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ScienceWeek
PUBLIC HEALTH: ON BACTERIAL INFECTIONS IN ILLICIT DRUG USERS
The following points are made by R.J. Gordon and F.D. Lowy (New Engl. J. Med. 2005 353:1945):
1) Illicit drug use is a worldwide health problem. Annually, approximately 5 percent of the global population, or 200 million people, use illicit drugs.[1] In a US survey, 19.5 million people 12 years of age or older, or 8.2 percent of the population, had used an illicit drug in the prior month.[2] Injection is one of the most harmful routes of administration. There are an estimated 13 million injection-drug users worldwide, 78 percent of whom live in developing nations.[3] Infections are among the most serious complications of drug use.[4,5] Drug use plays a major role in the transmission of human immunodeficiency virus (HIV), sexually transmitted diseases, and viral hepatitis. In addition to these infections, drug users risk acquiring a diversity of bacterial infections.[4]
2) Most bacterial infections among drug users are caused by the subject's own commensal flora, with Staphylococcus aureus and streptococcus species being the most common pathogens. Outbreaks among drug users that are caused by unusual organisms, such as clostridia species and Pseudomonas aeruginosa, may indicate that a particular drug or drug-use behavior is involved. Skin and soft-tissue infections are some of the most common infections among injection-drug users. Their incidence is difficult to estimate because such infections are often self-treated. A prospective study of injection-drug users in Amsterdam reported an approximate incidence of one abscess per three years of injection-drug use. A cross-sectional study of injection-drug users in San Francisco found that 32 percent had an abscess, cellulitis, or both, as confirmed by physical examination.
3) Inexperience with injection may predispose the drug user to soft-tissue infection. Experienced injection-drug users who lack viable veins for use commonly resort to "skin popping" (subcutaneous or intramuscular injection). Researchers have reported that injection-drug users who had skin-popped within the preceding 30 days had a higher risk of soft-tissue infection than those who injected only intravenously. Injecting "speedballs" (mixtures of cocaine and heroin), injecting more frequently, and being positive for HIV infection were also associated with skin abscesses. Using dirty needles, failing to clean the skin before injection, and "booting" (repeatedly flushing and pulling back during injection) may also increase the risk of abscess.
4) An upsurge in skin infections, primarily abscesses, as well as more invasive infections, among injection-drug users in California has been caused by community-associated methicillin-resistant S. aureus (MRSA). Six of 14 patients with necrotizing fasciitis due to community-associated MRSA at Harbor UCLA Medical Center were current or former injection-drug users. Community-associated MRSA infections have also been reported among prisoners, military recruits, and men who have sex with men who use crystal methamphetamine. These infections, most of which are positive for the mobile genetic element staphylococcal chromosomal cassette (SCC) mec type IV, in part reflect the clonal dissemination of toxin-producing (i.e., Panton Valentine leukocidin) strains with a predilection to cause cutaneous and respiratory tract infections.
References (abridged):
1. World drug report. Vol. 1. Analysis. New York: United Nations Office on Drugs and Crime, 2005
2. 2003 National Survey on Drug Use and Health. Rockville, Md.: Office of Applied Studies, Substance Abuse and Mental Health Services Administration, 2004
3. World drug report. Vol. 1. Analysis. New York: United Nations Office on Drugs and Crime, 2004
4. Scheidegger C, Zimmerli W. Infectious complications in drug addicts: seven-year review of 269 hospitalized narcotics abusers in Switzerland. Rev Infect Dis 1989;11:486-493. [Erratum, Rev Infect Dis 1990;12:165.]
5. Palepu A, Tyndall MW, Leon H, et al. Hospital utilization and costs in a cohort of injection drug users. CMAJ 2001;165:415-420
New Engl. J. Med. http://www.nejm.org
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Related Material:
ON THE TOBACCO INDUSTRY AND NICOTINE AS AN ADDICTIVE DRUG
Notes by ScienceWeek:
In 1994 the state of Minnesota filed suit against the tobacco industry, and although this trial is now history, there are many people who feel the legacy of the trial will carry on into the 21st century because of the revelations contained in the millions of pages of previously secret internal tobacco industry documents made public in the trial.
The following points are made by R.D. Hurt and C.R. Robertson (J. Am. Med. Assoc. 1998 280:1173):
1) The litigation tobacco industry documents reveal that for decades the tobacco industry knew and internally acknowledged that *nicotine is an addictive drug and that cigarettes are the ultimate nicotine delivery device. The following statements by executives, for example, are found in tobacco industry documents: "Very few consumers are aware of the effects of nicotine, i.e., its addictive nature and that nicotine is a poison." (H.D. Steele, Brown and Williamson Tobacco Company, 1978). And in another Brown and Williamson memo: "Nicotine is the addicting agent in cigarettes." (A.J. Mellman, Brown and Williamson Tobacco Company, 1983). Concerning cigarettes as a drug delivery device, the litigation documents reveal that C.E. Teague Jr., assistant director of research at R.J. Reynolds Tobacco Company, wrote in 1972 in an internal memorandum: "In a sense, the tobacco industry may be thought of as being a specialized, highly ritualized and stylized segment of the pharmaceutical industry. Tobacco products, uniquely, contain and deliver nicotine, a potent drug with a variety of physiological effects... Thus a tobacco product is, in essence, a vehicle for delivery of nicotine."
2) The authors report that perhaps their most surprising finding in the document review was the evidence of tobacco industry efforts spanning 3 decades to alter the chemical form of nicotine to increase the percentage of freebase nicotine delivered to smokers. Depending on pH, nicotine exists as a diprotonated salt, a monoprotonated salt, or an uncharged neutral species. The salt forms are called the "bound" forms, and the neutral species is called the "freebase" form. Nicotine favors the salt form at low values of pH (e.g., pH = 3) and the freebase form at high values of pH (e.g., pH = 8). Freebase nicotine apparently crosses biological membranes more easily than the charged counterparts, and this affects the physiological response to the drug.
3) The tobacco industry was apparently well aware of these properties of nicotine as far back as 1966, and for 3 decades the tobacco industry had a focus on developing high pH delivery of nicotine to increase its physiological effects. The authors conclude: "When the breadth and depth of tobacco industry actions are understood, it becomes evident that allowing a tobacco settlement that honors the industry demands for legal and financial immunity would be a public health disaster of epic proportions and would allow the industry to continue to promote its deadly product throughout the 21st century. Congress must use its power to stop the carnage of more than 400,000 Americans dying each year of cigarette-related diseases."
J. Am. Med. Assoc. http://www.jama.com
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Notes by ScienceWeek:
nicotine: The alkaloid nicotine [3-(1-methyl-pyrrolidyl)pyridine] is a tertiary amine composed of pyridine and pyrrolidine rings. The current consensus among neuropharmacologists is that nicotine is the psychoactive drug primarily responsible for the addictive nature of tobacco use. Nicotine is highly selective for so-called "nicotinic receptors" for *acetylcholine in the peripheral and central nervous systems, and activation of these receptors is the likely source of the psychoactive effects of the drug. The nicotinic-acetylcholine receptor is a molecularly well-characterized receptor, and its activation evidently leads to conformation changes in its 5 subunits that result in a transient increase of permeability of the neuron membrane to the sodium ion. The nicotinic-acetylcholine receptor is therefore characterized as a neurotransmitter-gated ion channel. Concentrations of nicotine in blood rise quickly during cigarette smoking and peak at its completion.
Nicotine is also deposited in the lungs, spleen, liver, and brain, where concentrations are typically twice those of measurable blood concentrations. Nicotine readily crosses the *blood-brain barrier, leading to the release of acetylcholine, *norepinephrine, *dopamine, *serotonin, *vasopressin, *growth hormone, *cortisol, *prolactin, *neurophysin 1, and *adrenocorticotropic hormone, and release of these substances causes various neuropharmacological effects. Apart from the neuropharmacological effects of nicotine, nicotine and other constituents in cigarette smoke elevate blood pressure, cause *tachycardia, *arrhythmia, and *vasoconstriction in *cutaneous tissue and skin; lower body temperature; inhibit *diuresis; increase *gastrointestinal tonus; antagonize ulcer healing; and decrease pain threshold.
acetylcholine: A prevalent *neurotransmitter substance, both in the brain and in the peripheral nervous system, where it controls the actions of skeletal and smooth muscle.
neurotransmitter substance: Neurotransmitters are chemical substances released at the terminals of nerve axons in response to the propagation of an impulse to the end of that axon. The neurotransmitter substance diffuses into the synapse, the junction between the presynaptic nerve ending and the postsynaptic neuron, and at the membrane of the postsynaptic neuron the transmitter substance interacts with a receptor. Depending on the type of receptor, the result may be an excitatory or an inhibitory effect on the postsynaptic nerve cell.
blood-brain barrier: A selective mechanism opposing the passage of most ions and large molecular-weight compounds from the blood to brain tissue, the mechanism operating in a continuous layer of endothelial cells connected by tight junctions between cells. (Endothelial cells are flat cells forming a layer lining blood vessels, lymphatic vessels, the heart, etc.)
norepinephrine: The principal neurotransmitter substance released from nerve endings of the sympathetic nervous system. (The sympathetic nervous system is a part of the autonomic nervous system involved in the mobilization of energy resources during stress and arousal.
dopamine: A neurotransmitter substance.
serotonin: A neurotransmitter substance involved in nearly everything occurring in the brain, including psychological states such as anxiety and depression, and dysfunctions producing migraine and epilepsy.
vasopressin: A peptide hormone important in the regulation of *diuresis.
growth hormone: A vertebrate polypeptide hormone that regulates growth. In general, hormones are signaling molecules secreted into the blood stream by endocrine cells and acting on target cells that possess receptors for the hormone.
cortisol: A corticosteroid hormone secreted by the adrenal gland.
prolactin: A polypeptide hormone synthesized and released by the pituitary gland.
neurophysin 1: Neurophysins are a family of proteins synthesized in the hypothalamus, and function as carriers in the transport and storage of a number of hypothalamic-pituitary hormones.
adrenocorticotropic hormone: (ACTH) A pituitary hormone.
tachycardia: Rapid beating of the heart, conventionally applied to rates over 100 per minute.
arrhythmia: Irregularity of the heartbeat.
vasoconstriction: Narrowing of the blood vessels.
cutaneous tissue: In general, tissue associated with skin.
diuresis: Excretion of large volumes of urine.
gastrointestinal tonus: In general, contraction of gastrointestinal muscle.
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Related Material:
NEUROBIOLOGY: ON ADDICTION IN RATS
The following points are made by Terry E. Robinson (Science 2004 305:951):
1) How do you tell whether a rat that has learned to self-administer a drug has become an "addict"? Mere self-administration is not evidence of addiction, because addiction refers to a specific pattern of compulsive drug-seeking and drug-taking behavior, one that predominates over most other activities in life. Indeed, most people have at some time self-administered a potentially addictive drug, but very few become addicts. What accounts for the transition from drug use to drug addiction, and why are some individuals more susceptible to this transition than others? Two recent studies (1,2) represent a major advance in developing realistic preclinical animal models to answer these questions. Specifically, the two studies ask: How do you tell whether a rat has made the transition to addiction?
2) Nonhuman animals learn to avidly perform an action if it results immediately in the intravenous delivery of a potentially addictive drug, a phenomenon first reported by Weeks in 1962 (3). This self-administration animal model is still the "gold standard" for assessing the rewarding properties of drugs of abuse. From this model, we have learned a great deal about the conditions that support drug self-administration behavior. For example, nonhuman animals will self-administer nearly every drug that is self-administered by humans [with a few notable exceptions, such as hallucinogens (4)]. We also know that potentially addictive drugs usurp neural systems that evolved to mediate behaviors normally directed toward "natural rewards" [such as food, water, shelter, and sex (5)].
3) However, despite enormous advances, drug self-administration studies have not provided much insight into why some susceptible individuals undergo a transition to addiction, whereas others can maintain controlled drug use or forgo use altogether. This is in part because there have been no good animal models to distinguish mere drug self-administration behavior from the compulsive drug self-administration behavior that characterizes addiction. Deroche-Gamonet et al. (1) and Vanderschuren and Everitt (2) approached this problem in a straightforward way. They identified three key diagnostic criteria for addiction and then simply asked whether rats allowed to self-administer cocaine for an extended period developed any of the symptoms of addiction described by the criteria.
4) The first diagnostic criterion selected is continued drug-seeking behavior even when the drug is known to be unavailable (1). This is reminiscent of the cocaine addict, who has run out of drug, compulsively searching the carpet for a few white crystals ("chasing ghosts") that they know will most likely be sugar. Deroche-Gamonet et al (1) measured this behavior with two signals: a "go" cue that drug is available and a "stop" cue that drug is not available. Normal rats quickly learn to work for drug only when the go cue is on, and refrain when the stop cue is on. Addicted rats keep working even when signaled to stop.
5) The second criterion selected is unusually high motivation (desire) for the drug (1). A defining characteristic of addiction is a pathological desire ("craving") for the drug, which drives a willingness to exert great effort in its procurement. This criterion was measured with a progressive ratio schedule in which the amount of work required to obtain the drug progressively increased. At some point, the cost exceeds the benefit and animals stop working; this "breaking point" is thought to provide a measure of an animal's motivation to obtain a reward. Addicted rats have an increased breaking point.
6) The final criterion is continued drug use even in the face of adverse consequences (1,2). Addicts often continue drug use despite dire consequences. This feature of addiction was modeled by asking whether rats would continue to work for cocaine even when their actions produced an electric shock along with the cocaine injection (1) or when the memory of past electric shocks was evoked (2). Addicted rats kept working despite negative consequences.
References (abridged):
1. V. Deroche-Gamonet, D. Belin, P. V. Piazza, Science 305, 1014 (2004)
2. L. J. M. J. Vanderschuren, B. J. Everitt, Science 305, 1017 (2004)
3. J. R. Weeks, Science 138, 143 (1962)
4. R. A. Yokel, in Methods of Assessing the Reinforcing Properties of Abused Drugs, M. A. Bozarth, Ed. (Springer-Verlag, New York, 1987), pp. 1-33
5. A. E. Kelley, K. C. Berridge, J. Neurosci. 22, 3306 (2002)
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