Immunotherapy for treatment of drug overdose

Treatment of the adverse effects of PCP is difficult for several reasons. PCP has a very high volume of distribution (6.2 liters per kilogram (L kg) in humans) and its clearance is primarily by metabolism (Cook et al. 1982) with only a small contribution from renal excretion. Its major sites of action in the central nervous system (CNS) are far removed from the beneficial effects of most traditional treatment methods such as dialysis. In addition, there is no specific antagonist for PCP's...

Summary And Conclusion

Individual differences in susceptibility to nicotine addiction, the likelihood of successful smoking cessation, and the development of adverse health effects of smoking are well recognized. The basis for these individual differences is as yet unknown. This chapter examines individual differences in the metabolism and kinetics of nicotine as a possible factor. Rare individuals appear to be deficient metabolizers of nicotine. Individual differences are described both in the pattern and rates of...

Introduction and background

Aliphatic cyclic tertiary amines constitute a major class of naturally occurring and synthetic drugs directed at central biogenic amine receptors. Microsomal metabolism of these amines is known to be associated with low levels of covalent binding and or suicide inactivation of the pertinent metabolizing P-450 isozymes two of the more notorious examples are phencyclidine (1-(1-phenylcyclohexyl)piperidine) (PCP) (Hoag et al. 1984) and nicotine (Shigenaga et al. 1988). Covalent binding was...

Characterization Of A Human Liver Cocaine Benzoyl Ester Hydrolase

An enzyme that catalyzes the hydrolysis of cocaine to ecgonine methyl ester and benzoate was purified from human autopsy liver by ion-exchange and affinity chromatography and gel filtration. The enzyme was purified approximately 8,700-fold and about 150 micrograms (g) of enzyme were obtained from 70 grams (g) of human liver. The enzyme catalyzed the hydrolysis of cocaine to ecgonine methyl ester and benzoate and the hydrolysis of methylumbelliferylacetate to methylumbelliferone. The Michaelis...

Flavin Containing Monooxygenase

The mammalian flavin-containing monooxygenase (FMO) is a widely distributed membrane-associated family of enzymes that catalyze the oxygenation of nucleophilic nitrogen-, sulfur-, and phosphorous-containing xenobiotics, drugs, and endogenous substances (Ziegler 1993). Nucleophilic tertiary amines such as nicotine are readily converted to relatively stable tertiary amine N-oxides that are more polar and readily excreted unchanged (Park et al. 1993). As described above, nicotine N-1'-oxygenation...

Alcohol Effect On Noxidative Metabolism Of Cocaine

In humans, N-demethylation of cocaine to norcocaine is catalyzed by a cytochrome P-450 enzyme either directly or following oxidation of cocaine to cocaine N-oxide by a flavin-adenine dinucleotide (FAD)-containing mono-oxygenase (figure 1, 4) (Kloss et al. 1983). The N-demethylation of benzoylecgonine to benzoylnorecgonine was demonstrated in the rat following administration of radiolabeled benzoylecgonine (figure 1, 5)(Misra et al. 1975). In animals pretreated with ethanol, metabolism of...

References

J Biol Chem 265 20053-20056, 1990. Ambre, J.J. Belknap, S.M. Nelson, J. Ruo, T.I. Shin, S. and Atkinson, A.A., Jr. Acute tolerance for cocaine in humans. Clin Pharmacol Ther 44 1-8, 1988. Barass, B.C. Blackburn, J.W. Brimblecombe, R.W. and Rich, P. Modification of nicotine toxicity by pretreatment with different drugs. Biochem Pharmacol 18 2145, 1969. Beckett, A.H. Gorrod, J.W. and Jenner, P. The analysis of nicotine-1'-oxide in urine, in the presence of nicotine and...

Effects of Ethanol on Cocaine Metabolism and Disposition in the

Bosron, Frederick M. Zachman, Jing Zhang, and Monica R. Brzezinski Abuse of cocaine in combination with other drugs is a widespread practice (Washton and Gold 1987) and the coabuse of alcohol is particularly common, with 99 percent of cocaine addicts reporting excessive use of ethanol in one study (Newcombe and Bentler 1987). Simultaneous ingestion of ethanol also is common, as reported by 77 percent of cocaine users (Grant and Harford 1990). Thirty percent of cocaine...

Abused Drugs as Cofactors in AIDSRelated Infections

Another area of interest relevant to this work is the role of drug abuse in the pathology of AIDS (Pillai et al. 1991). Two particular research areas that would generate valuable information are drug exposure in animals infected with opportunistic infections and the potential reconstitution of suppressed immunity by drug treatment. In the first instance, opportunistic infections are normally benign organisms that often lead to fulminant infections in immunocompromised hosts. Examples include...

Alcoholdependent Formation Of Cocaethylene

Cocaethylene was detected in all tissues from alcohol-pretreated animals, as previously observed following intraperitoneal (IP) coadministration of cocaine and alcohol (Dean et al. 1992). Based on area under the concentration curves (AUCs) from 2.5 to 60 minutes, the amount of cocaethylene in liver and lung was 14 and 11 percent of the measured cocaine, respectively. Peak cocaethylene concentrations in liver, lung, and kidney were noted within 2.5 minutes after cocaine administration, the...

Benzyl Acetate

Benzyl acetate is widely used as a flavoring agent in the food industry and as a fragrant ingredient in a variety of consumer products such as soaps and lotions. The NTP conducted two 2-year carcinogenicity studies in F344 rats and B6C3F1 mice, one using the daily gavage administration and the other using dosed-feed administration. Although the daily doses of benzyl acetate were comparable between the two studies, hepatic tumorigenicity was only observed in the gavage studies of mice. In...

Catalytic Antibodies and Catalytic RNA

As discussed above, in vitro selection techniques have been used to isolate biocatalysts useful in the development of catalytic antibodies (Tawfik et al. 1990). While the cocaine catalytic antibodies reported thus FIGURE 5 dlntrniJ iaJ fpit'H< w) of < n Miiiboii),. FIGURE 5 dlntrniJ iaJ fpit'H< w) of < n Miiiboii),. SUUltCE H& rkvw muLLane I V& & . far do not possess impressive hydrolytic catalytic rate accelerations, the selection technology has nevertheless allowed the...

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Rapaka, Nora Chiang, and Billy R. Martin The Potential Role of the Cytochrome P-450 2D6 Pharmacogenetic Polymorphism in Drug Edward M. Sellers, S. Victoria Otton, and Rachel F. Tyndale Human Liver Cocaine William F. Bosron, Robert A. Dean, Monica R. Brzezinski, and Evgenia V. Pindel Effects of Ethanol on Cocaine Metabolism and Disposition in the Robert A. Dean, William F. Bosron, Frederick M. Zachman, Jing Zhang, and Monica R. Brzezinski Individual Differences in Nicotine Kinetics and...

Conclusions

The authors expect these studies will identify some drugs of abuse for which the EM state, the PM state, or CYP2D6 inhibitors can modify the risk of abuse explain why some drugs of abuse are so attractive or so toxic to some individuals explain why some patterns of drug abuse are endemic and rarely epidemic (e.g., PMA, dextromethorphan, smoked methamphetamine, phenethylamine designer drugs) identify the location of CYP2D in the brain and determine its role and importance for variation in drug...

Effect of tolerance to and abstinence from ltrans 9tetrahydrocannabin

An experimental model of tolerance abstinence for tetrahydrocannabinol (THC) exposure was also developed as illustrated in figure 7, and was used to evaluate the effect of THC exposure on immune function (Bhargava et al., submitted). Mice were injected subcutaneously (SC) with THC (10 milligrams per kilogram (mg kg)) twice daily for 4 days. On day 5, analgesic and hypothermic responses to THC were determined. Multiple injections of THC resulted in the development of tolerance to both the...

Effect of tolerance to and abstinence from morphine

In vivo exposure to morphine via implantable pellets was evaluated in female B6C3F1 mice using the model illustrated in figure 4. This system, originally developed in the rat to investigate pharmacological parameters (Bhargava and Matwyshyn 1985), was modified to accommodate immunological assessment in the B6C3F1 mouse (Bhargava et al. 1994). The model indicated a reproducible induction of tolerance, and was subsequently used to evaluate the effect of tolerance abstinence on immune function....

Enamine Derived Metabolites

Evidence for oxidative metabolism of the endocyclic enamines has been obtained for both 1-BP and PCP. In a previously reported (Masumoto et al. 1991) preparative scale metabolism of 1-BP, it was found that in addition to the C -C . coupled dimer 3, small amounts of 1-benzyl-3- piperidol (1-BP-3-ol), 1-benzyl-4-piperidol (1-BP-4-ol), and 1-benzyl-3-piperidone (1-BP-3-one) were obtained (figure 5). It was further found that cyanide reduced greatly the levels of 1-BP-3-one metabolite but not the...

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In studies designed to begin characterization of MND (Flammang 1994), it was found that MND activity could be destroyed by delipidation of the microsomes (exposure to detergent), and that activity of the protein pellet could be restored by addition of dilauroyl phosphatidyl choline. Kinetic studies revealed activities associated with both a low- and high-affinity binding of NAD+ but with a singular binding affinity of the iminium (Flammang 1994). Also, microsomes obtained from...

Fray r e i strut iurtu of

The hydrolysis of the benzoyl ester group of cocaine to ecgonine methyl ester and benzoate (figure 1) is catalyzed by serum cholinesterase (Stewart et al. 1977), also called pseudocholinesterase or butyrylcholines-terase, and a human liver carboxylesterase (Dean et al. 1991). The hydro-lysis of the methyl ester group of cocaine to benzoylecgonine and methanol (figure 1) occurs spontaneously in aqueous solutions at neutral to alkaline pH. However, the half-life of cocaine at pH 7.2 and 40 is...

Functional and Molecular Characterization of CYP2D6

The activity of CYP2D6 is measured using a subclinical dose of debrisoquin or another probe drug such as dextromethorphan. Using dextromethorphan, the amounts of unchanged drug and metabolite excreted in urine over zero to 8 hours are measured and expressed as an O-demethylation ratio (ODMR) (i.e., the ratio of dextromethorphan dextrorphan or (dextromethorphan + 3-methoxymorphinan) (dextrorphan + 3- hydroy- morphinan)). The frequency distribution of the logarithm of these ratios is bimodal...

Identification of Substrates Inhibitors of Human Hepatic CYP2D6

The authors have been conducting studies to identify drugs of abuse that interact with CYP2D6 enzyme in human liver microsomes. The results provide drug candidates for further studies aimed at determining whether they are CYP2D6 substrates (e.g., PMA, 3, 4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA)) or inhibitors of CYP2D6 (e.g., fluoxetine, (-)-cocaine). In table 3, competitive inhibitors of CYP2D6-catalyzed formation dextrorphan from dextrometh-orphan are...

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In an effort to elucidate the nature of endocyclic iminium-derived species that give rise to metabolism-dependent covalent binding and to clarify what factors govern the balance between toxic activation and detoxication at the iminium stage of cyclic tertiary amine metabolism, the authors initiated a series of studies to examine the effects of systematic structural changes at the level of simple piperidine and pyrrolidine derivatives as prototypes for PCP and nicotine, respectively. These...

Neurotoxicity of Amphetamines and Their Metabolites

Gibb, Michel Johnson, Ikram Elayan, Heng Keang Lim, Lisa Matsuda, and Glen R. Hanson When amphetamine or an analog is administered in repeated high doses, neurochemical deficits in both the dopaminergic and serotonergic systems of selected areas of the brain are observed. Methamphetamine (10 to 15 milligrams per kilogram (mg kg)), administered every 6 hours for 5 doses, decreases rat tyrosine hydroxylase (TH) activity and dopamine (DA) content in the neostriatum within 18 hours after...

Oxazepam

Oxazepam is a widely prescribed benzodiazepine antianxiety agent and a common metabolite of many other benzodiazepines including diazepam and chlordiazepoxide. To aid in the assessment of risks associated with human use of this drug, the comparative toxicokinetic studies were conducted in F344 rats, B6C3F1 mice, and Swiss-Webster mice of both sexes after an IV dose of 20 mg kg and oral gavage doses of 50, 200, and 400 mg kg (Yuan et al. 19946). In addition, since the NTP 2-year toxicology study...

Oxidation chemistry of 5ht and da

Location is a central question relevant to studies of the oxidation reactions of 5-HT and DA and the role of such reactions (and resulting products) in mediating methamphetamine's neurodegenerative properties. This question is important because the course of these reactions and the putative aberrant oxidative metabolites formed are likely to be strongly dependent on whether they occur in the synaptic cleft (Seiden et al. 1988 Seiden and Vosmer 1984 Commins et al. 1987 Marek et al. 1990c) or...

P450 Inactivation

Data on the ability of various amines and metabolic intermediates to inhibit microsomal benzphetamine demthylase activity are listed in table 2. This is the standard assay for the phenobarbital-inducible P- TABLE 2.Inhibition of benzphetamine N-demethylase activity. TABLE 2.Inhibition of benzphetamine N-demethylase activity. activity after pelleting resuspension 99 A 1 57 A 5 75 A 9 96 A 3 85 A 3 81 A 4 43 A 3 105 A 3 58 A 2 81 A 2 101 A 3 89 A 8 2,6-DMBP, -G6PD 2,6-DMBP, + G6PD 2,6-DMBP-Im+, -...

Rationale and methodology

For the screening portion, the data were obtained following in vitro exposure of drugs to isolated splenic lymphocytes and macrophages. This experimental paradigm allows for a high degree of precision in drug concentration delivered to target cells, utilizes only small amounts of test material and a limited number of animals, targets only the cells of primary interest, and facilitates a high-output screening approach. In spite of these important advantages, this in vitro exposure system does...

Results from in vitro screening studies

In general, drugs selected for testing in this study may be grouped into three general categories abused drugs previously demonstrated to suppress the immune response (e.g., heroin, cocaine) abused drugs that have not previously been associated with immune function alterations (e.g., lysergic acid diethylamide (LSD), methylenedioxymethamphetaine (MDMA)) and drugs with therapeutic potential for treating drug abuse (e.g., ibogaine). For the purpose of summarizing the findings of the in vitro...

Shortterm effects of mdma metabolites

In the studies cited above, the authors determined the effects of MDMA metabolites 5 to 7 days after administering the drug. In other experiments (described below), rats were administered 1 mol of THA, THM, or DHM ICV and the response was determined 3 hours later. THA decreased TPH activity to 79 percent of control in the neostriatum, but in the hippocampus enzyme activity was markedly decreased to 8 percent of control. THM decreased striatal TPH activity to 87 and 54 percent of control in the...

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Uptake euaidtgradait n of t nandtw kit fry neurtjfalQStornit f rttid ullTttttU (G) I ttii ay a fitncUOn r> j JJrKf. f'tlf-Anandamide (12 nC i J htat added If the veil cuttHri. flWiffa. Vjr ffjJi jtVjir fiyt'iiiti-a tn> tn tfi4 Media and Cttti were flrraty& fj by find nuiomdiography to detect fitiated mantiumitff (A) md ta putative mfinbolibrn UttaLhidvnit atidiM i trishttfyi* (TGi. W cho tttftt ester (CF.y i 'hi'jj fit ltpKh fff iuinerf ill the (> ri i)t in one set of...

Volatilization of heroin

Heroin represents a logical choice for establishing inhalation procedures. Smoking and inhalation of heroin, known as chasing the dragon, have largely replaced opium smoking for almost a century. It has become the most popular method of heroin use in recent years due to searches for alternatives to IV injections and the drug's increased availability. The most common method of smoking heroin involves heating the drug on a piece of aluminum foil and inhaling the vapor. An often reported...

Biocatalysts in Detoxication of Drugs of Abuse

Detoxication of drugs of abuse has generally followed a traditional approach involving pharmacological intervention in the biochemical action of the abused substance. This intervention has usually taken the form of the development of inhibitors or antagonists of biological macromolecules such as central nervous system (CNS) receptors. Some of the shortcomings of this approach include the fundamental biological activity of the antagonist, the possible occurrence of side effects or...

Individual Differences in Nicotine Kinetics and Metabolism in Humans

Benowitz and Peyton Jacob III Cigarette smoking remains the major preventable cause of premature disability and death in developed countries (Peto et al. 1992). Cigarette smoking is maintained by addiction to nicotine. Nicotine addiction develops in most people before the age of 20 (Department of Health and Human Services 1994). Many youth experiment with cigarettes, but only about 25 percent of high school seniors become addicted smokers (Escobedo et al. 1993). Thus, there appears to...

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Nicotine is metabolized via cytochrome P450 (CYP 450) to nicotine iminium ion, and then by aldehyde oxidase to cotinine (figure 1). Cotinine is the major proximate metabolite of nicotine, with 70 to 80 percent of nicotine metabolized to cotinine in most smokers (Benowitz and Jacob 1994). Cotinine is, in turn, metabolized to trans-3'-hydroxy-cotine, which is the most abundant nicotine metabolite in the urine of most smokers. Nicotine-N'-oxide is formed via a flavoprotein enzyme and is a minor...

Individual variation in nicotine and cotinine kinetics

As expected by analogy to other weak bases that are extensively metabolized, there is considerable individual variability in the clearance of nicotine. Early studies on nicotine kinetics were performed by infusing nicotine in smokers who were abstinent from tobacco (Benowitz et al. 1982 Rosenberg et al. 1980). However, it is most relevant to investigate the disposition kinetics of a drug in the chemical environment where the drug is normally used. Using labeled compounds, one can study the...

Nicotine Disposition In Smokers And Nonsmokers

Cigarette smoke contains a variety of chemicals, including polycyclic aromatic hydrocarbons, that may affect the metabolism of various other drugs. For example, smokers are well known to have increased metabolic activity of liver CYP 1A2, which results in the accelerated metabolism of caffeine, theophylline, and other drugs (Dawson and Vestal 1982). Earlier research had suggested that smokers metabolize nicotine more rapidly than nonsmokers (Kyerematen et al. 1982, 1990). If true, this might be...

Deficient Coxidation Of Nicotine

While most people metabolize nicotine extensively into cotinine, a few individuals have been identified who generate very little cotinine. One such person, a 57-year-old woman, was identified in a smoking cessation trial. The subject was found to have unexpectedly low plasma concentrations of cotinine, but normal concentrations of nicotine (Benowitz et al. 1995b), both while smoking and while using nicotine patches. This individual was studied using a dual infusion of labeled nicotine and...

Ethnic differences in nicotine and cotinine metabolism

Ethnic differences in nicotine metabolism have been hypothesized to contribute to differences in health effects and or susceptibility to addiction in blacks versus whites (Henningfield et al. 1990). The intriguing observation has been made that cotinine levels per cigarette smoked were significantly higher in blacks versus whites (Wagenknecht et al. 1990). In contrast, plasma levels of thiocyanate, a marker of exposure to cigarette smoke in general, were similar. There is also evidence that...

Tobacco Addiction

Tobacco addiction is complex, and involves behavioral as well as pharmacologic factors. The importance of nicotine in tobacco dependence has been demonstrated in many studies (Benowitz and Jacob 1990 Surgeon General 1988). However, the neurochemical mechanisms of nicotine tolerance and dependence are not known, and the possibility exists that a reactive metabolite may be involved. Thus, identification of nicotine-derived electrophilic metabolites that covalently modify human proteins may...

The Cytochrome CYP2D6 Genetic Polymorphism

Cytochromes P-450 (P450s) are enzymes involved in the oxidative metabolism of a wide array of endogenous and exogenous molecules including steroids, plant metabolites, prostaglandins, biogenic amines, drugs, and chemical carcinogens. This broad spectrum of reactions is due to multiple P-450 isozymes with differing but overlapping substrate specificities. The mammalian P-450 superfamily consists of at least 12 families and over 400 individual genes (Nelson et al. 1993). Genetic variants of P-450...

Inhalation exposure of drugs of abuse in the mouse inhalation model pharmacological assessment

Although drug volatility can provide fundamental information about the inhalation potential for drugs of abuse, it is only one of many factors necessary for producing a pharmacological effect. Pharmacokinetic and pharmacodynamic considerations have considerable bearing on a drug's ability to produce an effect. Presently, relatively little is known about the potency of drugs of abuse after inhalation or smoking. In order to deter-mine the relationship between volatility and pharmacological...

Enzymes in snicotine metabolism and detoxication

Application Enzymes Diagnosis

( -Nicotine1 is one of the most widely used psychoactive drugs in the world. Almost 25 percent of adult Americans smoke despite convincing evidence of the health hazards of smoking (Surgeon General 1988). Nicotine causes complex CNS, behavioral, cardiovascular, and endocrine neuromuscular effects in humans (Benowitz 1988). Most notably, nicotine is the primary cause of tobacco addiction in humans (Surgeon General 1988). The molecular basis for tobacco addiction is unknown but it is possible...

Individual Differences In The Metabolism Of Nicotine To Cotinine

By simultaneously infusing labeled nicotine-d2 and cotinine-d4, and by measuring levels of cotinine-d2 generated from nicotine-d2, the fractional conversion of nicotine to cotinine can be determined (Benowitz and Jacob 1994). An example of data generated by such a study is shown in figures 6a and 6b. Using this approach in 20 smokers, it was determined that on average 72 percent of nicotine is converted to cotinine (range 55 to 92 percent) (figure 7). No differences in the clearances of...

Catalytic antibodies for treatment of drug abuse

Another experimental approach for the treatment of drug abuse is the use of catalytic antibodies. The idea behind this treatment is to create an artificial, antibody-based enzyme that can convert the parent drug to an inactive metabolite. This catalytic antibody would then be administered in medical emergencies for overdose or perhaps administered on a chronic basis to persons trying to withdraw from addiction to the drug. In the field of drug abuse, the possibility of using cocaine catalytic...

Relevance of CYP2D6 to Drug Abuse

A number of drugs of abuse are known substrates (e.g., codeine, hydrocodone, p-methoxyamphetamine, amphetamine) or inhibitors (e.g., (-)-cocaine, pentazocine) of CYP2D6. For some of these drugs, the pharmacokinetic differences due to the polymorphism will be so profound that they are likely to exceed pharmacodynamic sources of variation in response. For other drugs (e.g., hydrocodone to hydromorphone, codeine to morphine, oxycodone to oxymorphone), CYP2D6 may not contribute importantly to the...

Structurereactivity Relationships For Cocaine Carboxylesterases

The human liver cocaine methyl and benzoyl carboxylesterases catalyze the hydrolysis of the acetyl group of 4-methylumbelliferyl acetate with specific activities of 6.8 and 140 mol (min B mg protein), respectively. With cocaine as substrate, however, the cocaine methyl and benzoyl estereases exhibit lower specific activities, but show absolute specificity for the methyl ester group and the benzoyl ester group, respectively. A high specificity for binding of cocaine derivatives to proteins or...

Vapor pressure and volatility

In general, absorption of inhaled drug is dependent upon the physical characteristics of the drug, including particle size, lipid solubility, and volatility. Clearly, a drug's volatility would play an important role in determining its inhalation potential. Drug volatility is determined by many factors, including boiling point, melting point, and vapor pressure. Since many abused substances are less volatile than organic solvents and are smoked would be negligible. On the other hand, vapor...

CYP2D Enzyme in Brain

Catalytic, pharmacological, immunological, and molecular criteria have been used to identify cytochrome CYP2D in mammalian brain Fonne-Pfister et al. 1987 Niznik et al. 1990 Tyndale et al. 19916 . The initial observation of CYP2D in dog brain was made during screening of central and peripheral tissues with tritiated GBR-12935, which labels the dopamine transporter protein and the so-called piperazine acceptor site or mazindol-insensitive site in brain tissue Niznik et al. 1990 . High...

Robert V House Peter T Thomas and Hemendra N Bhargava introduction

Drug abuse is a problem of increasing worldwide significance. In addition to the obvious socioeconomic problems associated with the use of so-called street drugs, the abuse of ethical pharmaceuticals may also result in serious untoward health effects depending upon a wide range of variables Chiang and Goldfrank 1990 . One possible medical complication of drug abuse is modulation of the immune system, or immunotoxicity Pillai and Watson 1990 . The immune system is a highly regulated organ system...