Clinical Briefs in Primary Care
Donepezil and Memantine for Moderate-Severe Alzheimer's Disease
Source: Howard R, et al. N Engl J Med 2012;366:893-903.
The choice of if and when to employ pharmacotherapy in the management of Alzheimer's disease (ALZ) is not an easy one. Early in the disease process (mild-moderate ALZ) — where clinical trials have demonstrated beneficial outcomes, albeit of debatable clinically relevant magnitude — clinicians and caregivers may be least motivated to treat, since disease status is relatively less problematic and measureable benefits are smaller. In moderate-severe ALZ, memantine (MEM) has demonstrated beneficial effects. A single, never-replicated trial of the addition of MEM to donepezil (DON) in mild-moderate ALZ had favorable outcomes. Data on whether cholinesterase inhibitors provide improved outcomes as the disease progresses to the moderate-severe stages have been lacking. Indeed, there is some support for discontinuation of cholinesterase inhibition when ALZ progresses to the severe stage.
Howard et al randomized patients (n = 295) with moderate-severe ALZ already on treatment with DON to one of four groups: continued DON alone, MEM alone, continued DON plus MEM, or placebo alone. Patients were followed for 1 year, measuring outcomes by means of the Standardized Mini-Mental State Examination (SMMSE) and Bristol Activities of Daily Living Scale (BADLS). The minimum clinically important difference on these scales is 1.4 points and 3.5 points, respectively.
At 1 year, scores in the group that continued DON were superior to the placebo group as measured by the SMMSE (1.9 points difference); on the BADLS, the score was statistically significantly improved but failed to meet the minimum clinically important difference threshold. Neither substitution of MEM for DON nor addition of MEM to DON provided clinically important improvement.
In moderate-severe ALZ, these data support continuation of DON, but not substitution or augmentation with MEM.
Treating Hyperhidrosis with Systemic Therapy
Source:Walling HW. J Am Acad Dermatol 2012;66:387-392.
Even though hyperhidrosis (hhd) has a prevalence almost three times as great as rheumatoid arthritis (± 3% vs ± 1%), clinician awareness and management of this disorder are often suboptimal. Although the palms of the hands and plantar surfaces of the feet are the most commonly involved sites, axillary, craniofacial, and multisite involvement is reported. The HHD disease severity scale describes moderate HHD as "tolerable but sometimes interferes with daily activities," and severe as "barely tolerable to intolerable, that frequently to always interferes with daily activities." HHD is not just a quality-of-life issue; skin infections are more common in HHD sufferers.
The mainstay of HHD treatment for several decades has been topical drying agents, especially with those containing aluminum chloride. Iontophoresis, botulinum toxin, and even sympathectomy have demonstrated some efficacy, but the expense and inconvenience of such interventions is an obstacle.
Walling performed a chart review of HHD patients seen in an academic department of dermatology who had received one of three systemic agents to treat HHD: glycopyrrolate, oxybutynin, or clonidine.
Glycopyrrolate was effective in 30 of 45 patients; among glycopyrrolate treatment failures, six of 15 were non responders, and nine had adverse anticholinergic effects (e.g., dry mouth). Clonidine was effective in six of 13 patients; among clonidine treatment failures, three were noresponders and four experienced hypotension. A single patient responded favorably to oxybutynin (an anticholinergic typically used for overactive bladder).
Because no one treatment for HHD is uniformly effective, clinicians must become aware of alternative therapies. Previous literature has suggested that systemic treatments might not be well tolerated, yet efficacy in this data set was good with no serious adverse effects. Systemic treatments may help patients with HHD.
A New Intervention for Actinic Keratoses: Ingenol Mebutate Gel
Source: Rosen RH, et al. J Am Acad Dermatol 2012;66:486-493.
Actinic keratoses (ak) is biologically in situ squamous cell carcinoma, with the potential to become invasive in a minority of cases. However, because an individual patient may have many AK and it is not possible with certainty to identify which lesions are more likely to progress, it has been recommended that removal of AK be performed whenever possible. In the primary care setting, the three most prominent methods of destruction are cryotherapy, immune activators (e.g., imiquimod cream), and antimetabolites (e.g., 5-fluorouracil cream). Each of these methods has substantial limitations; for instance, the inflammatory response to appropriate use of imiquimod or 5-fluorouracil may be both painful and (at least transiently) cosmetically unwieldy. Additionally, traditional regimens of commonly used topicals require multiple applications over several weeks or more.
Ingenol mebutate (ING) is a recently approved topical agent that works by induction of lesion necrosis as well as by activation of antibody-directed cellular cytotoxic pathways. What this does for AK is produce a prompt and immediate kill effect on abnormal cells (within a few hours), which is coupled with a drug-mediated activation of B-cells that binds to abnormal (precancerous) cells over subsequent days and destroys them. This dual mechanism provides for short treatment regimens (2-3 days), with persistent post-treatment effects that obliterate evolving AK. The tolerability profile of ingenol, coupled with its dual mechanism of action and ease of administration, may give it a priority role in topical therapies for AK, although the clearance rates with the new product are not yet established to be at parity with older agents until head-to-head comparator trials are performed.
Colon Cancer Screening: Getting the Right Test Done
Source: Quintero E, et al. N Engl J Med 2012;366:697-706.
In its most recent update on colorectal cancer screening (CCS), the American Cancer Society, in concert with other interested parties, suggested that the best screening test for CCS is the one a person can get done. This is because in comparison to the other more widely used screenings (e.g., mammography, PAP testing, PSA), adoption of colonoscopy has been somewhat disappointing.
Fecal immunochemical testing (FIT) of the stool incorporates many of the advantages and circumvents some of the limitations of other screening tools. For instance, the specificity of FIT for human hemoglobin eliminates special dietary restrictions. Additionally, the presence of blood from the upper GI tract does not typically induce a positive result with FIT, eliminating unnecessary evaluation of the colon when upper GI blood is the cause.
Quintero et al report on initial results of the first wave of a comparison between FIT and colonoscopy in a very large population (n = 53,102) of asymptomatic adults age 50-69 years who were randomized to either traditional colonoscopy every 10 years or FIT every 2 years. FIT-positive patients were followed up with colonoscopy.
As is perhaps not surprising, compliance with FIT was about 30% greater than with colonoscopy. Colon cancer was detected in 0.1% of each group; however, the rate of detection of advanced adenomas was more than twice as high in the colonoscopy group (1.9% vs 0.9%).
These preliminary results are encouraging that a method for which patients find more advocacy — FIT — might find a more prominent role in CCS, especially when patients find other screening tools unacceptable. Because these results are preliminary (first 2-3 years of follow-up), we will likely need to wait until final results are completed in 2021 before the question of the role of FIT can be definitively answered.
Can Male Pattern Baldness Predict BPH?
Source: Arias-Santiago S, et al. J Am Acad Dermatol 2012;66:401-408.
Aside from genetic influences, testosterone (TST) and dihydrotestosterone (d-TST) play an important role in both benign prostatic hyperplasia (BPH) and male pattern baldness (also known as androgenetic alopecia). For BPH, conversion of TST to d-TST by means of 5-alpha-reductase (5-AR) results in stimulus for prostate gland growth. In the prostate, 5-AR of both type 1 and type 2 are operant. 5-AR blockers (e.g., finasteride, dutasteride) have been shown to shrink prostate size.
In the scalp, only 5-AR type 2 is functional. In susceptible individuals, conversion of TST to d-TST in the scalp results in follicular diminution, producing hair loss. Might the same susceptibility to male pattern baldness be reflected in an increased incidence or severity of BPH?
Arias-Santiago et al compared metrics pertinent to BPH in men with and without early-onset male pattern baldness. Although there was no difference between groups in levels of testosterone, prolactin, other gonadal steroids, or testosterone-binding proteins, the men with early male pattern baldness had significantly greater levels of PSA, more lower urinary tract symptoms consistent with BPH, greater prostate gland size as measured by ultrasound, and lower urinary flow rates.
Clinicians may wish to look for BPH-related symptoms in men with early androgenetic alopecia.
Donepezil and Memantine for Moderate-Severe Alzheimer's Disease; Treating Hyperhidrosis with Systemic Therapy; A New Intervention for Actinic Keratoses: Ingenol Mebutate Gel; Colon Cancer Screening: Getting the Right Test Done; Can Male Pattern Baldness Predict BPH?Subscribe Now for Access
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