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    <recommendedItem id="20100101_19_358"
                     title="Poststroke Antidepressant Boosts Mental Agility (CME/CE)"
                     score="0.01"
                     href="http://www.medpagetoday.com/Cardiology/Strokes/tb/18240?impressionId=1265797270225"
                     
      &lt;p&gt;Antidepressants in the first months after a stroke may aid cognitive recovery for patients without depression, according to a randomized trial analysis.&lt;/p&gt;
&lt;p&gt;Global cognitive function scores improved significantly more with escitalopram (Lexapro) than with problem-solving therapy or placebo (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.01), according to Ricardo E. Jorge, MD, of the University of Iowa in Iowa City, and colleagues.&lt;/p&gt;
&lt;p&gt;Memory scores rose significantly higher with the antidepressant as well (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.01), with both effects independent of those on depression, they reported in the February &lt;em&gt;Archives of General Psychiatry&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;&quot;Adjunctive restorative therapies administered during the first few months after stroke, the period with the greatest degree of spontaneous recovery, reduce the number of stroke patients with significant disability,&quot; the researchers concluded.&lt;/p&gt;
&lt;p&gt;The &lt;a href=&quot;http://www.medpagetoday.com/Cardiology/Strokes/9621&quot; mce_href=&quot;http://www.medpagetoday.com/Cardiology/Strokes/9621&quot; target=&quot;_blank&quot;&gt;primary analysis&lt;/a&gt; of the trial, reported in the &lt;em&gt;Journal of the American Medical Association on&lt;/em&gt; May 28, 2008, showed that prophylactic escitalopram treatment would prevent poststroke depression in one patient for every 7.2 treated &lt;em&gt;(P&lt;/em&gt;&amp;lt;0.001 compared with placebo). That article ultimately raised a controversy over an undisclosed conflict of interest.&lt;/p&gt;
&lt;p&gt;Escitalopram is a selective serotonin reuptake inhibitor (SSRI). Since serotonin plays a role in neuroplastic changes in the developing brain as well as in depression, Jorge&apos;s group analyzed whether there might be such an effect after a stroke.&lt;/p&gt;
&lt;p&gt;The study randomized patients to double-blind treatment with escitalopram (10 mg/d under age 65 or 5 mg/day age 65 and older) or placebo or unblinded problem-solving therapy (12 sessions of going through steps to arrive at a course of action for a patient-selected problem).&lt;/p&gt;
&lt;p&gt;The intent-to-treat analysis included 129 patients treated starting within the first three months after their mild to moderate severity stroke and who did not meet criteria for major or minor depression.&lt;/p&gt;
&lt;p&gt;Overall, global cognitive functioning was significantly changed between groups as measured on the Repeatable Battery for the Assessment of Neuropsychological Status (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.01).&lt;/p&gt;
&lt;p&gt;After controlling for change in depression score and type of stroke, escitalopram was associated with the best cognitive recovery, an adjusted mean change of 9.9 points compared with 1.9 for problem-solving therapy (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.01) and 4.0 for placebo (&lt;em&gt;P&lt;/em&gt;=0.02).&lt;/p&gt;
&lt;p&gt;Similarly, for delayed memory scores on the same test battery, escitalopram came out on top (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.01).&lt;/p&gt;
&lt;p&gt;After adjustment for depression score change and stroke mechanism, the antidepressant was associated with an 11.2 point improvement in delayed memory, compared with a change of -0.7 with problem-solving therapy (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001) and 3.9 with placebo (&lt;em&gt;P&lt;/em&gt;=0.02).&lt;/p&gt;
&lt;p&gt;On test of immediate memory, escitalopram again yielded the best recovery.&lt;/p&gt;
&lt;p&gt;The researchers found mean improvement of 13.4 points with the antidepressant compared with 2.0 with problem-solving therapy (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001) and 7.2 with placebo (&lt;em&gt;P&lt;/em&gt;=0.04), after adjustment for time between stroke and treatment, depression score change, and stroke type.&lt;/p&gt;
&lt;p&gt;These mental benefits appeared to have an impact on functional status as well.&lt;/p&gt;
&lt;p&gt;Cognitive domain scores on the Functional Independence Measure were better for escitalopram-treated patients than those who didn&apos;t get the drug (&lt;em&gt;P&lt;/em&gt;=0.05), as were memory domain scores on the same measure (&lt;em&gt;P&lt;/em&gt;=0.03).&lt;/p&gt;
&lt;p&gt;At baseline, the global cognitive functioning and delayed and immediate memory scores were nonsignificantly lower in the antidepressant group than in the other two groups, which could have biased the results.&lt;/p&gt;
&lt;p&gt;However, the treatment effects appeared to be real, Jorge explained in an interview.&lt;/p&gt;
&lt;p&gt;In an unpublished regression analysis, the baseline scores were not a significant covariate. &quot;If [the results were] related only to the difference in baseline, this would be significant but it wasn&apos;t,&quot; he told &lt;em&gt;MedPage Today&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;Moreover, with an initially lower score it might have been expected that the escitalopram-treated group would have had a lower score at the end of the study than the other groups, added co-author Robert G. Robinson, MD, also of the University of Iowa.&lt;/p&gt;
&lt;p&gt;But that wasn&apos;t the case, he said in an interview. With regard to delayed memory, for example, &quot;the escitalopram-treated group went from the most impaired to the best performing.&quot;&lt;/p&gt;
&lt;p&gt;The researchers didn&apos;t compare end scores for the escitalopram, problem solving therapy, and placebo groups, but they were: &lt;ul&gt; &lt;li&gt;For global cognitive functioning 89.8, 89.1, and 91.0 points, respectively&lt;/li&gt; &lt;li&gt;For delayed memory, 96.6, 89.1, and 94.2, respectively&lt;/li&gt; &lt;li&gt;For immediate memory, 95.1, 94.9, and 98.5, respectively&lt;/li&gt; &lt;/ul&gt;&lt;/p&gt;
&lt;p&gt;The treatment showed no effect on other individual cognitive measurements, including those for attention, language, and IQ. Nor were there significant differences in changes in occupational or living conditions.&lt;/p&gt;
&lt;p&gt;Although SSRIs such as escitalopram have been associated with hospitalization for GI bleeding and falls in prior studies, these complications did not occur in Jorge&apos;s study.&lt;/p&gt;
&lt;p&gt;&quot;Long-term administration of SSRIs appears to be an effective and safe treatment option to improve cognitive outcomes among patients with cerebrovascular disease,&quot; they concluded in the &lt;em&gt;Archives&lt;/em&gt; paper.&lt;/p&gt;
&lt;p&gt;The researchers cautioned that the study was limited by lack of CT or MRI scans and the younger age of escitalopram-treated patients, compared with other groups. That may have been a source of bias, although age did not appear to be a significant factor in the trial results.&lt;/p&gt;
&lt;p&gt;In this analysis, the researchers emphasized that the trial was not financially supported in any way by any drug company  --  a declaration hinting at the controversy that brewed last year over failure of one of the authors of the original &lt;em&gt;JAMA&lt;/em&gt; article to &lt;a href=&quot;http://www.medpagetoday.com/PublicHealthPolicy/HealthPolicy/13391&quot; mce_href=&quot;http://www.medpagetoday.com/PublicHealthPolicy/HealthPolicy/13391&quot; target=&quot;_blank&quot;&gt;properly disclose ties&lt;/a&gt; to Forest Pharmaceuticals, which makes escitalopram.&lt;/p&gt;
&lt;p&gt;Another scientist who discovered that omission published the information in a competing journal, inducing &lt;em&gt;JAMA&lt;/em&gt; to issue a gag rule on reporting of undisclosed conflicts of interest. That policy encourages those who discover such conflicts to report them to &lt;em&gt;JAMA&apos;s&lt;/em&gt; editors but prohibits them from disclosing the conflicts publicly pending an investigation by the journal.&lt;/p&gt;
&lt;p&gt;In the current analysis, the disclosure statement indicated that co-author Robertson, had received honoraria and speakers&apos; bureau fees from Forest, with the caveat that &quot;none of the design, analysis, or expenses (including the cost of medications) of this study were supported by monies, materials, or any intellectual input from Forest Laboratories.&quot;&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The study was supported solely by a grant from the National Institute of Mental Health.&lt;/p&gt;&lt;p&gt;Jorge reported having received travel awards to participate in national meetings from the former Hamilton Pharmaceutical Company and Avanir Pharmaceutical Company.&lt;/p&gt;&lt;p&gt;Co-authors reported financial conflicts of interest with Merck, NMT Medical, Eli Lilly, Centocor, Sanofi-Bristol-Meyers-Squibb, Boerhringer-Ingelheim, Schering-Plough, AstraZeneca, and GlaxoSmithKline, the former Hamilton Pharmaceutical Company, Avanir Pharmaceutical Company, Lubeck, Forest Laboratories, and Pfizer.&lt;/p&gt;&lt;p&gt;No pharmaceutical company donated medications for or had any financial interest in the study.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_252"
                     title="MS Walking Drug Gets FDA Nod"
                     score="0"
                     href="http://www.medpagetoday.com/Neurology/MultipleSclerosis/tb/18112?impressionId=1265797270225"
                     
      &lt;p&gt;WASHINGTON  --  The FDA has approved the first drug that improves walking in patients with multiple sclerosis, the tablet dalfampridine (Ampyra).&lt;/p&gt;
&lt;p&gt;The approval was based on clinical trial data that found patients could walk better with the drug than those treated with placebo.&lt;/p&gt;
&lt;p&gt;Patients who exceed recommended dosage, 10 mg twice a day, or who have moderate to severe kidney disease, may experience seizures the FDA said.&lt;/p&gt;
&lt;p&gt;Adverse events reported during clinical trials include urinary tract infection, insomnia, dizziness, headache, nausea, weakness, back pain, balance disorder, swelling of the nose or throat, constipation, diarrhea, indigestion, throat pain, and burning, tingling, or itching skin.&lt;/p&gt;
&lt;p&gt;The drug is manufactured by Elan of Dublin, Ireland and distributed by Acorda Therapeutics Inc. of Hawthone, NY.&lt;/p&gt;

    </recommendedItem>
    <recommendedItem id="20100101_19_219"
                     title="Oral MS Drugs Effective in Phase III Trials (CME/CE)"
                     score="-0.002"
                     href="http://www.medpagetoday.com/Neurology/MultipleSclerosis/tb/18069?impressionId=1265797270225"
                     
      Two oral drugs under investigation for multiple sclerosis reduced relapse rates and delayed onset of disability in separate trials reported online this week in the &lt;em&gt;New England Journal of Medicine&lt;/em&gt;.&lt;br&gt;
&lt;br&gt;Fingolimod, a novel agent also known as FTY-720, was more effective than both placebo and the standard of care for MS, interferon-beta-1a (Avonex), in two independent trials.&lt;br&gt;
&lt;br&gt;The studies, called FREEDOMS and TRANSFORMS, were reported by Ludwig Kappos, MD, of the University of Basel in Switzerland, and colleagues, and by Jeffrey Cohen, MD, of the Cleveland Clinic, and other researchers, respectively. Some researchers worked on both studies.&lt;br&gt;
&lt;br&gt;Cladribine, an oral drug already marketed for hematologic cancers under the trade name Leustatin, was clearly more effective than placebo in a third trial called CLARITY reported by Gavin Giovannoni, MB, BCh, PhD, of Queen Mary University in London, and colleagues.&lt;p&gt;&lt;/p&gt;
&lt;p&gt;&quot;The studies in this issue of the [&lt;em&gt;NEJM&lt;/em&gt;] provide a new horizon for patients with relapsing-remitting multiple sclerosis and a welcome increase in the range of treatment options,&quot; William M. Carroll, MBBS, MD, of Sir Charles Gairdner Hospital in Perth, Australia, wrote in an accompanying editorial.&lt;/p&gt;
&lt;p&gt;Oral drugs for MS would not only improve patient acceptance of treatment, but also &quot;further support a change in treatment approach to directly prevent immune-mediated injury,&quot; Carroll wrote.&lt;/p&gt;
&lt;p&gt;Existing disease-modifying therapies  --  interferon, glatiramer acetate (Copaxone), and natalizumab (Tysabri)  --  are all injectable drugs.&lt;/p&gt;
&lt;p&gt;&quot;Patients hate the shots and have been waiting 17 years for an oral drug,&quot; John Corboy, MD, a neurologist of the University of Colorado in Denver who was not involved in the study, told &lt;em&gt;MedPage Today&lt;/em&gt; and ABC news when contacted for comment.&quot;&lt;/p&gt;
&lt;p&gt;The National Multiple Sclerosis Society also expressed delight at the reports.&lt;/p&gt;
&lt;p&gt;&quot;The published results ... are wonderful news for people with MS,&quot; wrote John Richert, MD, the group&apos;s executive vice president of research and clinical programs, in a report to local chapters.&lt;/p&gt;
&lt;p&gt;&quot;Having oral therapies in the MS pipeline is real progress, and it should increase the number of people who choose to begin therapy earlier and who stay on therapy, which our experts say is the best way to combat future disease activity.&quot;&lt;/p&gt;
&lt;p&gt;Most of the studies&apos; key results had been presented last spring at the American Academy of Neurology&apos;s annual meeting. (See &lt;a href=&quot;http://www.medpagetoday.com/MeetingCoverage/AAN/14013&quot; mce_href=&quot;http://www.medpagetoday.com/MeetingCoverage/AAN/14013&quot; target=&quot;_blank&quot;&gt;AAN: Oral MS Drug with Novel Mechanism Beats Interferon-Beta1a&lt;/a&gt; and &lt;a href=&quot;http://www.medpagetoday.com/MeetingCoverage/AAN/13996&quot; mce_href=&quot;http://www.medpagetoday.com/MeetingCoverage/AAN/13996&quot; target=&quot;_blank&quot;&gt;AAN: Cancer Drug Shows Promise as Oral MS Therapy&lt;/a&gt;)&lt;/p&gt;
&lt;p&gt;But the journal reports included additional details, especially on adverse effects, as well as peer review.&lt;/p&gt;
&lt;p&gt;The two drugs target different aspects of T-cell biology. These cells are key players in the autoimmune attack on the myelin sheaths surrounding nerve fibers, which, in turn, causes the slow loss of peripheral nerve function.&lt;/p&gt;
&lt;p&gt;Cladribine induces active T cells to undergo apoptosis, which explains its utility in hairy cell leukemia, lymphoma, and certain other hematologic malignancies.&lt;/p&gt;
&lt;p&gt;Fingolimod has a different mechanism. It causes the sphingosine-1-phosphatase receptor, which normally sits on the surface of T and B cells, to withdraw into the cell interior.&lt;/p&gt;
&lt;p&gt;The effect is to leave the cells unresponsive to signals that instruct them to exit lymph nodes and head toward sites of inflammation. Keeping T cells bottled up in lymph nodes prevents them from attacking nerves in MS.&lt;/p&gt;
&lt;p&gt;The two placebo-controlled studies of fingolimod and cladribine both showed that relapse rates and disease progression were reduced.&lt;/p&gt;
&lt;p&gt;In the 1,272-patient fingolimod study, annualized relapse rates were 0.40 in the placebo group, 0.18 with 0.5 mg of the drug daily, and 0.16 with a 1.25-mg dose over a two-year period (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001 for both doses versus placebo).&lt;/p&gt;
&lt;p&gt;The hazard ratios for disability progression relative to placebo at the two-year evaluation were 0.70 and 0.68 for the low and high doses of fingolimod, respectively (&lt;em&gt;P&lt;/em&gt;=0.02 for both comparisons).&lt;/p&gt;
&lt;p&gt;Cladribine, a more toxic drug, was given in short bursts of treatment over the 96-week study.&lt;/p&gt;
&lt;p&gt;Two dosing regimens were tested, delivering cumulative totals of 3.5 or 5.25 mg/kg, along with placebo. Patients took one or two 10-mg tablets daily for the first four or five days of either two or four monthly periods starting at week zero, followed by two additional monthly courses starting at week 48.&lt;/p&gt;
&lt;p&gt;Results for the primary outcome of annualized relapse rate were 0.33 for placebo, 0.14 for the low cladribine dose, and 0.15 for the higher dose (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001 for both doses versus placebo).&lt;/p&gt;
&lt;p&gt;Hazard ratios for disability progression at week 96 for cladribine versus placebo were 0.67 with the low dose (&lt;em&gt;P&lt;/em&gt;=0.02) and 0.69 with the high dose (&lt;em&gt;P&lt;/em&gt;=0.03).&lt;/p&gt;
&lt;p&gt;Perhaps more striking were the findings in the other fingolimod trial, in which the drug was tested head-to-head against the current standard of care.&lt;/p&gt;
&lt;p&gt;The same two doses of fingolimod were used. Patients assigned to interferon received the drug in weekly intramuscular injections of 30 &amp;#956;g.&lt;/p&gt;
&lt;p&gt;The annualized relapse rate with interferon was 0.33, whereas it was significantly lower with fingolimod: 0.16 with the 0.5-mg dose and 0.20 for the 1.25-mg dose (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001 versus interferon for both).&lt;/p&gt;
&lt;p&gt;But the risk of disease progression did not differ significantly between treatment groups.&lt;/p&gt;
&lt;p&gt;Moreover, two patients receiving the higher fingolimod dose died of herpes zoster infections, disseminated in one case and causing encephalopathy in the other. Increased rates of herpes zoster infections were also seen in the other fingolimod trial and with cladribine. In the cladribine trial, lymphocytopenia was seen in about 14% of patients taking the drug, compared with less than 2% of the placebo group.&lt;/p&gt;
&lt;p&gt;Fingolimod also seemed to be associated with cardiac rhythm disturbances, including bradycardia (2.7% with fingolimod, 0.7% placebo) and atrioventricular conduction block, though the latter was mostly confined to the higher drug dose (five cases versus two each for the low dose and placebo).&lt;/p&gt;
&lt;p&gt;Leukopenia and lymphocytopenia were also seen with fingolimod in the placebo-controlled study, though at lower rates than with cladribine  --  about 3% to 6%, compared with less than 1% in the control group.&lt;/p&gt;
&lt;p&gt;Lymphocytopenia was less frequent overall in the interferon-controlled study, seen in 0.2% of the low-dose group and 1.0% of the high-dose group, compared with no cases in the interferon-treated patients.&lt;/p&gt;
&lt;p&gt;Hillel Panitch, MD, of the University of Vermont in Burlington, Vt., told &lt;em&gt;MedPage Today&lt;/em&gt; and ABC News that the findings were actually reassuring.&lt;/p&gt;
&lt;p&gt;&quot;The adverse events including herpes infections, malignancies, and bradycardia are much less of an issue than expected for these drugs, and with the proper oversight should not delay their use,&quot; Panitch wrote in an e-mail.&lt;/p&gt;
&lt;p&gt;Richert of the National MS Society also indicated that the reported adverse effects were not especially worrisome.&lt;/p&gt;
&lt;p&gt;&quot;Herpes infections are likely to occur with many different immune-modulating therapies, including some already approved for MS,&quot; he wrote in an e-mail to &lt;em&gt;MedPage Today&lt;/em&gt; and ABC News, adding that these usually respond to treatment.&lt;/p&gt;
&lt;p&gt;&quot;They should be something patients and doctors keep a lookout for,&quot; he wrote.&lt;/p&gt;
&lt;p&gt;Similarly, he said, the cardiac effects of fingolimod appeared transient and asymptomatic. But he suggested it may be necessary to avoid combining fingolimod with anti-arrhythmic drugs in at least some patients.&lt;/p&gt;
&lt;p&gt;But Colorado&apos;s Corboy was more concerned by the side effect profile. He pointed to the issue of progressive multifocal leukoencephalopathy (PML) seen with natalizumab (Tysabri) in MS patients, which kept the drug off the market for a time.&lt;/p&gt;
&lt;p&gt;&quot;The price you may have to pay for greater efficacy is greater risk,&quot; he wrote in an e-mail. He said some in the MS community would avoid the new oral drugs because of the risks, should they be approved.&lt;/p&gt;
&lt;p&gt;The manufacturers of both drugs have filed for FDA approval. Merck Serono was first to file, for cladribine, but the FDA informed the company in late November that it considered the application incomplete and refused to accept it.&lt;/p&gt;
&lt;p&gt;Company officials promised at the time that they would submit additional information requested by the agency. They did not respond to requests for an update.&lt;/p&gt;
&lt;p&gt;Novartis, maker of fingolimod, announced in mid-December that its FDA filing was imminent and a company representative confirmed that it had been submitted.&lt;/p&gt;
&lt;p&gt;Although the FDA has given both drugs fast-track status, the possibility that the agency will want an advisory committee review may push their final approvals into 2011.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The two fingolimod studies were funded by Novartis. The study of cladribine was funded by Merck Serono.&lt;/p&gt;&lt;p&gt;Authors of the placebo-controlled study of fingolimod reported relationships other than research funding with Novartis and many other firms including Accorda, Actelion, Allergan, Allozyne, Bayer Schering, Biogen Idec, Biogen-Dompe, Boehringer Ingelheim, Genmab, GlaxoSmithKline, Medicinova, Merck Serono, Roche, sanofi aventis, Santhera, Teva, UCB, Wyeth, Helvea, and Mediservice. Several co-authors were employees of Novartis.&lt;/p&gt;&lt;p&gt;Authors of the study of fingolimod versus interferon reported relationships other than research funding with Novartis and other firms including Biogen Idec, EMD Serono, Teva, sanofi aventis, Waterfront Media, Bayer Schering, AstraZeneca, Genentech, Lundbeck, Talecris, Roche, Wyeth, Medicinova, Biogen-Dompe, Medtronic, Accorda, Actelion, Allergan, Allozyne, Boehringer Ingelheim, Genmab, GlaxoSmithKline, Santhera, and UCB. Several co-authors were employees of Novartis.&lt;/p&gt;&lt;p&gt;Authors of the cladribine study reported relationships other than research funding with Merck Serono or EMD Serono and with other firms including Bayer Schering, Biogen Idec, Novartis, Teva-Aventis, UCB, Vertex, sanofi-aventis, Biogen-Dompe, Pfizer, and Genentech. Several co-authors were employees of Merck Serono.&lt;/p&gt;&lt;p&gt;Carroll reported relationships other than research funding with Biogen Idec, Bayer Schering, Merck Serono, and sanofi-a ventis. He also reported agreeing to serve on a Novartis advisory board but did not attend meetings and received no compensation.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;&lt;p&gt;&lt;em&gt;This article was developed in collaboration with ABC News. &lt;/em&gt;&lt;img src=&quot;http://www.medpagetoday.com/upload/2009/10/1/14357_1.jpg&quot; mce_src=&quot;http://www.medpagetoday.com/upload/2009/10/1/14357_1.jpg&quot; alt=&quot;&quot;&gt;&lt;/p&gt;
    </recommendedItem>
    <recommendedItem id="20090101_6_951"
                     title="Pediatric MS Linked to Cognitive Impairment"
                     score="-0.006"
                     href="