, distribution, metabolism and excretion. When drug-nutrient interactions occur, they usually affect absorptive processes more frequently. Specific transporter systems facilitate the absorption of many drugs. Little is known about how these transporter systems are affected by aging. Co-existing disease states in the elderly may exaggerate the action of a drug and represent a confounding factor in drug-nutrient interactions. While several different drug-nutrient interactions are important in the elderly, those affecting the cardiovascular system warrant special attention.

Toennes SW; Kauert GF. Excretion and detection of cathinone, cathine, and phenylpropanolamine in urine after kath chewing. Clinical Chemistry 48(10): 1715-1719, 2002. (21 refs.)

Introduction: The stimulating herbal drug kath is uncommon in most countries, and information on its detection and interpretation of analytical results is limited. Therefore, a study with kath was carried out to compare the efficiencies of different analytical techniques used to detect drug use. Methods: Four volunteers chewed kath leaves for 1 h; urine samples were collected up to 80 It afterward and analyzed by the Abbott fluorescence polarization immunoassay (FPIA), the Mahsan-AMP300 on- site immunoassay, the Bio-Rad Remedi HS HPLC system with photodiode array detection (DAD), and gas chromatography-mass spectrometry (GC- MS). Results: FPIA gave negative results, whereas positive results were obtained with the Mahsan test during the first day. With HPLC, one peak could be observed up to 50 It, but its DAD spectrum could not be identified by the system. Further investigations indicated that the kath alkaloids coeluted and produced a mixed DAD spectrum. With GC- MS, the specific kath ingredient cathinone was detected up to 26 h, whereas cathine and norephedrine were still detectable in the last samples. Maximum concentrations of cathinone, cathine, and norephedrine in urine samples from the study were 2.5, 20, and 30 mg/L, respectively, whereas in authentic cases the concentrations were much higher. Conclusion: GC-MS is superior to the screening techniques Mahsan- AMP300 and Remedi with respect to specificity and sensitivity for the detection of kath use in urine.

Tricker AR. Nicotine metabolism, human drug metabolism polymorphisms, and smoking behaviour. Toxicology 183(1/3): 151-173, 2003. (159 refs.)

Large interindividual differences occur in human nicotine disposition, and it has been proposed that genetic polymorphisms in nicotine metabolism may be a major determinant of an individual's smoking behaviour. Hepatic cytochrome P4502A6 (CYP2A6) catalyses the major route of nicotine metabolism: C-oxidation to cotinine, followed by hydroxylation to trans -3'-hydroxycotinine. Nicotine and cotinine both undergo N-oxidation and pyridine N-glucuronidation. Nicotine N- 1-oxide formation is catalysed by hepatic flavin-containing monooxygenase form 3 (FMO3), but the enzyme(s) required for cotinine N-1'-oxide formation has not been identified. trans- 3'--Hydroxycotinine is conjugated by O-glucuronidation. The uridine diphosphate-glucuronosyltransferase (UGT) enzyme(s) required for N- and O-glucuronidation have not been identified. CYP2A6 is highly polymorphic resulting in functional differences in nicotine C-oxidation both in vitro and in vivo; however, population studies fail to consistently and conclusively demonstrate any associations between variant CYP2A6 alleles encoding for either reduced or enhanced enzyme activity with self-reported smoking behaviour. The functional consequences of FMO3 and UGT polymorphisms on nicotine disposition have not been investigated, but are unlikely to significantly affect smoking behaviour. Therefore, current evidence does not support the hypothesis that genetic polymorphisms associated with nicotine metabolism are a major determinant of an individual's smoking behaviour and exposure to tobacco smoke.

Walker LA; Harland EC; Best AM; El Sohly MA. Delta 9-THC hemisuccinate in suppository form as an alternative to oral and smoked THC. IN: Nahas GG; Sutin KM; Harvey DJ; Agurell S; Pace N; Cancro R, eds. Marihuana and Medicine. Totowa: Humana Press, Inc., 1999. pp. 123-135. (16 refs.)

Although delta-9-tetrahydrocannabinol (THQ has demonstrated utility for several medicinal applications, several studies have reported the inconsistent bioavailability of the oral soft gelatin capsule formulation, because of erratic absorption and variable first-pass metabolism of THC. This problem limits the utility of THC for its approved indications, and also prevents efficient assessment of other potential therapeutic applications. In an effort to overcome these pharmacokinetic limitations, we have explored the utility of various ester prodrugs of THC in suppository formulations as alternatives for effecting the systemic delivery of THC. Studies designed to characterize the bioavailability and efficacy of these preparations are reviewed here. In addition, studies designed to confirm the behavior of THC-hemisuccinate (THC-HS) as a prodrug were conducted. In rodents and dogs, intravenous administration of THC and THC-HS produced identical pharmacological responses (hypothermia and potentiation of thiamylal sleep times in mice; bradycardia in dogs) except at very high doses. Pharmacokinetic evaluations after intravenous and rectal administration of TFIGHS also showed that the parent ester could not be detected in plasma, but that THC and its metabolite were detected in a fashion consistent with the immediate hydrolysis of THGHS to THC in the absorption process or in the plasma. Administration of the THGHS via suppositories resulted in excellent bioavailability, sustained plasma levels of THC, and improved efficacy as compared to the oral formulations, suggesting the feasibility of this route for the delivery of THC in various therapeutic applications.

Walsh SL; Strain EC. The pharmacology of methadone. IN: Strain EC; Stitzer ML, eds. Methadone Treatment for Opioid Dependence. Baltimore: Johns Hopkins University Press, 1999. pp. 38-52. (16 refs.)

This chapter provides a review of the pharmacology of methadone. It begins by defining and providing a brief overview of opioid receptors and the basic principles of drug action. In the discussion of pharmacology, the structure of methadone is provided, along with discussion of absorption, metabolism, excretion, half-life, and distribution throughout the body. The clinical pharmacological features of significance are reviewed, analgesic effects, respiratory depression, opioid blockade or cross-tolerance, withdrawal suppression, acute physiological effects, and psychological effects, anti-anxiety, antidepressant and antipsychotic effects, and effects of psychomotor and cognitive function. Several of its pharmacological properties make it particularly useful in treatment of opiate dependence -- its bioavailability when taken orally, permitting easy dosage typically through a liquid vehicle; its long half-life allowing dosage on a once per day basis; it suppression of opiate withdrawal; and it's cross tolerance to the effects of illicit opioid use, decreasing use when patients are maintained on methadone.

Watson CH; Polzin GM; Calafat AM; Ashley DL. Determination of tar, nicotine, and carbon monoxide yields in the smoke of bidi cigarettes. Nicotine & Tobacco Research 5(5): 747-753, 2003. (13 refs.)

A survey of the nicotine, tar, and carbon monoxide (CO) levels in mainstream smoke from 21 brands of bidi cigarettes and five brands of traditional cigarettes was conducted using a variation of the Federal Trade Commission (FTC) standardized cigarette smoking machine method. The primary difference between this method and the FTC method was a reduction of the 60-s puff interval to 15s. The shorter puff interval was required to prevent the bidi cigarettes from self-extinguishing and may represent a closer approximation to human usage. The goal of this study was to evaluate the smoke-delivery potential for tar, nicotine, and CO in mainstream smoke from bidi cigarettes compared with traditional domestic cigarettes smoked under identical conditions. Approximately half of the bidi brands examined were marketed as filtered varieties. Unlike traditional cigarettes, the filtered and unfiltered bidi brands yielded comparable smoke deliveries. Thus, a filtered bidi cigarette brand does not provide any harm-reduction benefit that might result from a reduction in levels of tar, nicotine, and CO compared with an unfiltered variety. Our findings indicate that bidi cigarettes can deliver high levels of tar (77.9 +/- 9.5 mg/bidi), nicotine (2.7 +/- .4 mg/bidi), and CO (39.2 +/- 5.7mg/bidi). In comparison, traditional cigarettes smoked using the bidi cigarette protocol have lower tar and CO yields, but have nicotine deliveries comparable with bidi cigarettes.

Werley MS; Coggins CRE; Lee PN. Possible effects on smokers of cigarette mentholation: A review of the evidence relating to key-research questions. Regulatory Toxicology and Phrmacology 47(2): 189-203, 2007. (83 refs.)

Menthol (2-isopropyl-5-methyl-cyclohexan-1-ol) is used in food, pharmaceutical, and tobacco products. Despite its long usage history and GRAS status, scientific literature on effects of cigarette mentholation is limited. Because African-American men have high lung cancer rates and predominantly smoke mentholated cigarettes, and because menthol's cooling effect might affect puffing and smoke inhalation, possible adverse effects of cigarette mentholation have been suggested. We review the evidence on the effects of mentholation on smokers, and we also identify areas for further study. Five large epidemiological studies provide no evidence that cigarette mentholation increases lung cancer risk. Mentholation cannot explain the higher risk for lung cancer in African-American male smokers, who also predominantly smoke mentholated cigarettes. Limited data on other cancers also suggest no risk from mentholation. The scientific literature suggests that cigarette mentholation does not increase puff number or puff volume of smoked cigarettes, and has little or no effect on heart rate, blood pressure, uptake of carbon monoxide, tar intake or retention, or blood cotinine concentration. Mentholation has little effect on other smoke constituents, and no apparent effect on nicotine absorption, airway patency and smoking initiation, dependency or cessation. Any toxicological effects of cigarette mentholation on adult smokers are probably quite limited.

Wilens TE; Spencer TJ. Pharmacology of amphetamines. IN: Tarter RE; Ammerman RT; Ott PJ, eds. Handbook of Substance Abuse. New York: Plenum Publishing Co., 1998. pp. 515-528. (109 refs.)

This chapter deals with the pharmacology of amphetamines, one of the oldest compounds available in the US. It was first synthesized in 1887 and marketed in the 1920s for treatment of asthma. The abuse of amphetamines and other stimulants appears to be a product of their anorectic , insomnia, and euphorgenic properties, coupled with their availability. This chapter reviews the structural relationships, their pharmacokinetics -- i.e. absorption half-lives -- metabolism and mechanism of action. Chronic use along with the appearance of tolerance and dependence is discussed.

Williams JM; Gandhi KK; Lu SE; Kumar S; Shen JW; Foulds J et al. Higher nicotine levels in schizophrenia compared with controls after smoking a single cigarette18. Nicotine & Tobacco Research 12(8): 855-859, 2010. (18 refs.)

Introduction: The increase in blood nicotine after smoking a single cigarette is nicotine boost. We hypothesized that smokers with schizophrenia (SCZ) have a greater nicotine boost than controls without this disorder. Methods: Twenty-one subjects (11 SCZ and 10 controls, CON) had repeated venous blood sampling before, during, and after smoking a single cigarette after 12-hr abstinence to measure nicotine concentrations. Blood samples were drawn at baseline (before smoking) and 1, 2, 4, 6, 8, 10, 20, 30, 60, 90, and 120 min after the first puff. Groups were similar in baseline characteristics, including gender and level of dependence, and all smoked 20-30 cigarettes/day. Area under the serum nicotine concentration-time curve (AUC(20)) was calculated for time up to 20 min after the start of smoking. Results: The mean difference in AUC20 was significantly greater for SCZ versus CON (135.4 ng-min/ml; 95% CI = 0.45-283.80). The shape of the nicotine concentration-time curve for SCZ was significantly different compared with controls (p < .01). Nicotine boost in the first 4 min of smoking was higher in SCZ versus CON (25.2 vs. 11.1 ng/ml, p < .01) with no difference in the total time spent smoking. Discussion: This technique improves on methods, which draw only two blood specimens to assess nicotine intake. Understanding how nicotine boost differs in SCZ from CON may explain high levels of addiction and low success in cessation in smokers with SCZ.

Yerger VB; Malone RE. Melanin and nicotine: A review of the literature. (review). Nicotine & Tobacco Research 8(4): 487-498, 2006. (190 refs.)

The role of melanin in nicotine uptake and metabolism has received little attention. Because nicotine has been shown to accumulate in tissues containing melanin, exploring links between melanin and nicotine may provide additional clues to understanding smoking behavior and disease effects. To examine the scientific literature on the relationship between melanin and nicotine, we conducted a PubMed search. We also searched online archives of internal tobacco industry documents. We retrieved and reviewed 82 published research papers related to melanin and nicotine or melanin and metabolism of other drugs, and 150 relevant internal tobacco industry documents. The published literature suggests that nicotine may accumulate in human tissues containing melanin and this retention may increase melanin synthesis. Existing research on the relationship between melanin and nicotine lacks an adequate consideration of this relationship's potential impact, if any, on nicotine metabolism, level of nicotine dependence, and ability to quit smoking. Differential accumulation of nicotine in melanin-containing tissues could have implications for individuals with high levels of melanin.