Tobacco smoking, genes, and dopamine

COMMENTARY

A paper by J M Sanchez-Nieto and colleagues5 from Barcelona yields new insights. In this prospective study, 51 patients with suspected VAP were allocated to investigation with quantitative analysis of non-invasively collected endotracheal aspirates alone or to this technique plus BAL and use of PSB. The plan was that the findings would be used to modify antibiotic treatment. For quantitative analysis of endotracheal aspirates, a threshold of 105 colony-forming units per mL was taken to distinguish tracheal colonisation from true VAP. It provided information similar to that obtained with BAL or use of PSB. No difference in morbidity, as measured by length of stay in the intensive-care unit and duration of mechanical ventilation, or mortality was noted between the two study groups. Although this pilot study was small and unblinded, it expands previous evidence6 that quantitative analysis of endotracheal aspirates offers a reliable alternative to invasive techniques and is not associated with worse outcomes. Further studies are needed to validate the promising results of this study, and find out whether, compared with non-quantitative techniques, quantitative ones (either invasive or noninvasive) for the diagnosis of VAP produce better patient outcomes as well as improve resource use and antibioticresistance patterns in intensive-care units. In the meantime, since non-invasive techniques are not available in some hospitals, any of the quantitative techniques should be used to increase the accuracy of diagnosis of VAP. Efforts to identify pathogens in patients with suspected VAP are justified for three reasons. First, the patient will profit from prompt and appropriate antimicrobial therapy, through a reduction in the risk of inadequate or unnecessarily prolonged empirical therapy. Second, microbiological diagnosis will narrow the spectrum of antimicrobial therapy and reduce selection pressure for resistant microorganisms in intensive-care units. Third, ruling out VAP will reduce antibiotic overuse and direct the diagnosis to other potential infectious foci or non-infectious disorders. There is no doubt that intensive-care units are one of the epicentres of multiresistant microorganisms in hospitals because of the overuse of antimicrobial agents7 and the severity of underlying host conditions.2 In the study by Sanchez-Nieto and colleagues,5 76% of patients had received antibiotics, mostly the latest broad-spectrum agents, before entering the study. Even when cultures were negative, antibiotics commonly continued to be prescribed. Such a practice invalidates the most important potential advantage of any diagnostic test for VAP—to start, stop, or adjust antimicrobial therapy.8 It also adversely affects patients’ outcome.9 The time has come to stop blind therapy of suspected VAP, to encourage quantitative sampling methods, and to stop giving antibiotics to patients without pathogenic microorganisms. Intensivists, clinical microbiologists, infectiousdisease specialists, and hospital epidemiologists should work together to develop better strategies to reduce and control the overuse of antimicrobial agents, and to improve management of patients with suspected VAP.

*Didier Pittet, Stephan Harbarth *Infection Control Programme, Department of Internal Medicine, University of Geneva Hospitals, Geneva 14, Switzerland; and Harvard School of Public Health, Boston, USA 1

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Papazian L, Bregeon F, Thirion X, et al. Effect of ventilator-associated pneumonia on mortality and morbidity. Am J Respir Crit Care Med

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1996; 154: 91-97. Pittet D, Harbarth S. The intensive care unit. In: Bennett JV, Brachman PS, eds. Hospital infections, 4th edn. Boston: Little, Brown, 1998: 381-402. Fagon JY, Chastre J, Hance AJ, Domart Y, Trouillet JL, Gibert C. Evaluation of clinical judgment in the identification and treatment of nosocomial pneumonia in ventilated patients. Chest 1993; 103: 547-53. American Thoracic Society. Hospital-acquired pneumonia in adults: diagnosis, assessment of severity, initial antimicrobial therapy, and preventive strategies: a consensus statement. Am J Respir Crit Care Med 1996; 153: 1711-25. Sanchez-Nieto JM, Torres A, Garcia-Cordoba F, et al. Impact of invasive and noninvasive quantitative culture sampling on outcome of ventilator-associated pneumonia: a pilot study. Am J Respir Crit Care Med 1998; 157: 371-76. Marquette CH, Copin MC, Wallet F, et al. Diagnostic tests for pneumonia in ventilated patients: prospective evaluation of diagnostic accuracy using histology as a diagnostic gold standard. Am J Resp Crit Care Med 1995; 151: 1878-88. Flaherty JP, Weinstein RA. Nosocomial infection caused by antibioticresistant organisms in the intensive-care unit. Infect Control Hosp Epidemiol 1996; 17: 236-48. Wunderink RG. Mortality and the diagnosis of ventilator-associated pneumonia: a new direction. Am J Respir Crit Care Med 1998; 157: 349-50. Rello J, Ausina V, Ricart M, Castella J, Prats G. Impact of previous antimicrobial therapy on the etiology and outcome of ventilatorassociated pneumonia. Chest 1993; 104: 1230-35.

Tobacco smoking, genes, and dopamine Why can some cigarette smokers give up the habit so readily, whereas others cannot abstain for long? This question continues to confound researchers and clinicians. Tobacco use reflects a complex interplay of pharmacological, psychological, and socioeconomic factors. Moreover, although not widely discussed, all three stages of the smoking habit—initiation, maintenance and cessation—seem to be influenced by genotype.1 The D2 dopamine receptor subtype has recently been identified as a candidate gene.2,3 To assess the potential importance of this finding, the reasons why smokers persist with their habit must be explored. This century has seen a sluggish but remarkable shift from psychoanalytical and anthropological accounts of smoking towards the current consensus that most smokers continue to smoke principally to obtain nicotine.4 Why is nicotine so addictive? Virtually all effects of nicotine are exerted via nicotinic acetylcholine receptors. The classic nicotinic receptors at the neuromuscular junction are rather insensitive to the drug; were this not so, tobacco would probably have few living adherents. Nicotinic receptors are also widely expressed on neurons, which are especially sensitive to “smoking doses” of the drug. Although some of the reinforcing effect of nicotine may derive from a spinal action, the brain is commonly regarded as the seat of nicotine addiction. Nicotinic receptors in the brain are widely distributed, which accounts for the plethora of effects of tobacco. Although avoidance of acute abstinence symptoms may be a strong motivator for continued tobacco use, little is known about the neurochemical concomitants of withdrawal. Nicotine can also exert reinforcing effects that occur even without withdrawal and may be relevant not only to day-to-day tobacco use but also to relapse after long-term abstinence.5 Here, evidence in rats indicates that activation of the mesolimbic dopamine system of the brain plays an important part. Thus mesolimbic neurons express nicotinic receptors,6 which makes these cells a direct target for nicotine, and nicotine increases mesolimbic dopamine release after systemic administration.7 Studies of reinforcing effects of nicotine in laboratory animals permitted to self-administer

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COMMENTARY

intravenous nicotine show that responding to nicotine decreased greatly when mesolimbic dopaminergic transmission was experimentally curtailed.8 Nicotine is not alone in producing at least some of its reinforcing effects by increasing mesolimbic dopamine tone. Animal studies suggest that this mechanism is central to the reinforcing effects of amphetamine and cocaine, and may contribute in the case of ethanol and opioids.9 The mesolimbic dopamine system is thought to form a component of a physiological system that processes natural as well as pharmacological reinforcers.10 Not surprisingly, then, various dopamine-related genes have been examined for their possible association with tobacco and other drug use. Among the five dopamine receptor subtypes identified so far, the D1 and D2 subtypes are prevalent in the mesolimbic system and are most clearly implicated in the reinforcing effects of drugs. Interest has focused on two polymorphisms, TaqIA and TaqIB, that reside in the D2 receptor gene. The less common alleles of TaqIA and TaqIB (A1 and B1, respectively) are reported to be disproportionately common among ever-smokers compared with neversmokers.2,3,11 The association may be stronger for the B1 allele than the A1 allele,3 although this result needs to be replicated in a wider population. Does possession of either A1 or B1 alleles hold any functional consequences, or is the association with smoking merely a correlation? The answer is unclear. Since the A1 allele is associated with reduced D2 receptor density, the proposal is that affected individuals may seek out drugs or other stimuli that counter an underlying hypodopaminergic state.11 However, loss of D2 receptors need not imply dopamine hypofunction, especially since some D2 receptors serve as inhibitory autoreceptors. Reports suggest that the A1 and B1 alleles do not confer susceptibility only to tobacco smoking, but are also associated with polydrug abuse and sensation seeking.11 Conceivably, if a causal link exists, it may be behavioural in nature and ultimately have little directly to do with whether the drug in question enhances dopaminergic transmission. The discovery of a specific genetic influence on tobacco use could aid in the identification of people at risk. However, only a minority of smokers possess either the A1 or B1 allele, and neither is an especially strong predictor of nicotine dependence.3 Another potential benefit of such a discovery would be the development of more effective, individualised pharmacotherapy. In this regard, it is interesting that the A1 allele is not only over-represented in alcoholics, but is also predictive of their therapeutic response to a dopamine agonist.12 Whether or not TaqI genotyping proves useful in smoking cessation, an intensified effort to identify the genetic influences on tobacco smoking should improve prospects for the millions who would otherwise die prematurely from the cigarette “habit”.

Paul B S Clarke Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada H3G 1YC 1 2

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True WR, Heath AC, Scherrer JF, et al. Genetic and environmental contributions to smoking. Addiction 1997; 92: 1277–87. Comings DE, Ferry L, Bradshaw-Robinson S, Burchette R, Shiu C, Muhleman D. The dopamine D2 receptor (DRD2) gene: a genetic risk factor in smoking. Pharmocogenetics 1996; 6: 73–79. Spitz MR, Shi H,Yang F, et al. Casecontrol study of the D2 dopanime receptor gene and smoking status in lung cancer patients.

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J Nat Cancer Inst 1998; 90: 358–63. Surgeon General (US Department of Health and Human Services). The health consequences of smoking: nicotine addiction. A report of the Surgeon General. Rockville, Maryland: Public Health Service, Office on Smoking and Health, 1988. 5 Rose JE, Corrigall WA. Nicotine self-administration in animals and humans: Similarities and differences. Psychopharmacology 1997; 130: 28–40. 6 Clarke PBS, Pert A. Autoradiographic evidence for nicotine receptors on nigrostriatal and mesolimbic dopaminergic neurons. Brain Res 1985; 348: 355–58. 7 Imperato A, Mulas A, Di Chiara G. Nicotine preferentially stimulates dopamine release in the limbic system of freely moving rats. Eur J Pharmacol 1986; 132: 337–38. 8 Corrigall WA, Franklin KBJ, Coen KM, Clarke PBS. The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology 1992; 107: 285–89. 9 Koob GF. Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci 1992; 13: 177–84. 10 Wise RA, Rompre P-P. Brain dopamine and reward. Annu Rev Psychol 1989; 40: 191–225. 11 Noble EP. The DRD2 gene, smoking, and lung cancer. J Natl Cancer Inst 1998; 90: 343–45. 12 Lawford BR,Young RM, Rowell JA, et al. Bromocriptine in the treatment of alcoholics with the D2 dopamine receptor A1 allele. Nat Med 1995; 1: 337–41. 4

In the blood: proposed new requirements for registering generic drugs “You can‘t really say ‘similar’ if it’s the same again you want. ‘Similar’ means something different.” —Enderby Outside, Anthony Burgess

Q. When is a drug not a drug? A. When it is a generic. Although most critics of the pharmaceutical industry can taste the difference between brands of coffee, many assume that generic and innovator pharmaceuticals are always equivalent: claims to the contrary can be dismissed as the squabbles between fat cats and copy cats. There is more, however, to making a drug than knowing what molecules go into it: developing a pharmaceutical formulation is a delicate business involving excipients, coatings, and perhaps devices, and scale-up to manufacture is often difficult.1 As most sponsors know to their cost from failed “bridging studies”, substituting one formulation for another is not always straightforward. However, it seems plausible that, in most cases, if two equally pure formulations show identical concentrationagainst-time profiles of the active ingredient in the blood, they must be equivalent.2 Since requiring generic companies to go through the same costly development as innovator companies would restrict their ability to compete on price, regulatory agencies have generally accepted that an in-vivo “bioequivalence” study of a generic bolstered by suitable in-vitro tests can provide proof of equivalence. The standard bioequivalence study is a pharmacokinetic clinical trial in which 12 to 40 healthy volunteers are given test and reference products on separate days in an AB/BA crossover.3 Blood samples are taken at regular intervals and the area under the concentration-time curve (AUC), and perhaps the concentration maximum (Cmax), and occasionally the time to reach a maximum (tmax) are compared.1 25 years ago, failure to find a significant difference would have been accepted as proof of equivalence. However, just as an acquittal for childmolesting is not an adequate reference for a job as a babysitter, so failure to find a difference cannot be regarded as a proof of equivalence.4 Of course, exact equality is impossible to prove. If two drugs cannot be shown to be identical twins, they may still be blood relatives. There is now international regulatory agreement that, if the 90% 85