Treatment for Methamphetamine Dependence

Dealing With Drugs

Dealing With Drugs

Get All The Support And Guidance You Need To Be A Success At Dealing With Drugs. This Book Is One Of The Most Valuable Resources In The World When It Comes To A Parents Guide To The Drug Talk.

Get My Free Ebook

Withdrawal from Harmful Drugs at Home

How to safely detox at home especially from drugs like methadone, benzodiazepines, alcohol, suboxone, oxycontin, cocaine, crack, heroin, crystal meth, pain killers. How to prepare your body before withdrawal and dramatically lower withdrawal symptoms. The dangers of withdrawing from methadone, benzodiazepines, alcohol, crack, cocaine and opiates, and how to avoid them. What to expect when going through withdrawal. (mentioned throughout the video) How to make withdrawal easier and safer. The best way to overcome sleeplessness when withdrawing. How to alleviate depression when withdrawing. What factors could cause you to have more severe withdrawal symptoms and what step to take to address them before attempting withdrawal. Whether you can die from methadone withdrawal. The difference between withdraw, detox and rehab. What to look for when comparing detox centers.

Withdrawal from Harmful Drugs at Home Overview


4.6 stars out of 11 votes

Contents: Ebook
Author: Tibor Palatinus
Price: $47.77

Download Now

Intravenous Drug Abuse

A syndrome of diffuse osteosclerosis was first reported with intravenous drug abuse in St. Louis (61). The syndrome is considered rare and its cause is unknown. Patients have presented with aching limbs and a generalized increase in density throughout the skeleton. One such subject, a 38-year-old Caucasian man underwent BMD measurements with DXA (QDR-2000) of the spine and proximal femur and of the spine using QCT (General Electric HiSpeed Advantage) (62). The BMD in all regions was dramatically increased compared to age- and sex-adjusted normal values. Spine values by DXA were 160 of predicted and by QCT, 185 of predicted. Values in the proximal femur ranged

Pain And Opioid Addictiona Continuum Approach

While pain and addiction can and sometimes do exist as comorbid conditions, they may also present as part of a dynamic continuum with pain at one end of the spectrum and addiction at the other extreme. In cases when the identified substance of misuse is one in which there can be no doubt about the medical inappropriateness of ongoing use, such as with alcohol or cocaine use, a comorbid pain and substance-use disorder should be considered. When the drug in question can arguably be both the problem and the solution, depending on clinician training and perspective, a continuum model may better apply. This can be the

Cocaine and Methamphetamine

Although the argument often goes unchallenged in court, all drugs do not, by definition, produce impairment. Even though some US states define being under the influence as synonymous with the presence of any drug, some drugs do improve performance. In fact, low to moderate acute doses of cocaine and amphetamine can be expected to increase positive mood, energy, and alertness, especially in nontolerant individuals (74). It has been known since World War II that use of d-amphetamine can increase the ability to sustain attention for prolonged periods when performing monotonous tasks. For that reason, radar operators and pilots of both Allied and Japanese armies were issued supplies of amphetamine. Many of the performance tasks related to driving can be improved, at least in the laboratory, by treatment with stimulants (75). Although the results of one retrospective autopsy study suggest that methamphetamine users seem more likely to be involved in traffic accidents (76), a driving...

Opioid Peptides Cannabinoids and Cocaine and Amphetamine Regulated Transcript

The appetite-stimulating effect of marijuana in humans has been well known for centuries 38 . Endogenous cannabinoids, in particular anan-damide, increase appetite and food intake via the activation of specific receptors known as CB1 39 , which are expressed in hypothalamic and central areas involved in the control of feeding behaviour 40, 41 . In fact, CB1 receptor mRNA is co-expressed with CRH, cocaine- and amphetamine-regulated transcript (CART), melanin-concentrating hormone (MCH) and prepro-orexin 42 . Cocaine- and amphetamine-regulated transcript is co-expressed in ARC in POMC neurons 3,44 , and is directly modulated by leptin 44 . It is also expressed in PVN, NTS, lateral and dorso-medial hypothalamus and nucleus accumbens 45 . At the peripheral level, CART is expressed in the myenteric gut plexus, vagus nerve, pancreatic somatostatin cells, and antral gastrin cells 45 . Until now, no specific receptors for CART have been identified 45 , thus a full description of the...

Hepatitis Caused by Injecting Illicit Drugs and Intranasal Cocaine

The sharing of needles, syringes, and other equipment for the injection of illicit drugs is responsible for a substantial proportion of both HBV and HCV infections. Prevention efforts may be instituted by primary care physicians through routine inquiry about the use of injection illicit drugs by their patients. Advice to discontinue drug use, discussion of substance abuse treatment, and, where available, participation in needle-exchange programs may be effective. If the latter are not available, education concerning appropriate sterilization techniques may be implemented. Unfortunately, because percutaneous transmission through shared injection equipment is highly efficient for both HBV and HCV, these approaches are likely to be effective only if instituted very early after drug use begins (1). Current evidence suggests that needle-exchange programs reduce the risk of HIV infection, but their role in the control of HCV is more enigmatic. Higher concentrations of HCV and a higher...


Cocaine (see also Local anaesthetics, p. 422) use is a widespread and ancient practice amongst South American peasants who chew coca leaves with lime to release the alkaloid. It is claimed to give relief from fatigue and hunger from altitude sickness in the Andes, experienced even by natives when journeying by car or other 'fast' transportation and also to induce a pleasant introverted mental state. Remarkable feats of endurance attributed to chewing coca leaves have been reported, but there is no sound scientific confirmation of them. A United Nations enquiry into coca-leaf chewing reported that there was psychological but no physical dependence. It also reported that its use caused physical exhaustion rather than the reverse, and advocated gradual suppression in the interest of the populations concerned. But what may have been (or even still may be) an acceptable feature of these ancient stable societies has now developed into a massive, criminal business, not for leaf chewing, but...

Cocaine and Crack

Cocaine occurs naturally in the leaves of the coca plant Erythroxylum coca, which grows predominantly in South America. Cocaine hydrochloride is a white powder that is usually snorted but can be taken orally. Crack is prepared by mixing cocaine hydrochloride with sodium bicarbonate and water and heating it. The cocaine base precipitates out and forms small rocks as it cools. Crack may be smoked in a pipe or heated on foil with the vapor inhaled. Both crack and cocaine may be injected. The onset-of-action and plasma half-life varies depending on the route of use, rapidly if taken intravenously or smoked compared with when it is snorted. The duration of effects will also vary with administration route (70). Ingestion of stimulant drugs, such as cocaine or amphetamine, result in activation of the sympathetic nervous system with resulting euphoria followed by irritability, depression, insomnia, and paranoia (Table 12). Effects of Cocaine and Amphetamine Intoxication Cocaine produces a...

Burger Memorial Edition

The Sixth Edition of Burger's Medicinal Chemistry and Drug Discovery is being designated as a Memorial Edition. Professor Alfred Burger was born in Vienna, Austria on September 6, 1905 and died on December 30, 2000. Dr. Burger received his Ph.D. from the University of Vienna in 1928 and joined the Drug Addiction Laboratory in the Department cf Chemistry at the University of Virginia in 1929. During his early years at WA, he synthesized fragments of the morphine molecule in an attempt to find the analgesic pharmacophore. He joined the W A chemistry faculty in 1938 and served the department until his retirement in 1970. The chemistry department at W A became the major academic training ground for medicinal chemists because of Professor Burger.

Inborn Errors of Metabolism

MEKC has been applied to therapeutic drug monitoring. Using MEKC theophylline and its analogues have been separated in plasma. In addition, it has been used to detect and quantitate serum levels of digoxin (44,45). MEKC can also efficiently separate and quantitate antiepileptic drugs that are used in combination, especially ethosuxamide, phenobarbitol, pheny-toin, and carbamazepine (46). (See Chapter 17 for a detailed discussion of the use of CE in therapeutic drug monitoring.) CE has also been used in the clinical and forensic arena (see Chapter 19). In these cases, the use of urine to identify intoxication and or drug abuse of opiates, barbiturates, benzodi-azepines, stimulants, and doping screening is possible within a few minutes (47-51). It is also possible to use CE to screen post mortem fluids for illicit drugs or elevated levels of legal drugs (see Chapter 20). CE has also been applied to determine the tissue concentration of 5-Fluorouracil (5-Fl) in tumor and subcutaneous...

Cannabis And North America

As in Europe, it was not until the 1960s that cannabis use became very widespread. Legal restrictions were extended to the isolated active principle (tetrahydrocannabinol) in 1968. In 1970, the Comprehensive Drug Abuse Prevention and Control Act was introduced. However, by the early 1970s, US tolerance of the drug was such that a Presidential Commission in 1972 recommended 'decriminalisation' of cannabis. In 1973, Oregon was the first state to rescind legislation which prohibited the personal use of cannabis. Subsequently many states issued similar laws. These State Laws do not allow users to grow cannabis. In 1977, President Carter's government supported legalised possession of small amounts of the drug (Musto, 1991). Since then the popularity of cannabis in the US has waxed and waned, but not all new laws have been in favour of liberalisation in 1990, for example, the people of Alaska voted to re-criminalise the possession of cannabis.

Hair Head and Pubic 51 Forensic Evidence

Hair is most commonly sampled to detect body fluids or retrieve foreign hairs or particles. It has been known for many decades that numerous ingested, prescribed, and illicit drugs (e.g., barbiturates, amphetamines, opiates, cocaine, benzodiazepines, y-hydroxy butyrate, and cannabis) are deposited in the hair (44). Although toxicology of hair was originally used to detect drugs that had been repeatedly ingested, recent advances in analytical techniques have meant that toxicology may be useful after single-dose ingestion as would occur in a substance-facilitated sexual assault (45,46). This is particularly pertinent because complainants of possible drug-facilitated sexual assaults frequently do not report the incident expeditiously because of amnesia and or doubt about what might have happened, and drugs may be accessible to analysis for longer periods in hair compared to blood or urine (47). In addition, it may be used as a reference sample for DNA analysis.

7 High Content Metabolic Assays

Efforts for the rapid screening of drug adsorp- tion metabolism have intensified as the imports tance and relevance of the parameters for drug discovery have become more apparent with every failed and recalled drug. The cyto- chrome P450 (CYP) enzymes metabolize xe-I nobiotics and evolved as a defense against ac-I cidentally ingested toxic compounds. Drug pharmacokinetics are modulated in part by metabolism and patients on multi-drug regimens can experience unexpected changes, both positive and negative, in drug mean residence time and maximum serum levels. Drug I inhibition of CYPs can lead to increased drug levels and increased risk of toxic side effects. Several high-throughput assays for test comI pound inhibition of CYPs have been reported I (36-38).Most are based on changes in the flur orescence of a known CYP substrate and speI cificCYP isoform inhibition in the presence of I test compounds. Increased CYP activity can result in toxicity as well. The nuclear hormone I receptor...

Imaging The Dopaminergic System

Direct measurements of dopamine transporter binding sites are possible with 11C cocaine (77), or the cocaine analogs 20-carbomethoxy-30- 4-iodophenyl tropane (0-CIT) and tropane (FP-CIT), labeled with either 18F or 11C for PET or 123I for SPECT (78-80). Other dopamine transporter ligands include tropane ( 123I IPT) (81), its 4-fluorophenyl analog 123I altropane

Druginduced myocardial damage

Increases in cardiac troponin have been described in (1) patients treated with certain types of antineoplastic agents, (2) patients presenting to hospitals following alcohol and drug abuse, and (3) patients with therapeutic drug-induced cardiac toxicity. The release of cardiac troponin into the circulation following therapy with antineoplastic agents has been well documented (71-74). Both acute (within hours) and chronic (days to weeks) myocardial toxicity manifested by ischemia, arrhythmias, myocarditis, pericarditis, cardiomyopathy, and or MI after dosing with the anthracyclines 5-fluorouracil, doxorubicin, and daunorubicin have been associated with minimal and large increases in cTnl. Reports have documented that a medication dose-dependent pattern of myocyte injury is responsible for increases in troponin, even without electrocardiographic or echocardiographic abnormalities. Studies have shown that in patients undergoing high-dose chemotherapy, an increase in cardiac troponin...

Decriminatisation and legalisation

Nobody knows what would happen if the production, supply and use of the major drugs, cannabis, heroin and cocaine, were to be legalised, as tobacco and alcohol are legalised (with weak selling restrictions). There are those who, shocked by the evils of illegal trade, consider that legalisation could only make matters better. The debate continues about what kinds of evils affecting the individual and society can be tolerated and how they can be balanced against each other.

Route Of Administration And Effect

With the i.v. route or inhalation much higher peak plasma concentrations can be reached than with oral administration. This accounts for the 'kick' or 'flash' that abusers report and which many seek, likening it to sexual orgasm or better. As an addict said The ultimate high is death' and it has been reported that when hearing of someone dying of an overdose, some addicts will seek out the vendor since it is evident he is selling 'really good stuff'.6 Addicts who rely on illegal sources are inevitably exposed to being supplied diluted or even inert preparations at high prices. North American addicts who have come to the UK believing themselves to be accustomed to high doses of heroin have suffered acute poisoning when given, probably for the first time, pure heroin at an official UK drug dependence clinic.

Supply Of Drugsto Addicts

In the UK, supply of officially listed drugs (a range of opioids and cocaine) for the purpose of sustaining 6 Bourne P 1976 Acute drug abuse emergencies. Academic addiction is permitted under strict legal limitations. Addicts must be notified by the physician to the Home Office and in the case of some opioids and cocaine, the physician requires a special licence. By such procedure it is hoped to limit the expansion of the illicit market, and its accompanying crime and dangers to health, e.g. from infected needles and syringes. The object is to sustain young (usually) addicts, who cannot be weaned from drug use, in reasonable health until they relinquish their dependence (often over about 10 years).

Treatment Of Dependence

Young illicit users by i.v. injection (heroin, benzodiazepines, amphetamine) have a high mortality. Either death follows overdose, or septicaemia, endocarditis, hepatitis, AIDS, gas gangrene, tetanus and pulmonary embolism ensue from the contaminated materials used without aseptic precautions (schemes to provide clean equipment mitigate this). Smugglers of illicit cocaine or heroin sometimes carry the drug in plastic bags concealed by swallowing or in the rectum ('body packing'). Leakage of the packages, not surprisingly, may have a fatal result.7 7 A 49-year-old man became ill after an international flight. An abdominal radiograph showed a large number of spherical packages in his gastrointestinal tract, and body-packing was suspected. As he had not defaecated, he was given liquid paraffin. He developed ventricular fibrillation and died. Post mortem examination showed that he had ingested more than 150 latex packets, each containing 5 g of cocaine, making a total of almost 1 kg...

Starting and stopping use

If the patient is heavily tobacco-dependent and severe anxiety, irritability, headache, insomnia and weight gain (about 3 kg) and tension are concomitants of attempts to stop smoking, an anxiolytic sedative (or (3-adrenoceptor blocker) may be useful for a short time, but it is important to avoid substituting one drug-dependence for another.

Individual substances

Tenamfetamine ('ecstasy', MDMA methylenedioxy-methamphetamine) is structurally related to mescaline as well as to amphetamine. It was originally patented in 1914 as an appetite suppressant and has recently achieved widespread popularity as a dance drug at 'rave' parties (where it is deemed necessary to keep pace with the beat and duration of the music popular names reflect the appearance of the tablets and capsules and include White Dove, White Burger, Red and Black, Denis the Menace). Tenamfetamine stimulates central and peripheral a-and p-adrenoceptors thus the pharmacological effects are compounded by those of physical exertion, dehydration and heat. In susceptible individuals (poor metabolisers who exhibit the CYP450 2D6 polymorphism) a severe and fatal idiosyncratic reaction may occur with fulminant hyperthermia, convulsions, disseminated intravascular coagulation, rhabdomyolysis, and acute renal and hepatic failure. Treatment includes activated charcoal, diazepam for...

Xanthinecontaining Drinks

Occur in habitual coffee drinkers (5 or more cups day) 12-16 h after the last cup they include headache (lasting up to 6 days), irritability, jitteriness they may occur with transient changes in intake, e.g. high at work, lower at the weekend. Habitual tea and coffee drinkers are seldom willing to recognise that they have a mild drug dependence.

Guide To Further Reading

315 1664-1668 Gawin F H, Ellinwood E H 1988 Cocaine and other stimulants actions, abuse, and treatment. New England Journal of Medicine 318 1173-1182 Green A R, Goodwin G M 1996 Ecstasy and Lancet 352 1611-1616 Hollander J E 1995 The management of cocaine-associated myocardial ischaemia. New England Journal of Medicine 333 1267-1272 Lange R A, Hillis L D 2001 Cardiovascular complications of cocaine use. New England Journal of Medicine 345 351-358 MacAuley D 1996 Drugs in sport. British Medical Journal 313 211-215 Mendelson J H, Mello N K Management of cocaine abuse and dependence. New England Journal of Medicine 334 965-972 Ness R B et al Cocaine and tobacco use and the risk of spontaneous abortion. New England Journal of Medicine 340 333-339 Nutt D J 1996 Addiction brain mechanisms and their treatment implications. Lancet 457 31 (see also other articles in this series on pages 97,162, 237, 301,373)

Optic Nerve Carotid Artery

Ciliospinal Center Budge

Lower concentrations of phenylephrine (about 2 ) are well suited to the pharmacologic detection of weakened pupillary dilators. Among infants, one often finds an aniso-coria with normal pupillary light reactions and no ptosis that persists after instillation of topical cocaine. If the an-isocoria persists after instillation of 2.5 solution of phenylephrine, it can be concluded that the dilator of the smaller pupil is probably hypoplastic. This is a benign disorder not associated with any other abnormalities of anterior segment development, and it commonly normalizes with the passage of time.

Social Attitudes and Public Perceptions

Surveys of cannabis usage have been produced in many countries. These address frequency of recreational use, distinction of gender or occupation of user, and form of drug abused. In contrast, in Malaysia in the 12 years from 1975 to 1986, heroin was by far the most available drug of abuse (80 ), with much less cannabis seized, and synthetic drugs were very uncommon. This is not surprising, given the geographical proximity to South East Asian sources, but penalties for trafficking are very severe. Their National Drug Abuse Monitoring System recorded that during this period known addicts rose 11-fold, from 68 to 755 per million inhabitants.

Desacyl Ghrelin as an Anorexigenic Peptide

Peripheral administration of des-acyl ghrelin showed an increase in c-Fos expression in the hypothalamic arcuate nucleus and in the paraven-tricular nucleus. The anorexigenic cocaine- and amphetamine-regulated transcript (CART) and urocortin 25 , as well as corticotropin-releasing factor type 2 receptor, but not type 1, are involved in this action 26 . Peripheral des-acyl ghrelin may directly activate the brain receptor by crossing the blood-brain barrier 27 but not by the activation of vagal afferent pathways 2, 25 . According to these results, the intracisternal administration of des-acyl ghrelin decreased food intake in food-deprived rats and inhibited gastric emptying without altering small intestine transit 11 .

Cytokine Peptide Interactions

Other endogenous cytokine-peptide interactions relevant to wasting, cachexia and the cachexia-anorexia syndrome include reciprocal cytokine-leptin (a member of the long-chain helical cytokine family)-neuropeptide Y-corti-cotropin-releasing hormone-glucocorticoid interactions, and perhaps also among cytokines and other CNS neuropeptide regulators involved in the control of energy balance including cocaine- and amphetamine-regulated transcript, melanin-concentrating hormone, agouti-related protein, a-melanocyte-stimulating hormone, and hypocre-tins orexins 8,10,12, 22,27 . Various of these can affect metabolic processes directly (e.g. gluconeo-genesis, glycogenolysis). The hypothalamus plays a critical role with multiple neuronal groups involved, including the arcuate nucleus, the paraventricular nucleus, the ventromedial nucleus, and the lateral hypothalamus. The arcuate nucleus has leptin-responsive neurons with different functions, e.g. the pro-opiomelanocortin-producing neurons that...

Physiology And Pharmacology

All psychostimulants appear to elevate synaptic levels of dopamine and norepinephrine. In addition, cocaine and, to a lesser extent, some of the other agents also raise synaptic levels of serotonin. It is the current consensus that elevated dopamine levels lead to CNS stimulation and are responsible for the reinforcing properties of stimulants (72-78). Nevertheless, recent studies have begun to focus attention on glutamate systems as potential key components of the actions of psychostimulants. For example, Swanson et al. (79) have shown that repeated cocaine administration leads to long-term attenuation of group I metabotropic glutamate receptor function in the nucleus accumbens. In particular, this functional reduction was related to significantly reduced mGluRS immunoreactivity in the medial nucleus accumbens. Even more exciting is the recent report that mGluR5 knockout mice do not display the reinforcing and locomotor effects of cocaine, in spite of the fact that cocaine...

Recent And Future Developments

Ing the monoamine transporters at the molecular level. Whereas it has been known in pharmacology for many years that cocaine targeted an energy-dependent reuptake pump, the cloning and expression of these transporters has given access to high purity proteins that are amenable to more detailed study. These proteins have all been sequenced, and shown to be membrane bound with 12 membrane-spanning helical segments. a large number of site-specific mutations have been used to correlate specific residues in the protein with specific functions. Nevertheless, it will likely take a technical breakthrough to obtain a crystal structure of one of these transporters or one of their homologs, an accomplishment that will no doubt lead to much greater understanding of how transporters function. Inability to crystallize these proteins is not a problem that is unique to monoamine transporters, but continues to plague the study of all membrane-bound transporters and receptors, and other membrane-bound...

Pharmacological Mechanism of Addiction and Craving

Dopamine plays the most important role in this system. Nicotine interferes with this dopamine rewarding system by influencing the concentration of dopamine directly at the receptor or indirectly influencing the neurotransmission via GABA, opioid, serotonin, acetylcholine or norepi-nephrine, thus being an inhibitor or stimulator of this dopamine rewarding system.5 Nicotine, alcohol, heroin, and cocaine influence this system at various levels. Direct activation of the rewarding system leads to euphoric feelings. This is essential in the development of dependency and addiction. Neuroadaptation develops when nicotine is used regularly. The change in the brain is permanent at molecular, cellular, structural, as well as functional levels. This is the cause of craving. Craving can remain, even when the nicotine has been stopped for a very long time. Craving is closely related to the phenomenon of relapse, the essence of addiction. As a result of this neuroadaptation, tolerance and withdrawal...

Postsynaptic Da Function

Because RAC has a low affinity to D2 receptors, PET imaging with this tracer has been widely used to measure DA release under interventions that modulate dopaminergic systems. The amount of release is estimated by the percentage reduction in RAC binding as a result of the competition between external stimulation and endogenous DA. It has been reported that stri-atal RAC binding relative to baseline is reduced in PD after acute levodopa administration, most notably in the posterior putamen (18 ), followed by the anterior putamen (12 ), and the caudate nucleus (6 ) (38). The magnitude of reduction is correlated with the drug-free disability of motor function. This gradient of DA release is consistent with the topographic pattern of DA lesions portrayed by presynaptic PET imaging markers. Another study has recently demonstrated that pharmacological challenge with methamphetamine produces significantly reduced DA release in striatum, but normal levels of prefrontal DA release in advanced...

Prolongation Of Action By Vasoconstrictors

The effect of a local anaesthetic is terminated by its removal from the site of application. Anything that delays its absorption into the circulation will prolong its local action and can reduce its systemic toxicity where large doses are used. Most local anaesthetics, with the exception of cocaine, cause vascular dilation. The addition of a vasoconstrictor such as adrenaline (epinephrine) reduces local blood flow, slows the rate of absorption of the local anaesthetic, and prolongs its effect the duration of action of lidocaine is doubled from one to two hours. Normally, the final concentration of adrenaline (epinephrine) should be 1 in 200 000, although dentists use up to 1 in 80 000.

Imaging Of Postsynaptic Da Receptors

PET with RAC is capable of measuring synaptic DA release from embryonic nigral transplants. This was performed in a PD patient demonstrating the sustained and marked clinical improvement, as well as gradual increase of FDOPA uptake to normal during a period of 10 yr after grafting in the unilateral putamen (95). RAC binding to DA D2 receptors was measured with saline or methamphetamine infusion. Binding at baseline was normal in the grafted putamen but upregulated in the

Substance Misuse and Fitness for Interview

Withdrawal states can pose a bigger problem for the doctor assessing fitness for interview. Although most confessions made in these circumstances are reliable (74), it should be recognized that the person suffering from drug withdrawal may be particularly vulnerable to providing a false confession. Such persons may believe that compliance will result in early release and that the risks entailed in providing a false confession may seem worthwhile in the presence of an overwhelming desire to re-establish access to their supply of drugs (75). Although symptoms of mild withdrawal from opiates, for example, is considered unlikely to be a barrier to interview (62,73), the physical and mental distress occasioned by established withdrawal may seriously impair a suspect's fitness to undergo the somewhat threatening and difficult experience of police interrogation.

Effect of Charge on Drug Binding Tonic Versus Use Dependent Block

LAs including lidocaine, procaine, and cocaine, exist in two forms at physiological pH (Hille 1977 Liu et al. 2003 Strichartz et al. 1990). The uncharged form accounts for approximately 50 of the drug, while the protonated charged form is in equal proportion. The uncharged base form is highly lipophilic and therefore easily crosses cell membranes and blocks Na+ channels intracellularly. Quaternary ammonium (QA) compounds are positively charged permanently

Polymorphic structure of cannabinoid receptor genes

And association of the marker with schizophrenia indicating that CBX Cnr gene is not a gene of major aetiological effect for schizophrenia but might be a susceptibility locus in certain individuals with schizophrenia, particularly those whose symptoms are apparently precipitated or exacerbated by cannabis use (Dawson, 1995). Comings et al. (1997), hypothesized that genetic variants of CBX Cnr gene might be associated with susceptibility to alcohol or drug dependence and analyzed the triplet repeat marker in the CBX Cnr gene. They found a significant association of the CBj Cnr gene with a number of different types of drug dependence (cocaine, amphetamine, cannabis), and intravenous drug use but no significant association with variables related to alcohol abuse dependence in non-Hispanic Caucasians. In addition, this group also reported that a significant association of the triplet repeat marker in the CBX Cnr gene alleles with the P300 event related potential that has been implicated...

The Behavioral Activation or Behavioral Approach System

Gray (e.g., 1973) cited the famous work of Olds and Olds (1965) on rewarding electrical self-stimulation, identifying this effect as focusing on the medial forebrain bundle and the lateral hypothalamus, along with projections of the medial forebrain bundle to the septal area. By 1983, Gray and colleagues (Gray, Owen, Davis, & Tsaltas, 1983), referring to the brain processes that mediate responses to stimuli associated with reward and nonpunishment, said that the picture is now more ambiguous than ever before, that self-stimulation provides a poor guide to the functions of the region of stimulation, and that the authors were unable to contribute much to the physiology of reward (pp. 210-211). Four years later, however, Gray (1987, pp. 308309, 330) identified the mesolimbic dopaminergic projections from the brainstem ventral tegmental area to the ventral striatum (including the nucleus accumbens) as playing a key role in transmitting incentive motivation to motor systems (p. 308) and...

Answers To Case 13 Cirrhosis Probable Hepatitis C Related

Summary A 49-year-old woman presents with new-onset abdominal swelling. Her history reveals a blood transfusion with postpartum hemorrhage and cocaine use. On examination, her temperature is I00.3 F, heart rate 88 bpm, and blood pressure 94 60 mmHg. Her sclerae are icteric. Her abdomen is distended, with mild diffuse tenderness, shifting dullness to percussion, and a fluid wave, consistent with ascites. She has no peripheral edema. Laboratory studies show the following levels Na 129 mmol L, albumin 2.8 mg dL, prothrombin time 15 seconds, hemoglobin 12 g dL with MCV 102 fL, and platelet count 78,000 mm3.

Management in Custody

Necrotizing fasciitis and septic thrombophlebitis are rare but life-threatening complications of intravenous drug use. Any detainee suspected of either of these needs hospital treatment. Advice about harm reduction should also be given. This includes encouraging drug users to smoke rather than inject or at least to advise them to avoid injecting into muscle or skin. Although most IDUs are aware of the risk of sharing needles, they may not realize that sharing any drug paraphernalia could be hazardous. Advice should be given to use the minimum amount of citric acid to dissolve the heroin because the acid can damage the tissue under the skin, allowing bacteria to flourish. Drugs should be injected at different sites using fresh works for each injection. This is particularly important when speedballing because crack cocaine creates an anerobic environment. Medical help should be requested if any injection site become painful and swollen or shows signs of pus collecting under the skin....

Ghrelin as a New Factor in the Control of Energy Balance Appetite and Food Intake

AgRP causes only a modest effect on the orexi-genic effect of ghrelin, simultaneous genetic ablation completely abolishes ghrelin's modulatory action on food intake 55 . However, other agents are likely to be involved in mediating the impact of ghrelin on appetite, food intake and energy balance these include orexins, pro-opiomelanocortin (POMC), cocaine- and amphetamine-related transcript (CART), MCH, ciliary neurotropic factor (CNTF), gamma amino butyric acid (GABA), galanin, corticotropin-releasing hormone (CRH) and somatostatin 46, 50,56 . Besides the increase of appetite and food intake, reduced cellular fat oxidation and promotion of adipogenesis reportedly contributes to increased fat mass induced by ghrelin 10,50 .

Periodontal Treatment Protocol

Ihe patient's health status should be determined from the health history, physical evaluation, and consultation with his or her physician, treatment decisions will vary depending oil the patient's stale of health. For example, delayed wound healing and increased risk of postoperative infection are possible complicating factors in AIDS patients, hut neither concern should significantly alter treatment planning in an otherwise healthy, asymptomatic, HIV-infected patient with a normal or near-normal CD4 count and a low viral bioload.'1 It is important to obtain information regarding the patient's immune status. What is the CIM 14 lymphocyte level What is the current viral load How do current ( I> 4 14 cell and viral load counts differ from previous evaluations How often are such tests performed How long ago was the HIV infection identified Is it possible to identify the approximate date of original exposure Is there a history of drug abuse, sexually transmitted diseases, multiple...

Structureactivity Relationships

Boat Conformation 180

Amphetamine S-(+)-methamphetamine, 18 , phentermine (19), phenmetrazine (Preludin, 20), and phendimetrazine (21). Diethylpro-pion (Tenuate 16) is used as an appetite suppressant and, although it has the amphetamine skeleton, its effects are much weaker as a stimulant than those of the other structures listed here. The stereochemistry at the a side-chain methyl group is the same for the most potent enantiomer of each structure, although the pure enantiomer has not generally been marketed except for the cases of (+)-amphet-amine (10)and (+)-methamphetamine (18). 5.1.2 Nitrogen Substituents. Nitrogen sub-stituents are very limited. The primary amine (amphetamine)and the AT-methylamine (meth-amphetamine) are the most potent compounds (135). An N-methyl increases the potency of both amphetamine and cathinone (2) (136). Larger alkyl groups (135,137) or N,N-dialkylation, either dramatically attenuate or completely abolish stimulant activity (138). Nevertheless, iV,iV-dimethylamphetamine has...

Approach To Hypertensive Emergencies

Hypertensive crises are uncommon but occur most often in patients with an established history of so-called essential hypertension, that is, hypertension without an apparent underlying cause. A crisis may be precipitated by use of sympathomimetic agents, such as cocaine, or by conditions that produce excess sympathetic discharge, such as clonidine withdrawal. Hypertensive crises also result from underlying diseases that cause hypertension, such renovascular disease (e.g., renal artery stenosis), renal parenchymal disease (e.g., glomerulonephritis), and pheochromocytoma.

Implication for the medical use of marijuana

The use of cannabis for both recreational and medicinal purposes dates back to thousands of years. In recent times, there has been an increase in calls for marijuana to be legalized for medicinal use in AIDS, cancer, multiple sclerosis and other medical conditions where patients might benefit from the biological effects of cannabis. Synthetic cannabinoids such as dronabinol, marinol and nabilone already have an established use as antiemetics in nausea and vomiting associated with cancer chemotherapy. The reported beneficial effects in cancer and AIDS patients might reflect improved weight gain, owing to the well-documented anti-emetic and appetite stimulating effects of cannabinoids. This might be a major advantage for cancer patients undergoing rigorous chemotherapy, or advanced AIDS patients. Interestingly, although cannabis is widely used as a recreational drug in humans, only a few studies revealed an appetitive potential of cannabinoids in animals. However, evidence for the...

Caveats in Interpreting Electrophysiologic Data in Substance Abuse Research

Perhaps the most important aspect regarding the usefulness of EEG and ERP measures in substance abuse research is the issue of specificity. Namely, whether the electrophysiological changes observed are unique to the specific drug or condition tested. Most of the data available to date suggests that EEG and ERP measures have limited diagnostic specificity. For instance, acute administration of either ethanol, cocaine or marihuana all result in significant increases in alpha activity (Lukas et al., 1986, 1990, 1991, 1995), these increases are not only indistinguishable from each other but are also similar to those observed during transcendental meditation (Lindsley, 1952 Brown, 1970 Wallace, 1970). Given the association between alpha activity and pleasurable states, these findings suggest that the drug-induced increases in alpha activity represent a neurophysiologic response associated with reinforcement in general. Even though electrophysiological measures are not always specific...

Presynaptic Da Function

Imaging of dopamine transporter (DAT) is another way for probing the impaired nigrostriatal dopaminergic system in PD. DAT is expressed on dopaminergic nigral terminals, and quantification of striatal DAT appears to be directly related to the extent of nigral cell degeneration (24). This has received more attention in recent years as radiotracers that bind to the striatal DAT have been successfully developed for both PET and SPECT imaging. The most common agents are the cocaine analogs, such as (123I)P carbomethoxy-iodophenyl tropane (CIT) and (18F)FP-PCIT (25, 26), as well as P -carbomethoxy-3 P -(4-fluorophenyl) tropane (CFT) labeled with (18F) and (11C) (27-29). DAT binding is estimated by an uptake ratio or distribution volume ratio between the striatum and a reference tissue such as cerebellum.

The Physiological Importance Of Creb

There is also considerable evidence that CREB has a role in other aspects of neuronal physiology, including drug addiction (29), circadian rhythmicity (30), and neuronal survival (31). Mice deficient in CREB exhibit excess apoptosis in sensory neurons (32), and CREB mediates many of the prosurvival effects of neurotrophins (31).

Molecular Basis For The Side Effects Of Anticholinergics

The most widely used mode cf approach in the design cf anticholinergics is based on the use cf tropine alkaloids as models of prototypes, from which congeners or homologs or analogs have been designed. Tropine alkaloids have many pharmacological activities and interact at many cholinergic sites. In drug design the main purpose is to increase one pharmacological action at one particular site of action while concomitantly suppressing other pharmacological activities at other sites. It is not always possible to abolish all pharmacological effects other than the desired activity by molecular modification. Though the desired activity is useful in its therapeutic applications, other pharmacological activities manifest themselves as side effects. For example, atropine, scopolamine, and cocaine are structurally related, each having atropine nucleus. They differ in some of their pharmacological activities. Atropine stimulates the CNS, scopolamine depresses the CNS, and cocaine is a local...

Parts of Plant Fruiting Flowering Tops Aerial Parts Stalk Seed Nonviable

Further forensic uncertainty may arise where there is need for legal discrimination of the flowering tops from the axial buds and lower leaves (which may still be a moderate source of cannabinoid congeners). The forensic difficulty experienced in the UK was not a problem in US Federal Law in the 1970s, when the definition of marihuana subsumed flowering fruiting tops and lower leaf and viable seed. Moreover, the US Drug Abuse Prevention & Control Act DAPCA 1970 also had a very much broader description of synthetic variants of tetrahydrocannabinols see discussion in 1.8 below.

Clinical Approach

Numerous medications and substances may contribute to palpitations. Among these are alcohol, caffeine, street drugs (cocaine), tobacco, ephedra (found in weight loss drugs), diuretics (causing electrolyte disturbances), digoxin. -agonists (e.g., albuterol), theophylline, and phenothiazine. Patients should be questioned about their use of over-the-counter medications, herbs, and supplements, as they often will not provide this information unless specifically asked.

Radioligands Used In The Study Of Da Metabolism

Presynaptic markers directed to DAT are mostly tropane derivatives (cocaine analogs), such as 11C - or tropane (CFT, also known as 11C - or 18F -WIN 35,428), carbomethoxy-iodophenyl tropane (CIT), and 11C -RTI-32 (36). CIT can also be modified with either a fluoroethyl or fluoropropyl group. Because of the delayed time to equilibrium, the 18F-labeled FP-CIT is more suitable than its 11C analog, which has a much shorter half-life (37). nC -D-ihreo-methylphenidate (MP) may also be used to target the DAT, with a higher affinity and better pharmacokinetic properties than the majority of the tropanes (38). Although the DAT (but not all of its ligands) is fairly specific for DA, it has the disadvantage of being subject to up- or down-regulation by dopaminergic drugs and in response to extracellular levels of DA (39-41). Thus, findings may be attributable to disease or a consequence of its treatment. Numerous tropanes have been labeled with I-123 for SPECT imaging of the DAT, and there is to...

Introduction Analysis Of Urinary Drugs In Clinical And Forensic Toxicology

Clinical and forensic toxicology is concerned with the detection, identification, and measurement of toxic compounds and their metabolites in human body fluids and tissues. Most often the toxic compounds are drugs taken either accidentally or intentionally in quantities sufficient to cause an adverse reaction or death. Analysis and identification of a possible drug or drug combinations, toxicological drug screening and confirmation should encompass as many different classes of drugs as possible. The most important classes being salicylate, paracetamol, antiepileptics, antidepressants, neuroleptics, hypnotics (benzodiazepines, barbiturates, diphenhydramine), digoxin, and theophylline, as well as many illicit drugs, such as opiates, methadone, D-lysergic acid diethylamide (LSD), cocaine, and or its major metabolite benzoylecgonine, cannabinoids and amphetamines. Currently, urinary drug monitoring has established itself as the basis of clinical and forensic toxicology. It is also the...

Rapid Unexplained Deaths During Restraint

The individuals who die during restraint are not infrequently under the influence of drugs (particularly cocaine) or alcohol they may be suffering from some underlying natural disease (particularly of the cardiovascular system), or they may have suffered some trauma. These additional factors are sometimes seized by pathologists and courts to explain the death, sometimes even in the face of expert opinion that excludes the additional factor from playing a major part in the death. It would seem that there is a subgroup of the population that is either permanently or temporarily susceptible to the effects of restraint, whether those effects be mediated entirely or partially through decreased respiratory effort or some other factor.

Sex Differences In Personality Traits Coping And Stressrelated Psychiatric Disorders

There also appear to be some sex differences in physiological and behavioral coping with traumatic and chronic adverse life events. For example, women are more likely than men to develop posttraumatic stress disorder (PTSD) following traumatic events (Weiss, Longhurst, & Mazure, 1999 Widom, 1999). Furthermore, experiences of early trauma, such as physical and childhood sexual abuse, have been found to confer a greater susceptibility to developing psychiatric illness and illicit drug abuse on women than on men (MacMillan et al., 2001). The well-known association between adverse life events and increased risk of major depression is significantly higher in women than in men (Maciejewski, Prigerson, & Mazure, 2001). Early life trauma is associated with an increased HPA reactivity to acute and chronic stressors in women (Heim et al., 2000 Nemeroff, 1996). Women with major depression show greater abnormalities in HPA axis responses as compared to men (Young, 1995 Young & Korszun,...

Basic Science Of Addiction

Drugs of misuse act at local cellular and membrane sites that are within a neurochemical system that is called the Reward and Withdrawal Pathway (11). This pathway is in the meso-limbic dopamine system, and it involves, among other structures, the ventral tegmental area, nucleus accumbens, amygdala, and prefrontal cortex of the primitive brain. Addiction is a neurobiological disease that causes disruption of this pathway. This disruption is mediated via receptor sites and neurotransmitters. Central to this reward and withdrawal pathway is the neurotransmitter dopamine, which has been shown to be relevant not only to drug reward, but also to food, drink, sex, and social reward (12,13). Disruption of this neurochemical pathway by drugs of abuse may lead to addiction. Drug withdrawal can intensify with repeated drug use and can persist during prolonged periods of drug abstinence, a symptom complex known as the protracted abstinence syndrome (14). This sensitization of a neural process...

Diagnostic and Statistical Manual of Mental DisordersIV

(7) Continued substance use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance (e.g., continued cocaine use despite recognition of cocaine-induced depression, or continued drinking despite recognition that an ulcer is made worse by alcohol consumption)

Deborah B Diercks MDa J Douglas Kirk Md Facepa Ezra A Amsterdam Md Faccb

Chest pain evaluation units provide a safe and cost-effective means for risk stratification of patients who present to the emergency department (ED) with chest pain and no evidence of myocardial infarction (MI) or ischemia on initial evaluation. A standardized protocol is often used that combines serial measurements of cardiac injury markers, repeat electrocardiograms (ECG), and telemetry monitoring followed by secondary risk stratification by additional diagnostic testing for coronary artery disease (CAD). The latter usually comprises provocative testing with exercise or pharmacologic stress. Although these units rely heavily on a protocol-driven approach, appreciation of the limitations of this method in certain patient populations is essential. In particular, the inclusion of women, diabetics, patients with a history of CAD, and those with chest pain after stimulant use (eg, cocaine, methamphetamine) may necessitate additional consideration in the choice of diagnostic testing. Some...

Universal Precautions In Pain Medicine

Surprisingly, some clinicians struggle with the idea of taking a drug and alcohol history in all patients. Even asking about drug and alcohol misuse is seen as minimizing or dismissing the patients' complaints of pain. In no other area of medicine would such an attitude exist. The fact is that alcohol and drug addiction is present in virtually all areas of medicine, without particular respect for socioeconomic status, race, age, or sex. While the nature and distribution of these problems vary, it is unwise to limit one's inquiry into substance use based on classical societal stereotypes.

Approach To Illicit Drug Effects

Drug abuse is common and pervasive in our society. Contrary to popular belief, many highly educated and socioeconomically advantaged persons are involved in the illicit use of street drugs, legal drugs, or prescribed medications. The physician must have a high index of suspicion to be able to offer appropriate therapy and to prevent the disastrous consequences of such use. Alcohol and tobacco are the most commonly abused drugs however, this discussion focuses on common street drugs that are known to have serious medical consequences with both acute and chronic use. Cocaine is a stimulant, vasoconstrictor, and local anesthetic derived from the leaves of the coca plant. The drug can be snorted, administered intravenously, or smoked. It blocks the reuptake of norepinephrine, serotonin, and dopamine at the receptor, which leads to elevated mood, heart rate, blood pressure, and temperature. Cocaine has a short half-life of approximately 1 hour, and its metabolites are detectable in the...

Box 3 Unique factors in diabetics that affect stress test results

The use of stimulants such as cocaine and methamphetamines is of epidemic proportions. According to recent data, 25 million people in the United States have reported using cocaine 48,49 , and it is likely that these numbers are similar for methamphetamine. The cardiovascular complications of cocaine have been well studied. It has been reported that the risk of MI is 24 times baseline risk in the hour after cocaine use 50 . In patients under the age of 45 years with acute MI, approximately 25 are cocaine related 51 . Of patients who present to the ED with cocaine-related chest pain, 6 have MI and the rate of cardiac arrhythmia has been reported to be over 2 52 . Because there are no prospective studies in the methamphetamine patient population, data for cocaine are often extrapolated to the methamphetamine patients. A small study of patients admitted to the hospital with a positive screen for methamphetamine reported an in-hos-pital event rate of 8 , and in this selected group of...

Roles and pain behaviour

There is evidence that sexual abuse has a link with later pain experiences, particularly with respect to pelvic and gastro-intestinal pain. This is with relation to self-reported sexual abuse. The actual incidence of abuse is difficult to estimate and perhaps is irrelevant. Repeated studies have demonstrated this link as reviewed by Thomas (1997), who related it back to the work of Engel (1959), and by Linton (1997). Linton et al. (1996) confirmed this link, in particular with musculo-skeletal pain, and also demonstrated that with females, physical abuse increased the risk of pronounced pain by five-fold and sexual abuse increased it by four-fold (Linton 1997). Goldberg et al (1999) found significant relationships between childhood abuse and later alcoholism, drug addiction and chronic pain. They argue that from their study, childhood abuse is a wider

The Scale of the Problem

In this study, urine was tested by immunoassay for the following drugs alcohol, amphetamines, methyl amphetamines (including ecstasy), cannabis, cocaine, opiates, methadone, lysergic acid diethylamide, benzodiazepines, and tricyclic antidepressants. The incidence of medicinal drugs likely to affect driving had not significantly changed from the 1985-1987 study (67). However, illicit drug taking in drivers had increased sixfold in percentage terms, and there was a comparable increase among passengers. In addition, an in- Cannabis 28 Cocaine

Adverse reactions

Blood disorders (< 3 10 000 patient years) are most common in the first 2 months of treatment. Routine leucocyte counts have been advocated in order to detect blood dyscrasia before symptoms develop but agranulocytosis may be so acute that the counts give no warning. Patients must be advised to stop the drug and have a leucocyte count performed if symptoms of a sore throat, fever, bruising or mouth ulcers develop. Any suggestion of anaemia should be investigated. Cross allergy between the drugs occurs sometimes, but must not be assumed for agranulocytosis. Treatment of agranulocytosis consists of drug withdrawal, admission to hospital, and administration of broad-spectrum antibimi-crobials plus granulocyte colony stimulating factor (where available).

Family Therapy Outcome

One study that is not directly related to our case in hand reported that on the basis of meta-analyses for the efficacy of family therapy with adolescent drug abuse with the objective of abstinence, family therapy produced medium-sized effects and superior outcome, both for children and adolescents (Sack and Thomasius, 2002).

Automated Immunoassay Methods

Automated immunoassay techniques are often the method employed for drug screens, just as they are for therapeutic drugs. Considerable improvements in specificity and sensitivity have been made with newer generations of the immunoassays. The precision of several commercial immunoassay systems for drug-of-abuse screening is adequate to detect drugs below standardized lower limits of detection, but care should be used to interpret the results based on manufacturer's recommendations and federal guidelines for cutoff values. Knowledge of the positive predictive values of screening immunoassays at lower cutoff concentrations could enable efficient use of confirmatory testing resources and improved detection of illicit drug use.27 In a commonly employed enzyme immunoassay, enzyme-labeled drug competes with patient drug for a limited amount of specific antibody. Excess free enzyme-labeled drug reacts with substrate to form product. Color reaction is directly proportional to amount of patient...

Candidates for HCV Vaccine

Appropriate candidates for a HCV vaccine may include newly identified injection drug users or intranasal cocaine users, renal failure patients at risk for hemodialysis, patients with blood-clotting disorders, and other recipients of multiple blood products, the sex partners of HCV-infected individuals, and possibly sex workers. Patients with other chronic liver diseases would be targeted, as well. Although the prevalence of infection appears to be low in health care personnel, those regularly exposed to blood and body fluids might be considered for immunization. If early administration, e.g., shortly after birth, of a HCV vaccine to the neonates of infected women could protect the neonates, then identification pre-delivery of pregnant HCV-infected women would become critically important. Because vaccine delivery to injection drug users early in their careers remains problematic, it seems likely that a targeted approach to high-risk individuals is likely to fail. If this concept is...

Alcohol and Substance Use Disorders

More recent studies of comorbid SUDs or AUDs in bipolar patients have also demonstrated an increase in suicide risk associated with substance and alcohol abuse (Dalton et al. 2003 Hoyer et al. 2004). SUD and AUD comorbidity may be particularly damaging in bipolar disorder and may reveal a unique factor of the disorder. The added suicide risk observed in bipolar patients with comorbid SUDs or AUDs may not be present in unipolar patients (Hoyer et al. 2004). Comparisons of suicide risk associated with comorbid AUDs versus that associated with co-morbid SUDs have not yielded a clear difference. Dalton et al. (2003) demonstrated that drug use may present greater risk than alcohol use, with a twofold increase in suicide risk for bipolar patients with comor-bid substance abuse. However, Tondo et al. (1999) did not find a similar difference. Additionally, they suggested that not all substances are associated with greater suicidality they specify polysubstance abuse, heroin, cocaine, and...

Applications in Substance Abuse Research

Perhaps the greatest advantage of PET and SPECT lies in their tremendous flexibility for studying a variety of brain functions, an attribute based on the virtually unlimited number of biologically relevant compounds that lend themselves to radiola-beling. To date, studies in substance abuse disorders have taken advantage of these techniques to study the in vivo pharmacology of drugs of abuse as well as the effects of abused drugs and or drug addiction on neuronal activity metabolism and brain chemistry. A majority of substance abuse studies have focused on cocaine addiction, and this disorder will be emphasized to illustrate the types of applications. Since all drugs of abuse are fundamentally organic (i.e., carbon containing) molecules, 11C radiochemistry makes PET uniquely suited to the study of their pharmacokinetics (i.e., since insertion of the radiolabel does not alter the native pharmacology of the parent drug). In fact, PET radiotracers currently exist for 11C cocaine, 11C...

Performance Enhancement

For events in which output of energy is explosive (100 m sprint) stimulants, e.g. amphetamine, bro-mantan, carphendon, cocaine, ephedrine and caffeine (> 12 mg 1 in urine). Death has probably occured in bicycle racing (continuous hard exercise with short periods of sprint) due to hyperthermia and cardiac arrhythmia in metabolically stimulated and vaso-constricted subjects exercising maximally under a hot sun.

Extension of the Matching

An interesting test of the matching law was reported by Conger and Killeen (1974). These researchers assessed human performance in a group-discussion situation. A group was composed of three experimenters and one subject. The subject was not aware that the other group members were confederates in the experiment and was asked to discuss attitudes toward drug abuse. One of the confederates prompted the subject to talk. The other two confederates were assigned the role of an audience. Each listener reinforced the subject's talk with brief positive words or phrases when a hidden cue light came on. The cue lights were scheduled so that the listeners gave different rates of reinforcement to the speaker. When the results for several subjects were combined, the relative time spent talking to the listener matched relative rate of agreement from the listener. These results suggest that the matching law operates in everyday social interaction.

Behavioral Economics Choice and Addiction

Choice and concurrent schedules of reinforcement may be analyzed from a microeconomic point of view (Rachlin, Green, Kagel, & Battalio, 1976). Behavioral economics involves the use of basic economic concepts and principles (law of demand, price, substitutability, and so on) to analyze, predict, and control behavior in choice situations. One of the more interesting areas of behavioral economics concerns laboratory experiments that allow animals to work for drugs such as alcohol, heroin, and cocaine. Thus, Nader and Woolverton (1992) showed that monkeys' choice of cocaine over food was a function of drug dose, but that choosing cocaine decreased as the price (number of responses per infusion) increased. That is, the reinforcing effects of the drug increased with dose, but these effects were modified by price, an economic factor. In another experiment, Carroll, Lac, and Nygaard (1989) examined the effects of a substitute commodity on the use of cocaine. Rats nearly doubled their...

TABLE 164 Psychotic Disorders

Prominent hallucinations or delusions may be induced by intoxication or withdrawal from a substance such as alcohol, cocaine, or opioids. For this diagnosis, these symptoms should not occur exclusively during the course of delirium. The substance should be judged to be causally related to the symptoms.

Synopsis Of The Novel

In part 2 it is mid-April, and Rabbit and Janice return to springtime Brewer. While Janice looks for a job, Rabbit reflects on his dismal past, visiting his ill lover, Thelma, whose disease, systemic lupus erythema-tosus, has depleted her family's income and spirit. Rabbit learns from her that Nelson is a cocaine addict, causing Rabbit additional worry about AIDS. He visits Springer Motors, discovering Nelson has taken down his old basketball star photos, has hired a woman, and that the homosexual AIDS-inflicted bookkeeper refuses to show him the books. Janice takes Penn State extension real estate courses, while Rabbit frets about Nelson. They talk about Nelson's drug addiction and bleeding the company then receive threatening calls from his unpaid drug dealers. They are guilt-ridden for raising Nelson to be so troubled. Rabbit asks his friend Charlie Stavros for advice, and they discuss Brewer's drug problem at large. Late one evening after the drugged-up Nelson attacks Pru, she...

Essential Commonalities Of Addictive Drugs

Millions of chemicals are listed in such standard compendia as Chemical Abstracts, yet only a few score of these have addictive liability. Those with addictive liability have neither chemical nor classical pharmacological commonalities. For example, the chemical structures of opiates (e.g. heroin) do not in the least resemble those of the psychostimulants (e.g. cocaine, amphetamines), and the classical pharmacological actions of opiates (e.g. analgesia, sedation) do not in the least resemble those of the psychostimulants (e.g. arousal, locomotor activation, anxiety). In fact, for decades it was not clear that any commonalities existed amongst drugs with addictive potential. However, in recent years it has become evident that the essential commonality is a drug-induced enhancement of CNS reward functions (for reviews, see Gardner, 1997, 2000 Gardner and David, 1999), which appears to have face validity in view of the fact that most human drug addicts report that their first drug use...

Other Magnetic Resonance Methods

The 3DTOF technique acquires multiple thin slice ( 1.5 mm thick) images of brain which are used to reconstruct composite images of the brain vascular system. The composite images are known as maximum intensity projections (MlPs) and include only the brightest pixels from each source image which presumably are from flowing blood. It is possible to produce maximum intensity projection images in many different orientations using 3DTOF data. Angiographic techniques may be particularly useful in characterizing the blood flow abnormalities associated with acute and chronic drug abuse.

The Acetate Derived Fragment

The first evidence that challenged the accepted scheme came from the investigations by Leete of the biosynthesis of methyl ecgonine (19), the base portion of cocaine (20). (19) had long been thought to arise from pyrrolinium salt (10) in a fashion analogous to that shown in Scheme 5 for the formation of tropine. It was assumed that the biogenetic differences between methyl ecgonine and tropine biosynthesis were, firstly, the retention of C-1 of acetoacetate after condensation with (10) in the case of (19) and, secondly, the different stereochemistry of the C-3 hydroxy group of (19) when compared to (1). According to the classical hypothesis, the bridgehead carbon atom C-1 of (19) is derived from C-2 of the pyrrolinium salt (10) (Path C, Scheme 6) and C-2 of (19) originates from C-2 of acetoacetate. Incorporation experiments with 1-15N,2-13C pyrrolinium salt (10) in Erythroxylon coca brought an unexpected result 35 . It was observed that the carbon atom derived from C-2 of (10) was not...

Additional synaptic inputs to the core reward system

There are several additional neural inputs to the core reward system that may modulate drug reward by modulating DA function within the core system. GABAergic efferents from the nucleus accumbens form a feedback loop to the ventral tegmental area, and nucleus accumbens medium spiny GABAergic neurons also project to other GABAergic neurons synaptically linked to both the accumbens and ventral tegmental area (Alexander and Crutcher, 1990 Kalivas et al., 1993 Van Bockstaele and Pickel, 1995). Endogenous opioid peptidergic neurons also provide synaptic regulation of core mesoaccumbens DA function and of the accumbens-ventral pallidal projection (Alexander and Crutcher, 1990 Heimer and Alheid, 1991 Zahm and Brog, 1992 Kalivas et al., 1993 McGinty, 1999). Both the ventral tegmental area and the nucleus accumbens also receive serotonergic inputs, and manipulation of these serotonergic inputs appears to modulate reward functions. In fact, serotonergic lesions appear to make cocaine more...

Direct Treatment of Problem Behavior

Following a baseline period of assessment, a behavioral plan of action may be negotiated between the behavior therapist, the client, and concerned others (e.g., Azrin et al., 1994, for treatment program aimed at drug abuse). This plan usually includes a statement of target responses, consequences that follow different actions, and long-term goals. In many cases, a detailed behavioral contract is drawn up that objectively specifies what is expected of the client and the consequences that follow behavior (Hall & Hall, 1982). Figure 13.1 outlines the major principles of behavioral contracts. At a minimum, the behavior analyst should clearly identify the problem behavior and the contract should specify in a straightforward manner the reinforcement for meeting behavioral objectives, the people who provide reinforcement, and the contingencies of reinforcement.

Genetic variation in cannabinoid effects on CNS reward substrates

At the human level, evidence from family, twin, and adoption studies all support a substantial genetic component in both initial vulnerability to drug addiction and in continued drug dependence (for review, see Uhl et al., 1995). As vulnerability to drug addiction at the human level does not follow clear Mendelian patterns of inheritance, most genetic studies in the field have been association studies - statistical correlations between an inherited condition and polymorphisms occurring in strong candidate genes (Lander and Schork, 1994 Elston, 1995). Given the wealth of animal research data on the importance of DA CNS reward mechanisms in drug addiction, polymorphisms in genes that regulate DA neurotransmission have been considered prime candidates as vulnerability factors for addiction (Koob and Bloom, 1988). A meta-analysis of published studies supports a positive association between drug and alcohol addiction and DA D2 receptor polymorphisms (Uhl et al., 1994). At the animal level,...

Cannabinoid Withdrawal Effects On Cns Reward Substrates

Cannabinoids appear to interact with these CNS substrates of drug withdrawal in a fashion strikingly similar to that shown by other addictive drugs. The present author has reported that significant elevations in brain-stimulation reward thresholds (i.e., inhibition of CNS reward substrates) are seen during acute withdrawal from low doses of A9-THC (Gardner and Lepore, 1996 Gardner and Vorel, 1998). And Rodriguez de Fonseca and colleagues (1997) have shown that acute cannabinoid withdrawal is accompanied by marked CRF elevations in the central nucleus of the amygdala, with maximal CRF elevations correlated with maximal cannabinoid withdrawal signs. These data suggest that cannabinoid withdrawal - at least with respect to effects on CNS reward substrates - is strikingly similar to that seen with other addictive drugs.

Endogenous Opioid Mediation Of Cannabinoid Effects On Cns Reward Substrates

As noted above, acute enhancement of CNS reward substrates appears to be the single essential commonality of drugs with addictive potential. Strikingly, this drug-induced enhancement of CNS reward substrates is blocked or attenuated by such highly specific and selective opiate antagonists as naloxone and naltrexone. This holds not only for addictive drugs of the opiate class but also for non-opiates such as ethanol, amphetamines, cocaine, barbiturates, benzodiazepines, and phencyclidine (for review, see Gardner, 1997). Such findings - from dozens of laboratories over a span of more than 20 years - clearly implicate endogenous opioid mechanisms in mediating the rewarding actions of such drugs. To determine whether cannabinoid-induced enhancement of CNS reward substrates might be similarly blocked or attenuated by opiate antagonists, the author's research group carried out a series of experiments using both electrical brain-stimulation reward and in vivo brain microdi-alysis (Chen et...

Endogenous Cns Cannabinoid Involvement In Opioid Effects On Cns Reward Substrates

Since endogenous CNS opioid mechanisms are so clearly involved in mediating at least some cannabinoid effects on CNS reward substrates, it might logically be asked whether endogenous CNS cannabinoid systems are involved in mediating opioid effects on CNS reward substrates. There is little work addressing this possibility, but the few published studies are highly provocative to this reviewer's mind, notably the facts that morphine's rewarding properties and its ability to enhance nucleus accumbens DA are both markedly reduced in knockout mice lacking the CBX cannabinoid receptor (Ledent et al., 1999 Mascia, 1999 Cossu et al., 2001). In contrast, CBX receptor knockout mice retain their normal responses to the rewarding effects of cocaine, d-amphetamine, and nicotine - as assessed by intravenous self-administration (Cossu et al., 2001). Furthermore, CBX receptor knockout mice also retain their normal responses to the DA-enhancing effects of cocaine, as assessed by in vivo brain...

Sites of cannabinoid action on CNS reward substrates

As noted above, different addictive drugs enhance reward by acting at different sites within the reward substrates of the CNS. Nicotine, ethanol, benzodiazepines, and barbiturates appear to act - transsynaptically - within somatic and dendritic regions of the second-stage DA neurons in the ventral tegmental area cocaine, amphetamines, and dissociative anesthetics appear to act primarily on the axon terminal projections of the second-stage DA neurons within the nucleus accumbens. Opiates act on reward substrates within the ventral tegmental area, nucleus accumbens, and ventral pallidum (Gardner, 1997). The site(s) of cannabinoid action on CNS reward substrates has been addressed in several ways - some direct and some inferential. One of the direct ways used in the present author's laboratory has been to study the effects of local intracranial cannabinoid microinjections on DA levels in the nucleus accumbens as measured by in vivo brain microdialysis

Mechanisms of cannabinoid action on CNS reward substrates

Just as different addictive drugs act at different sites of action within the CNS to enhance reward substrates, so too do different addictive drugs enhance reward substrates by acting through different mechanisms. Amphetamines (and probably some phencyclidine-like dissociative anesthetics) act as presynaptic DA releasers, cocaine as a presynaptic DA reuptake blocker, opiates and nicotine as transsynaptic enhancers of DA neuronal firing, and other addictive drugs by yet other mechanisms (for review, see Gardner, 1997). The mechanisms of action by which cannabin-oids alter reward have been addressed using a variety of experimental approaches. As noted in the previous section on CNS sites of cannabinoid action, studies using local intracerebral A9-THC microinjections have led to the conclusion that a major cannabinoid site of action on CNS reward substrates is proximal to the second-stage DA axon terminals in the nucleus accumbens (Chen et al., 1993). As also noted above, A9-THC's...

Factors That Modulate ECG and Arrhythmic Manifestations of the Brugada Syndrome

ST segment elevation in the Brugada syndrome is often dynamic. The Brugada ECG is often concealed and can be unmasked or modulated by sodium channel blockers, a febrile state, vagotonic agents, a-adrenergic agonists, -adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, hyperkalemia, hypokalemia, hypercalcemia, and by alcohol and cocaine toxicity (Brugada et al. 2000bc Miyazaki et al. 1996 Babaliaros and Hurst 2002 Goldgran-Toledano et al. 2002 Tada et al. 2001 Pastor et al. 2001 Ortega-Carnicer et al. 2001 Nogami et al. 2003 Araki et al. 2003). These agents may also induce acquired forms of the Brugada syndrome (Table 1). Until a definitive list of drugs to avoid in the Brugada syndrome is formulated, the list of agents in Table 1 may provide some guidance. 2. Cocaine intoxication (Ortega-Carnicer et al. 2001 Littmann et al. 2000)

Chiral Ce Of Urinary Drugs And Metabolites Assays For Enantiomer Screening Of Misused Abused And Banned Substances

Drug Separation Enantiomers

CE has proven to provide a simple, inexpensive, and effective approach for the separation of enantiomers after the addition of a chiral selector to the buffer. The separation by CE of the enantiomers of several drugs of interest in toxicology and doping control has been investigated. By using various cyclodextrins it was possible to effect the chiral differentiation of the optical isomers of racemethorphan and racemorphan (45), amphetamines, cathine, cathinone, cocaine, and others (68), as well as of urinary mephenytoin and phenytoin (69), urinary methadone (28,29), urinary MDMA (Ecstasy) (37), and various amphetamines in urine (35). the d-(+) and l-(-) isomers of 3-methoxy-N-methylmorphinan, respectively. Aumatell and Wells (45) demonstrated that these enantiomers could easily be distinguished using a chiral CZE assay that was developed for urinary analysis of the optical isomers of racemethorphan and racemorphan. Distinction of these compounds is not only of interest in forensic...

Human Correlational Studies

Low MAO levels are also found in various forms of psychopathology, including attention-deficit hyperactivity disorder, antisocial and borderline personality disorders, alcoholism and drug abuse, pathological gambling disorder, and paranoid schizophrenia (see Table 3.2). With the possible excep- Relatives of alcoholics Drug abuse Bipolar disorder Relatives of bipolar disorder Pathological gamblers

Identifying Evaluating and Exploring Client Problems and Goals

Common problems presented by clients include anxiety, depression, and relationship conflicts. Other problems include eating disorders, alcoholism or drug addiction, social skill deficits, physical or sexual abuse, stress reactions, vocational confusion, and sexual dysfunction. Because of the wide range of symptoms or problems clients present, it is crucial that interviewers have at least a general knowledge of psychopathology and DSM-IV-TR (American Psychiatric Association, 2000). However, every problem

Initial Evaluation History and Physical Examination

A detailed history and physical examination on the initial patient-physician encounter, will provide the most important early information leading to the therapeutic plan, and ultimately aid in managing the potential side effects of treatment. Taking a detailed history from the patient with chronic viral hepatitis will provide the approximate time and source of infection in many cases, symptoms of liver disease, if present, and disease co-factors, such as alcoholism and drug addiction. Furthermore, significant co-morbidities, such as uncontrolled depression or heart disease, which would be contraindications to treatment, will also be identified by the initial patient history (see Table 1).

Exploring Your Personal Attitudes Toward Substances

In one way or another, everyone has a personal substance use or abuse history and an attitude toward alcohol and drug use worth examining. Whether you grew up in a family with strong prohibitions against drinking alcohol or a family with members suffering from cocaine addiction, your family experiences undoubtedly shaped how you think about people who use (or do not use) alcohol, cocaine, and other drugs. To become more effective in working with substance-abusing clients, you should reflect on your personal alcohol and drug history, your current attitude toward substances, and your family's alcohol and drug history (almost every family has someone perhaps an uncle, a father-in-law, or a sister-with substance use problems).

Utility of Event Related Potentials in Substance Abuse Research

Herning et al., 1990), they can provide additional information on subtle cognitive impairments during acute intoxication that may not be severe enough to be identified by these other measures. Also, repeated ERP testing after drug administration can provide important information on the duration of the drug's effects on cognition. For instance, we have found that acute administration of cocaine (0.9 mg kg) results in a significant reduction in P300 amplitude as early as 10 min post-cocaine administration. These impairments persist for about 40 min and are still present when most of the subjects no longer report feeling intoxicated. This example illustrates the utility of ERPs when studying the acute effects of drugs of abuse and highlights the importance of combining electrophysiological measures with behavioral and subjective tests. Because ERPs are sensitive indices of the functional integrity of the brain (Hillyard et al., 1978 Donchin, 1979), they are also useful measures of...

Newer Imaging Methods for Triaging Patients Presenting to the Emergency Department with Chest Pain

Patients had 30-day follow-up by phone call for adverse events such as MI (as defined by World Health Organization criteria), coronary artery bypass surgery, percutaneous intervention, or sudden cardiac death. The population was 71 African-American, Hispanic 19 , 19 White, and 1 Asian, and comprised 84 (63 ) women and 50 (37 ) men. The mean age was 53 + 2 years. There were 86 (64 ) patients who had a positive scan and 48 (36 ) patients who had a negative scan. In the entire group there were seven (5 ) adverse cardiac events, including four MIs, two coronary artery bypass surgeries, and one percutaneous intervention. Among the 48 patients who had normal coronary calcium scores, there was one (2 ) adverse event. This patient was a 45-year-old man who suffered a MI after cocaine use. Of the patients who had an abnormal coronary calcium scan, there were six (12 ) adverse events. These findings indicated the low event rate associated with the absence of elevated coronary calcium, and the...

Etiologies Of Rhabdomyolysis

Drug abuse (cocaine, amphetamines, LSD, heroin, phencyclidine) Medications (diuretics, narcotics, theophylline, corticosteroids, benzodiazepines, phenothiazides, tricyclic antidepressants) Trauma 55.1 A 22-year-old man presents to the emergency room 30 minutes after smoking crack cocaine with the complaint of crushing substernal chest pain. His ECG shows early repolarization with a heart rate of 116 but no other changes, and his cardiac troponin levels are negative. His urine drug screen is positive for cocaine. Which of the following is the best next step E. Give flumazenil to reverse the action of the cocaine 55.1J C. The patient should be given oxygen, aspirin, sedation, and nitrates for vasodilation and will require some evaluation for an acute coronary syndrome. Beta-blockers are relatively contraindicated because they can worsen vasoconstriction. There is no indication for thrombolytics. Flumazenil is the antagonist for benzodiazepines and would have no effect on cocaine.

Marijuana Withdrawal Syndrome

The proponents of legal reform pertaining to marijuana maintain that its use among adults should not be curtailed any more than that of alcohol or tobacco. Our own opinion that no currently illicit drug, including marijuana, should be placed on the open market as a legal substance for non-medical purposes, is based on public health considerations, and is in no small way influenced by the fact that the currently legal drug tobacco is responsible for over 400,000 deaths a year in the United States. In addition, we have great concern that, if marijuana was to be legalised, it would be distributed by the tobacco industry and marketed aggressively to youth in a fashion similar to that in which cigarettes are currently marketed. According to the National Institute on Drug Abuse (NIDA), Scientists at the University of California, Los Angeles, found that daily use of one to three marijuana joints appears to produce approximately the same lung damage and potential cancer risk as smoking five...

Approach To Suspected Mi

Acute coronary syndromes, which exist on a continuum ranging from unstable angina pectoris to NSTEMI to STEMI, usually are caused by in situ thrombosis at the site of a ruptured atherosclerotic plaque in a coronary artery. Occasionally, they are caused by embolic occlusion, coronary vasospasm, vasculitis, aortic root or coronary artery dissection, or cocaine use (which promotes both vasospasm and thrombosis). The resultant clinical syndrome is related to both the degree of atherosclerotic stenosis in the artery and to the duration and extent of sudden thrombotic occlusion of the artery. If the occlusion is incomplete or if the thrombus undergoes spontaneous lysis, unstable angina results. If the occlusion is complete and remains for > 30 minutes, infarction occurs. In contrast, the mechanism of chronic stable angina usually is a flow-limiting stenosis caused by atherosclerotic plaque that causes ischemia during exercise without acute thrombosis (Table 1-1).

Identification of Novel DAT Inhibitors through 3D Pharmacophore Based Database Search

Mission by taking up dopamine released into the synapse. There is no experimental structure available for DAT. However, an extensive of DAT inhibitors (mostly cocaine analogs) is available. DAT is involved in several diseases such as drug addiction and attention deficit disorder (200). For example, ritalin ( )-threo-methylphenidate , a DAT inhibitor, is marketed for treating attention deficit disorders in children (200, 201). Until recently, all efforts in synthesizing DAT inhibitors were focused on creating analogs around the tropane, piperazine, methylphenidate, and cores. It was shown that, despite structural differences, DAT inhibitors share one or more common 3D pharmacophore models (95, 202, 203). In an effort to identify new chemical cores for developing DAT inhibitors with new pharmacological profiles, a pharma-cophore-based 3D database search was proposed (95). For this purpose a pharmacophore model was derived based on two known potent DAT inhibitors R-cocaine and...

Coexisting chronic diseases

With drug abuse being an increasingly common behavior for the younger generation, it is not surprising that it has been linked to renal injury. Heroin nephropathy is a well-described cause of focal sclerosing glomerulonephritis with associated nephrotic syndrome 112, 113 . This particular pathologic entity often progresses to ESRD and may account for up to 10 of such patients in cities with large addictive populations 114 . Although cardiac and or cerebral ischemia is the more common acute presentations of cocaine inhalation, renal ischemia also occurs 115 . The most frequent cause of cocaine associated ARF occurs in the setting of rhabdomyolysis 116 however, a more recent association between habitual cocaine abuse and accelerated or malignant hypertension leading to deterioration of renal function have been identified 117 . Intravenous amphetamine or speed can induce pol-yarteritis nodosa with progressive renal failure and severe hypertension 118 . Recently, Bingham and co-workers...

Electroencephalographs Studies of Chronic Substance Abusers

Before the evidence for EEG, EP, or ERP anomalies in patients with histories of alcohol or drug dependence is reviewed, it would be valuable to highlight some of the methodological and interpretive problems that are inherent in studying patients with drug use histories as well as several problems that are created by researchers themselves. These problems are not specific to EEG EP ERP research. Rather, they generalize across all of the neuroimaging modalities. In a 1997 study which excluded individuals with these complications (Fig. 1), we found no evidence of quantitative EEG abnormalities in a group of 19 heroin dependent patients, abstinent for 1-5 mo, compared to healthy controls (Costa and Bauer, 1997). Importantly, the patients in our study failed to exhibit the same enhancement of EEG beta power demonstrated in cocaine or alcohol dependent patients via the same

Recreational Drugs and the Nervous System

Used legally to treat obesity, asthma, and narcolepsy. Herbal products containing ephedra, a drug originally procured from the Mah huang plant and also synthesized in laboratories, have been marketed as treatments for weight loss and for performance enhancement. Methamphetamine is an illegal amphetamine. A crystalline form of methamphetamine called ice is smoked to produce effects similar to crack cocaine.

Baseline Maximum Taper High DowM M

Comparison of representative brain SPECT images of heroin- and cocaine-abusing men enrolled in a placebo-controlled trial of the partial opiate agonist buprenorphine for the treatment of polydrug dependence. Images are from three subjects, receiving high or low dose buprenorphine (12 or 6 mg, respectively) or placebo, and studied at three separate time points (at baseline, at maximum dose during buprenorphine treatment, and following a taper off treatment). A comparable midcortical slice includes the basal ganglia, thalamus, and frontal, temporal, parietal, and occipital cortex. Arrows indicate perfusion defects. The subject receiving high dose buprenorphine shows marked improvement in perfusion, seen as dark (purple) areas becoming light (orange or yellow), whereas the patient receiving the low dose shows more mild improvement. The patient receiving placebo shows no improvement in perfusion. Following drug taper, buprenorphine treatment groups show reduced perfusion. These...

Risk Factors

Definite Intravenous drug abuse Vertical transmission to neonate from infected mother Inadequate sterilization of needles or medical devices Hepatitis B or HIV infection Alcohol abuse and alcoholic liver disease Accidental needlestick Possible Nasal cocaine Tattooes Body piercing Acupuncture Prior surgery when there was risk for transfusion Prior dental procedures Surrogates Use of cocaine Use of marijuana Divorced or separated Income below poverty level 12 yr or fewer education Not a Risk Factor Infant breastfeeding from infected mother Race or ethnicity The NHANES III study suggested that CHC was more prevalent in users of marijuana and cocaine, and that risk increased with increasing use of either illicit substance (2). Other risk factors included high-risk A large case-control study of U.S. blood donors indicated that injection drug users, sex with an injection drug user, and past history of blood tranfusion are the three greatest risk factors for hepatitis C (8). Weaker...