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Pharmacoepidemiology, the study of the effects of drugs in large numbers of people, is a relatively new discipline that applies the methods of epidemiology to clinical pharmacology. Premarketing clinical trials remain the only way to scientifically determine whether a drug is causally effective, yet these trials do not provide information that allows for estimates about rare, late, or off-label toxicities associated with the drug in question. Increasing concern about common and debilitating adverse effects of medications has highlighted the need for enhanced postmarketing surveillance to follow up on clinical trials. There is a further concern regarding the broader issue of the risk-benefit ratio of certain medications. Computerized databases are a good source of information on which to lay the foundations of postmarketing research. A system of cross-linked computerized medical records may better enable researchers and physicians to realistically monitor postmarketing safety and incorporate monitoring benefits. The same research could also elucidate the net public health effect of regulatory decisions. The Veterans Affairs database in the United States and PHARMO in the Netherlands may represent good models on which to base future postmarketing surveillance studies.
In this expert roundtable supplement, Brian L. Strom, MD, provides an overview of the appropriate use of large computer databases in pharmacoepidemiology studies. Philip Wang, MD, DrPH, discusses the advantages of pharmacoepidemiologic studies over clinical trials in correctly detecting drug safety issues. Francesca Cunningham, PharmD, reviews a large computer database that is currently in use within the VA healthcare system, and Ron M.C. Herings, PharmD, PhD, discusses the development of the PHARMO system in the Netherlands.
The fundamental basis of addiction is learning which is mediated by neuroplasticity. Treatment of addiction usually begins with detoxification. The signs and symptoms of withdrawal are usually opposite to the changes produced by the acute effects of the drug, appearing as a kind of rebound. The first treatment to use cross-tolerance as a maintenance strategy was discovered in heroin addiction by Vincent Dole and colleagues in the early 1960s. Researchers have been working for decades to learn the mechanism of action of important medications such as opioids. Another approach to the treatment of opioid addiction developed in preclinical laboratories involves the use of partial opioid agonists. The next advance in the treatment of tobacco dependence was the serendipitous discovery that the antidepressant bupropion reduced craving for cigarettes and improved abstinence rates. The clinical effects are analogous to the effects of buprenorphine in opioid addicts.
To demonstrate that nosocomial transmission of vancomycin-resistant enterococci (VRE) can be terminated and endemicity prevented despite widespread dissemination of an epidemic strain in a large tertiary-care referral hospital.
Two months after the index case was detected in the intensive care unit, 68 patients became either infected or colonized with an epidemic strain of vanB vancomycin-resistant Enterococcus faecium despite standard infection control procedures. The following additional interventions were then introduced to control the outbreak: (1) formation of a VRE executive group; (2) rapid laboratory identification (30 to 48 hours) using culture and polymerase chain reaction detection of vanA and vanB resistance genes; (3) mass screening of all hospitalized patients with isolation of carriers and cohorting of contacts; (4) environmental screening and increased cleaning; (5) electronic flagging of medical records of contacts; and (6) antibiotic restrictions (third-generation cephalosporins and vancomycin).
A total of 19,658 patient and 24,396 environmental swabs were processed between July and December 2001. One hundred sixty-nine patients in 23 wards were colonized with a single strain of vanB vancomycin-resistant E. faecium. Introducing additional control measures rapidly brought the outbreak under control. Hospital-wide screening found 39 previously unidentified colonized patients, with only 7 more nonsegregat-ed patients being detected in the next 2 months. The outbreak was terminated within 3 months at a cost of $2.7 million (Australian dollars).
Despite widespread dissemination of VRE in a large acute care facility, eradication was achievable by a well-resourced, coordinated, multifaceted approach and was in accordance with good clinical governance.
We present first results from a coordinated multiwavelength study of the neutron star low-mass X-ray binary EXO 0748 676. Fast UV, X-ray, and optical data were obtained including both spectral and timing information. We discuss how this study allows us to probe the temperature distribution within the binary and hence the geometry and efficiency of X-ray irradiation.
This paper will review a new technique of detecting companion stars in LMXBs and X-ray transients in outburst using the Bowen fluorescence NIII lines at 4634-4640. These lines are very efficiently reprocessed in the atmospheres of the companion stars and, thereby, provide estimates of the K2 velocities and mass functions. The method has been applied to Sco X-1, X1822-371 and GX339-4 which, in the latter case, provides dynamical evidence for the presence of an accreting black hole. Preliminary results from a VLT campaign on V801 Ara, V926 Sco and XTE J1814-338 are also presented.
Charles A. Dackis, Treatment and Research Center, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA,
Charles P. O'brien, Treatment and Research Center, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
Although neuroscientists have made considerable progress investigating and characterizing the brain regions that are involved in addiction, the integration of this information with clinical practice is still in its infancy. The neurobiology of addiction addresses the dynamic interaction between addictive drugs and the brain, ranging from drug intoxication to chronic neuroadaptations such as withdrawal, tolerance and craving. While psychological, psychosocial and environmental factors play important roles, addiction is primarily a brain disease (Leshner & Koob, 1999), and a greater understanding of its neurobiology should uncover new and effective treatments. Currently, there is an urgent need for medications capable of reducing craving and recidivism, perhaps by reversing brain disruptions associated with chronic substance abuse. Aside from refining treatment, addiction research has also shed light on the brain's reward centres that so dominate our lives. These centres have evolved over millions of years to reinforce feeding, mating, and other survival-related activities. Tampering with brain reward circuitry, through the process of addiction, produces many of the dangerous and lethal consequences that are associated with addictive illness.
Through the development of technological advances, scientists have developed sophisticated probes into the brain regions that are involved in drug reward. Addictive agents affect different neurotransmitter systems at various anatomical sites, creating distinct ‘fingerprints’ on the reward circuitry. However, the administration of all addictive substances increases extracellular dopamine (DA) levels in the nucleus accumbens (NAc), a location that has been named the ‘universal addiction site’. This remarkable fact will be our starting point in a discussion of pathways that interconnect the midbrain, limbic system, and medial prefrontal cortex (PFC). Repeated administration of addictive drugs often produces opposite brain effects, and evidence of impaired DA neurotransmission has been reported with chronic cocaine, opiate, alcohol and marijuana exposure. Other neuroadaptations have also been identified and will be reviewed, by substance, in an attempt to integrate brain mechanisms with clinical phenomena such as drug withdrawal, craving and progression.
The nature of addiction
The hallmark of addiction is a progressive loss of control over drug intake, regardless of negative consequences. The willingness of drug addicts to risk death, disease, incarceration, job loss, financial ruin and family strife may seem counterintuitive. However, when the dynamics of addiction are understood, the lack of control exhibited by drug addicts becomes more comprehensible.
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