Urine drug screening: a valuable office procedure.

Urine drug screening can enhance workplace safety, monitor medication compliance, and detect drug abuse. Ordering and interpreting these tests requires an understanding of testing modalities, detection times for specific drugs, and common explanations for false-positive and false-negative results. Employment screening, federal regulations, unusual patient behavior, and risk patterns may prompt urine drug screening. Compliance testing may be necessary for patients taking controlled substances. Standard immunoassay testing is fast, inexpensive, and the preferred initial test for urine drug screening. This method reliably detects morphine, codeine, and heroin; however, it often does not detect other opioids such as hydrocodone, oxycodone, methadone, fentanyl, buprenorphine, and tramadol. Unexpected positive test results should be confirmed with gas chromatography/mass spectrometry or high-performance liquid chromatography. A positive test result reflects use of the drug within the previous one to three days, although marijuana can be detected in the system for a longer period of time. Careful attention to urine collection methods can identify some attempts by patients to produce false-negative test results.

What should we eat? Evidence from observational studies.

Observational studies provide a wealth of important correlations between diet and disease. There is a clear pattern of dietary habits that is associated with reduced rates of a multitude of common illnesses, including heart attack, cancer, stroke, diabetes, and hypertension. In some cases, interventional studies have proven the benefits of dietary change; in others, there is insufficient evidence to prove causation. Based on the existing evidence, the optimal diet should emphasize fruits and vegetables, nuts, unsaturated oils, whole grains, and fish, while minimizing saturated fats (especially trans fats), sodium, and red meats. Its overall calorie content should be low enough to maintain a healthy weight.

Of doctor conventions and drug companies.

Pharmaceutical companies provide the majority of financial support for staging the American Academy of Family Physicians (AAFP) Annual Scientific Assembly. In return they are allowed to dominate the physical and mental environment. The assembly is opulent and entertaining, but undoubtedly much of the expense is passed to the health care consumer in the form of high-priced brand-name prescription drugs. Additionally, public perception of such spectacles threatens the image that the AAFP has been careful to nurture--that family physicians are the ultimate advocates for our patients and, by extension, the health care-consuming public. Family physicians and our representative AAFP must recognize our complicity with and vulnerability to media forces. We must further adjust our role, not only to avoid the appearance of impropriety but to rededicate ourselves to our science, our intellectual basis, and ultimately our patients.

Vicious cycles within the neuropathophysiologic mechanisms of Alzheimer's disease.

Rigorous scientific research has identified multiple interactive mechanisms that parallel and are likely causative of the development of Alzheimer's disease (AD). Causative mechanisms include genomics, the creation of amyloid beta (Abeta), factors inhibiting the Abeta removal process, the transformation of Abeta to its toxic forms (various forms of Abeta aggregation), and lastly the oxidative, inflammatory, and other effects of toxic Abeta. Fibrillar beta-amyloid peptide, a major component of senile plaques in AD brain, is known to induce microglial-mediated neurotoxicity under certain conditions, but some recent studies support the notion that Abeta oligomers are the primary neurotoxins. Abeta-42 oligomers that are soluble and highly neurotoxic, referred to as Abeta-derived diffusible ligands (ADDLs), assemble under conditions that block fibril formation. These oligomers bind to dendrite surfaces in small clusters with ligand-like specificity and are capable of destroying hippocampal neurons at nanomolar concentrations. Evidence is presented that AD is triggered by these soluble, neurotoxic assemblies of Abeta rather than the late stage pathology landmarks of amyloid plaques and tangles. The premise is that AD symptoms stem from aberrant nerve cell signaling and synaptic failure rather than nerve cell death, which nevertheless follows and exacerbates the initial pathologies of AD. The defective clearance of amyloid leads to amyloid angiopathy that in turn perpetuates hypoperfusion that affects formation as well as absorption of CSF thereby altering clearance of amyloid and promoting vascular and parenchymal deposition[1]. Hypoperfusion, the defective clearance of amyloid, and resultant increase in amyloid deposition thus represent a vicious cycle. Chronic vascular hypoperfusion-induced mitochondrial failure results in oxidative damage, which drives caspase 3-mediated Abeta peptide secretion and enhances amyloidogenic APP processing. Intracellular Abeta accumulation in turn promotes a significant oxidative and inflammatory mechanism that generates a vicious cycle of Abeta generation and oxidation, each accelerating the other. Abeta activates astrocytes that add to the oxidative imbalance, upregulate the expression of APP via TGF-beta, and are capable of expressing BACE1. Each of these 3 actions accelerates the larger cycle of cholinergic neuron destruction. As oxidative stress induces lesions of cholinergic nuclei producing a reduction in cholinergic neurotransmission, a subsequent increase in cortical APP involving PKCepsilon leads to accelerated amyloidogenic APP metabolism. The linkage of cholinergic activation and APP metabolism completes an additional feedback loop wherein the damage wrought by Abeta accelerates further Abeta production. A comprehensive vision of the neuropathophysiologic mechanisms that result in AD reveals several vicious cycles within a larger vicious cycle, that is to say, a number of interactive systems that each, once set in motion, amplify their own processes, thus accelerating the development of AD.

Current status and future promise of pharmacotherapeutic strategies for Alzheimer's disease.

BACKGROUND AND OBJECTIVE: The pharmacotherapy of Alzheimer's disease (AD) is evolving rapidly. Unless new discoveries continue to emerge to facilitate prevention and effective treatment of the disease, the anticipated burden of this disease on caregivers and society at large will overwhelm resources. The objective of this paper is to review the state of development of approaches likely to yield effective interventional measures with regard to AD in the future. DESIGN: A comprehensive systematic search of MEDLINE using focused search criteria, a search of reference lists from these studies and reviews, a review of the Cochrane Database of Systematic Reviews, and a hand search of relevant journals was conducted. Selection of articles was based on the clinical focus. Additional inclusion criteria preferentially selected key articles that contained higher-level evidence in accordance with explicit, validated criteria. RESULTS: Pharmaceutical interventions are being developed and tested that confer neuroprotective benefits by targeting causative mechanisms. CONCLUSION: The paradigm that AD is pharmacologically unresponsive is shifting. Our understanding of the molecular mechanisms of neurodegeneration will soon allow us to more specifically target and interrupt the processes that contribute to this dementia.

Current status and future promise of pharmacotherapeutic strategies for Alzheimer's disease.

BACKGROUND AND OBJECTIVE: The pharmacotherapy of Alzheimer's disease (AD) is evolving rapidly. Unless new discoveries continue to emerge to facilitate prevention and effective treatment of the disease, the anticipated burden of this disease on caregivers and society at large will overwhelm resources. The objective of this paper is to review the state of development of approaches likely to yield effective interventional measures with regard to AD in the future. DESIGN: A comprehensive systematic search of MEDLINE using focused search criteria, a search of reference lists from these studies and reviews, a review of the Cochrane Database of Systematic Reviews, and a hand search of relevant journals was conducted. Selection of articles was based on the clinical focus. Additional inclusion criteria preferentially selected key articles that contained higher-level evidence in accordance with explicit, validated criteria. RESULTS: Pharmaceutical interventions are being developed and tested that confer neuroprotective benefits by targeting causative mechanisms. CONCLUSION: The paradigm that AD is pharmacologically unresponsive is shifting. Our understanding of the molecular mechanisms of neurodegeneration will soon allow us to more specifically target and interrupt the processes that contribute to this dementia.

Hypertension and atherosclerosis: clinical implications from the ALLHAT Trial.

By failing to recognize the heterogeneity of hypertension, the authors of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study used a faulty premise to conduct a poorly designed clinical trial. By failing to control blood pressures equally across study drug groups, ALLHAT cannot be considered to be a definitive comparative trial. Being neither a monotherapy trial nor a trial that initiated therapy for blood pressure control, ALLHAT provided no data to recommend first-line therapy for hypertension, making the conclusions invalid. Thiazide-type diuretics increase angiotensin II and consequently promote atherosclerosis and arteriolarsclerosis. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers retard atherosclerosis and are nephroprotective. Multiple randomized controlled trials show beneficial clinical outcomes, including cardioprotection and nephroprotection, with the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These agents, and not thiazide-type diuretics, should be used as first-line agents to retard the process of atherosclerosis and its clinical outcomes in the setting of arterial hypertension.

Pharmacotherapeutic approaches to the prevention of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of cognitive impairment in older patients and is expected to increase greatly in prevalence. Interventions that could delay disease onset would have a major public health impact. OBJECTIVE: The objective of this article is to review evidence from epidemiologic studies and controlled trials addressing whether AD can be prevented. METHODS: Data were gathered through a comprehensive, systematic search of MEDLINE using focused search criteria and spanning a 6-year period from January 1998 through January 2004; a hand search of reference lists from these studies and reviews; a review of the Cochrane Database of Systematic Reviews; and a hand search of relevant journals. Selection of articles was based on the clinical focus. Additional inclusion criteria were used to select key articles that contained higher-level evidence in accordance with explicit, validated criteria. RESULTS: Preventive interventions for AD include vitamins, nonsteroidal anti-inflammatory drugs, and agents that protect the endothelium (eg, statins). Good control of hypertension with angiotensin-converting enzyme inhibitors and long-acting dihydropyridines also confers neuroprotective benefits. CONCLUSIONS: The paradigm that AD is pharmacologically unresponsive is shifting as more effective pharmacotherapies for prevention and treatment rapidly emerge. Our understanding of the molecular mechanisms of neurodegeneration will soon allow us to more specifically target and interrupt the processes that contribute to this progressive dementia.

Alcohol consumption: an overview of benefits and risks.

Published health benefits of regular light-to-moderate alcohol consumption include lower myocardial infarction rates, reduced heart failure rates, reduced risk of ischemic stroke, lower risk for dementia, decreased risk of diabetes and reduced risk of osteoporosis. Numerous complimentary biochemical changes have been identified that explain the beneficial effects of moderate alcohol consumption. Heavy alcohol consumption, however, can negatively affect neurologic, cardiac, gastrointestinal, hematologic, immune, psychiatric and musculoskeletal organ systems. Binge drinking is a significant problem even among moderate drinkers and is associated with particularly high social and economic costs. A cautious approach should be emphasized for those individuals who drink even small amounts of alcohol. Physicians can apply the research evidence describing the known risks and benefits of alcohol consumption when counseling their patients regarding alcohol consumption.

Pharmacotherapeutic approaches to the treatment of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD), a progressive degenerative disorder of the brain, is the most common cause of cognitive impairment in the elderly. The pharmacotherapy of AD is evolving rapidly. Cholinergic stabilization with cholinesterase-inhibitor (ChEI) therapy implies neuroprotection and a resultant slowing of disability and disease progression. The moderate-affinity N-methyl-d-aspartate (NMDA)-receptor antagonist memantine may block neural excitotoxicity. OBJECTIVE: The purpose of this review was to examine the evidence for the responsiveness to pharmacotherapy of established AD; specifically, the extent to which the benefits of therapy have been proved, the extent to which currently available ChEIs support cholinergic neurotransmission, and the extent to which currently available ChEIs and memantine provide neuroprotection. METHODS: Relevant studies were identified through a comprehensive search of MEDLINE for articles published between January 1999 and February 2004 using the terms Alzheimer's pharmacotherapy, cholinesterase inhibitor therapy, Alzheimer's disease, donepezil, rivastigmine, galantamine, glutamatergic system modifiers, and memantine; a search of the reference lists of identified articles; and a manual search of pertinent journals. Articles were selected that contained higher-level evidence, based on explicit validated criteria. RESULTS: ChEI therapy was associated with quality-of-life improvements that included enhanced performance of activities of daily living, reduced behavioral disturbances, stabilized cognitive impairment, decreased caregiver stress, and delay in the first dementia-related nursing home placement. In large clinical trials in moderate to severe AD (a stage that is associated with distress for patients and caregiver burden, and for which other treatments are not available), memantine showed an ability to delay cognitive and functional deterioration. The combination of memantine and ChEI therapy was significantly more efficacious than ChEI therapy alone (P < 0.001) and was well tolerated. CONCLUSIONS: The idea that AD is pharmacologically unresponsive appears to be changing. With the use of ChEI and NMDA-receptor antagonist therapy, the symptoms and outcomes of this devastating neurodegenerative disease can be improved and its course altered.

A family physician questions the conclusions from ALLHAT.

A key Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) conclusion is that thiazide diuretics should be preferred for first-step antihypertensive therapy. ALLHAT was not a monotherapy trial, and rational drug combinations were discouraged by study design in the lisinopril limb. The ALLHAT conclusion that recommends chlorthalidone for initial hypertension therapy seems unjustified because ALLHAT was not a trial that initiated therapy for hypertension. ALLHAT was not of sufficient length to detect the poorer outcomes that are inevitable with increased rates of diabetes in the chlorthalidone limb. The heart failure subset analysis was not prospectively established. ALLHAT was not designed to make the conclusions claimed by its authors.