At Home Drug Withdrawal

Sobriety Success

The dependence on sobriety is defined as the state of sobriety. When a person is sober, they can live on a daily basis without their thoughts and behaviors being controlled by substance dependence. They do not feel obliged to use it because they manage to live without it. They see and appreciate so much the benefits of living without substance that they do not feel they have to use drugs or alcohol. Therefore, they refrain from using it to continue enjoying this new, healthier lifestyle. The success product of sobriety is a step-by-step manual for everyone. The product has been said to be beneficial for many people around the world. The reason why the product is gaining so much popularity among individuals. They see and appreciate so much the benefits of life without substance that they do not feel they have to use drugs or alcohol. Therefore, they refrain from using it to continue enjoying this new, healthier lifestyle. This strategy encourages you to maintain the long-term vision of recovery. Recognize that this is not a one-off thing, something you try for a few weeks to several months, then return to your previous life. You will be in recovery if you decide it's the life you want to live for the rest of your life. As such, there is no immediate timeline to which you must adhere, nor should you strive to achieve goals that you are clearly not ready to face. Read more...

Sobriety Success Summary

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The State of Drug Abuse

Abuse of drugs is a critical problem in the United States and the rest of the world. Common drugs of abuse (DOA) include cocaine, cannabinoids, amphetamine, phencyclidine, and benzodiazepines. Recreational use of cocaine dates back to the Incas in South America 5000 yr ago. In the 1980s, cocaine was a popular DOA. Currently, in the United States, cocaine use is responsible for more emergency-room visits than any other drug. An estimated 25 million people between the ages of 26 and 34 yr have used cocaine at least once (1). For centuries, marijuana has also been widely used as a recreational drug. This drug is very popular among young adults. A-9-Tetrahydrocannabinol (THC) is the principal active ingredient of Cannabis sativa, a hemp plant. Hashish, the resin extract from the tops of the flowering plants, may have a THC concentration of over 10 . Amphetamine, another popular DOA, was first synthesized in 1887 and was introduced into the United States in tablet forms in 1937 for the...

Medical Alcohol Drug Abuse or Dependence Detoxification or Other Symptom Treatment with CC

Psychoactive substances are drugs or chemicals that have an effect on the central nervous system (CNS). The National Institute of Drug Abuse defines drug abuse or drug dependence as a condition in which the use of a legal or illegal drug causes physical, mental, emotional, or social harm. Drug usage impairs one's ability to function in daily activities of living and in work environments. Relationships with family and friends become impaired and dysfunctional. Most of the abused drugs fall into two main categories, CNS depressants and CNS stimulants. CNS depressants include narcotics, sedatives, barbiturates, tranquilizers, and inhalants. The desired effect by the user is a sense of increased self-esteem, euphoria, relaxation, and relief from pain and anxiety. CNS stimulants include amphetamines, hallucinogens, and cocaine. The desired effect by the user is a sense of well-being, alertness, excitation, overconfidence, and increased initiative.

Cocaine Self Administration

Extracellular dopamine has previously been measured during cocaine self-administration with both electrochemical (27) and microdialysis techniques (28). The preliminary data presented here were obtained by monitoring extracellular dopamine using fast-scan cyclic voltammetry with much better temporal resolution (25-12,000+ times greater) than previous studies. Rats (n 3) were surgically implanted with indwelling jugular catheters. Following 1 wk of recovery, they were trained to self-administer cocaine over a 2-h behavioral session. Each active lever-press response (fixed-ratio 1 schedule with 20 s time out) resulted in a 0.33 mg of intravenous infusion of cocaine (6 s) paired with a tone houselight stimulus (20 s). Once stable self-administration behavior was seen for at least 3 consecutive days, voltammetry surgery was performed. Following recovery, rats were allowed to self-administer cocaine until stable behavior was reestablished (1-2 d). On the experimental day, a carbon fiber...

Cocaine user

Film autoradiograms showing the preprodynorphin mRNA expression in the striatum of human controls and cocaine users. Note the heterogeneous expression pattern of the hybridization signal with higher expression in the patch compartment and higher mRNA expression levels in association with cocaine use.

Temporal and Anatomical Sequence of Changes in Gene Expression

A variety of studies using different addictive drugs, given in different dosing regimens and employing different withdrawal periods, have shown that repeated administration of addictive drugs produced short, intermediate, and enduring changes in gene expression. Figure 1 illustrates the sequence of changes in gene expression associated with repeated cocaine administration. Five categories of cocaine-induced changes in gene expression are outlined, ranging from increases in immediate early gene (IEG) expression that diminish with repeated injections to changes in gene expression that appear only after a period of withdrawal. The data outlined in Fig. 1 are specific for cocaine-induced changes in gene expression, and using these data as a guide certain temporal patterns of drug-induced changes in gene expression can be discerned from the extant literature. Similarly, anatomical patterns of gene expression related to various times during the chronic injection and withdrawal periods can...

Rapid Response and Tolerance Widespread in Dopamine Terminal Fields

Temporal pattern of changes in gene expression produced by repeated injections of cocaine. Fig. 1. Temporal pattern of changes in gene expression produced by repeated injections of cocaine. as c-fos and zif268 (9,10). However, both cytosolic IEGs such as homeria and arc and extracellular IEG-like proteins such as the pentraxin narp are also induced in a number of brain regions by acute administration of cocaine (11). The increase in these proteins is thought to initiate changes that partly mediate the acute effects of drugs, as well as provide a background upon

Slow Progressive Change and Rapid Return Predominately in the Ventral Tegmental Area

Another category of changes in gene expression are those that gradually accumulate with repeated administration but disappear within a few days after the last injection. Interestingly, many changes in gene expression in this category are found in dopamine or nondopamine cells in the ventral tegmental area (VTA). Included are proteins encoded by genes that are directly related to dopamine transmission, such as tyrosine hydroxylase and dopamine transporters (12-14). In addition, genes associated with dopamine receptor signaling such as Gia undergo a short-term change in expression after the last cocaine injection (15). Notably, the expression of genes related to glutamate transmission such as GluRl and NMDAR2 are also included in this category (16,17). Taken together these changes in gene expression appear to facilitate glutamatergic activation of cells in the VTA while simultaneously diminishing the capacity of D2 dopamine autoreceptors to provide negative regulation of dopamine cell...

Slow Change Slow Return Predominately in the Striatal Dopamine Terminal Fields

This category of cocaine-induced changes in gene expression has recently received considerable attention as possible mediators of the transition from casual to addictive patterns of drug-taking (24). Some of these genes are IEG-like in that they are induced by acute drug administration. However, the proteins have a relatively long half-life. As a result elevated protein levels are present for an extended period, as long as weeks after the last drug injection. The classic gene in the category is A-fosB, which has been shown to accumulate in the striatum with repeated psychostimulant exposure (25). Notably, the increased expression is also associated with a redistribution of cellular expression into different striatal compartments (26). In addition, changes in gene expression and protein function associated with D1 receptor signaling fall into this category, including an induction in protein kinase A, mitogen-activated protein (MAP) kinase, and phospho-cAMP response element binding...

Changes Only During Withdrawal Enduring for Weeks Predominately in the Prefrontal Cortex and Nucleus Accumbens

Members of this category of genes have undergone recent intensive study and the changes in expression generally appear after only a week or more of withdrawal from repeated drug administration. The changes are almost exclusively in the prefrontal cortex and nucleus accumbens and include a variety of gene products involved in neurotransmission, cell signaling, and glial function. However, the changes are notable in that they endure for weeks and involve a predominance of genes affecting glutamate transmission relative to dopamine transmission. Genes in this category altered by cocaine encode mGluR1, mGluR2 3, homer1bc, GluR5, A1 adenosine receptor, TrkB, BDNF, AGS3, Gia, GFAP, and vimentin. These changes in expression combine to produce a generalized decrease in signaling through group I and group II mGluR and in general serve to decrease excitability of cells in the nucleus accumbens (30,35,36). In addition, the changes in glial fibrillary acidic protein (GFAP) and vimentin suggest an...

Human Immunodeficiency Virus HIV

The emergence of HIV in the 1980s has had a devastating impact on the world's population. Although transmission in the USA is primarily through exchange of contaminated blood associated with male homosexual intercourse and illicit drug use, it is also increasingly transmitted by heterosexual intercourse, which is the primary mode of transmission in many parts of the world. Not only has the spread of HIV been a huge stimulus for new drug discovery and development, but also it has led to a revolution in the way clinical trials are conducted, including the use of surrogate markers, expedited Food and Drug Administration (FDA) review and expanded access to experimental agents outside of formal clinical trials. Numerous studies also now demonstrate that surrogate markers can be useful substitutes for the measurement of a drug's effect on disease progression and death. Changes in CD4 counts were initially, with some caveats, shown to be a reliable predictor for death. More recently,...

Historical Aspects of Drugsof Abuse Testing in the United States

This chapter examines the early history of testing for abused drugs, starting in Vietnam, and traces its growth and expanded applications in the workplace, criminal justice, and schools. It also examines the role played by drug abuse-related accidents on the USS Nimitz and Amtrak in shaping the field of drug testing. Standardization and process have been applied to this field of analysis through government regulation of mandated testing for government employees. The chapter examines the collection process, laboratory testing, review of test results, and the role of third-party administrators for workplace testing. These methods have also been applied to testing for the private sector. Standards for testing have also been influenced by a combination of technological advances that allow more accurate and useful test results, and government regulations that help ensure the reliability of the testing process.

Growth of Drug Testing

By the mid-1970s, the field of drug testing had begun to take root, as many young Americans, both military and civilian, experimented with illegal drugs such as marijuana (tetrahydrocannabinol, or THC), lysergic acid diethyl-amide (LSD), and cocaine. Most urine testing for illicit drugs was being done either by forensic laboratories or in methadone treatment programs. In these programs, patients undergoing methadone substitution therapy for heroin addiction were monitored for illicit drug use and compliance with the methadone therapy (4). A modest amount of drug testing was being conducted in the workplace by innovative companies that recognized the productivity value of promoting a drug-free work environment. Throughout the 1980s, urine drug testing continued to grow in the civilian world as well, with many Fortune 500 companies adopting the policies of, and the procedures for, a drug-free workplace. Some unions adopted these policies as well and undertook testing programs for their...

Introduction Addiction as a Form of Glutamate Dependent Plasticity

An open question is how drugs of abuse, which initially target monoamine receptors, are able to influence mechanisms of synaptic plasticity. Glutamate is a key transmitter for synaptic plasticity, and many neuronal pathways implicated in addiction are glutamatergic (4). Historically, studies of behavioral sensitization, a well-established animal model for addiction, were important in directing drug addiction research toward glutamate (5). Behavioral sensitization It is now acknowledged that the development of sensitization requires glutamate transmission in the midbrain, where dopamine (DA) cell bodies are located, whereas its maintenance and expression are associated with profound changes in glutamate transmission in limbic and cortical brain regions that receive dopaminergic innervation. To understand the role of glutamate transmission in sensitization, many studies have examined drug effects on glutamate transmission in these brain regions. This review focuses on cocaine and...

Role of the VTA in Behavioral Sensitization

Many lines of evidence have suggested that the development of behavioral sensitization is associated with an increase in excitatory drive to VTA DA neurons (8). This provided the impetus for examining whether glutamate transmission is enhanced in the VTA during the early phase of drug withdrawal. The first evidence to support this hypothesis came from in vivo single-unit recording studies demonstrating that VTA DA neurons recorded from cocaine-or amphetamine-sensitized animals were more responsive to the excitatory effects of iontophoretic glutamate (9). A subsequent study showed that increased responsiveness was selective for acid (AMPA) (there was no change in sensitivity to -methyl-d-aspartate NMDA or a metabotropic glutamate receptor agonist) and transient, present 3 but not 10-14 d after discontinuing repeated drug adminis tration (10). Recently, we have shown that AMPA receptor supersensitivity can also be demonstrated in microdialysis experiments, by monitoring the ability of...

Results in the VTA and Substantia Nigra

Using Western blotting, Nestler and colleagues found increased GluRl levels in the VTA of rats killed 16-18 h after discontinuation of repeated cocaine, morphine, ethanol, or stress paradigms (12,13). Increased GluR1 was not observed in the substantia nigra after repeated cocaine or morphine treatment (12). The substantia nigra was not examined in stress studies (12), but after repeated ethanol administration, there was a greater increase in GluR1 in the substantia nigra than in the VTA (13). Repeated cocaine also increased NR1 in VTA but had no effect on GluR2, NR2A B, or GluR6 7 (12). Churchill et al. (14) treated rats with saline or cocaine for 7 d (15 mg kg on d 1 and 7, 30 mg kg on d 2-6), measuring locomotor activity after the first and last injections those rats that showed > 20 increase in locomotor activity were defined as sensitized. Then, protein levels of glutamate receptor subunits were determined by Western blotting 24 h or 3 wk after daily injections were...

Summary VTA and Substantia Nigra

As reviewed in Subheading 2.1., both neurochemical and electrophysi-ological studies suggest that there is an enhancement in the responsiveness of VTA DA neurons to the excitatory effects of AMPA shortly after discontinuing repeated psychostimulant administration. An increase in AMPA receptor expression in the VTA would provide a simple explanation for these results. However, although Western blotting studies have found increased GluR1 and NR1 levels in the VTA shortly after cocaine administration is discontinued, this is not observed with immunoautoradiography following either cocaine or amphetamine administration (see 15 for discussion). More importantly, after the same drug regimens and withdrawal times that are associated with increased responsiveness of VTA DA neurons to AMPA, no changes in GluR1 are observed. Thus, although considerable evidence suggests that enhanced responsiveness of VTA DA neurons to AMPA is closely linked to the induction of sensitization, the mechanisms are...

Results in the NAc and Striatum

We have measured glutamate receptor subunit mRNA levels and immuno-reactivity in rats treated for 5 d with 5 mg kg of amphetamine or saline and perfused 3 or 14 d after the last injection. For AMPA receptor subunits, quantitative in situ hybridization studies showed no changes in GluR1-3 mRNA levels in the NAc after 3 d, but decreases in GluRl and GluR2 mRNA levels were observed after 14 d (41). Parallel changes were observed at the protein level using quantative immunoautoradiography (42). Similarly, mRNA and protein levels for NR1 in the NAc were not altered by repeated amphetamine at the 3-d withdrawal time, but both were significantly decreased after 14 d of withdrawal (24). The decreased levels of GluR1, GluR2, and NR1 subunits in amphetamine-treated rats may be functionally significant. Single-unit recording studies performed in the NAc of rats treated with the same amphetamine regimen, or a sensitizing regimen of cocaine, revealed that NAc neurons recorded from drug-treated...

Summary NAc and Striatum

Ated with behavioral sensitization and drug-seeking behavior. There is some agreement that GluR1 and NR1 levels are not altered in the NAc after short withdrawals (1-3 d) from repeated cocaine or amphetamine administration. At longer withdrawal times (2-3 wk), cocaine-treated rats may show increases in GluR1, NR1, and NR2B, whereas amphetamine-treated rats show decreases in GluRl, GluR2, and NR1. There may also be persistent changes in the expression and function of group I mGluRs. The delayed onset of many of the reported changes in glutamate receptor expression is consistent with a role for the NAc in the long-term maintenance of sensitization and other drug-induced behavioral changes. However, it is difficult to reconcile opposite effects of cocaine and amphetamine on glutamate receptor expression with a role for these changes in the maintenance and expression of sensitization, as both drugs produce similar behavioral effects (augmented locomotor response) in sensitized rats. It...

Summary PFC and Other Cortical and Limbic Regions

Glutamate receptor expression in the PFC undergoes complex changes after drug administration is discontinued that depend on the withdrawal time and probably differ between cocaine and amphetamine, at least for NR1. In general, some results suggest that AMPA receptor subunit expression changes at early withdrawal times whereas NMDA receptor subunit expression is altered after longer withdrawals. Because relatively few studies have assessed glutamate transmission in the PFC of sensitized rats using electrophysiological or neurochemical approaches, it is difficult to assess the functional significance of observed changes. An exception is the correlation between increased responsiveness of PFC neurons to glutamate (67), and increased expression of GluR1 in the PFC (41,42), after short withdrawals from repeated amphetamine administration. It will be important to conduct studies on additional brain regions implicated in addiction, such as the amygdala.

Regulation of Adult Neurogenesis and Gliogenesis by Abused Substances

Studies on dopaminergic roles in the regulation of adult cytogenesis are just emerging. Two recent reports have demonstrated that the midbrain dopa-minergic transmission that underlies major biological actions of psychostimulants can be a powerful regulator of adult cytogenesis. Teuchert-Noodt and co-workers found that acute treatment with methamphetamine at a high dose (25 or 50 mg kg) suppresses dentate granule cell proliferation by 28-34 in the adult gerbil hippocampus (36). Experiments carried out in this laboratory also define the amphetamine regulation of proliferation and differentiation of striatal progenitors in adult rats (13). Like the effect of methamphetamine on hippocampal cytogenesis, acute administration of amphetamine (10 mg kg) induces a rapid and transient decrease in the number of proliferating cells in the striatum, although amphetamine has no significant effect on differentiation of newborn cells. These results indicate that dopaminergic inputs control cell...

Implications in Psychostimulant Dependence and Medication

With limited studies, how drug exposure influences brain cytogenesis and how altered cytogenesis contributes to addictive properties of drugs of abuse can only be hypothesized at present. As described in the preceding, amphetamine exposure decreases total cell proliferation in the striatum (13). Morphine, heroin, and methamphetamine decrease hippocampal neurogenesis (36,40). However, alteration in proliferation of a given population of cells in the affected areas remains unidentified. It is possible that one specific phenotype of neuronal and or non-neuronal cells is either increased or decreased in response to drug stimulation. In this case, a decreased generation of cells that normally exert an inhibitory influence on the formation of drug addiction may result in disinhibition of addictive processes. On the contrary, an increased generation of cells that are involved in the mediation of drug effects may facilitate drug addiction. In sum, drugs may develop their dependence via...

Factors Such As Charge That Affect Drug Absorption Distribution And Excretion

Charged drugs or other molecules do not readily pass through lipid membranes. However, this often leads to the mistaken conclusion that drugs that are strong acids or bases, i.e., mostly ionized at physiological pH, will not be absorbed from the gut or pass the blood-brain barrier. If a drug is a strong base and has a p a of 9.4, the ratio of ionized to un-ionized will be 100 1 at pH 7.4, but that still means that approximately 1 of the drug is un-ionized and free to go through a lipid membrane. And there is always about 1 that is un-ionized because the equilibrium is virtually instantaneous therefore, the effect of the drug being a strong base or acid is that it decreases the effective concentration available to diffuse across the membrane. This slows the rate of diffusion but not the ultimate amount absorbed given adequate time for absorption. With absorption from the gut, the surface area is quite large and transit time in the small intestine, where most absorption occurs, is...

Role of Oxidative and Bioenergetic Stress in MDMA Neurotoxicity

In addition to a role of oxidative stress in MDMA-induced neurotoxicity, alterations in energy metabolism also may contribute to the process of neuro-toxicty induced by psychostimulant drugs. Methamphetamine reduces brain concentrations of ATP (78) and increases the extracellular concentration of lactate (79). In addition, the administration of energy substrates attenuates dopamine neurotoxicity elicited by methamphetamine (79,80). These findings suggest that psychostimulants may acutely impair mitochondrial function. Indeed, methamphetamine and MDMA acutely inhibit the activity of the mitochondrial enzyme cytochrome oxidase (72). Furthermore, the combined administration of methamphetamine and malonate, a complex II inhibitor of mitochondrial function, synergize to deplete striatal dopamine concentrations (81,82). The intrastriatal administration of malonate and MDMA, neither of which alone depletes tissue 5-HT concentrations, together produces significant reductions in striatal 5-HT...

Why Associative Learning

Drug addiction is generally defined as compulsive use of drugs despite adverse consequences. It typically features periods of ongoing drug use, in which drugs are actively sought and taken, and periods of drug abstinence, terminated by relapse. The proclivity to relapse is central to addiction It is Humans have particular brain mechanisms for allowing specific acquired behaviors to be persistently expressed, and we call this associative learning. Associative mechanisms are therefore excellent candidates for both the specificity and the persistence of relapse liability. However, most learning models of addiction have had difficulty providing a compelling model of compulsion the apparent loss of control over drug-taking. (The meaning of loss of control is obviously critical, and is discussed further in Subheading 7.) Individuals frequently face situations of conflicting goals and desires, and need to make decisions about which course of action to pursue. If addicts are able to state...

Exaggerated Habit Learning and Compromised Executive Control

As described in the preceding, reinforcement learning is normally under cognitive control both evaluation and expectation are key determining factors gating striatal dopamine release. This is a large part of the reason for the normal connection beween reward (i.e., a positively evaluated result) and other processes involved in positive reinforcement (such as consolidation of actions). It also forms a natural brake on normal habit learning. Actions that produce fully expected consequences do not generally undergo further plasticity, and so asymptotically stabilize. Abused drugs that directly enhance striatal dopamine release can foil such natural constraints (1,83). The behavioral features of human drug addiction are consistent with increasingly strong habit learning. Actions involved in drug intake generally become increasingly stereotyped (ritualized), automatic, and stimulus-bound (84), and there is an overall diminution of behavioral repertoire (85). The inability to regulate or...

Habit Learning and Synaptic Plasticity

Long-term potentiation (LTP) of the strength of corticostriatal connections can readily occur in vivo (104,105) and stimulation of dopamine neurons recently has been shown to modulate corticostriatal synaptic strength in direct correlation with behavioral reinforcement (106). Although LTP can involve a host of cellular and subcellular mechanisms, especially in early phases (107), the persistent substrate for much synaptic plasticity is generally believed to be structural changes in synaptic connectivity patterns (108-110). It is likely that the persistent effects of addictive drugs on habit learning are also ultimately manifested through altered structural patterns of synaptic connectivity (1). Repeated doses of amphetamine, cocaine, morphine, and nicotine can all provoke dendritic growth and synaptic change in rat ventral striatum and PFC (111-114) conversely, removal of striatal dopamine causes broad decreases in measures of synaptic connectivity (115-118). Into this overall scheme...

Time required for study conduct

The washout period between treatment periods in a crossover design is critical to ensure that there are no carryover effects from one period to another. This study design is inappropriate for drugs with long half-lives, for drugs with late toxicity, and if sensitization or tolerance develops. This study design is generally not used for FIH studies due to the general lack of information needed to rule out late toxicity, sensitization, tolerance, or to select an appropriate washout period. Sensitization is a phenomenon whereby the effects of a drug are augmented. Although it might sound counterintuitive, the same drug can evoke both tolerance and sensitization. Behavioral sensitization is a well-documented effect of repeated exposure to drugs such as amphetamine and cocaine (Pierce and Kalivas, 1997). Unlike transient drug effects, such as tolerance and withdrawal, behavioral sensitization can last as long as a year after the last drug administration in rats. The persistence of these...

Yasmin L Hurd 1 Introduction

Stimulant drugs such as cocaine, amphetamine, and methylphenidate induce their primary pharmacological actions through elevation of dopamine levels in the brain. The most dense innervation of dopamine nerve terminals in the central nervous system (CNS) is found within the striatum (caudate nucleus, putamen, and nucleus accumbens) (1). This brain region is central to the wide range of actions of psychostimulant drugs on motor behavior, cognition, motivation, and reward and is intricately linked with mesocorticolimbic structures, also innervated by dopamine, such as the amygdaloid complex and prefrontal cortex. The neuroanatomical organization and regulation of the striatal dopaminergic system as well as its relevance to motor function and drug reinforcement have been well studied. Elevation of striatal dopamine levels as a consequence of psychostimulant drug administration leads to activation of distinct dopamine receptor subtypes (Dj-D3) that are differentially expressed within...

Effects of maternal drug ingestion

Infants of mothers who take drugs such as opiates, cocaine, amphetamines, barbiturates, benzodiazepines and some other medical drugs may develop a withdrawal syndrome with irritability, poor feeding, apnoea and fits. The babies of mothers who have high alcohol or nicotine intake may also exhibit withdrawal. Wherever possible the mother and baby should be kept together in many cases breastfeeding in not contraindicated. If a history of maternal drug abuse was known antenatally a plan of management can be agreed before birth and a referral to the social work team may be appropriate. Management of a baby at risk of drug withdrawal involves careful observation and skilled nursing. If withdrawal is severe treatment with opiates may be required. Naloxone should never be given to infants at risk of opiate withdrawal as it can provoke convulsions. Many labour wards no longer stock nalox-one for fear it will be given inadvertently to an infant of a substance-abusing mother.

What are the types of observational studies

Other case reports have led to a faster regulatory response and drug withdrawal, e.g, the association between Guillain-Barre syndrome and the antidepressant zimeldine (Zelmid) and the connection between serious ventricular arrhythmias and the antihistamine terfenadine (Seldane). Although the clinical value of case reports is usually limited, they can sometimes give important warning signals for serious, unexpected or rare adverse events.

John Q Wang 1 Introduction

A large number of in vivo studies in the last decade have confirmed that abused drugs are able to up-regulate gene expression in striatal neurons. For example, acute or chronic exposures to psychostimulants, cocaine and amphetamine, increased basal levels of mRNA and protein products of immediate early genes (c-fos, zif 268, AFosB, etc.) in the rodent striatum (1-3). Similarly, acute administration of cocaine and amphetamines induced robust mRNA expression of preprodynorphin (PPD) and substance P (SP) in striatonigral projection neurons and preproenkaphalin (PPE) in striatopallidal projection neurons (4-6). The increased immediate early gene and neuropeptide expression is mediated via selective activation of dopamine receptors (primary D1 subtype) (7,8). Glutamatergic transmission also significantly contributes to the genomic effect of stimulants (9,10). The altered gene expression has been considered to be an essential molecular step for the development of psychoplasticity in the...

Transmission and Tissue Tropism

As with other viruses that persist in the blood of infected individuals, HBV is transmitted by heterosexual and homosexual contacts percutaneously (for example by skin puncture with contaminated shared needles for illicit drug use) and by inoculation with contaminated blood and blood products and perinatally from infected mothers to their newborn infants. Very few infants of HBV-infected mothers are infected in utero. Different HBV carriers may have greatly different degrees of contagiousness for contacts. This is due to different levels of virus replication in the liver and quantity of infectious virus in the blood and body fluids of different carriers. Serum HBeAg and levels of viral DNA-containing virions in the blood are reliable markers indicating the presence of infectious virus. Some HBsAg carriers with no detectable serum HBeAg or viral DNA and reactive for anti-HBe may have no infectious virus in the blood and do not transmit infection.

Stephen J Walker Travis J Worst and Kent E Vrana 1 Introduction

The reverse transcription-polymerase chain reaction (RT-PCR) has become a standard tool in gene expression analysis studies (1,2). Starting with a very small amount of material (usually total RNA), the investigator is able to copy the RNA by reverse transcription (RT) to produce single-stranded, complementary DNA (also known as first-strand cDNA). The cDNA, which is much less prone to degradation than RNA, can then be amplified by PCR and quantified to determine the relative abundance of expressed genes within and between sample groups. Two of the most common uses of this technology in the field of drug abuse are (1) to compare relative or absolute levels of expression of genes between control and treatment groups or, more recently, (2) for confirmation of gene expression (mRNA) changes identified in a primary screen (e.g., hybridization array analysis). The great utility of the technique is that if one has access to a real-time PCR thermocycler and is interested in comparing relative...

Host Range and Virus Transmission

The two main routes of transmission of HIVs are blood and blood products and sexual contact. The efficiency of blood transmission (transfusion, needles, i.v. drug abuse) depends on several factors number of virus particles, volume of blood, immune status of the receiver. Infection is particularly efficient in i.v. drug abusers.

Sample Preparation and Matrix Effects

As discussed earlier, preparing a liquid sample of a hair specimen is the first step in hair analysis. Enzymatic digestion of samples for testing in biological assays, coupled with RIA assays of the hair digests for the drugs cocaine, opiates, PCP, (MDMA), and cannabinoids, have been cleared by the FDA and used by this laboratory since 1985 (7,21).

Strategies to improve cell productivity

A clear example of success in obtaining high productivity is that of tropane alkaloids (Verpoorte et al., 1999). These are a well-recognized group of structurally related natural products and have long been known to have anticholinergic, antiemetic, parasympatholytic, anaesthetic, and many other actions. This class of alkaloid includes such important medicinal alkaloids as cocaine, scopolamine and atropine. The genera Atropa, Datura, Duboisia, Hyoscyamus and Scopolia, which belong to the Solanaceae, are especially rich sources of tropane alkaloids.

Spontaneous Intracerebral Hemorrhage

Spontaneous intracerebral hemorrhage (ICH) accounts for approximately 10 of cases of stroke. Arterial hypertension is by far the most common cause of ICH other causes are the intracranial aneurysms, vascular malformation, bleeding diathesis, cerebral amyloidosis, brain tumors, vasculitis, or drug abuse.

Applications of Hair Analysis in Criminal Justice and Rehabilitation Settings

Mieczkowski et al. (57) have reported on use of hair testing as an objective measure of drug treatment outcome in a criminal justice diversionary treatment program for first-time, nonviolent offenders. Violations of the program conditions, including drug use, result in dismissal from the program. Hair samples were taken at intake to the program and at approx 2-mo intervals during the program, with random urine testing also being employed. Hair analysis at intake showed 50 of the 91 subjects positive for cocaine, 35 for marijuana, 3 for opiates, 1 for PCP, and none for amphetamines. Urinalysis done at the same time showed 12 positive for cocaine, 24 for marijuana, 1 for opiates, and none for PCP or amphetamines. These results highlight the diagnostic value of hair analysis in assessing the status of subjects as they enter a rehabilitation setting. In another study, Mieczkowski and Newel (44) reported that hair analysis detected cocaine use at three times the incidence indicated by...

Medical Applications of Hair Analysis

A number of investigators have applied hair testing to detect prenatal drug exposure (61-70). The retrospective power of hair analysis allows, at the time of birth of an infant, an assessment of drug intake for as long a portion of the gestation period as the length of the mother's hair specimen permits. The first example of determining prenatal drug exposure by hair analysis, reported in 1987, was that of a mother who had ingested PCP during her pregnancy (61). This study and that of Grant et al. (66) demonstrated that determining the pattern of drug usage over the term of the pregnancy by segmental hair analysis may be especially useful in evaluating effects on neurodevelopmental outcomes of varying levels of drug use during specific trimesters. Callahan et al. (67), in comparing hair, meconium, and urine analyses for identifying cocaine use in mothers, found hair and meconium (when performed by GC-MS) to be about equivalent, whereas urine was about half as effective. The Hospital...

The Present and Future of Hair Testing

The unique characteristics of hair that allow estimation of dose and approximate dates of use, re-sampling and retesting, and other advantages make hair analysis of great value as either an alternative to other body fluids or as a complementary test. Effective washing of hair samples is a prerequisite for valid hair-testing results. There are additional benefits of hair analysis relative to the other body fluids in the case of specific analytes. For example, in analysis of opiates, hair does not produce a positive opiate result from consumption of even very high amounts of poppy seed (21). Hair analysis of well-washed samples also allows distinction between heroin use and morphine use, as only heroin produces the metabolite 6-MAM, and significant amounts of morphine are not usually found in hair due to use of codeine. In the case of methamphetamine, the use of Vicks Inhalers has not produced false-positive results in washed hair samples. For some amphetamine-class substances such as...

Multiple Lumbar Spine Surgery Failed Back Syndromes

Patients with profound emotional disturbances and instability (e.g., alcoholism, drug abuse, depression) and those involved with compensation and litigation should undergo a thorough psychiatric evaluation. Even if they are found to have a genuine neurosurgical problem, the psychosocial problem should be dealt with first, as additional low back surgery would otherwise fail again. After exclusion of the psychosocial group of patients, a smaller group of patients with back and or leg pain due to mechanical instability or scar tissue remains only those patients with mechanical instability will benefit from additional surgery.

To The Point Of Collection

The decentralization of laboratory services to the point of collection is made possible by the improved sensitivity and specificity of drug detection by lateral-flow DOA (LFDOA) testing devices. In the early 1990s, the sensitivity rate of LFDOA testing devices was approx 93 of the thresholds required for standardized workplace drug testing (then referred to as the National Institute of Drug Abuse NIDA cut-off levels). Tracking the progress of monoclonal techniques and antibody-antigen sensitivity and specificity demonstrated that overall, DOA sensitivity levels would improve at the rate of approx 1 annually. Beginning in 1993, it was expected that sensitivity rates for LFDOA devices would approach the sensitivity rate of laboratory-based immunoassays (then at 99 ) by 1999. Once the sensitivity rate of LFDOA was equal to or better than laboratory-based immunoassays, one could easily argue for not sending negative samples to the laboratory.

Changeable Bar Code Prelude to Digital Drug Testing

Confirmation laboratory can positively identify the drug. Removing the drug names from the cassette means that if all the color lines are present, as is the case with most strips, no drugs are detected in the specimen (i.e., the result is negative). If one or more color lines are absent from the series, the result is presumptively positive. It does not matter which drug is detected, because in every case, the outcome is the same. The specimen must be sent to a confirmation laboratory for further testing. From the bar code prospective, this argument presents a unique opportunity to translate the lines and spaces on the LFDOA test strips into a digital code, or a series of 0s and 1s. Consider the presence of a target line as indicated by a 1 and a space by a 0, then a five-drug test with one control line would be translated by a barcode reader into 10101010101 (six lines and five spaces) when the sample is negative and all six lines appear. If, for example, the THC test in the second...

Primary Nursing Diagnosis

If the patient has developed endocarditis as a result of IV drug abuse, an addiction consultation is essential, with a possible referral to an appropriate treatment program. Surgical replacement of the infected valve is needed in those patients who have an infecting microorganism that does not respond to available antibiotic therapy and for patients who have developed infectious endocarditis in a prosthetic heart valve. (See Coronary Artery Disease, p. 248, for a full discussion of the collaborative and independent management of a patient following open heart surgery.)

Anticipated Results in the Striatum

To be applied prior to the immunostaining procedures to visualize a high throughput of cells containing phosphorylated proteins. Such manipulations can be achieved by application of psychostimulants (cocaine or amphetamine) or the metabotropic glutamate receptor agonist (5-8).

Steffany A L Bennett and David C S Roberts 1 Introduction

In this chapter, we describe standard protocols for protein detection in lysates prepared from microdissected brain tissue using antibody-sandwich ELISAs. To illustrate methods, cerebral changes in expression of connexin32 (Cx32) following chronic cocaine self-administration are presented. Connexins

Protein Extraction from Rat Brain

Male Wistar rats (275-300 g, Charles Rivers, St Foie, PQ) were lethally injected intraperitoneally with 80 mg kg of sodium pentobarbital (Somnotol) and euthanized by decapitation. Brains were rapidly removed for dissection. In the present example, rats had been previously allowed to self-administer 38 injections of 1.5 mg kg of cocaine over a 14-d period (4). Animals were killed at 2, 7, or 21 d after the last cocaine self-administration session and Cx32 protein expression was compared to drug-naive, age-matched controls (4).

Protein Capture onto Microtiter Plates

In the protocol described, Cx32 protein was immobilized on 96-well polystyrene plates coated with rat monoclonal R5 (provided by Dr. David Paul, Harvard Medical School). This assay was designed not to quantify absolute protein levels but to establish whether relative Cx32 expression changes over time in various tissues following cocaine self-administration (4). As a result, a standard curve was not included. If a sufficient amount of purified protein is available, this protocol can be modified to quantify absolute protein concentration by inclusion of a standard curve with known amounts of target protein (see Subheading 3.2.2., step 1).

Detection of Bound Antigen Antibody Complex

Microplate Layout for Experimental Detection of Cx32 in Medulla, Parietal Temporal Cortex, Cerebellum, Thalamus, Dorsal Striatum, Nucleus Accumbens, and Globus Pallidus Ventral Lateral Striatum in Drug-Naive (Control) Animals and in Chronic Cocaine Self-Administrators After 2, 7, and 21 d of Cocaine Withdrawal Microplate Layout for Experimental Detection of Cx32 in Medulla, Parietal Temporal Cortex, Cerebellum, Thalamus, Dorsal Striatum, Nucleus Accumbens, and Globus Pallidus Ventral Lateral Striatum in Drug-Naive (Control) Animals and in Chronic Cocaine Self-Administrators After 2, 7, and 21 d of Cocaine Withdrawal Layout of a 96-well plate and loading of experimental samples as described in Subheading 3.2.2. is illustrated. Blank Wells were coated with R5 capture antibody and blocked with blocking solution. In all subsequent steps, wells were incubated with the appropriate buffers in the absence of protein lysate or antibodies. These values are set to 0 by the microplate reader...

Personality Assessment

But, more functionally, personality assessment should provide pragmatic recommendations and action plans that decrease or resolve current child and adolescent problems such that they can be prevented in the future. Moreover, from a health and mental health perspective, personality assessment should also provide parents and educators with insight and direction into such problems as truancy drug abuse dropping out teenage pregnancy suicide and the emotional impacts of divorce, poverty, rejection, and academic failure. In totality, then, personality assessment is a process of collecting valid data to explain the causes for or contingencies relevant to a student's social-emotional, behavioral, or affective difficulties. This assessment is only meaningful when linked with viable, acceptable, and socially valid interventions that are successfully implemented with ongoing attention to treatment integrity and evaluation.

Nitrites As Urine Adulterants

Leads to decomposition of ions of A-9-THC and its internal standard. The authors reported that using a bisulfite step at the beginning of sample preparation could eliminate this interference. The group also investigated the effect of nitrite on immunoassay screening of other drugs. These drugs include cocaine metabolites, morphine, THC metabolites, amphetamine, and phencyclidine. Nitrite at a concentration of 1.0 M had no effect on the Abuscreen assay. At a higher nitrite concentration, the amphetamine assay becomes more sensitive and the THC assay becomes less sensitive. The GC-MS analyses of BE, morphine, amphetamine, and phencyclidine were not affected, whereas recovery of the THC metabolites was significantly reduced. Again, this interference could be eliminated by bisulfite treatment.

Challenges in Studies of the Postmortem Human Brain

Microarray studies have unequivocally proven that in rodents environmental enrichment significantly shapes the brain transcriptome (Rampon et al., 2000), and this is undoubtedly even more pronounced in the human brain (Francis et al., 2002). The lifetime experiences from our surroundings constantly shape our transcriptome profile. This process starts from the intrauterine formation of the CNS and continues until death. Some of these influences will leave behind long-lasting structural changes that are obvious many years after the removal of the primary insults (Stanwood et al., 2001), whereas others are rapidly reversible and related to environmental influences relatively close to the time of death. Smoking, drug abuse, physical activity, and many other lifestyle events are all potent modulators of the CNS transcriptome, and these influences interact with gene expression diversity that occurs as a result of differences in age, sex, and race.

Jianhua Zhang and Ming Xu 1 Introduction

Drug addiction is a chronic relapsing disease with psychological and social factors (1). Compulsive drug-taking is a central feature of drug addiction (2-4). A major goal of drug abuse research is to understand the cellular and molecular mechanisms underlying the development of the loss of control over drug-taking (2-4). Because the neurobiological mechanisms underlying the development of uncontrolled drug-taking behaviors are associated with the brain dopaminergic and glutamatergic systems (5-8), animal models are obviously needed for the various investigations. With the development of the gene targeting approach (9-13), genetically engineered mouse models have become increasingly useful for studying molecular mechanisms underlying drug addiction. Gene targeting allows a direct assessment of the contribution of individual genes to specific behaviors in mice. This technology provides a very useful alternative as opposed to pharmacological approach to dissect complex biological...

Gender Ethnicracial And Life Span Considerations

MI is the single largest cause of death among American men and women, including white, African American, and Hispanic Latino populations. The risk of MI increases with age, and it occurs most commonly in people older than 45 years of age. MIs also occur in young adults, such as individuals who use cocaine, those who are insulin-dependent diabetics, and those who have hypercholesterolemia and a positive family history for early coronary disease.

Risk Taking and Substance Abuse

Although people who have affective disorders might use drugs as a form of chemical self-treatment, independent of this possible relationship between drugs and affective disorders, the same brain anomaly that makes people susceptible to drug abuse might serve to enhance curiosity, risk taking, and creativity. For example, studies of large cohorts of college students found that the students who use marijuana tend to be novelty seeking and more creative than the students who did not use this drug (Eisenman, Grossman, & Goldstein, 1980). The mechanism underlying the relationships between substance abuse, novelty seeking, risk taking, and creativity has not been determined. One hypothesis, however, is that drugs enhance creative performance, but studies of creativity under normal states versus intoxicated states do not reveal that drugs enhance the production of creative works (Lang, Verret, & Watt, 1984). As I mentioned, depression might not enhance...

Market Volume Across Europe

Adopted a zero-tolerance policy, cracking down on drug abuse at all levels, the two other Benelux regions, along with Denmark, have yet to authorize roadside testing. In Luxembourg and the Netherlands, a stricter enforcement of existing laws has been suggested as an alternative to testing people suspected of driving under the influence of drugs (5). Germany and Italy have traditionally been classified as high-volume consumers of diagnostic assays. This trend, however, does not apply to drug testing. In these two countries, workplace drug testing is prohibited by law. Further accounting for the low level of DAT usage, both Germany and Italy have recently experienced a reduction in healthcare spending, with Germany in particular suffering from a period of economic instability. Consequently, drug testing is now categorized as a low priority, especially in the health care sector. Although other consumers, such as the police, prisons, and the military, have expressed an interest in...

Prevention Strategies

Schools should implement effective strategies including tobacco-free policies, research-based prevention programs, stop-smoking programs, and strong extracurricular programs. Educators typically use one of three types of prevention programs factual lectures like Drug Abuse Resistance Education (DARE), affective curriculum that enhances self-esteem, and social behavioral skills such as LifeSkills Training (LST) (Botvin, 1999). However, research shows that these prevention programs are not equally effective.

Survey of Drugs and Medicines That Have Detrimental Impacts on Drivers Performance

A literature survey of drugs and medicines that have detrimental impacts on drivers' performance (3) focused on studies related to the effects of drugs on driving. Information was compiled in table form categorizing the available medicinal drugs according to their influence on driving in different systems in different countries. Driving is a complex task whereby the driver constantly receives information, analyzes it, and reacts to it. Substances that have an influence on brain functions or on mental processes involved in driving will clearly affect driving performance. Stimulant drugs, such as amphetamines, methylene-dioxymethamphetamine (MDMA ecstasy) and cocaine enhance risk-taking behavior. These drugs are also dangerous because of the fatigue that sets in after the high or after a full weekend of drug-taking and dancing. Moreover, they dilate the pupils, and drivers can be blinded by the increased amount of light. Cannabis causes euphoria, somnolence, a change of visual and...

Survey of Stateofthe Art Roadside Testing Devices Available for Urine Sweat and Saliva Matrices

For urine testing, there are three kinds of test designs a dip test (test strip or test card the device is partially immersed in the urine for a few seconds), a pipet test (test cassette a few drops of urine are deposited in the device with a dropper), and a cup test (the testing device is built into the side or top of a cup). Several manufacturers supplied single-parameter and multiple-parameter tests for the dip- and pipet-type devices. Most of the tests were available for the detection of amphetamines, methamphetamine, cannabinoids, cocaine, opiates, and phencyclidine. Eighty percent of the urine devices also included benzodiazepines and barbiturates in their panels. Fifty percent included methadone, and only 30 offered a test for tricyclic antidepressants.

Survey of Operational User and Legal Requirements Across Member States of the European Union for Roadside Testing

The following classes of drugs were considered to be important enough (in decreasing order of frequency) to be included in the testing cannabis, benzodiazepines, amphetamines, cocaine, and opiates. In Europe, cannabis is the most popular drug of abuse appearing in street traffic. This is followed by benzodiazepines, which are components of several prescribed medicines and are easily accessible. The amphetamine group also includes such designer drugs as methamphetamine, methylenedioxyamphetamine (MDA), and MDMA. Their use is very prevalent among people under 25 yr of age.

Treatment of narcolepsy

In addition to modafinil, commonly used stimulants include methylphenidate, dextro-amphetamine, and methamphetamine. Side-effects are not uncommon with any stimulant or alerting agent. Agitation, anxiety, tremor, and palpitations are just a few of the commonly reported side-effects associated with traditional stimulants. Some patients may report a rebound hypersomnia as the dose wears off, and tolerance may occur with time. Traditional stimulants are still an important resource in the arsenal ofmedications for the treatment of narcolepsy, but in our clinical practice they have become second-line agents behind sodium oxybate and or modafinil for treatment of EDS associated with narcolepsy (see Table 9.2).

Applications in Biology and Medicine

Winograd and co-workers have pioneered the adoption of fast-freezing and in situ freeze-fracture methodology in SSIMS analysis of frozen hydrated specimens using a variety of liposome and cellular systems (9,37-39). Using characteristic phospholipid fragments, they observed fusion and mixing events between DPPC and cholesterol-containing liposomes using imaging TOF-SIMS (9). The same freeze-fracture methodology was applied to successfully image components of the outer membrane and organelles of frozen hydrated red blood cells (9,38) and to image the distribution of cocaine doped into the single-celled organism Paramecium (39) TOF-SIMS imaging has been combined with bright-field and fluorescence microscopy to image frozen hydrated, freeze-fractured rat pheochromocytoma (PC12) cells (40,41). This integrated approach aids identification of the fracture plane and subsequent interpretation of the TOF-SIMS data. Recently, the group used TOF-SIMS and PCA to demonstrate the heterogeneous...

Sleepwalking and sleep terrors overview and clinical description

Categorized as non-violent (NV, N 26, 11 male), potentially harmful (PH, N 12, 6 male), and violent (V, N 26, 22 male). Histories of childhood abuse were found in 4 female cases (3 NV, 1 PH). Current DSM-III axis I diagnoses were described in 13 64 (20 ) of cases. Alcohol abuse (as a stressor associated with sleep-related behavior, not necessarily an axis I disorder) was noted in 11 64 (17 ) and some prior history of drug abuse in 24 64 (38 ). There was no systematic association between the sleep disorders and any psychiatric diagnosis and, on the SCL 90, there was no difference between the three groups 44 .

Expected Drug Levels in Hair of Proven Drug Users

Analyses of the hair from drug users who have tested positive in urinaly-sis provide a reference range of drug concentrations to be expected of such hair. Large studies of this nature have been performed by this laboratory for cocaine (19), opiates (21), methamphetamine (20), and marijuana (21). PCP was also studied, but with few users identified (21). These studies also included negative control groups wherein hair samples from 60-80 nondrug-using subjects were collected and tested negative by both screening and confirmation analyses. In these studies, the cut-off levels (concentrations of the parent drugs in hair above which samples are considered positive) were 5 ng 10 mg hair for cocaine and methamphetamine, 2 ng 10 mg hair for morphine, 3 ng 10 mg hair for PCP, and 1 pg 10 mg hair for carboxy-THC, the metabolite found in hair as a result of marijuana use. All results of the studies were obtained by LC-MS-MS, GC-MS, or GC-MS-MS after application of our laboratory's wash procedures...

Poor Plax And Sax Views

Classification Dissection

In the aortic isthmus distal to the ligamentum arterio-sum. Cardiac surgery is also associated with a risk of aortic dissection, in particular bypass surgery and aortic valve replacement. Patients with Takayasu's disease and other inflammatory collagen vascular diseases are also at increased risk. Corticosteroid use has also been associated with increased risk of dissection. Aortic dissection has also been reported to occur in association with cocaine use, particularly crack cocaine, presumably owing to abrupt elevations in systemic blood pressure. Cocaine abuse

Glutaraldehyde As a Urine Adulterant

Glutaraldehyde solutions are readily available in hospitals and clinics as a cleaning and sterilizing agent. A 10 solution of glutaraldehyde is also available from pharmacies as over-the-counter medication for treatment of warts. The addition of glutaraldehyde at a concentration of 0.75 volume to urine can lead to false-negative drug-screening results for cannabinoid tests using EMIT II immunoassays. Amphetamine, methadone, benzodiazepine, opiate, and cocaine metabolite tests can be affected at glutaraldehyde concentrations of between 1 and 2 using the EMIT screen. At a glutaraldehyde concentration of 2 by volume, Braith-waite (18) found that the assay of cocaine metabolite was significantly affected, with an apparent loss of 90 of assay sensitivity. A loss of 80 sensitivity was also observed with the benzodiazepine assay. Wu et al. (19) reported that glutaraldehyde also interfered with the CEDIA immunoassays for screening of abused drugs. Goldberger and Caplan (20) reported that...

Regurgitation And Defecation Of Allelochemicals

When tactilely stimulated, acridid grasshoppers readily regurgitate, and this discharge, fortified with plant natural products, is very repellent to ants. Similarly, larvae of the moth Eloria noyesi regurgitate when molested. The enteric discharge, which contains cocaine extracted from the larval food plant, is very repellent to ants.

Concerns About Accuracy of Analysis

Further complicating POCT is the shift in analysis from the laboratory to the point of collection. Decentralizing the analytical process of DOA testing places the burden of responsibility for analytical interpretation on the collector and potentially unskilled personnel. Visually read endpoints of test results, although quite simple in most pregnancy tests, is dramatically more complicated in DOA testing. Most DOA tests contain multiple analyses, testing for cannabinoid (tetrahydrocannabinol THC), cocaine, amphetamine, morphine, and phencyclidine (PCP) on one or more lateral-flow strips. Included on each lateral-flow strip is a control, ensuring that the sample has migrated across the test area. A five-drug test will have one target zone for each drug analyte and one target control zone for each strip. Hence, a two-strip, five-drug panel will have a total of seven target zones. Most competitive binding assays produce a color indicator in the absence of the analyte. However, some tests...

Michael I Schaffer and Virginia A Hill

Compounds trapped in hair during growth collect and remain in the mature hair strand. Defined lengths of the hair strand can be analyzed to provide information on ingestion of a substance during the window of time corresponding to the growth period of the segment of hair analyzed. Both screening (immunoassay) and confirmation (liquid chromatography-tandem mass spectrometry, gas chromatography-mass spec-trometry, gass chromatography-tandem mass spectrometry) methods for drugs in hair require methods of liquefaction and or extraction of the solid hair fiber. Extensive washing of hair samples to remove external contamination and or drugs from sweat prior to analysis is integral to a meaningful hair result, particularly to distinguish use from contamination and to utilize the hair's ability to reflect dose. Some results of drugs-of-abuse analysis in washed hair of proven drug users ranged (in ng 10 mg hair) from the cut-offs to 2270 (cocaine), 559 (morphine), 79 (methamphetamine), and 150...

Pyridinium Chlorochromate As a Urine Adulterant

Besides simple household chemicals, more sophisticated substances are advertised commercially as adulterants for urine drug tests. Wu et al. (13) reported that the active ingredient of Urine Luck is 200 mmol L of pyridinium chlorochromate (PCC). The authors reported that Urine Luck caused a decrease in response rate for all EMIT II drug screens and for the Abuscreen morphine and THC assays. In contrast, Abuscreen amphetamine assay produced a higher response rate, and no effect was observed on the results of BE and PCP. This adulteration of urine did not alter GC-MS confirmation of methamphetamine, BE, and PCP. However, apparent concentrations of opiates and THC were reduced.

Preliminary Screening Assays for Drugs of Abuse in Hair

Analysis for the presence of the drug opiates in hair was performed using RIA as early as 1979 (22). This was followed soon after with tests for phen-cyclidine (PCP) (23) and cocaine (24). In fact, it was the availability of RIA as an ultrasensitive analytical tool that initially prompted the pioneering testing of drugs in hair. As enzyme immunoassays develop greater sensitivity, nonradio-active immunoassays are increasingly being used for hair testing. A review of the immunological methods for testing drugs in hair from the early period to the year 2000 has been presented by Spiehler (25). MS confirmation methods took a few additional years to achieve the necessary sensitivities.

Adulterant Effects on Positive Drug Specimens Over Time

The kinetics of adulterant effects were studied by Tse and Bogema (20). In these experiments, urine controls containing two times the cut-off levels of THC, MOR, AMP, PCP, and cocaine (COC) were set up. The samples were divided into three groups. To the first group, Urine Luck Formula 6.3 was added according to the manufacturer's instructions. To the second group, Stealth was added. The third group served as positive control, with no adulterants added. Within 5 min after the addition of adulterants, samples from each group were taken and simultaneously tested for presence of drugs and adulterants. The tests were repeated at 30 min and at 1,2, 3, 5, 8, 24, and 30 h after addition of adulterants. Detection of drugs was performed using Monitect, whereas adulterants were detected using Intect 7.

Potential Causes Of Recurrent Miscarriage

We've all heard about the dangers of tobacco, alcohol, and street drugs. They just aren't part of a healthy lifestyle. This is especially true as you try to conceive and also during your pregnancy. If you smoke during pregnancy, you are more likely to experience vaginal bleeding and miscarriage. Women who drink excessive alcohol or engage in illicit drug use have a definite increased risk of miscarriage.

Bernard E Bulwer MD MSc and Scott D Solomon MD

At the time of presentation, his medications included captopril, lasix, digoxin, potassium chloride, aspirin, multivitamins, and unspecified dietary supplements. He had no known drug allergies. His family history was significant for coronary heart disease. He smoked more than two packs of cigarettes daily for more than 20 yr, and averaged almost a quart of alcoholic beverages of various descriptions. He admitted no intravenous drug use, but occasionally used cocaine.

Enzymes Associated With Fatty Acid Ethyl Ester Synthesis

In studies on the FAEE synthase enzyme, it was demonstrated by Tsujita and Okuda that carboxylesterase is capable of catalyzing the FAEE synthesis reaction (Tsujita, 1992 Tsujita, 1994b). They demonstrated that purified carboxylesterase was able to promote the synthesis of FAEEs in a number of organs. In support of the findings of Tsujita et al., who showed that carboxylesterase can promote the synthesis of FAEE, we reported that purified FAEE synthase also has cocaethylene (an esterification product of ethanol and cocaine) synthetic capacity (Heith, 1995). Cocaethylene synthase, like FAEE synthase, has been shown to have carboxylesterase activity (Dean, 1991), linking FAEE synthesis again to carboxylesterase.

Behavioral Assessment

Begin compressed conditioning paradigm (two sessions per day see Note 10). Close the doors in the dividers that separate the compartments of the apparatus. In the morning, administer saline (1 mL kg) and place each rat in the nondrug-assigned compartment. Turn the lights off in the test room, and condition the rats for 1 h. After the conditioning session, return the rats to their home cages and the vivarium. Clean the entire apparatus with isopropyl alcohol wipes, and leave the tops open to minimize trapped odors. In the afternoon (at least 3 h later), administer the drug under study (e.g., cocaine) and place each rat in the drug assigned compartment. Turn the lights off in the test room, and condition the rats for 1 h. After the conditioning session, return the rats to their home cages and the vivarium. It is particularly important to remove the rats from the apparatus immediately at the end of the cocaine conditioning sessions,

Assessment

Obtain an obstetric history. Determine the date of the last menstrual period to calculate the estimated day of delivery and gestational age of the infant. Inquire about alcohol, tobacco, and drug usage, and any trauma or abuse situations during pregnancy. Ask the patient to describe the onset of bleeding (the circumstances, amount, and presence of pain). When obtaining a history from a patient with an abruption, recognize that it is possible for her to be disoriented from blood loss and or cocaine or other drug usage. Generally, patients have one of the risk factors, but sometimes no clear precursor is identifiable.

Rebounding IEG

This is a category that to date contains a single gene product, nac-i (38,39). This protein has expression characteristics of the IEG class in that levels are induced by acute drug administration, and progressive tolerance to this induction occurs with repeated administration. However, similar to late expressing genes, the levels of nac-i rise at i wk of withdrawal and are maintained for at least 3 wk thereafter. Experiments using viral overexpression of nac-i and antisense oligonucleotide inhibition of protein expression reveal that nac-i is important in the development of behavioral sensitization and in the acquisition of cocaine self-administration.

Conclusions

In gene expression and neuronal function in these brain regions following a bout of drug-taking. Although the studies outlined in this chapter are promising in pointing to a common point of intervention in addiction to various chemical classes of drugs, it is important to note that such a generalization based primarily on work with psychostimulants is premature, and verification will require substantially more research using other classes of drugs. Also, the temporal sequence of neuroadaptive changes during drug withdrawal points to the possible utility of targeting different pharmacotherapies at different stages of withdrawal. Thus, in early withdrawal drugs affecting dopamine transmission may be more effective, while in later withdrawal modulation of glutamate transmission may be more efficacious.

The Beginning

Drug abuse has been part of our society for centuries, but the technology to test body fluids for drugs has only been available for less than 50 yr. Testing for illicit drugs first began in Vietnam (1). In the late 1960s, an unusually large number of soldiers began returning home from Southeast Asia as heroin addicts. Identifying these GIs proved difficult. The unpopularity of the Vietnam War was already a public relations disaster for the Nixon administration, and sending our soldiers home as heroin addicts was another war tragedy that the Administration did not want. White House staffers began to look for tools that could be used to rapidly screen thousands of GIs before they returned to the United States. The search ended in 1970, when SYVA Company, a small research organization located in Palo Alto, California, developed a rapid test system capable of detecting opiates in urine. The system used an innovative homogeneous methodology based on the tumbling action of free radicals in...

Results in the PFC

Cocaine also exerts complex effects on glutamate receptor subunit expression in the PFC. Churchill et al. (14) found no changes in PFC levels of GluR1, GluR2 3, or NMDAR1 (using Western blots) 3 wk after discontinuing a week of daily cocaine injections (see Subheading 2.2. for more details on this study). In another study, rats were treated with cocaine, tested for sensitization after 10 d of withdrawal, and killed 1 wk after the test for sensitization (44 see Subheading 3.2. for more details). Small increases ( 20 ) were observed for NR1 and NR2B in the PFC, but these were not significant, and there was no change in GluR1. Loftis and Janowsky (23) measured NR2B levels using immunohistochemical methods in VTA and NAc (see Subheadings 2.2. and 3.2.), as well as dorsolateral neostriatum, the hippocampal formation (CA1, CA3, and dentate gyrus), and the cortex (medial frontal cortex, lateral frontal cortex, and parietal cortex). Rats were killed 24 h, 72 h, or 14 d after discontinuation...

Dopamine

It is unclear what role, if any, dopamine (DA) plays in vigilance state regulation. Substantia nigra and mid-brain dopaminergic neurons project to wakefulness-related brain regions, including BF and prefrontal cortex 62,63 . These neurons fire in bursts, correlated to arousal and reward 64 . Single-unit recordings in the substantia nigra and ventral tegmental area, though, were not able to determine firing rate fluctuation between wakefulness versus sleep states 65 . Recently, another group of dopaminergic neurons in the ventral periaqueductal gray (vlPAG) was described, where c-Fos protein expression correlated most strongly with wakefulness 66 . These neurons were located near the dorsal raphe nucleus, interspersed with serotonergic wakefulness-active cells, and projected to many of the wakefulness-related nuclei. Further investigations, including electrophysiological profiling of these neurons, will allow conclusive evidence of a role these neurons may play in vigilance state...

Ttttt t t

More specifically, it was argued that the ability of addictive drugs to evoke exaggerated habit learning in cortical-basal ganglia circuits is likely responsible for the persistent and compulsive aspects of addiction. Compared to other contemporary accounts of the role of learning in addiction (5,83), this view thus places more emphasis on the reinforcing, rather than rewarding, actions of abused drugs. Maladaptive behavior is seen largely as the result of acting in a habitual mode in which adaptive decision-making is not properly engaged. So far, animal models of drug self-adminstration have provided fascinating information about the neural substrates of motivated behavior, which is highly relevant to the general phenomenon of drug abuse. The challenge they face is to reveal more about the processes of control and loss of control over drug intake that characterize addiction. This is particularly true for experiments examining reinstatement of drug taking following extinction, which...

Horners Syndrome

CLINICAL SYMPTOMS Muller's sympathetic eyelid muscles contribute to retraction of both the upper and lower eyelids. In Horner's syndrome there is a minimal ptosis of the upper lid of about 1 to 2 mm, associated with elevation of the lower eyelid. Thus, the interpalpebral fissure is narrowed. The pupil is mildly constricted and there may be loss of sweating on the ipsilateral face and dryness of the mouth. In congenital Horner's syndrome the affected iris is lighter in color resulting in heterochromia. Diagnosis is facilitated by pharmacologic testing with 4 cocaine where the affected pupil does not dilate but he normal pupil does. If the denervation involves the third order neurons between the superior cervical ganglion and the eye, the pupil is supersensitive to epinephrine and will dilate with 1 1000 dilution of epinephrine, a concentration that does not affect the normal pupil.

Specific History

A simple scratch or nick can trigger an episode. On the face and head, infection may be secondary to fissuring of chronic eczema or may complicate trauma to the auditory meatus as patients manipulate the canal while relieving the itch of a chronic dermatitis. In children, periorbital cellulitis has been associated with middle-ear infections, and orbital cellulitis has been associated with chronic sinusitis in older children and in adults. On the lower extremities, Assuring from dermatophytosis or chronic stasis ulceration is a predisposing factor. These conditions often act in concert with long-standing lymphatic injury from old trauma or chronic phlebitis. A recently defined syndrome of recurrent cellulitis of the lower extremities has been reported in cardiac bypass patients where vessel harvesting in the lower extremities has disrupted the normal venous and lymphatic return. Diabetes mellitus, neutropenia, IV drug abuse, and immunosuppression predispose patients to the more severe...

How Ddpcr Works

Since the original report by Liang and Pardee (4), a great number of DDPCR variants have been described in the scientific literature. The version described here (Fig. 1) is modified from Liang et al. (5) and has been used to identify dopamine- and cocaine-induced striatal genes (2,3).

Incidence

Growth restriction, or maternal disease. The remainder are due to preterm labour and delivery. The incidence of spontaneous preterm labour is at its lowest in women in their 20s. The risk is increased in teenagers and in women over 30. There is a higher incidence of preterm labour in first pregnancies. Higher parity alone is not a risk factor for preterm labour. Indeed there is a progressively lower risk with each successive term birth. Marital status, cigarette smoking, environmental stress, poor nutrition and use of alcohol, coffee and street drugs (especially cocaine) have all been linked to an increased risk of preterm birth. Many of these factors are, however, interlinked and are all factors associated with social disadvantage.

Anorectics

Leptin is a 146-amino acid protein mainly produced by adipocytes its circulating levels reflect, to a great extent, the degree of adiposity or the amount of energy stored in adipose tissue (105). Although leptin has pleiotropic actions including neuroendocrine, metabolic, reproductive, hematopoietic, and metabolic regulation, its role in energy balance has received the most attention. It is the product of the OB gene, which is mutated in the genetically obese (ob ob) mouse its receptor is mutated in the diabetic (db db) mouse and the fatty (fa fa) rat, which are also obese. Mutations in either leptin or its receptor, although quite rare, have been reported in humans these result in hyperphagia and early-onset obesity (106,107). Binding of the peptide to its receptor on hypothalamic neurons leads to increased expression of anorexigenic (appetite-suppressing) pep-tides, such as melanocyte-stimulating hormone (a-MSH), cocaine- and amphetamine-regulated transcript (CART), and...

Epidemiology

Chancroid was endemic in most parts of the world well into the 20th century. In Europe and North America, a steady decline was seen after the discovery of penicillin in 1943. 21 Reduction started, however, with changes toward reduced prostitution and improved sanitary conditions. Nowadays, the prevalence of chancroid is less than 1 in developed countries. 22 The few cases that are detected are usually imported from endemic countries or are associated with commercial sex work (CSW) and the use of crack cocaine and other illegal drugs. 7 Periodic health examinations and treatment of sex workers and other high-risk groups have largely contributed to the near-eradication of chancroid in these European coun-tries. 21 In some cities in the United States, however, especially among high-risk communities, the H. ducreyi

Mass Spectrometry

Simple EI, a single-quadrupole mass analyzer, has been the cornerstone of identification in forensic urine drug-testing facilities. However, in most cases, this method is totally inadequate for determining the lower concentrations of drugs and their metabolites found in hair. Because of this fact and matrix effects seen with hair analysis, more sensitive and more specific MS technology has been developed. Psychemedics, the authors' laboratory and one which performs the most commercial hair analysis, presently uses the Finnigan TSQ 7000 MS analyzers operating in negative ion chemical ionization (NICI) GC-MS-MS for the determination of marijuana in drug samples, detecting the tetrahydro-cannabinol (THC) metabolite carboxyTHC (cTHC), which is also the target ana-lyte monitored in forensic urine drug testing. All confirmation procedures need to go through vigorous validation studies. Psychemedics also uses positive ion chemical ionization (PICI) LC-MS-MS for the determination of cocaine,...

Platforms

This laboratory focuses most of its efforts on the use of the macroarray platform for the identification of gene expression changes in drug abuse. The macroarray experiment requires that the two populations of RNA be radioactively labeled and then used to query identical, but separate, membranes. This has an obvious disadvantage because the use of two different membranes provides an opportunity for hybridization error and therefore experimental variability. Macroarrays do, however, offer increased sensitivity over fluorescence-based methods, a feature that can be very advantageous especially when looking for rare genes. In addition, we find that this platform has an increased ability to detect small changes in gene expression (50 increases and 33 decreases). The experimental description that follows details how to perform a hybridization array using the macroarray platform.

Acknowledgements

Chen, J.G., Sachpatzidis, A., and Rudnick, G., 1997, The third transmembrane domain of the serotonin transporter contains residues associated with substrate and cocaine binding. J. Biol. Chem. 272 28321-28327. Galli, A., DeFelice, L.J., Duke, B.J., Moore, K.R., and Blakely, R.D., 1995, Sodium-dependent norepinephrine-induced currents in norepinephrine- transporter-transfected HEK-293 cells blocked by cocaine and antidepressants. J. Exp. Biol. 198 2197-2212. Norregaard, L., Loland, C.J., and Gether, U., 2003, Evidence for distinct sodium-, dopamine-, and cocaine-dependent conformational changes in transmembrane segments 7 and 8 of the dopamine transporter. J. Biol. Chem. 278 30587-30596.

Substances

Insomnia, ES, and parasomnias can be related to substance use. Chronic and excessive use of substances may lead to substance use disorders, which are characterized by either abuse or dependence. Stimulants such as caffeine, amphetamines, and cocaine classically disrupt sleep. Sedatives such as opiates and analgesics cause ES. Alcohol, at low dosages, can help with sleep initiation, yet chronic and excessive use can lead to disturbed sleep and the complaint of insomnia 29 . The effects of substances on sleep are reviewed in greater detail in Chapter 19 Sleep in substance use disorders.

Spread in the Host

Direct entry of virus into the bloodstream without any preceding replication in the host ('passive viremia') is a rare event. It can occur in association with intravenous drug abuse or during transfusion of infected blood or blood products. The bite of an arthropod vector may also allow direct entry of virus into the bloodstream. More commonly, viremia follows an initial phase of virus replication in the host ('active viremia'). Important sites of primary replication include subcutaneous tissue, brown fat, skeletal muscle, endothelial cells and regional lymphatic tissue. Virus enters the bloodstream from these sites ('primary viremia'), and is further disseminated to reticuloendothelial organs (bone marrow, liver, spleen) and endothelial cells. Additional replication is followed by a 'secondary viremia', which is typically of longer duration and higher magnitude than the initial viremia. This sequence of events was originally described for experimental mousepox (ectromelia) infection....

Entomotoxicology

Over the past 2 decades, drug-related deaths have increased in the United States and other countries. In many instances, these deaths are not immediately reported and the remains may be undiscovered for several days. Because of decomposi-tional processes, estimations of the time of death or postmortem interval are based on analyses of insects and other arthropods infesting the remains. The data most frequently employed are those associated with insect development rates and successional patterns. Recently, the accuracy of these estimations has been questioned in deaths involving narcotic intoxication. Relatively few studies are currently available detailing the effects of drugs, such as cocaine and heroin, in decomposing tissues on the rates and patterns of development of carrion-feeding arthropods. Additionally, there are few data dealing with effects of other tissue contaminants, such as toxins and environmental pollutants, in decomposing tissues on rates and or developmental...

Drug Targets

In Europe today, routinely tested DOA are shown in Table 1. In a typical screening assay, it is quite common to see combinations of these drugs being tested. At roadside screening, it has been reported that cannabis, opiates, cocaine, amphetamines (including methamphetamines), and benzodiazepines represent the most regularly tested DOA (6,7). Codeine, cotinine, salicylate, and tricyclic antidepressants may also be present in test panels. Phencyclidine (PCP), regularly included in the Substance Abuse and Mental Health Services Administration (SAMHSA)-5 panel of drugs in the United States, is rarely included in European DATs, especially on the POC format. Commonly abused in the United States, PCP is consumed at much lower levels in Europe. The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) recently reported that opiates are the class of drugs for which most people seek treatment (8). In methadone clinics, the main drug being tested is heroin, as opposed to the less...

Prisons

Interventions such as drug testing are thought to have a positive effect in the reduction of drug-related crime. As a result, DATs have become an increasingly important weapon at all levels of the criminal justice systems, particularly across northern Europe. DATs are not restricted to offenders officers may also be randomly tested for drug abuse owing to their potential contact with drugs. As a result, prospective candidates looking to join the prison service or police force may also be subjected to a drug screen as part of their pre-employment assessment. Just as drugs are easily obtainable in the community, drugs are also readily available in prisons. Being in prison or in young-offender institutes has never equated to the total cessation of drug abuse. According to recent EMCDDA data (8), approximately one-third of the entire European inmate population in 2002 had admitted to consuming drugs while in prison. Prisons in Germany and Spain were believed to have the highest rates of...

Biotechnology

The applications of phage display for biotechno-logical progress range from identification of molecular recognition elements between interacting proteins and ligands to targeted drug delivery for treatment of diseased mammalian cells. Biomedical applications include (1) antibody selection using a phage-displayed epitope library to facilitate the design of vaccines with optimal binding affinity for target epitopes (2) immunopharmacotherapy for cocaine addiction, in which cocaine-sequestering antibodies displayed on a filamentous ssDNA bacteriophage are delivered to the central nervous system intranasally (3) in vivo visualization of p-amyloid plaques by delivery of phage-displayed anti-p-amyloid antibodies to the brain with subsequent staining with fluorescent-labeled anti-phage antibody and (4) cell-targeted gene and drug delivery, in which the phage is essentially a therapeutic nanocourier. Filamentous ssDNA bacteriophage display systems have also been successfully applied for...

Police

It has been estimated that driving under the influence of drugs (DUID) is responsible for at least 4500 deaths and up to 250,000 serious injuries per year in Europe (9). In the zero-tolerant countries of Sweden, Germany, and Belgium, DATs are regularly employed by traffic police to combat DUID. In other countries, such as Finland, Sweden, and Germany, the assessment of blood and urine samples has already been included in their general codes of judicial procedure. In contrast, roadside screening devices for drug abuse, based on sweat, oral fluid, and saliva, are still being evaluated in the United Kingdom, Italy, and France. In these regions, the arrival of the equivalent of a drunk-driving breathalyzer is eagerly awaited.

Package Insert

Tions, adverse reactions, drug abuse and dependence, over-dosage, dosage and administration and how supplied. Proposed labeling must be submitted at the time of the NDA BLA ANDA filing. The package insert must accurately reflect the data generated during drug development, and claims in the label must be supported by data. To better assist the FDA in substantiating the claims made in the package insert, an annotated version is provided in the submission. All information in the package insert must be cross-referenced to the appropriate section of the submission that supports the labeling statement. Depending on the type of product, a sponsor may elect to develop a patient package insert, which assists patients with product usage and also requires FDA review and approval.

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