Saturday, January 25, 2020

Enantioselective Disposition of MDMA and its Metabolites

Enantioselective Disposition of MDMA and its Metabolites INTRODUCTION Amphetamine-type stimulants (ATS) are a group of drugs, mostly synthetic in origin, that are structurally derived from ÃŽ ²-phenethylamine (Figure 1). Amphetamine (AMP, Speed) was initially synthesized in Berlin in 1887 as 1-methyl-2-phenethylamine. It was the first of several chemicals, including methamphetamine (MET, Ice) and 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy), which have similar structures and biological properties, and are referred to collectively as amphetamines (Cody, 2005). Since 1887, amphetamine was thought to be a human invention (Berman et al., 2009), but the compound was found in 1997, along with methamphetamine, nicotine and mescaline, within two species of Texas acacia bushes (Clement, Goff and Forbes, 1998). AMP and MET are most commonly abused drugs. They have asymmetric centre and exists as one of the two possible enantiomers (see Figure 2) (Cody, 2005). In attempt to maintain anorexic activity while limiting undesirable side effects, substitutions have been made to amphetamine and methamphetamine. Others have been made to enhance the stimulatory activity or to avoid legal restrictions on the manufacture and use of the drugs (Cody, 2005). The related groups of amphetamine derivatives are shown in Figures 3 and 4. Figure 5 shows another group of precursor drugs that is metabolized by the body into AMP and MET. Administration and neurotoxicity of amphetamines Amphetamines are generally administered as oral capsules. This route results in a gradual increase in drug concentration, which peaks in around an hour and maintains effective drug levels for 8 – 12 hours. Amphetamines can also be injected into the circulation (Parrott et al., 2004). Amphetamines readily cross the blood-brain barrier to reach the sites (Berman et al., 2009) of action in the brain. The acute administration of amphetamines produce a wide range of dose-dependent behavioral changes, including increased arousal or wakefulness, anorexia, hyperactivity, perseverative movements, and, in particular, a state of pleasurable affect, elation, and euphoria, which can lead to the abuse of the drug (Berman, 2009). This causes amphetamines to be associated with acts of violence. Acute drug abusers will develop tolerance, where the same dose of drug has diminishing physiological and psychological effects. They need to increase their dosage if they wish to generate the same stre ngth of effect. Cross-tolerance will also occur as tolerance to one drug affects another drug with similar neurochemical profile. As a result, drug abusers will seek for another class of drug and become polydrug users (Parrott et al., 2004). Chronic drug abusers usually take in amphetamines through injection or smoking ice amphetamines. These abusers suffer many health problems and a reduced life expectancy. They are more susceptible to HIV (human immunodeficiency virus), AIDS (acquired immunity deficiency syndrome) and SIDS (sudden infant death syndrome) (Parrott at al., 2004). Clinical uses In accordance with the Convention on Psychotropic Substances of 1971, amphetamines are enlisted as narcotic compounds in the List of psychotropic substances under international control. The list is prepared by the International Narcotics Control Board. These compounds are prohibited to be imported and exported in countries like Japan, Nigeria, Pakistan, Thailand and etc (International Narcotics Control Board, 2003). Amphetamines and related compounds are clinically used for narcolepsy (sudden day-time onset sleep) and Attention Deficit Hyperactivity Disorder (ADHD) in young children. It was formerly used as a short-term slimming agent, as an antidepressant and to boost athletic performance (Parrott et al., 2004). 3,4-METHYLENEDIOXYMETHAMPHETAMINE (MDMA, ECSTASY) History of MDMA abuse MDMA, also known as ecstasy, ETC, or Adam, is one of the most commonly abused amphetamine derivatives that was re-synthesised by Alexander Shulgin during his research career at the Dow Chemical Company in 1970s. Soon MDMA was being synthesised in illicit laboratories, and became popular as recreational drug since then. As MDMA does not have any clinical/medical use, it is scheduled as Class I illicit drug by the American Drug Enforcement Agency in 1985 (Parrott et al., 2005). Also, MDMA other ring-substituted phenylethylamines were generically classified under the Misuse of Drugs Act as Class A drugs, in United Kingdom (Wikipedia, 2009). Chemical Properties of MDMA The methylenedioxy analogues of amphetamine (see Figure 3) are series of compounds referred to designer drugs. They include methylenedioxyamphetamine (MDA), methylenedioxyethylamphetamine (MDEA) and MDMA (Hensley and Cody, 1999). The synthesis of N-alkyl-MDA derivatives only produces ( ±) racemic mixtures. As a results, only racemic forms of (capsules, loose powder or tablets) the compounds are sold in the illicit market and abused (Matsushima, Nagai and Kamiyama, 1998; Fallon et al., 1999). MDMA is chiral, possessing two enantiomers, S-(+)-MDMA and R-(-)-MDMA (see Figure 6), with S-(+)-MDMA is more potent than R-(-)-MDMA (Lyon, Glannon and Titeller, 1986; Shulgin 1986). The basic structure of MDMA is ?-phenylisopropylamine group (see Figure 6), with a methylenedioxy group forming a 5-membered ring including C-3 and C-4 of the benzene ring (Cho and Segal, 1994). The empirical formula of MDMA is C11H15NO2 (Shulgin, 1986). MDMA is a phenylisopopylamine derived from safrole, aromatic oil found in sassafras, nutmeg, and other plants. The methyl group on ÃŽ ±-carbon (R2) (see Figure 6) of MDMA confers resistance to oxidative deamination of this compound and, therefore, increased its metabolic half-life (Cho and Segal, 1994). According to Cone and his colleague Huestis (2009), S(+) isomer of MDMA is responsible for its psychostimulant and empathic effects and the R(-) isomer for its hallucinogenic properties. Uptake, absorption, metabolism and elimination of MDMA in human body MDMA is usually formulated in tablets of its racemate (1:1 mixture of its enantiomers) in doses ranging from 50 to 200 mg (Pizarro et al., 2004), which is most commonly sold in batches of 3–5 for ?10 (Wikipedia, 2009). MDMA powder is also found in the market at a higher price, indicating that it has higher purity. MDMA powder is not usually insufflated (snorted) as it causes sneezing, pain and nosebleeds. MDMA cannot be smoked and is very rarely injected intravenously (AMCD, 2008). MDMA is absorbed into the blood streams and distributed in body. Postmortem analysis by Letter et al. (2002) shows that MDMA is distributed in cardiac muscle, both lungs, liver, both kidneys, spleen, the four brain lobes, cerebellum and brainstem, adipose tissue, serum, vitreous humor, urine, hair and bile upon administration. Rapid distribution of MDMA in body is mainly due to its basic property of pKa around 9.9 and low plasma protein binding, MDMA can diffuse across biological matrices that is more acidic than blood (Pichini, 2005). After an oral administration of MDMA, the plasma concentration peaks in within 1.5 to 2 hours (Cone and Huestis, 2009). MDMA is metabolized by multiple pathways (see Figure 7), primarily involving N-demethylation and O-demethylenation. The enzymes involved in the pathway are a group of cytochrome P450 isoenzymes, including CYP1A2, CYP3A4, and CYP2B6. Firstly, MDMA is O-demethylenated to 3,4-dihydroxymethamphetamine (HHMA) followed by O-methylation to 4-hydroxy-3-methoxymethamphetamine (HMMA). The enzymes involved in the metabolic process are CYP2D6 and catechol-methyltransferase respectively. At a lower rate, MDMA is N-demethylated to 3,4-methylenedioxyamphetamine (MDA) (a reaction regulated by CYP2B6), which is further metabolized to the catechol intermediate (3,4-dihydroxyamphetamine) and finally O-methylated to 4-hydroxy-3-methoxyamphetamine (HMA). In the reactions, the ÃŽ ±-carbon responsible for stereochemical properties of MDMA is not affected and all the metabolites are chiral compounds that may be presented as a mixture of their enantiomers. In addition to these major compounds, some other minor metabolites derived from the activity of monoamine oxidase on the amine residue are also formed (Kolbrich et al., 2008; Pizarro et al., 2004). N-demethylation of MDMA yields 3,4-methylenedioxyamphetamine (MDA), an active metabolite exhibiting similar pharmacological properties as the parent drug. A further O-demethylenation of MDA produces 3,4-dihydroxyamphetamine (HHA) which is mainly regulated by CYP2D6. Additional metabolites are formed by O-methylation of HHMA to 4-hydroxy-3-methoxymethamphetamine (HMMA) and of HHA to 4-hydroxy-3-methoxyamphetamine (HMA), deamination, and conjugation (Cone and Huestis, 2009). The metabolic pathway mainly happens in the liver. Some people with reduced CYP2D6 shows lower metabolic rate of MDMA and thus are more susceptible to MDMA toxicity (ODonohoe et al., 1998; Schwab et al., 1999). Physiological and psychological effects of MDMA Berman et al. (2009), Hensley and Cody (1999) and Piper (2008) reported an increased alertness and euphoria, increased heart rate, blood pressure, respiration and body temperature upon administration of MDMA. United Nation Office on Drugs and Crime (2006) conveys that chronic amphetamines abuse causes agitation, tremors, hypertension, memory loss, hallucinations, psychotic episodes, paranoid delusions, and violent behavior. Withdrawal from high doses of amphetamine-type stimulants (ATS) could result in severe depression. MDMA impairs the temperature control by hypothalamus. This causes MDMA users to die of hyperthermia (Piper, 2008) and some die from hyponatraemia, i.e. the dilution of blood due to excessive fluids taken to counteract heat exhaustion (Parrott et al., 2004). Neurotoxicity of MDMA Nichols (1986) and Vollenweider et al. (1998) categorize MDMA as entactogens, a special class of drug that produce changes in mood, social interactions or feelings of interpersonal closeness and changes in perception. MDMA shares some of the pharmacological effects of stimulants and serotonergic hallucinogens (Cami et al. 2000; Gouzoulis-Mayfrank et al. 1999; Liechti Gamma and Vollenweider, 2001; Tancer and Johanson 2003). MDMA acts an agonists on various neurotransmitters action especially serotonin. Boost in serotonin turnover induced by MDMA tends to generate feelings of contentment, elation, liveliness and intense emotional closeness to others. This causes people to enjoy themselves without their normal concerns and inhibitions. MDMA is classified as neurotoxin. Studies have found evidence for dopaminergic nerve destruction in higher brain regions. As shown in Table 2, the higher brain function such as memory, information processing and storage, complex stimulus analysis and decision making of MDMA users are impaired. CHIRAL DRUG ANALYSIS Chirality Chirality is formally defined as the geometric property of a rigid object (like a molecule or drug) of not being superimposable with its mirror image (McConathy and Owen, 2003). Achiral molecules can be superimposed on their mirror images. Molecules that are not superimposable with their mirror images are said to be chiral. Each chiral molecule will have at least one chirality centre or stereogenic centre (Leffingwell, 2003). Chirality centre of an organic molecule is usually a carbon atom, bonded to four different groups of atoms. Chiral molecules with one chirality centre exist in two enantiomeric forms (see Figure 8). The two mirror images are termed enantiomers. Both molecules of an enantiomer pair have the same chemical formulae and can be drawn the same way in 2 dimensions but in chiral environments such as the receptors and enzymes in the body, they will behave differently. Enantiomers are identical in all physical properties except for their optical activity, or direction in which they rotate plane-polarized light (McMurry, 2004). Some optically active molecules rotate polarized light to the left (levorotatory) while others to the right (dextrorotatory) (Baker, Prior and Coutts, 2002). A racemate (often called a racemic mixture) is a mixture of 1:1 amount of both enantiomers of (+) and (-) enantiomers and is optically inactive. The optical inactivity results from the rotation caused by one enantiomer canceling out that produced by its complementary enantiomer (Beesley and Scott, 1998). The absolute configuration at a chirality center is designated as R or S to unambiguously describe the 3-dim ensional structure of the molecule. R is from the Latin rectus and means to the right or clockwise, and S is from the Latin sinister for to the left or counterclockwise (McConathy and Owen, 2003; Baker, Prior and Coutts, 2002). Pharmacological aspect of chiral drugs In pharmacology, chirality is an important factor in drug efficacy. About 56% of the drugs currently in use are chiral compounds, and about 88% of these chiral synthetic drugs are used therapeutically as racemates (Leffingwell, 2003). As previously mentioned, MDMA is a chiral drug that exists in two enantiomeric forms as shown in Figure 6. Chemical modification at the positions R1 to R9 (refer to Figure 9) of MDMA results in unlimited number of pharmacologically active compounds, some of which are more potent stimulants than others. Although there are several possibilities for side chain modification, substitution on the aromatic ring contributes the most to substantial qualitative differences in pharmacological effects. Hence, it is important to discriminate between the enantiomers present in the drugs administrated as both the enantiomers of a chiral drug may differ significantly in their bioavailability, rate of metabolism, metabolites, excretion, potency and selectivity for receptors, transporters and/or enzymes, and toxicity (McConathy and Owen, 2003). The difference in interaction between a chiral drug and its chiral binding site is illustrated in Figure 10. The different domain of a drug molecule has different binding affinity towards the active site of biochemical molecules in the body. As shown in Figure 10, it is obvious that the active enantiomer has a 3-dimensional structure that allows drug domain A to interact with binding site domain a, B to interact with b, and C to interact with c. In contrast, the inactive enantiomer cannot be aligned to bind the same 3 sites simultaneously. Due to the difference in 3-dimensional structure, binding of the active enantiomer exerts a biological effect, while the inactive enantiomer does not possess any (McConathy and Owen, 2003). The hypothetical interaction of drug enantiomers is supported by the studies done by Matsushima, Nagai and Kamiyama (1998) and Kolbrich et al. (2008) shows that stereoselective cellular transport of MDMA allows the drug to accumulate at different extent in biological matrices. According to ODonohoe et al. (1998) and Schwab et al. (1999), stereoselectivity also affects genetic differences in the expression of metabolic enzymes that are responsible to metabolize MDMA in the body. For example, CYP2D6 is expressed as 2 phenotypes; one being extensive and another as poor metabolizers. Thus, it is obvious that the stereospecificity of a chiral drug can alter absorption, elimination and cellular transport of the drug itself. Analytical aspect of chiral drugs Approximately 50% of marketed drugs are chiral, and of these approximately 50% are racemix mixtures of enantiomers rather than single enantiomers (McConathy and Owen, 2003). Differences in pharmacokinetic and pharmacodynamic activities of the enantiomers of drugs administered as racemates are increasingly appreciated (Porter, 1991). Thus, quantification and qualification of drugs of abuse play important roles in the prediction of and protection from the risk to human health (Nakashima, 2006). Two main approaches to chiral drug analysis have been taken. In the indirect approach, the drug enantiomers are derivatized with an optically pure chiral reagent to form a pair of diastereomers, which may then have sufficiently different physical properties for separation to occur on conventional chromatographic columns (UNODC, 2006; Porter, 1991). In the direct approach, the enantiomers form transient rather than covalent diastereomeric complexes with a chiral selector present either in the mobile or the stationary chromatographic phase (Porter, 1991). Each of these analytical approaches has advantages and disadvantages prevail, depending upon factors such as time, purity, chemical processing, and inherent side reactions (Carvalho et al., 2006). Indirect chiral drug analysis In order to successfully resolve the enantiomers, a stable, optically pure chiral derivatizing reagent (CDR) has to be available for the covalent formation of diastereomeric derivatives (Porter, 1991). Diastereoisomers of amphetamine-type stimulants can be prepared using different reagents such as acylchlorides, alkylsulphonates, isothiocyanates, chloroformates. Moshers acid [R(+) or S(-)-methoxy(trifluoromethyl)phenylacetic acid], Moshers acid chloride, and N-trifluoroacetyl-1-prolyl chloride (TPC, also known as TFAP-Cl) are the most popularly used chiral derivatizing agents (UNODC, 2006). The reaction scheme may be illustrated as follows: The purity of the chiral derivatizing agent is vital in the process of separation of the racemic mixture. The resolution of a racemic drug by the R-enantiomer of a CDR contaminated with its S-enantiomer causes an additional pair of diastereoisomers to be formed, each of which is the enantiomer of one of the first pair (Porter, 1991), as shown in Figure 12. As a result, the enantiomers R-R, S-S and S-R, R-S would coelute in conventional chromatographic systems due to their similar physical properties. Racemization during the reaction would bring about analytical error especially when attempting to quantitate small quantities of one enantiomer in the presence of a large excess of its antipode (Porter, 1991). Methods using chiral derivatization are essentially less expensive and do not require specialized equipment or columns. The use of normal, achiral columns allows easy integration of chiral separations into routine analysis schemes (UNODC, 2006). Thus, considerable flexibility in chromatographic conditions is available to achieve the desired resolution and to eliminate interferences from metabolites and endogenous substances. Moreover, a reasonably good selection of chemically and optically pure CDRs is available for derivatizing various functional groups (Porter, 1991). Direct chiral analysis Chiral gas chromatography (GC), High Performance Liquid Chromatography (HPLC) or Capillary Electrophoresis (CE) are popular methods in direct analysis of illicit drugs (UNODC, 2006). Direct analysis does not require a CDR for covalent diastereomeric complexation. Instead, separation of chiral drugs occurs via the interaction between the enantiomers and a chiral selector. The chiral selector is an optically active compound that may be present in the mobile phase for use with conventional HPLC columns or it may be incorporated into the stationary phase to provide specialized chiral stationary phases (Porter, 1991). Calvalho (2006) lists the most successful chiral packing materials i.e. amylose, Pirkle type stationary phase, cyclodextrin, proteins, and cellulose ester and carbamate derivatives used in GC. Sometimes, derivitization may be carried out with a nonchiral reagent, in order for appropriate molecular interactions with the chiral discriminator to occur and/or to impart requisite spectral or fluorescent properties to the molecule (Porter, 1991). HPLC with fluorescence detection method is done by Al-Dirbashi et al. (1999) in attempt for the determination of methamphetamine in human hair. Nakashima (2006) claimed that the use of a chiral stationary phase in GC to separate pairs of enantiomers after suitable derivatization with an achiral reagent is able to achieve a powerful separation. Recently CE has become a highly competitive tool for chiral analysis of many compounds since it allows for the highly efficient separation of enantiomers without derivatization and specialty columns (capillaries) (Porter, 1991; Ramseier, Caslavska and Thormann, 1999). For the separation of amphetamine-type stimulant using CE, chiral additives such as hydroxyl-propyl beta-cyclodextrin are added in the running buffer. This eliminates the need of derivatization in analysis of chiral drugs commonly used (Iio et al., 2005; Ramseier, Caslavska and Thormann, 1999). Separation of chiral drugs using gas chromatography UNODC (2006), Pirnay, Abraham and Huestis (2006) and Rouen, Dolan and Kimber (2001) agree that gas chromatography/mass spectrometry (GC/MS) is the most common instrumental technique for analysis of amphetamines and derivatives. However, GC/MS still has its limitations. Chiral gas chromatography is selected as the separation technique if the materials are volatile and stable at elevated temperatures. In addition, if the solutes can be derivatized to form a sufficiently volatile product without racemizing the enantiomers, or changing their racemic proportion, then GC may be the choice. GC offers much higher efficiencies, much higher peak capacities and significantly higher sensitivities than LC. It follows, that GC can easily contend with multicomponent mixtures, especially mixtures from biological samples. In addition, the columns have short equilibrium times, trace impurities are easily assayed, and the analyses are shorter providing much faster sample throughput (Beesley and Scott, 1998). Prior to analysis by GC, compounds containing functional groups with active hydrogens such as COOH, OH, NH, and SH have to be derivatized. This is because these compounds tend to form intermolecular hydrogen bonds, hence reducing volatility of the compounds in the machine. They are also thermally unstable and can interact with either fused silica or the stationary phase, causing peak broadening (Danielson, Gallgher and Bao, 2000). Most underivatized amphetamine-type stimulants (ATS) have fragment ions of low m/z ratio, low intensity, and only one fragment ion of higher abundance (base peak). Derivatized ATS usually produces fragment ions of higher m/z ratio and higher abundance. Molecular ions with greater molecular mass have greater diagnostic value, due to the reason that they are not affected by interfering background ions such as column bleed or other contaminants (UNODC, 2006). Capillary electrophoresis as a complementary method in the analysis of MDMA According to Meng et al. (2006), capillary electrophoresis (CE) can be used to complement GC and HPLC methods of amphetamines analysis due to their high efficiency, accuracy, very high resolution, and tolerance to biological matrices. Capillary electrophoresis utilizes the electrical nature of charged molecules and enables the separation of molecules based on charged in an applied electrical field (Landers, 1995). MDMA is an organic compound and so its enantiomers are not charged. Hence, for the separation of enantiomers of MDMA, micellar electrokinetic chromatography (MEKC) is utilized (Beesley and Scott, 1998). This is a modified electrophoresis system in which the chiral selector is added to the electrolyte as additives, or be immobilized on the capillary tube surface as a traditional type of stationary phase (Beesley and Scott, 1998). The applied voltage causes the analytes to migrate through the capillary and being separated (Landers, 1995). Figure 13 shows the instrument used for micellar electrokinetic chromatography (MEKC). As seen in the figure, during sample separation, the individual analytes are driven in the appropriate direction by their inherent electrophoretic mobility (neutral species are static, anionic species move towards the anode, and cationic species move towards the cathode) with a magnitude represented by the arrows. Concurrently, the EOF of buffer towards the cathode, with a magnitude greater than the individual electrophoretic mobilitles, results in electrophoretic zone formation as all analytes (neutral, positive, and negative) are swept past the detector (Landers, 1995). The detector produces an electropherogram that is almost the same as the one obtained from the gas chromatography (see Figure 14). The chiral selector used in micellar electrokinetic chromatography is usually beta cyclodextrin. Cyclodextrin is an oligosaccharide with an external hydrophilic surface and a hydrophobic cavity, in which they can include other compounds by hydrophobic interaction (Tagliaro, Turrina and Smith, 1996). This allow for the separation of molecules with different sizes, charges and polarity. The aim of this literature review is to investigate the effectiveness of GC/MS and CE in the analysis of MDMA enantiomers. Not only that, the enantioselective disposition of MDMA in hair and urine is also reviewed. The use of hair and urine as a medium for drug detection is also explored. CASE STUDY Urine analysis Urine is the most widely used biological specimen for the analysis of illicit drugs (Nakashima, 2006; Rouen, Dolan and Kimber, 2001). According to Ramseier, Caslavska and Thormann (1999), urinary screening of drugs of abuse is usually performed with immunoassay, whereas GC/MS is the standard approach employed for confirmation of the presence and absence of a specific drug or metabolite. The goal of urine drug testing may be stated as the reliable demonstration of the presence, or absence, of specified drugs or metabolites in the specimen (Chiang and Hawks, 1986). Despite a number of persistent shortcomings, such as its susceptibility to tampering, urinalysis is a well-researched technology in which most of the problems have been identified and addressed, if not resolved. It offers an intermediate window of detection making test scheduling an important issue in many situations (Rouen, Dolan and Kimber, 2001). The Physiology of Urine Production Blood is drained through the kidney in the rate of 1.5 litres per minute. Ultrafiltration of blood that occurs at the kidney leads to the production of urine continuously. During urine production the kidneys reabsorb essential substances. Excess water and waste products, such as urea, organic substances and inorganic substances, are eliminated from the body. The daily amount and composition of urine varies widely depending upon many factors such as fluid intake, diet, health, drug effects and environmental conditions. The volume of urine produced by a healthy adult ranges from 1-2 litres in a 24 hour period but normal values outside these limits are frequently reported (Rouen, Dolan and Kimber, 2001; Pichini, 2005). Incorporation of Drugs into Urine The possible ways of drug disposition in the human body is shown in Figure 15. When a drug is smoked or injected, absorption is nearly instant and excretion in urine begins almost immediately. According to Pichini (2005), 80% of the drug is metabolized by the liver, leaving 20% of the drug to be excreted unaltered. However, absorption is slower when a drug is orally administered and excretion may be delayed for several hours. Generally, a urine specimen will contain the highest concentration of parent drug and metabolite within 6 hours of administration. As for MDMA, the peak concentration is reached after 2 hours of administration (Cone and Huestis, 2009). As drug elimination usually occurs at an exponential rate, for most illicit drugs a dose will be eliminated almost completely within 48 hours. A number of factors influence the detection times of drugs in urine including the quantity of drug administered, parent drug and its metabolite half-life, cut-off level used, and a number of physiological factors. Fallon et al. (1999) reported that the plasma half-life in humans of (R)-MDMA (5.8  ± 2.2 h) was significantly longer than that of (S)-MDMA (3.6  ± 0.9 h). It is also noted that for many of drugs, frequent, multiple dosing over extended periods of time can cause the drug to accumulate in the body resulting in significantly extended detection times, and leads to the possibility of hair analysis which will be discussed in the later part. The detection times in urine are significantly greater than the detection times in blood because most drugs are rapidly eliminated from blood both by the bodys metabolic system and by excretion into urine (DuPont and Baumgartner, 1995). As the bladder is emptied only a few times during the day, the urine becomes a reservoir of drugs and metabolites (AIC Research and Public Policy, 2003). According to DuPont and Baumgartner (1995), most abused drugs, including their metabolites, fall to low levels in the blood within a few hours of last drug use and so urine samples generally have a short surveillance window (SW) of about l-3 days (see Table 3). AIC Research (2003) also reported that longer detection time of drugs is due to high doses and high urine pH. Despite of its small detection time, urine testing is still a reliable and convenient way of investigating whether a person has abused drugs in the past few days. The comparison between commonly used specimens for drug analysis is shown in Table 3. Case Study One: Stereochemical Analysis Of 3,4-Methylenedioxymethamphetamine And Its Main Metabolites In Human Samples Including The Catechol-Type Metabolite (3,4-Dihydroxymethamphetamine) Objectives This case study aims to determine the enantioselective disposition of MDMA and its major metabolites, 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (HHMA) and 4-hydroxy-3-methoxymethamphetamine (HMMA) in human urine. The R versus S enantiomer of MDMA and its metabolites in urine samples after administration of known amount of MDMA is also calculated. Other than that, the use of indirect method in determining concentration of MDMA and its metabolites by chemical derivatization is also illustrated. Results and Discussion Urine samples were obtained from seven healthy recreational users of MDMA. They were given a single 100-mg oral dose of (R,S)-MDMA ·HCl (Pizarro et al., 2004). Participants were phenotyped with dextromethorphan for CYP2D6 enzyme activity and all were categorized as extensive metabolizers (Schmid et al., 1985). Urine samples were collected before and after drug administration at 0 to 2, 2 to 6, 6 to 12, 12 to 24, 24 to 48 and 48 to 72 hour time periods, acidified with HCl, and stored at around 20 °C until analysis (Pizarro et al., 2004). The samples and standard solutions were analyzed by GC/MS using achiral column with 5% phenyl 95% dimethylpolysiloxane cross link (15 m Ãâ€" 0.25 mm Ãâ€" 0.25  µm film thickness) before and after a chiral derivatization. MDMA in the urine sample was derivatized using (R)-(-)-ÃŽ ±-methoxy-ÃŽ ±-trifluoromethylphenylacetyl chloride (Figure 16) in ethyl acetate/hexane (50:50) that contained 0.015% triethylamine as described by Pizarro et al. (2003). Derivatization step functions to induce volatility to the sample for GC analysis (Beesley and Scott, 1998). A baseline enantiomeric separation was obtained for all the studied compounds in a single run. Chiral analysis of plasma and urine samples was carried out by combining the extraction procedure developed for the high performance liquid chromatography analysis method for HHMA quantification (Segura et al., 2002) and derivatization steps developed for GC/MS determination of enantiomers of MDMA, MDA, HMMA, and HMA (Pizarro et al., 2003). Extraction and derivatization coupling was not achieved easily because chemical properties of extracted samples make it impossible for the target compounds to be derivatized. The presence of considerable amounts of HCl in t he elution mixture was responsible for the formation of the corresponding amine chlorhydrate salts making amine reaction unfeasible. An attempt using evaporation of extracts to eliminate HCl be

Friday, January 17, 2020

Examine the Ways in Which Feminist Sociologist Have Contributed to Our Understanding of Family Roles and Relationships.

Examine the ways in which feminist sociologist have contributed to our understanding of family roles and relationships. Feminist believe that women in society are oppressed and exploited by men, they are not seen as equal purely based on their gender. Women are therefore are expected to be subordinate to men resulting in women being disadvantaged in life. Radical feminists believe the family oppress women by patriarchal structures and the family itself.They believe the family benefits men as marriage acts as a prison, men do little in the family compared to women the sexual division in the family exploits women , since their responsibilities for domestic labour and childcare are unpaid, undermines their position in paid employment and increases dependency on men. It thereby maintains an unequal patriarchal society. Therefore radical feminist support divorce as it allows women to escape from marriage, they also support family diversity e. . , single parent families and same sex relati onships. Liberal feminism view the family as optimistic they see a gradual change, through persuasion women are getting men to become more involved in sharing the household and child rearing tasks and society has become fairer through its laws such laws as the sex discrimination act (1970) equal pay act (1970) the symmetrical family is becoming a reality women are getting more jobs and men are getting more involved around at home.D. H. J Morgan point out that not all families fit the model of the nuclear family with a married couple with children, where the husband is the breadwinner and the wife the housewife alone in fact, this is becoming less common and more women now work (1975). However liberal feminist don’t support family diversity and different family structures. Liberal feminists want to raise families in a heterosexual partnership; they don’t see means the enemy unlike radical feminist.They still, by think more can be achieved, by socialised to view the gend ers as equal which would eliminate gender roles. Difference feminist assumes families in general disadvantage women and benefit men. Helen Carby (1892) who was a black feminist believes that racism alongside patriarchal as a form of domination. They agree that for many black women the family can be an oppressive institution. However black women and men are oppressed by racism and that the family often acts a source of support and resistance to racial discriminations and harassment. Postmodern highlight differences etween groups of women in the family situation they avoid making generalisations and see each women situation different. Marxist feminist see the family serve the need of the ruling class. By socialising children into ruling class norms and values leading to a submissive and obedient workforce, with false consciousness and stability for capitalism. Women sever capitalism in two ways: as mothers they have children who will become the next generation of capitalists wage slav es, and as wives, women serve their husbands by doing everything with the family whilst he works.Parsons described the family as a warm bath, he believed that the family helps to relieve stress and tension from work, so he is refreshed for work the next day where he will be able to contribute to society. However for Marxist feminist, they believe the women freshens the man for work every day. This can be changed with the overthrow of capitalist and replacing it with communism will see men and women working alongside each other and becoming equal, childcare therefore will become communal responsibility.

Thursday, January 9, 2020

Research Proposals on Analyzing The Success Rate Of The Western Nations In Resolving The Arab-Israeli Conflict

Summary This research is aimed at getting in depth to the agenda of war between Israel and the Arabs. The Middle East conflict between these two nations has been growing larger with time. The impacts and relevance of this cold war cannot be overlooked by the international community and other nations, especially the Western countries. As a result, these countries have made certain endeavors in trying to end amicably this war. The big question however, concerns their collective mode of operations and efforts in relation to the levels of success achieved or yet to be achieved. Literature Review The fact that the Arab-Israeli conflict dominates international affairs is evident since a person can hardly go a day without finding this conflict in the newspapers. The significance of these countries to the western nation lies in various fields. Importantly though, is the fact that there is an economic interest of the western nations in relation to these Middle East countries. Recent trends and development of further interest by the western nations in relation to this conflict have amplified. Numerous individuals believe that the oil deposits in the Middle East, especially the one’s that are in the state of Israel, are of major interest to the western countries (Sapir, 2011, p 76). This is further amplified by the fact that the Arabs tie oil deposits to politics (Rubin, 1996, p 4). However the concerned nations, with the United States inclusive, tend to deny this fact. This is because linking oil questions to this matter is likely to increase Arab leverage on the United Sta tes. Further it may alarm the Israelis and hence make them reluctant in responding positively, or even considering concessions. The perception of the involvement of the United States in the conflict are widespread and varying (Allen Pijpers, 1984, p 193). The fact that the United States may be biased in dealing with this conflict is debatable. To a large extent, the United States government seems to be supporting the Israelites (Rea Wright, 1997, p 54). Further, the larger American citizens believe that the government is not being even in dealing and handling of this crucial matter (Shannon, 2003, p 197). Clearly, there is a burden of conflicting expectations from Israel and the Arab states, which in turn place the United States in a delicate position. This statement is fully supported by the actions of former President Bush and his secretary Baker (Hartley, Lea, and Rowe, 2004, p 147). Research Questions Are the western nations willing to resolve the Israeli-Arab conflict? What are some of the measures taken by western nations to reduce the Israeli-Arab conflict? Is there goodwill from the conflicting parties to have western nations as arbitrators to the conflict? What are some of the interests that western nations have in the Middle East? Approach The research will use a qualitative approach to collect data and arrive at its findings. This will involve collecting data from secondary sources and also interviewing people that are affected by the conflict. Provisional Chapter Outline Chapter 1: What the western nations have achieved so far in resolving the Israeli-Arab conflict. Chapter 2: Literature Review The strategies being used by western nations to resolve the Israeli-Arab conflict. Efforts by individual western countries to resolve the conflict. Chapter 3: Findings The reasons why the western countries are interested in the Israeli-Arab conflict. Whether there is goodwill from the conflicting parties to have the conflict resolved by the western countries. References Phillips, W. (2009). Solving the Arab-Israeli Conflict: A practical way forward that allows both sides to negotiate a solution in good-faith. New York: Create Space. Rubin, B. (1996). The Arab-Israeli Conflict Is Over. Middle east Quarterly,3 (3), 3-12. 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