A common antibiotic added to the usual treatment plan for some patients with chronic obstructive pulmonary disease can reduce acute exacerbations — sudden onsets of worsened cough, wheezing and labored breathing — and improve quality of life, according to findings from the COPD Clinical Research Network reported in the Aug. 25, 2011, issue of the New England Journal of Medicine.

The Lung Health Center at the University of Alabama at Birmingham is one of the 10 sites participating in the COPD Clinical Research Network.

The findings indicate that the antibiotic azithromycin is effective in reducing COPD exacerbations, which are typically caused by bacteria, viruses or a combination of both. Azithromycin is already prescribed for a variety of bacterial infections, including pneumonia and strep throat.

“Exacerbations account for a significant part of the COPD health burden,” said mark T. Dransfield, M.D., director of the UAB Lung Health Center and associate professor in the Division of Pulmonary, Allergy and Critical Care Medicine. “These promising results with azithromycin may help us reduce that burden and improve the lives of patients at risk of these acute attacks.”

Previous studies of cystic fibrosis and other pulmonary diseases suggested that azithromycin might be effective in reducing COPD exacerbations. The study, begun in 2005, enrolled more than 1,000 subjects, 140 of them at UAB and the Birmingham Veterans Affairs Medical Center.

 The 570 study participants, who took 250 mg. of azithromycin daily for a year in addition to their usual care, averaged 1.48 acute COPD exacerbations annually, compared to 1.83 exacerbations for the 572 participants who received their usual care without azithromycin. The participants taking azithromycin also responded more favorably on questionnaires that asked them to assess their breathing ability and overall well-being.

Eighty percent of the study participants already were taking other medications normally used to manage COPD, such as inhaled steroids and long-acting bronchodilators.

Side-effects of this commonly prescribed antibiotic were minimal. Azithromycin increased the presence of antibiotic-resistant microbes in some patients, although no one developed an infection. It also caused slight hearing loss in a small fraction of participants.

Dransfield says azithromycin may be indicated for up to a quarter of the 12 million people in the United States with COPD, particularly those with  moderate to severe disease who require oxygen or who have a history of exacerbations within the past year.

COPD is a progressive disease of the lungs and is now the third leading cause of death in this country, having recently surpassed stroke. There is no cure, though a combination of drugs and lifestyle changes can help manage the symptoms, reduce exacerbations and improve quality of life.

The study was funded by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health.  The COPD Clinical Research Network is an NHLBI-funded consortium of research centers located throughout the United States that was established to identify new treatments for COPD.

Collaborators on the study at UAB are William C. Bailey, M.D., and J. Allen D. Cooper, Jr., M.D., professors of pulmonary, allergy and critical care medicine. Cooper also is chief of pulmonary medicine at the Birmingham VA Medical Center.

I am a practicing neurologist in CT, which is practically at the epicenter of Lyme disease in the US (in fact, the disease is named after Lyme CT where it was first described). So I have seen my fair share of Lyme disease and a form a late Lyme disease known as chronic neurolyme. it is without a doubt a real and serious disease. however, it is also the basis for what I consider to be a fake disease, chronic Lyme. I was therefore very happy to see an excellent article in the new England Journal of Medicine critically analyze this troublesome fake syndrome.

Throughout history there has always been a number of popular fake diseases or syndromes – although the specifics have changed over time. Sometimes the disease is completely fictional, like electromagnetic hypersensitivity. Sometimes the diagnosis is really just a name being applied to a laundry list of non-specific symptoms, like “asthenia,” (a diagnosis popular a century ago). And often the fake diagnosis is based upon a real disease but overextends the diagnosis to incorporate those without the specific symptoms of the disease but who have nonspecific or vague symptoms. in this latter category I would place chronic fatigue syndrome, fibromyalgia, and chronic Lyme.

The phenomenon of the fake diagnosis is driven by several realities, most importantly that people often have symptoms for which there is no established diagnosis or where the diagnosis is undesirable. People often suffer from what we call “symptoms of life,” meaning common aches and pains that plague everyone, increasingly as we get older. often people can get joint or muscle pain, headaches, fatigue, mild forgetfulness, and vague bowel symptoms without there being a specific underlying disease or disorder. the human machine is imperfect, it wears out over time, and these minor ailments are an unfriendly reminder of our frailty and mortality.

These symptoms can range from annoying to debilitating, and it is understandable that people want to minimize and avoid them. it is reasonable to seek a professional opinion when a new such symptom appears, and to seek symptomatic relief and also to pursue methods to stave off the onset of symptoms.

But sometimes people are not happy with this approach. for some reason they are convinced that there is a specific underlying disease attacking their body and this disease must be diagnosed and cured. Sometimes this is in fact the case, but when all such possibilities are ruled out and the symptoms are non-specific and do not point to a particular disease, the simple explanation of “wear and tear” is appropriate. Unwilling to accept this, many patients (often referred to as the “worried well”) create the demand for a label to attach to their symptoms of life, and thus are borne the wide variety of fake diagnoses to meet this demand.

Another source of this demand are those patients who do have a specific underlying disorder, but it is unrecognized, or they are unhappy with the answer. A common underlying problem is sleep disorders. Chronic sleep deprivation can cause fatigue, muscle aches, and even poor concentration and memory. Also, depression and anxiety can lead to the onset or exacerbation of common symptoms but some patients may find these diagnoses unacceptable or stigmatized, or may misinterpret them as a dismissal of their symptoms.

In the early to mid 20th century one of the more common fake diagnoses was tertiary syphilis. Obviously syphilis is a real disease, and it does have a chronic form that can involve the nervous system. it is also a great mimicker, meaning it can manifest in many ways. this is a good setup for a fake diagnosis – eventually any bizarre or non-specific syndrome was blamed on syphilis. it was the favorite diagnosis of quacks of the time, and the target of many snake oil claims.

It is probably not a coincidence that Lyme disease is also caused by a spirochete (a type of bacteria), as is syphilis, and that both diseases have a late neurological phase, and that both have a wide range of possible symptoms. what happens is that cases are reported where a patient has some weird syndrome and goes undiagnosed for a time and in the end it turns out they had syphilis (or Lyme disease) the whole time. this leads clinicians to think – “Hey, maybe my patient with a weird and undiagnosed list of symptoms also has syphilis/Lyme disease.” (Or, of course, the patient may follow this line of reasoning themselves.) It’s really that short a trip to the creation of a fake diagnosis. Throw in a little confirmation bias, a couple of logical fallacies, and you’re home.

With Lyme disease the story is very typical and instructive. Lyme is an infectious disease, so there should be some symptoms and signs of infection. There are also specific laboratory tests that can confirm the diagnosis – a Lyme titer, which looks for antibodies to Borrelia burgdorferi (the spirochete that causes Lyme in the US) or a Lyme western blot – a more specific antibody test. Finally, there are antibiotics to which B. burgdorferi is sensitive, and if treated aggressively and long enough should eradicate the infection.

But the Lyme phenomenon, like syphilis before it, has taken on a life of its own, propelled by patients in search of a diagnosis and by misguided or unscrupulous clinicians. There are many people walking around today with the label of Lyme disease who do not have, and never had, any signs or symptoms specific for infection or of Lyme, who have a negative antibody titer, and who have not responded typically to antibiotics. Then how can anyone say they have Lyme? good question.

Physicians who have made this diagnosis have fallen prey to the “invisible dragon” fallacy – or systematically rendering a hypothesis (in this case a diagnosis) unfalsifiable. what they are saying, in essence, is that their patient has an atypical presentation of Lyme that lacks all the specific signs, that it is seronegative (the antibody tests are negative) and it is resistant to standard treatment. I submit that Occam’s razor would favor the alternative hypothesis that the patient simply does not have a Lyme infection. this NEJM review article also comes to the same conclusion.

The story of Lyme, however, has been made more complex by the modern quack innovation of the fake diagnostic test to support the fake diagnosis. for example, there are labs that will run their own Lyme serological tests that show Lyme where none exists. their tests have not been validated, or they use low thresholds for positivity that are guaranteed to cause false positives.

Another example is the SPECT scan – single positron emission computed tomography. this is a scan that creates a map of blood flow to the brain. it has legitimate uses, but some Lyme true believers can see in the blobs of computer generated color the telltale signs of neurolyme disease – again without any validation. how more difficult is it for the public to distinguish scientific medicine from this slick imitation, when the purveyors of fake diagnoses have laboratory tests and fancy imaging studies to back them up?

Before one is tempted to claim that making such a fake diagnosis causes no harm and serves to comfort the patient, or that it is worth a try to treat for possible Lyme even in the absence of clear evidence – let me assure you that there is real harm. first, making a fake diagnosis often results in the premature end to the search for the real diagnosis. I have seen patients settle on the diagnosis of Lyme disease when in fact they had something else entirely – something that therefore went untreated.

Also, the treatment for chronic Lyme is far from benign. it usually involves months or years of chronic oral or intravenous antibiotics, with real risks and side effects.

It is also important to point out that the question of whether or not co-called chronic Lyme disease responds to long term antibiotics is a separate and specific question that has been addressed by research. the NEJM study also reviewed this evidence and concludes that antibiotic treatment for chronic Lyme is not effective.

This is a very important distinction. I often teach my students that whether or not a patient has a specific diagnosis is often not definitively answerable, and may be a matter of definition. But further, it is actually a proxy question. the real, and far more important question, is whether or not a patient meeting certain objective criteria would benefit from a specific treatment. So we can put aside the question of whether or not patients can have atypical seronegative treatment-resistant chronic Lyme disease and ask instead, do such people respond to any treatment. the answer, according to this review, is no.

It is also worth pointing out that there does seem to exist a real, if rare, post-Lyme syndrome – people who have persistent symptoms after treatment for Lyme disease. These represent the vast minority of patients diagnosed with chronic Lyme, and they don’t respond to antibiotic treatment either.

It remains to be seen what effect, if any, this review published in a prestigious journal by recognized experts will have on the chronic Lyme subculture. I predict none. the evidence and arguments were all already there. Also, the chronic Lyme true believers are a self-selective group that have already proven resistant to logic and evidence.

But this article is an excellent reference for the practicing physician or patients suffering from chronic symptoms. it also makes my job easier, at least in reference to this specific form of quackery.

Perhaps the most important lesson in this whole affair (and the one most likely to be overlooked) is that it demonstrates that it is possible for so many patients and practitioners to fool themselves for so long. often belief in a phenomenon is used to justify the existence of the phenomenon, using the “where there is smoke there is fire” logic. But often the smoke is just an illusion, or an artifact of sloppy thinking. the story of chronic Lyme adds one more historical example of this, a cautionary tale for anyone putting forward their own pet unfalsifiable hypothesis.

This article is also reviewed by mark Hoofnagle over at denialism.

23:01 | 09.02.2011 PRESS RELEASE: Novartis drug Afinitor® extends -3-

PRESS RELEASE: Novartis drug Afinitor® extends progression-free survival in patients with advanced pancreatic NET, study published in NEJM shows

Novartis International AG /Novartis drug Afinitor® extends progression-free survival in patients withadvanced pancreatic NET, study published in NEJM showsProcessed and transmitted by Thomson Reuters.the issuer is solely responsible for the content of this announcement. * RADIANT-3 trial shows everolimus more than doubled median progression-free survival from 4.6 to 11.0 months versus placebo[1] * no tumor growth after 18 months in 34% of the patients treated with everolimus versus in 9% of those treated with placebo[1] * these data, previously reported at oncology congresses, support worldwide regulatory submissions for treatment of advanced neuroendocrine tumors (NET), which has received priority review designation by US FDA Basel, February 9, 2011 – the new England Journal of Medicine (NEJM) published astudy today that shows Afinitor® (everolimus) tablets plus best supportive care(BSC) more than doubled progression-free survival (PFS), or time without tumorgrowth, versus placebo plus BSC in patients with advanced pancreaticneuroendocrine tumors (NET)[1]. Data from the study, RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors), werefirst presented last year at the 12th World Congress on Gastrointestinal Cancerin Barcelona[2]. Regulatory submissions for everolimus to treat this patientpopulation are underway worldwide. Results from the trial showed that everolimus more than doubled median PFS from4.6 to 11.0 months when compared with placebo and reduced the risk of cancerprogression by 65% (hazard ratio=0.35 [95% confidence interval (CI), 0.27 to0.45]; p=20%) were stomatitis/oral mucositis/ulcers(64% everolimus vs. 17% placebo; includes stomatitis, aphthous stomatitis, mouthulceration and tongue ulceration), rash (49% vs. 10%), diarrhea (34% vs. 10%),fatigue (31% vs. 14%), infections (23% vs. 6%), nausea (20% vs. 18%), peripheraledema (20% vs. 3%) and decreased appetite (20% vs. 7%); most were grade one ortwo. Grade three and four adverse events (>=5%) include stomatitis/oralmucositis/ulcers (7% vs. 0%; includes stomatitis, aphthous stomatitis, mouthulceration and tongue ulceration), anemia (6% vs. 0%) and hyperglycemia (5% vs.2%). Median exposure to everolimus was 2.3-fold longer than exposure to placebo(38 vs. 16 weeks)[1]. about RADIANT-2RADIANT-2 is a Phase III randomized, double-blind, placebo-controlled,multicenter study. the trial examined the efficacy and safety of everolimus plusSandostatin® LAR® (octreotide acetate for injectable suspension) versus placeboplus octreotide LAR in 429 patients with advanced carcinoid tumors. Patients whomet the study’s entry criteria were randomized 1:1 to receive either oraleverolimus (10 mg daily) plus octreotide LAR (30 mg intramuscularly every 28days) or placebo daily plus octreotide LAR. Patients had radiologicaldocumentation of disease progression within 12 months prior to randomization[9]. the study did not meet its primary endpoint of PFS as assessed by independentradiological review (p=0.026 vs. p=0.0246 predefined) (hazard ratio=0.77 [95%CI, 0.59 to 1.00]). Secondary endpoints from the trial include safety, overallresponse rate and overall survival[9]. In the initial review of the data an imbalance in baseline characteristics wasobserved between the two treatment arms, including prior treatment withchemotherapy, primary tumors located in the lung and a poorer World HealthOrganization (WHO) performance status (an assessment of each patient’sfunctional/physical performance). Further, inconsistencies were found betweenanalyses of radiology scans, which resulted in censoring of patients from thetrial. these imbalances and the censoring of data seem to favor the control armand may have impacted the outcome of the study. Additional analyses to adjustfor imbalances in the treatment arms show everolimus plus octreotide LARsignificantly reduced risk of disease progression (hazard ratio=0.60 [95% CI,0.44 to 0.84])[9]. In the study, the most frequent all grade drug-related adverse events witheverolimus plus octreotide LAR were stomatitis, rash, fatigue, diarrhea, nauseaand infections; most were grade one or two. Grade three and four adverse events(>=5%) with everolimus plus octreotide LAR were stomatitis (7%; includesstomatitis, aphthous stomatitis, mouth ulceration and tongue ulceration),fatigue (7%), diarrhea (6%), infections/infestations (5%) and hyperglycemia(5%)[9]. about neuroendocrine tumors (NET)Neuroendocrine tumors arise from cells that can produce and secrete a variety ofhormones that regulate bodily functions[10]. There are many types of NET thatcan occur throughout the body; however, most are found in the GI tract, pancreasand lungs[6,11]. Many patients with NET have no symptoms or nonspecificsymptoms, such as flushing and diarrhea, which often lead to delays in diagnosisof five to seven years[12,13]. As a result, many patients with NET often haveadvanced disease when diagnosed, meaning the cancer has spread to other parts ofthe body and has become more difficult to treat[3,5]. Approximately 64% ofpatients with pancreatic NET are diagnosed in advanced stages[6]. about Afinitor (everolimus)Afinitor® (everolimus) tablets is approved in the European Union (EU) for thetreatment of patients with advanced renal cell carcinoma (RCC) whose disease hasprogressed on or after treatment with vascular endothelial growth factor (VEGF)-targeted therapy and also in the US for the treatment of patients with advancedRCC after failure of treatment with sunitinib or sorafenib. Afinitor is also approved in the US to treat patients with subependymal giantcell astrocytoma (SEGA) associated with tuberous sclerosis who requiretherapeutic intervention but are not candidates for curative surgical resection.the effectiveness of Afinitor is based on an analysis of change in SEGA volume.Clinical benefit such as improvement in disease-related symptoms or increase inoverall survival has not been shown. Novartis has submitted marketingapplications for everolimus to the European Medicines Agency (EMA) and the SwissAgency for Therapeutic Products (Swissmedic), and additional regulatorysubmissions are underway worldwide. In the EU, everolimus is available in different dosage strengths under the tradename Certican® for the prevention of organ rejection in heart and kidneytransplant recipients. In the US, everolimus is available in different dosagestrengths under the trade name Zortress® for the prophylaxis of organ rejection

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PRESS RELEASE: Novartis drug Afinitor® extends -2-

in adult patients at low-moderate immunologic risk receiving a kidneytransplant. Everolimus is exclusively licensed to Abbott and sublicensed to BostonScientific for use in drug-eluting stents. not all indications are available in every country. As an investigationalcompound the safety and efficacy profile of everolimus has not yet beenestablished in NET. Access to everolimus outside of the approved indications hasbeen carefully controlled and monitored in clinical trials designed to betterunderstand the potential benefits and risks of the compound. because of theuncertainty of clinical trials, there is no guarantee that everolimus willbecome commercially available for NET or any additional indications anywhere inthe world. Important Safety Information about Afinitor (everolimus) tabletsAfinitor is contraindicated in patients with hypersensitivity to everolimus, toother rapamycin derivatives or to any of the excipients. Cases of non-infectious pneumonitis have been described; some of these have beensevere and occasionally fatal. Management of pneumonitis may require doseadjustment and/or interruption, or discontinuation of treatment and/or additionof corticosteroid therapy. Afinitor is immunosuppressive. Localized and systemic bacterial, fungal, viralor protozoal infections (e.g., pneumonia, aspergillosis, candidiasis, hepatitisB reactivation) have been described; some of these have been severe andoccasionally fatal. Pre-existing infections should be treated prior to startingtreatment. Patients and physicians should be vigilant for symptoms and signs ofinfection; in case of emergent infections, appropriate treatment should bepromptly instituted and interruption or discontinuation of Afinitor should beconsidered. Patients with systemic invasive fungal infections should not receiveAfinitor. Hypersensitivity reactions have been observed. Mouth ulcers, stomatitis and oral mucositis have been seen. Topical treatmentsare recommended; alcohol- or peroxide-containing mouthwashes should be avoided. Monitoring of renal function, blood glucose and complete blood counts isrecommended prior to initiation and periodically during treatment. Cases ofrenal failure, some fatal, have been observed. Afinitor is not recommended in patients with severe hepatic impairment. Use of live vaccines should be avoided. Afinitor is not recommended during pregnancy or for women of childbearingpotential not using contraception. Afinitor may cause fetal harm in pregnantwomen. Women taking Afinitor should not breast feed. Male fertility may becompromised by Afinitor. Avoid concurrent treatment with strong CYP3A4 and PgP inhibitors and use cautionwith moderate inhibitors. Avoid concurrent treatment with strong CYP3A4 or PgPinducers. In advanced RCC, the most common adverse reactions (>=10%) include stomatitis,rash, fatigue, asthenia, diarrhea, anorexia, nausea, mucosal inflammation,vomiting, cough, infections, peripheral edema, dry skin, epistaxis, pneumonitis,pruritus and dyspnea. Common adverse reactions (>=1 to =1 to =1/10) adverse drug reactions in clinical studies with SandostatinLAR were diarrhea, abdominal pain, nausea, constipation, flatulence, headache,cholelithiasis, hyperglycemia and injection-site localized pain. Common(>=1/100, =1/1000,

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PRESS RELEASE: Novartis drug Afinitor® extends -3-

patients and societies. Focused solely on healthcare, Novartis offers adiversified portfolio to best meet these needs: innovative medicines, cost-saving generic pharmaceuticals, preventive vaccines, diagnostic tools andconsumer health products. Novartis is the only company with leading positions inthese areas. In 2010, the Group’s continuing operations achieved net sales ofUSD 50.6 billion, while approximately USD 9.1 billion (USD 8.1 billion excludingimpairment and amortization charges) was invested in R&D throughout the Group.Headquartered in Basel, Switzerland, Novartis Group companies employapproximately 119,000 full-time-equivalent associates (including 16,700 Alconassociates) and operate in more than 140 countries around the world. For moreinformation, please visitnovartis.com. Novartis is on Twitter. Sign up to follow @Novartisattwitter.com/novartis. References[1] Yao, et al. Everolimus for Advanced Pancreatic Neuroendocrine Tumors. NewEng J Med 2011;364:514-23.[2] Yao, et al. Everolimus versus placebo in patients with advanced pancreaticneuroendocrine tumors (pNET) (RADIANT-3). 12th World Congress onGastrointestinal Cancer, Barcelona. July 1, 2010.[3] National Library of Medicine and the National Institutes of Health.Pancreatic islet cell tumor. Availableatnlm.nih.gov/medlineplus/ency/article/000393.htm. Accessed February2011.[4] American Cancer Society Detailed Guides. Pancreatic Cancer. Availableatcancer.org/Cancer/PancreaticCancer/DetailedGuide/pancreatic-cancer-what-is-pancreatic-cancer. Accessed February 2011.[5] Halfdanarson, et al. Pancreatic neuroendocrine tumors (PNETs): incidence,prognosis and recent trend toward improved survival. Annals of Onc19: 1727-1733, 2008.[6] Yao, et al. One Hundred Years after “Carcinoid:” Epidemiology of andPrognostic Factors for Neuroendocrine Tumors in 35,825 Cases in the UnitedStates. Journal of Clinical Oncology. June 20 2009; vol. 26, number 18.[7] Motzer, et. al. Phase 3 Trial of Everolimus for Metastatic Renal CellCarcinoma. Cancer 2010 Sep; 116(18):4256-4265.[8] US Food and Drug Administration. Fast Track, Accelerated Approval andPriority Review. Availableatfda.gov/forconsumers/byaudience/forpatientadvocates/speedingaccesstoimportantnewtherapies/ucm128291.htm. Accessed February 2011.[9] Pavel et al. a randomized, double-blind, placebo-controlled, multicenterphase III trial of everolimus + octreotide LAR vs placebo + octreotide LAR inpatients with advanced neuroendocrine tumors (NET) (RADIANT-2). 35th EuropeanSociety for Medical Oncology Congress. October 9, 2010.[10] National Library of Medicine and the National Institutes of Health.Neuroendocrine Tumor. Available atcancer.gov/dictionary/?CdrID=44904.Accessed February 2011.[11] American Cancer Society Detailed Guides. Gastrointestinal Carcinoid Tumors.Availableatcancer.org/Cancer/GastrointestinalCarcinoidTumor/DetailedGuide/gastrointestinal-carcinoid-tumors-key-statistics. Accessed February 2011.[12] Modlin, et al. Priorities for Improving the Management ofGastroenteropancreatic Neuroendocrine Tumors. J Natl Cancer Inst2008;100:1282-1289.[13] National Library of Medicine and the National Institutes of Health.Carcinoid syndrome. Availableatnlm.nih.gov/medlineplus/ency/article/000347.htm. Accessed February2011. # # # Novartis Media Relations Central media line : +41 61 324 2200 Eric Althoff Heather Bochner Novartis Global Media Relations Novartis Oncology +41 61 324 7999 (direct) +1 862 778 5092 +41 79 593 4202 (mobile) e-mail: Novartis Investor Relations Central phone: +41 61 324 7944 Susanne Schaffert +41 61 324 3769 North America: Pierre-Michel Bringer +41 61 324 1065 Richard Jarvis +1 212 830 2433 Thomas Hungerbuehler +41 61 324 8425 Jill Pozarek +1 212 830 2445 Isabella Zinck +41 61 324 7188 Edwin Valeriano +1 212 830 2456 e-mail: e-mail: — End of Message — Novartis International AGPostfach Basel WKN: 904278;ISIN: CH0012005267; Media release (PDF):hugin.info/134323/R/1487280/422737.pdf This announcement is distributed by Thomson Reuters on behalf ofThomson Reuters clients. the owner of this announcement warrants that:(i) the releases contained herein are protected by copyright and other applicable laws; and(ii) they are solely responsible for the content, accuracy and originality of the information contained therein. Source: Novartis International AG via Thomson Reuters ONE [HUG#1487280] novartis.com

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