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Content 7

 

The Doctor and the Pharmacist

Radio Show Articles:
July 19, 2014

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Sunshine on My Shoulders Makes Me High
Behavioral Interventions Help Maintain Weight Loss in Obese Adults
A Medication for Celiac Disease
Regular Use of Aspirin Linked to Reduced Risk for Pancreatic Cancer
Epidural Steroids Generally Are Ineffective for Lumbar Spinal
Stem-Cell Transplantation for Middle-Aged Patients with Myelofibrosis
Long-Term Outcomes of Stem-Cell Transplantation for Sickle Cell Disease
Retraction Dissolves Credibility of Acid-Bath-generated Stem Cells

MM: I find it interesting how different people read the same study and get different conclusions. I see that people are naturally encouraged to get sunlight exposure, thereby indicating to me that it has restorative and positive effects. The commentator on this article sees that by providing anti-opioid treatment, people can be discouraged from sun exposure and reduce the potential for skin cancer. Pro or con sunlight, this article demonstrates that sunlight is a natural high and explains, at least in part why many people are "sun-worshippers".
  
Cell 2014 Jun 19; 157:1527
Sunshine on My Shoulders Makes Me High
A skin peptide, β-endorphin, suppressed pain and affected behavior in UV-exposed mice. Kenneth
The recent enactment of statewide bans against indoor tanning for minors is a testament to growing public acknowledgement that ultraviolet (UV) light exposure is the major risk factor for skin cancer. Nevertheless, tanning behavior is pervasive, and sunscreen use typically falls far below recommended levels. The notion that tanning may be an addictive behavior is not new. Several groups have shown that β-endorphin levels are elevated in humans after tanning and that opioid antagonists produce withdrawal symptoms in tanners.
To study how UV exposure can drive addictive behaviors, Fell and colleagues irradiated mice at a suberythemal dose equivalent to 20 to 30 minutes of ambient midday summer sun exposure in Florida on Fitzpatrick skin types 2–-3. Within 10 days, mice exhibited significantly elevated pain thresholds. Objective responses such as Straub tail (an involuntary, opioid-dependent tail response) also occurred and were reversed with the opioid antagonist naloxone, which caused withdrawal symptoms. Cross-tolerance to morphine analgesia also occurred.
Most interesting were the behavioral tests, in which mice were established to have a clear preference for specific environments in a conditioned place preference/aversion test. UV-conditioned mice were tested to see if they preferred an environment (colored box) associated with naloxone versus saline administration. Indeed, following UV exposure, mice avoided environments associated with naloxone administration, thus showing a proactive behavior driven by UV conditioning.
Comment: This interesting study suggests that opioid-driven responses to UV exposure can drive behavioral choices. It is possible that pharmacologic and behavioral interventions designed to change addictive behaviors may boost the efficacy of sun avoidance programs and so reduce skin cancer risk.
Citation(s): Fell GL et al. Skin β-endorphin mediates addiction to UV light. Cell 2014 Jun 19; 157:1527.
(http://dx.doi.org/10.1016/j.cell.2014.04.032)
  
http://www.ncbi.nlm.nih.gov/pubmed/24949966?access_num=24949966&link_
type=MED&dopt=Abstract

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MM: In general, weight loss medications are an abysmal failure. When used in combination with aggressive lifestyle modification and dietary modification then they may be a useful "temporary crutch" . I am not in favor of using appetite suppressants at all, as people tend to get dependent upon them and their usefulness is very limited except at the very beginning of a weight loss protocol where the perceived impulsivity of snacking may be an issue.
  
BMJ Med 2014 May 14; 348:g2646
Behavioral Interventions Help Maintain Weight Loss in Obese Adults
Interventions focused on both diet and physical activity slowed weight regain during the first year after weight loss.
Behavioral and pharmacological interventions can induce weight loss in obese adults, but whether such interventions help maintain weight loss is unclear. In this systematic review and meta-analysis of 45 randomized trials, investigators assessed the effectiveness of nonsurgical interventions for long-term weight-loss maintenance in 7800 obese adults.
Behavioral interventions that focused on both food intake and physical activity blunted the average amount of regained weight by 1.6 kg at 12 months and by 2.0 kg at 18 months, compared with control (or no) interventions. Orlistat (Alli, Xenical) combined with behavioral interventions prevented an average of 1.8 kg of weight regain at 12 months; 120 mg thrice daily was more effective than 60 mg or 30 mg thrice daily.
Comment: In obese adults who have lost weight, behavioral interventions focused on food intake and physical activity, with or without orlistat, are effective in slowing weight regain. Obese patients who have lost weight should be encouraged to embrace behavioral interventions for lifelong weight maintenance.
Citation(s): Dombrowski SU et al. Long term maintenance of weight loss with non-surgical interventions in obese adults: Systematic review and meta-analyses of randomised controlled trials. BMJ 2014 May 14; 348:g2646.
(http://dx.doi.org/10.1136/bmj.g2646)
  
http://www.bmj.com/content/348/bmj.g2646?ijkey=cd60e748b3aa20cc898526b3
b72af2dc1df28664&keytype2=tf_ipsecsha

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MM: Although it is quite welcoming to think that we can merely take a pill and then lead a "normal" dietary life by inhibiting the function of a dietary process. Unfortunately, we do not yet know the function or the risk of suppression of the different enzymes that are affected by these medication approaches. At this point, a much better option for the celiac and non-celiac patient alike may be taking a non-prescription gluten and dairy enzyme combination supplement. Combine this with a L-glutamine product to stabilize the gut and a great deal of inflammation may be avoided. These products are available at Mark Drugs. Please contact us for more information.
  
Gastroenterology 2014 Jun; 146:1649
A Medication for Celiac Disease
Oral glutenase prevented mucosal damage to the small intestine.
Glutenases are proteases that can break down gluten peptides and thereby potentially prevent stimulation of the immune response in celiac disease. In the current industry-funded, randomized, controlled trial, investigators assessed the efficacy of an oral glutenase in celiac disease.
Patients with stable celiac disease on a gluten-free diet were challenged with gluten and received either an oral glutenase (not yet FDA-approved) or placebo, administered daily at the time of gluten ingestion. The endpoints were the ratio of villous height to crypt depth and the density of intraepithelial lymphocytes, both of which were similar between the two groups and essentially normal before the gluten challenge.
Sixteen patients who received glutenase and 18 patients who received placebo were eligible for efficacy evaluation. In the placebo group, the mean villous-height-to-crypt-depth ratio decreased from 2.8 before challenge to 2.0 afterwards (P=0.0007), and the density of CD3-positive, intraepithelial lymphocytes increased from 61 to 91 cells/mm after challenge (P=0.003). However, these mucosal parameters were maintained in patients who received a gluten challenge plus glutenase. The adverse effects seemed minimal but could not be separated from the effects of the gluten challenge.
Comment: These findings show that glutenase given orally can prevent the effects of gluten on the small bowel mucosa in patients with celiac disease. However, the exact role of glutenase in celiac disease remains to be defined, as we currently do not understand its cost or toxicity. Presumably, most patients would still be best and adequately treated by strict gluten avoidance. In phase II trial findings reported at Digestive Disease Week 2014, larazotide, an oral peptide that prevents epithelial tight junctions from opening in response to gluten, reduced symptoms in celiac disease. Thus, we are entering an era of specific anti–celiac disease pharmacologic therapy.
Citation(s): Lähdeaho M-L et al. Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease. Gastroenterology 2014 Jun; 146:1649. (http://dx.doi.org/10.1053/j.gastro.2014.02.031)
  
http://www.ncbi.nlm.nih.gov/pubmed/24583059?access_
num=24583059&link_type=MED&dopt=Abstract

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MM: I think that this may be a stretch. First, it's a retrospective study. Second, there are numerous risk factors associated with pancreatic cancer that are not cyclooxygenase-II associated, third, there are much better ways to reduce systemic inflammation that do not carry the same risk factors as daily aspirin use. Granted, pancreatic cancer generally has a horrible survival prognosis but it also has a fairly low presence in the general population meaning that the risks associated with aspirin and the general public are likely much greater than the potential benefits unless there is a patient who has a familial pre-disposition to pancreatic cancer, in which case they would be a much better candidate for its use.
  
Regular Use of Aspirin Linked to Reduced Risk for Pancreatic Cancer
By Amy Orciari Herman
Edited by André Sofair, MD, MPH, and William E. Chavey, MD, MS
Daily use of aspirin is associated with a significant reduction in the risk for pancreatic cancer, according to a case-control study in Cancer Epidemiology, Biomarkers & Prevention.
Some 360 patients newly diagnosed with pancreatic cancer were matched by age and sex to roughly 700 controls. All participants were interviewed about their use of aspirin.
Participants who'd ever used aspirin regularly (usually daily) had a significantly lower pancreatic cancer risk relative to those who'd never used aspirin regularly (odds ratio, 0.52). In particular, each year of low-dose aspirin use was associated with a significant decrease in risk (OR, 0.94).
The authors speculate that aspirin might reduce risk by inhibiting the expression of cyclooxygenase-2, which has been shown to be upregulated in pancreatic cancer precursor lesions. However, they point out several study limitations and note the "appreciable bleeding complications" with aspirin that "necessitate risk-benefit analysis for individual applications."
http://cebp.aacrjournals.org/content/early/2014/06/19/1055-9965.EPI-13-1284.abstract
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MM: Steroidal injections have been thought to be an optimal, low risk, low cost treatment option prior to back pain surgical intervention. This is a misguided approach and one that is promoted and required by many insurance companies in order to obtain back surgery or other interventions. Steroidal injections in the joint, and especially in the spine cause degradation of the bone locally, suppress adrenal function necessary for the body to accommodate for the stressor of injury or surgery, show little short term benefit and statistically, show NO long term benefit. Additionally, they may impair immune function and pre-dispose the individual to additional infection. Overall, a bad treatment option but one that will continue to be used and frequently required as long as medical treatment protocols are determined by payors who are not required to use evidence based medicine when determining what to cover.
  
N Engl J Med 2014 Jul 3; 371:11
Epidural Steroids Generally Are Ineffective for Lumbar Spinal
At 6 weeks, a steroid-lidocaine combination was no better than lidocaine alone.
Despite widespread use of epidural steroid injections to treat patients with spinal stenosis, high-quality evidence to support their efficacy is nonexistent. In this multicenter, double-blind US study, researchers randomized 400 patients with symptomatic central lumbar spinal stenosis to receive an epidural injection of either lidocaine alone or lidocaine plus a glucocorticoid. All patients had moderate-to-severe pain (with pain in the buttock or leg greater than that in the back) and functional disability. About 40% of patients in each group requested and received a second injection at 3 weeks.
During 6 weeks of follow-up, mean scores on pain and disability scales (the primary outcomes) improved substantially in both the steroid and no-steroid groups. However, at 6 weeks, no significant differences were observed between groups for either of these primary outcomes. At 3 weeks, small, statistically significant differences favored the steroid group (a 0.6-point difference in pain on a 10-point scale, and a 1.8-point difference in disability on a 24-point scale), but these differences were deemed clinically unimportant. The proportions of patients with at least 30% improvement in pain or disability at 6 weeks were similar in the two groups. Interestingly, 10% of patients in the steroid group (but <1% of those in the no-steroid group) had morning serum cortisol levels <3 μg/dL at 3 weeks, suggesting a surprisingly long duration of adrenal suppression after a single epidural injection in some cases.
Comment: At best, epidural steroids provide minimal transient benefit for patients with painful, disabling central lumbar spinal stenosis. (According to a recent meta-analysis, the same is true for epidural steroid injections in patients with sciatica: NEJM JW Gen Med Dec 13 2012.) An editorialist notes that some insurance companies require epidural injections as part of nonsurgical treatment before spinal stenosis surgery is approved; that policy obviously is misguided.
Citation(s): Friedly JL et al. A randomized trial of epidural glucocorticoid injections for spinal stenosis. N Engl J Med 2014 Jul 3; 371:11.
(http://dx.doi.org/10.1056/NEJMoa1313265)
Andersson GBJ.Epidural glucocorticoid injections in patients with lumbar spinal stenosis. N Engl J Med 2014 Jul 3; 371:75.
(http://dx.doi.org/10.1056/NEJMe1405475)
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MM: Both of the following articles are very positive and discuss tremendous success under specific conditions. Although the specific patient requirements severely limit the groups that may expect to see dramatic results, those who fit the criteria see remarkable benefits. An encouraging aspect of the research is that stem cell treatment is becoming a reality. It is more than merely a hopeful avenue that some scientists are dreaming about. I predict that future research will focus on providing a more generic presentation of stem cells that will open the treatment to a much greater population. This may be only a couple of years away.
  
Blood 2014 Jun 24
Stem-Cell Transplantation for Middle-Aged Patients with Myelofibrosis
The benefits of allogeneic hematopoietic stem-cell transplantation outweigh the risks, but only with sibling donors.
Myelofibrosis is a progressive disease that culminates in fatal cytopenias or leukemic transformation. The only curative therapy is allogeneic hematopoietic stem-cell transplantation (AHSCT), but the feasibility of this approach in older patients has been unclear.
To examine the safety and effectiveness of reduced-intensity AHSCT in this setting, investigators conducted a prospective, multicenter, phase II study involving 66 patients with primary myelofibrosis (median age, 55; range 30–65; about half had JAK2 V617F mutation); 32 had sibling donors, and 34 had unrelated donors. All patients received fludarabine and melphalan for conditioning. Those receiving grafts from unrelated donors also received rabbit antithymocyte globulin. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and methotrexate.
Neutrophil and platelet engraftment occurred in 97% and 88%, respectively, of the sibling-donor group, but in only 76% and 59% of the unrelated-donor group. The overall graft-failure rate was 6% with sibling grafts and 36% with unrelated-donor grafts. Approximately 40% of all patients had acute GVHD, and about a third had chronic GVHD. At a median follow-up of 25 months, significantly more patients with sibling grafts than with unrelated-donor grafts were alive (75% vs. 32%; P<0.001); 59% of the deaths in the unrelated-donor group were due to transplant-related complications.
The overall response rate in the 46 patients who survived at least 180 days was 93% in the sibling group and 69% in the unrelated donor group. The median event-free survival had not been reached in the former, but was only 6 months (95% confidence interval, 2–25) in the latter, and these patients also had a trend toward a worse survival if they had the JAK2 mutation or a higher-risk clinical stage (intermediate-2 or high risk).
Comment: This study demonstrates that reduced-intensity AHSCT achieves clinical responses in middle-aged patients with myelofibrosis, but the benefit outweighs the risk only if the stem cells are obtained from matched-sibling donors. Whether pretreatment with JAK2 inhibitors will broaden the indications for AHSCT is currently under investigation.
Citation(s): Rondelli D et al. MPD-RC 101 prospective study of reduced intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. Blood 2014 Jun 24; [e-pub ahead of print].
(http://dx.doi.org/10.1182/blood-2014-04-572545)
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JAMA 2014 Jul 2; 312:48
Long-Term Outcomes of Stem-Cell Transplantation for Sickle Cell Disease
Nonmyeloablative transplantation ameliorated many clinical manifestations of SCD.
The quality of life for many patients with sickle cell disease (SCD) is dismal because of recurrent hospitalizations for crises, persistent pain, strokes, and cognitive decline. In 2009, NIH investigators reported promising initial results of a phase I and II trial of a nonmyeloablative allogeneic hematopoietic stem-cell transplantation (HSCT) regimen for patients with severe SCD (NEJM JW Oncol Hematol Dec 15 2009). The investigators now report outcomes at a median follow-up of 3.4 years (range, 1.0–8.6).
Donor leukocyte engraftment occurred in 26 of 29 patients (87%); 1 year after HSCT, 25 patients (83%) had full donor-type hemoglobin. A concomitant decline in measures of hemolysis was seen, including significant increases in hemoglobin (11.9 g/dL in women and 12.1 g/dL in men) and decreases in lactate dehydrogenase, bilirubin, and reticulocyte counts (P<0.001 for all comparisons vs. pretransplant values). The level of hemoglobin S (HbS) was 35.3% if the donor had sickle-cell trait versus 0% if the donor had normal hemoglobin.
Following engraftment, mean donor chimerism occurred more rapidly with myeloid cells (CD14 or CD15) than with T-cells (CD3); at a median follow-up of 3.6 years, mean chimerism was 86% for donor myeloid cells and 48% for donor T-cells. Immunosuppression with sirolimus was discontinued after 1 year in 15 patients who achieved 50% CD3 chimerism. Subsequently, the percentage of chimerism, HbS, and total hemoglobin remained stable, and graft-versus-host disease did not develop.
Following successful HSCT, no new strokes occurred, tricuspid regurgitant velocity significantly decreased (P=0.01), and liver-function tests improved. In addition, it became possible to institute phlebotomy for patients with prior iron overload, and ferritin levels fell to <300 ng/mL in seven patients. Overall narcotic usage declined, and six chronic users were successfully weaned from their drugs.
Comment: The salient observations of this trial are that nonmyeloablative HSCT in most adult patients with SCD ameliorates many of the clinical manifestations of this disorder and that immunosuppression can be discontinued after 1 year in many patients without precipitating graft failure or graft-versus-host disease. However, HSCT requires the availability of an HLA-identical donor, a sophisticated transplant center, financial resources, and other supportive therapy.
Citation(s): Hsieh MM et al. Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA 2014 Jul 2; 312:48.
(http://dx.doi.org/10.1001/jama.2014.7192)
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MM: Sad but true. Sometimes those professionals that we place on pedestals end up having weak ankles and knees and come toppling off into infamy. That is the case with these Japanese researchers who less than one year ago were being lauded as probable Nobel Prize candidates. But, fear not. Stem cell research is still an exciting field with wonderful potential. These failures of some very smart and ambitious people will merely serve as an impetus to others to achieve greatness now that the pathways have been identified and the doors opened.
  
Retraction Dissolves Credibility of Acid-Bath-generated Stem Cells
By Joe Elia
Edited by Susan Sadoughi, MD, and Lorenzo Di Francesco, MD, FACP, FHM
Sadly, what seemed too good to be true now is: subjecting adult cells to an acid bath does not transform them into pluripotent stem cells, and the Nature papers reporting the effect have been retracted.
After initial excitement over the findings in January, a number of laboratories reported having trouble duplicating the results. Then in April, the RIKEN Center (where lead author Haruko Obokata did much of the work) conducted an investigation and accused her of "an act of research misconduct involving fabrication."
A Nature editorial points out that after findings of manipulated photographs and plagiarized text, the papers' co-authors concluded that they could not stand behind the results.
The editorial concludes with a plea for better behavior across the research enterprise, "to ensure that the money entrusted by governments is not squandered, and that citizens' trust in science is not betrayed."
http://www.nature.com/news/stap-retracted-1.15488

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