Postgraduate medicine
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Postgraduate medicine · Nov 2009
ReviewNeurogenetics of dopaminergic receptor supersensitivity in activation of brain reward circuitry and relapse: proposing "deprivation-amplification relapse therapy" (DART).
It is well known that after prolonged abstinence, individuals who use their drug of choice experience a powerful euphoria that often precipitates relapse. While a biological explanation for this conundrum has remained elusive, we hypothesize that this clinically observed "supersensitivity" might be tied to genetic dopaminergic polymorphisms. Another therapeutic conundrum relates to the paradoxical finding that the dopaminergic agonist bromocriptine induces stronger activation of brain reward circuitry in individuals who carry the DRD2 A1 allele compared with DRD2 A2 allele carriers. Because carriers of the A1 allele relative to the A2 allele of the DRD2 gene have significantly lower D2 receptor density, a reduced sensitivity to dopamine agonist activity would be expected in the former. Thus, it is perplexing that with low D2 density there is an increase in reward sensitivity with the dopamine D2 agonist bromocriptine. Moreover, under chronic or long-term therapy with D2 agonists, such as bromocriptine, it has been shown in vitro that there is a proliferation of D2 receptors. One explanation for this relates to the demonstration that the A1 allele of the DRD2 gene is associated with increased striatal activity of L-amino acid decarboxylase, the final step in the biosynthesis of dopamine. This appears to be a protective mechanism against low receptor density and would favor the utilization of an amino acid neurotransmitter precursor like L-tyrosine for preferential synthesis of dopamine. This seems to lead to receptor proliferation to normal levels and results in significantly better treatment compliance only in A1 carriers. ⋯ We propose that low D2 receptor density and polymorphisms of the D2 gene are associated with risk for relapse of substance abuse, including alcohol dependence, heroin craving, cocaine dependence, methamphetamine abuse, nicotine sensitization, and glucose craving. With this in mind, we suggest a putative physiological mechanism that may help to explain the enhanced sensitivity following intense acute dopaminergic D2 receptor activation: "denervation supersensitivity." Rats with unilateral depletions of neostriatal dopamine display increased sensitivity to dopamine agonists estimated to be 30 to 100 x in the 6-hydroxydopamine (6-OHDA) rotational model. Given that mild striatal dopamine D2 receptor proliferation occurs (20%-40%), it is difficult to explain the extent of behavioral supersensitivity by a simple increase in receptor density. Thus, the administration of dopamine D2 agonists would target D2 sensitization and attenuate relapse, especially in D2 receptor A1 allele carriers. This hypothesized mechanism is supported by clinical trials utilizing amino acid neurotransmitter precursors, enkephalinase, and catechol-O-methyltransferase (COMT) enzyme inhibition, which have resulted in attenuated relapse rates in reward deficiency syndrome (RDS) probands. If future translational research reveals that dopamine agonist therapy reduces relapse in RDS, it would support the proposed concept, which we term "deprivation-amplification relapse therapy" (DART). This term couples the mechanism for relapse, which is "deprivation-amplification," especially in DRD2 A1 allele carriers with natural D2 agonist therapy utilizing amino acid precursors and COMT and enkepalinase inhibition therapy.
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In 2007, the American College of Chest Physicians (ACCP) and the American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) published updated guidelines on pulmonary rehabilitation (PR). For patients with chronic obstructive pulmonary disease (COPD), PR is now considered to be the standard of care for those with at least moderately severe COPD as well as those patients with COPD of mild severity (as determined by spirometry) who, following maximal medical care, remain symptom-limited in exercise capacity or functional status. The goal of PR is for the patient to become more physically active and maintain independence longer. ⋯ In reality, primary care physicians perform most of the long-term management of COPD patients and thus are left to create ad hoc PR programs in their own communities. This article outlines each of the ACCP/AACVPR recommendations for PR and provides commentary on how these recommendations apply to COPD management in primary care. A discussion of reimbursement issues and future directions for PR guidelines is also provided.
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Obesity is at epidemic proportions in the United States and in other developed and developing countries. The prevalence of obesity is increasing not only in adults, but especially among children and adolescents. In the United States in 2003 to 2004, 17.1% of children and adolescents were overweight, and 32.2% of adults were obese. ⋯ This will allow health care professionals to identify and implement appropriate interventions to reduce patient risk and mortality. A systematic search strategy was used to identify published literature between 1995 and 2008 that reported data from prospective longitudinal studies of obesity and comorbid medical conditions. This article will review evidence for significant associations of obesity with comorbidities to provide information useful for optimal patient management.
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Postgraduate medicine · Sep 2009
ReviewDefining the importance of daily glycemic control and implications for type 2 diabetes management.
Glycemic control remains an elusive goal for most patients with type 2 diabetes. Questions concerning glucose targets that have emerged from recent outcomes studies further complicate glucose control strategies. Navigating through these challenges requires an understanding of the relationship between hyperglycemia, glycemic variability, and risk, as well as how to combine antidiabetic agents safely and effectively to minimize complications. ⋯ Dipeptidyl peptidase-4 inhibitors, which enhance endogenous incretin function, are well suited for combination with other agents to promote daily glycemic control without increasing the risk of hypoglycemia or weight gain. Results of recent outcomes studies suggest that a lifetime strategy for diabetes management might involve aggressive efforts to control glycemia daily and early in type 2 diabetes, with less stringent glucose targets and avoidance of hypoglycemia as patients acquire comorbidities, such as advanced cardiovascular disease. Dipeptidyl peptidase-4 inhibitors have the potential to play a vital role in diabetes management at all stages of the disease.
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Postgraduate medicine · Sep 2009
ReviewThe impact of weight gain on motivation, compliance, and metabolic control in patients with type 2 diabetes mellitus.
Patients with type 2 diabetes, approximately 85% of whom are overweight or obese, often have an increased incidence of cardiovascular disease (CVD) risk factors such as hypertension and dyslipidemia. Both type 2 diabetes and obesity are independent risk factors for CVD. Unfortunately, many therapies aimed at maintaining and improving glucose control are associated with weight gain. ⋯ Patients with type 2 diabetes are at an increased risk for both diabetes- and CV-related outcomes, and weight reduction is an important component of diabetes management. Weight gain in patients with type 2 diabetes can contribute to patient frustration and may negatively impact their compliance to therapeutic regimens. The selection of antidiabetes agents that not only improve glucose control but reduce or have a neutral effect on weight with beneficial effects on lipids are ideal options for managing patients with type 2 diabetes.