Podcasts about Celecoxib

On this episode of the Real Life Pharmacology podcast, I cover medications 51-55. They are eszopiclone, celecoxib, estrogen, moxifloxacin, and donepezil. Eszopiclone is a "Z" drug used for insomnia. Its adverse effect profile is very similar to benzodiazepines. Celecoxib is a COX-2 Inhibitor used for pain and inflammation. I discuss how this medication differs from traditional NSAIDs. Estrogen therapy is used for menopausal symptoms but carries a risk of cancer and blood clots. Moxifloxacin is a quinolone antibiotic. Binding drug interactions, boxed warnings, and QTc prolongation are potential concerns. Donepezil is a medication used for dementia. I discuss its mechanism of action and common adverse effects.

Visit: https://nursing.com/140meds to request your free copy of "140 Must Know Meds" Generic Name Celecoxib Trade Name Celebrex Indication Osteoarthritis, rheumatoid arthritis, acute pain Action Decreases pain and inflammation by inhibiting synthesis of prostaglandins Therapeutic Class Antirheumatics/NSAID Pharmacologic Class Cox 2 inhibitor Nursing Considerations • Use caution with cardiovascular disease • Increases risk for MI, CVA, thrombosis • May cause GI bleeding, Stevens-Johnson syndrome, dermatitis • Notify provider for new-onset abdominal pain or black stool

Dr. Westin and Dr. Justin C. Brown discuss how physical activity can improve disease-free and overall survival in colorectal cancer and its potential application across all cancer types.   TRANSCRIPT   The guest on this podcast episode has no disclosures to declare. Dr. Westin: Hello, everybody, and welcome to another episode of JCO After Hours, the podcast where we get in depth on recent manuscripts published in the Journal of Clinical Oncology. And it is my great pleasure today to tell you we're going to be talking about a really important manuscript: “Physical Activity in Stage III Colon Cancer: CALGB/SWOG 80702 Alliance Study.” And this was published in the JCO on August 9th, 2022.   All participants in the podcast have no conflicts of interest.   And I am very excited to welcome the first author on this important paper, Dr. Justin C. Brown. He is the Director of the Cancer Metabolism Program and Assistant Professor in Cancer Energetics at the Pennington Biomedical Research Center at Louisiana State University.   Welcome, Dr. Brown. Thank you for being here. Dr. Justin C. Brown: Thanks so much for having me. Dr. Westin: So, this is some really important work, and I think we're starting to see more and more really objective data around the importance of physical activities. But before we get too far down the road, I do want to level set because this was a study in colon cancer. So, just because we have a really mixed audience, give us a quick bit of information about the standard treatment for colon cancer and where we are with survival outcomes. Dr. Justin C. Brown: Yeah. So, for most patients with early colon cancer, they'll get upfront surgery. And then a subset of patients who have high-risk features for recurrence, or have positive lymph nodes or tumor deposits, will get three or six months of chemotherapy. And outcomes have improved over time for this population, but there is still a lot of heterogeneity, in that, some patients do better than others. And you know, a lot of patients ask as they finish therapy or as they're starting therapy, "Are there things I can do that potentially could improve my outcomes?" And so, we think that this data will provide physicians with a lot of really important information regarding the benefits of physical activity during chemotherapy, as well as after therapy, for patients with stage three colon cancer. Dr. Westin: Okay, that's great. And so, again, continuing on that level-setting piece, before this study, what did we know about the impact of physical activity on outcomes in colon cancer? Dr. Justin C. Brown: So, we knew that there was some association between physical activity during chemotherapy and after chemotherapy with disease-free survival and overall survival. There have been studies that have linked those two things. There was some uncertainty about, what is the best exercise or physical activity prescription? And so, a lot of the current recommendations before this study basically said encourage patients to avoid sedentary behavior, encourage them to be as active as they can be, because some activity provides benefits over no activity. But for the patient who really wanted the specifics of how much should I be doing, when should I be doing it, what types of activities should I be doing, should I avoid certain things, the evidence was really absent. And so, what this study provides is a lot of important clarity for both physicians and patients about the types of activities that can maximize their disease-free survival and overall survival. Dr. Westin: I think that's so important because you're exactly right. We all have those patients that you give them a vague, and they're like, "No, I need instructions. I need to know how much time. I need to know what I'm doing." And it can be really frustrating because—I know personally, I'm like, "Well, this is what I do.” And I'm like, is that enough? I have no idea. So, this is really important work.   And before we get into the specifics of the work, can you just give our listeners a little information? Do we know anything else about physical activity in other cancer types? Like, beyond colon cancer, is this something that's broad-based across everybody?   Dr. Justin C. Brown: Yeah. So, there is emerging observational evidence that physical activity after diagnosis of early breast cancer, of early prostate cancer, is associated with improved disease outcomes, so disease-free survival, overall survival; that's observational data. We do have randomized clinical trial data on other quality of life endpoints and biologic endpoints in a variety of tumor types. And we know that patients who engage in physical activity or exercise during and after treatment tend to have better quality of life, they have less fatigue, they have improved physical functioning, they have reduced inflammation, improved insulin sensitivity. So, there's a variety of short, medium and potential long-term benefits to being physically active after your diagnosis of cancer. Dr. Westin: Perfect. And how did you end up here? What made you interested in this work? Dr. Justin C. Brown: So, my story dates back all the way to 2002. So, my father died from metastatic colorectal cancer. Dr. Westin: I'm sorry. Dr. Justin C. Brown: No, no, it's okay. I mean, if that didn't happen, I wouldn't be here today. And so, he is with me every day. And, when he asked his physician, "Is there anything I can do to improve my long-term outcome?" This was 2002 before we knew how patient lifestyle factors really improved or impacted disease outcomes. And so, my whole life's mission has been focused on trying to empower cancer survivors, so people from the point of diagnosis on, with information about how the choices they make outside of the oncology clinic have a profound impact on how they feel, function, and survive. And so this has come full circle for me because now I'm able to generate evidence that hopefully will inform clinical practice about how patients who are exactly like my dad and wanted to know what they could do to improve their outcomes, we now have the data that we can provide more precise recommendations about what patients might consider doing to improve their long-term disease outcomes. Dr. Westin: Great. Wow. It's so inspiring, and again, I am sorry for your loss. But I'm glad that you're really transitioning it into positive things. So, let's help everybody understand first just the overall design of the trial that you utilized, the CALGB/SWOG 80702 clinical trial. Dr. Justin C. Brown: Yeah. So this trial was a two-by-two factorial trial, and it randomized patients to three years of Celecoxib; the anti-inflammatory drug, or three years of placebo. And that was the primary analysis. The primary hypothesis was that Celecoxib would improve disease-free survival versus placebo. And that paper was published by my mentor, Jeff Meyerhardt, in JAMA last year. And that analysis showed that Celecoxib did not improve disease-free survival over placebo. The other factor of the two-by-two design was a randomization to three months of FOLFOX therapy, 5- fluorouracil and oxaliplatin, or three months of FOLFOX. And that analysis contributed to an international pooled consortium called the IDEA Consortium. And that analysis was published in 2018 in New England Journal of Medicine, and the follow-up overall survival analysis was published in Lancet Oncology in 2020. And that showed that while overall, three months of FOLFOX was not inferior to six months, there were some lower-risk patients that achieved good disease control with a shorter regimen of chemotherapy. And so, that has changed practice, and now there are certain lower-risk patients that are getting treated with three months of FOLFOX chemotherapy instead of six months. But patients with high-risk features still continue to get six months of therapy. That was the primary questions that that study was designed to answer: the Celecoxib versus placebo and then the contribution to the international pooling project to answer the question of three versus six months of postoperative therapy. Dr. Westin: Well, that's a really clever design. And then I love how you have an additional question built in here. So, why don't you explain how you incorporated your exercise objectives and also what this nested cohort design is? Dr. Justin C. Brown: Yeah. So, this is a unique opportunity to leverage an ongoing clinical trial to conduct an observational study. So, what we did is, about midway through chemotherapy, we asked patients if they wanted to participate in a lifestyle substudy. And if they chose to participate in the lifestyle substudy, they were asked questions about their physical activity and their dietary patterns and how much they weighed. And we measured those things midway through chemotherapy, and then we also measured them again about six months after patients finished their chemotherapy. And so, what this allowed us to do is to leverage all of the amazing resources that were put into place in the randomized clinical trial—that is, a homogenous patient sample, uniform treatments—and systematically ascertain disease outcomes to answer a question in an observational setting—that is, "Does physical activity relate to disease-free survival and overall survival?" So that is the nested cohort within the larger randomized clinical trial. Dr. Westin: Okay, perfect. And then just tell us how you measured the physical activity and the questionnaire that you utilized. Dr. Justin C. Brown: Yeah. So physical activity was measured by a self-reported questionnaire, and the questionnaire is included as a supplement to the JCO paper. So, if people are interested in using this questionnaire, it is available. And it asks 10 different types of physical activities, and it asks the frequency with which those activities are done in the past two months. And using the answers that the patients provided, we were able to calculate which patients were more physically active versus those that were less physically active. And we were also able to understand were the activities that they participated in more vigorous or less vigorous. So, it provided us with a lot of important details regarding the types of physical activities that patients reported during and after chemotherapy. Dr. Westin: Great. That's so interesting. And then, of course, we know diet is important, right? So, you did assess diet as well in this group. You want to give us a little bit of detail on that? Dr. Justin C. Brown: Yeah. So, we measured diet with what's called a Food Frequency Questionnaire, and it asks a series of questions regarding habitual dietary intake. And we know that people who are more physically active tend to be more mindful about what they eat. And so, that's an important confounding variable in trying to understand the relationship between physical activity and disease-free survival. So, we measured diet using that questionnaire. At the same time, we measured physical activity during and after chemotherapy. And that was included in our analysis so that we can attribute the association that we observed to the physical activity per se. Dr. Westin: Okay. And how often did you assess these time points? I'm sorry if I missed it. Dr. Justin C. Brown: So, we measured physical activity and diet two times. We measured it midway through chemotherapy, and then about six months after patients finished their chemotherapy. Because we know that activity, as well as diet, changes from when patients are being actively treated to after they finish their systemic therapy. Dr. Westin: Okay. Perfect. Great. All right, so let's hear it. What were your primary findings? Dr. Justin C. Brown: So, the benefit for the simple messaging is that any activity is better than no activity. That is, if patients need to know the bottom line, my advice is that they find an activity that they like to do and they do it for the rest of their life. For patients who want a little bit more precision, we can think about physical activity on a spectrum of intensity. So the examples I would give a patient is we can do walking, we can do jogging, and we can do running. And jogging is more intense than walking, and running is more intense than jogging. And so, if you decide to do more intense activities, you don't have to do them as much in a week. If you choose to do walking, you need to do more walking than if you choose to do running. And so, this will help to clarify what types of activities are beneficial. So, some people might choose to play tennis, which is a vigorous activity, one day a week. And that would provide them—from our analysis, that provides them with a disease-free survival and overall survival benefit. If a patient says, "My joints are too old and too achy that I can't play tennis, but I can walk around my neighborhood," then we know that those patients may need to do a little bit more activity, maybe a 20 to 30 minutes a day, three to five days a week, in order to achieve a meaningful disease-free survival benefit. So, this helps us to understand with a little bit more precision what we should be advising patients. And if patients say, "I can't do this” or “I prefer to do that," that helps us to have evidence-based recommendations about what is likely to be beneficial and worthwhile to improve their long-term disease outcomes. Dr. Westin: It's so awesome. And I think it's so great to have just very clear guidelines that we can give our patients. I know I've said it already during this podcast, but every time I—because I think we all get so frustrated with these vague recommendations, like, "Okay, drink water, eat healthy." You know, really, I want bullet points of what I can do. Now, we talked a little bit about some of the findings in other cancer types that were already existing. So, can we extrapolate your findings to other cancer types? Dr. Justin C. Brown: I think there is a reasonable expectation that our findings can probably generalize to early-stage breast cancer and maybe to prostate cancer. And the reason I say this is because these are tumor sites where there is existing evidence that being more physically active is associated with improved long-term disease outcomes. Now, the specific magnitude of benefit, I'm not sure if that will generalize. But I do think that this study provides a framework to start thinking about how we can understand the specific characteristics of physical activity that might be more or less important in terms of maximizing long-term disease outcomes. Dr. Westin: That is perfect. So, tell me, what are your next steps with this work? Dr. Justin C. Brown: So, one of the findings that this study reported was that patients who were more physically active during their chemotherapy were more likely to receive more of their planned chemotherapy. They had a higher chemotherapy RDI. So, some of us on this paper have been very fortunate that we received funding from the National Cancer Institute to launch a Bayesian Adaptive Trial of exercise, aerobic exercise, during chemotherapy, and the primary study endpoint is chemotherapy relative dose intensity. So, what we're going to be able to do is to understand, in a randomized clinical trial setting, does different doses of aerobic exercise have a causal effect on improving chemotherapy RDI? Because one of the hypothesized mechanisms through which we think physical activity may improve disease-free survival and overall survival is it enhances a patient's ability to tolerate systemic therapy. And so, we have the funding. We are in the process of planning that study. It should begin later this year, and that will provide us with concrete randomized evidence to understand if exercise during chemotherapy for colon cancer has a causal effect and can improve adherence to systemic therapy. Dr. Westin: That's outstanding. And can our listeners potentially participate in that? Are you looking for sites? Dr. Justin C. Brown: So this study will be launched at Pennington Biomedical Research Center, where I am, in Baton Rouge. This study will also take place at Kaiser Permanente, Northern California, so if there are people on the West Coast listening, as well as at Dana-Farber Cancer Institute in Boston. And so, we are part of a larger consortium of four studies that are trying to understand the benefits of both exercise as well as nutrition and their role in impacting how patients feel, function, and tolerate anti-cancer therapy in a variety of cancer sites. And we are focused on colon cancer, specifically. Dr. Westin: Well, that's great. I hope our listeners will get involved. And those of our listeners that are survivors, you heard some very clear data on what you can do to help impact your overall survival, as well as quality of life. So, I hope you'll implement that. Thank you again so much for being here, Dr. Brown. The time just flew by. And again, for the listeners, this was the JCO manuscript published August 9th, 2022, “Physical Activity in Stage III Colon Cancer: The CALGB/SWOG 80702 Trial.” And until next time, we'll see you at JCO After Hours. Take care.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  

Celecoxib is a non-steroidal anti-inflammatory drug, or NSAID. Ciprofloxacin is an antibiotic that is used to treat a number of bacterial infections. The former has been trialed unsuccessfully in ALS. However, according to preclinical evidence and a phase 1 trial conducted by Neurosense, a biotech company based in Israel and Cambridge, MA, these two FDA-approved drugs may hold some promise for people with ALS when combined into one treatment. Neurosense's formulation of these two drugs is known as Prime C. The first participants were recently enrolled in a Phase 2b trial of the treatment, and it is also currently undergoing a pharmacokinetic trial in healthy volunteers. Recently, several members of Neurosense's team joined Endpoints to help us learn more about the company's mission, the science behind prime C, and what's next for the potential ALS Treatment. Episode Guide: 1:22 – NeuroSense's Company Story 5:58 – The Science Behind Prime C 15:13 –Details about Prime C in Clinical Trials Support the show: https://www.als.net/donate/ See omnystudio.com/listener for privacy information.

Download the cheat: https://bit.ly/50-meds  View the lesson: https://bit.ly/CelecoxibCelebrexNursingConsiderations    Generic Name Celecoxib Trade Name Celebrex Indication Osteoarthritis, rheumatoid arthritis, acute pain Action Decreases pain and inflammation by inhibiting synthesis of prostaglandins Therapeutic Class Antirheumatics/NSAID Pharmacologic Class Cox 2 inhibitor Nursing Considerations • Use caution with cardiovascular disease • Increases risk for MI, CVA, thrombosis • May cause GI bleeding, Stevens-Johnson syndrome, dermatitis • Notify provider for new-onset abdominal pain or black stool

Here are the links for everything discussed in Episode 71. Times are also below so feel free to skip around and get to the drugs that interest you.  (1:18) Interchangeable MAB - Cyltezo approval (5:50) Seglentis approved for pain management (8:24) FDA authorizes EUA for Pfizer COVID19 vaccine Updated CDC recommendations for Pfizer COVID vaccine boostersConnect with The Rx Daily Dose:Twitter      Instagram      YouTube      Linkedin       WebsiteEmail: therxdailydose@gmail.comConnect with Ian Parnigoni PharmD. on social media:Twitter       Instagram       Linkedin  ★ Support this podcast on Patreon ★

The FDA, Shock Troops for the Pharmaceutical Industrial Complex   Richard Gale and Gary Null PhD Progressive Radio Network, May 17, 2021     As of this week, over 194 million doses of the Covid-19 vaccines have been administered in the US. Consequently, a growing majority of Americans are delighted that life may return to normal because most believe they are now protected from infection. Clearly that is not the case. Bill Maher tested positive for Covid last week and had to cancel his television show for his first time since 1993. This was despite Maher having been fully vaccinated. Moreover the vaccines’ serious adverse effects are being downplayed by health officials and the media. Who will experience an adverse effect appears to be arbitrary; therefore, it is a game of Russian Roulette as to whether a person will be critically injured or be protected from the virus. One of the world’s most accomplished rock guitar musicians Eric Clapton received both doses of AstraZeneca’s Covid vaccine and had such severe reactions he feared he might never play the guitar again.  Clapton posted a message:   “About six weeks later [after receiving the first shot] I was offered and took the second AZ shot, but with a little more knowledge of the dangers. Needless to say the reactions were disastrous, my hands and feet were either frozen, numb or burning, and pretty much useless for two weeks, I feared I would never play again, (I suffer with peripheral neuropathy and should never have gone near the needle.) But the propaganda said the vaccine was safe for everyone.”   However it is not simply a miniscule few who are suffering undesirable Covid-vaccine events such as blood clots and other cardiovascular complications, anaphylaxis, severe allergic reactions, various neuropathies, abnormal menstrual bleeding and suspected miscarriages, extreme muscle weakness, fatigue, etc.  If this were the case, an argument could be made for siding with benefits over risks. Covid vaccines have only been administered for less than six months, and it is becoming increasingly clear that the risks may outweigh the benefits. Suspected numbers of miscarriages following Covid vaccines is especially worrisome. A government study published in the New England Journal of Medicine attempted to analyze and downplay the risk. Yet at the same time, the study observed a trend of 11.6% of spontaneous abortions occurring less than 13 weeks after the mRNA vaccination.  It is becoming increasingly obvious that these vaccines’ safety profiles is far less than Anthony Fauci, the FDA and the CDC are touting   More younger adults are experiencing adverse vaccine symptoms than from the risks due to acquiring a wild coronavirus. Worldwide reported adverse effects and deaths are escalating dramatically. In the CDC’s Vaccine Adverse Events Reporting System (VAERS), reported Covid-19 vaccine deaths have now reached 4.434 as of May 13th 2021 which is more vaccine-related deaths from conventional vaccines recorded in VAERS during the past 21 years.  Since VAERS is a passive reporting system, the actual serious adverse effect rate may be as high as 1in 10 shots. No other vaccine on the CDC’s vaccination schedule has such a poor record of safety.   As with Bill Maher, fully vaccinated people are still being infected and testing positive. Younger healthy adults, who earlier had an insignificant chance of becoming sick or dying from the SARS-CoV-2 virus, are now being injured and in some cases dying from the vaccines.    A recent study published in JAMA observed delayed hypersensitivity vaccine reactions well after injections. The University of Pennsylvania estimates that between 5 to 10 percent of recipients of the mRNA vaccines have “severe adverse reactions” – an inordinately high percent compared to every other non-Covid vaccine. And a group of medical institutions including the University of Greifswald School of Medicine, and the Medical University of Vienna are proposing a new medical condition, “vaccine-induced prothrombotic immune thrombocytopenia,” now be associated with the AstraZeneca and Johnson and Johnson vaccines. A recent paper warns about the dangers of vaccine-induced prion disease. The list of adverse effects continues to mount.  Pfizer document refers to the possibility of Covid vaccine shedding to the unvaccinated.  Doctors are coming forward and accusing the CDC of scrubbing the statistics of actual vaccine-related deaths. The risks were quite obvious in the vaccine makers’ own clinical trial documents before the FDA awarded Covid vaccines with emergency use approval to launch a nation-wide vaccination program. Whether or not health officials at the CDC or FDA thoroughly deliberated on the many warnings or simply ignored them is open to debate.  But the evidence strongly leans towards the latter.   Earlier, we presented the historical evidence of widespread corruption at the CDC; however, the FDA is far more influential because it is the final watchdog that determines a drug’s efficacy and safety profile. In the most perverse scenario, the FDA relies upon outside experts to sit on its advisory committees to review a drug’s or a vaccine’s safety. Many of these experts have a gross conflict of interests with the pharmaceutical industry.  This institutional dilemma is steeped into the FDA’s very DNA. As far back as 2006, Public Citizen discovered that 1 out of 3 of outside consultants and advisory members to the FDA had financial conflicts. The situation has only worsened over the years.   A Pogo investigation in October last year, uncovered several advisers on the FDA’s Vaccines and Related Biological Products Advisory Committee who had direct ties with the Covid-vaccine companies, including direct payments for consulting fees. Dr. Archana Chatterjee, for example, has received over $200,000 from agreements with these companies. The same is true for the Committee’s chairman, University of Michigan Dr. Arnold Monto who received fees from the largest vaccine firms including  Pfizer, Sanofi, GlaxoSmithKline and Novartis. The previous chair, Dr. Hana El Sahly from Baylor University, had to recuse herself due to her role in supervising Moderna’s Covid-19 vaccine clinical trials. Earlier, Monto was the principal investigator for Sanofi’s influenza vaccine. Another is the president of Meharry Medical College where coronavirus clinical trials were conducted. Three other Committee members likewise held close conflict-of-interest relationships with vaccine makers.  Shortly before issuing emergency use approval, a second Pogo analysis concluded that the FDA Committee whitewashed the warnings indicated by the Covid-19 vaccine trials. The meeting was adjourned by the FDA director for the Office of Vaccines Research and Review in favor of green-lighting the vaccines before Committee members suspicious of the clinical results could weigh-in. Prof. Carl Elliott, a medical ethicist at the University of Minnesota, summarized the problem of corporate bias now plaguing the FDA. “You do something positive for a company that you feel confident is going to pay you back for it later on,” Elliot stated. “And they do.”  The FDA‘s current rules regarding conflict of interest is strictly limited to the honor system.  In Europe, on the other hand, the European Medicines Agency strictly prohibits experts with ties to private industry from sitting on its advisory committees.    Even with FDA efforts to crack down on conflicts of interests due to Congressional pressure, the industry has found other means to get their representatives onto advisory panels. And the heads of the agency willingly turn a blind eye.  A Science exposé reported on the growing strategy of “pay after” conflicts of interests. Outside advisors will declare no conflicts but then rule in favor of a drug or vaccine only to be reimbursed afterwards. The journal’s review of compensation records uncovered “pay after” schemes for the approval of 28 psychopharmacologic, arthritis, cardiac and renal drugs.” The investigation also uncovered:   “Of the more than $24 million in personal payments or research support from industry to the 16 top-earning advisers—who received more than $300,000 each—93% came from the makers of drugs those advisers previously reviewed or from competitors.”   Probing still deeper, the Pacific Legal Foundation released an analytical review of 2,952 rules issued by the Department of Health and Human Services over a 17-year period. The Foundation determined that 75 percent of these rules were unconstitutional and “issued by low-level officials and employees with no authority to issue rules.” With respect to the FDA dozens had no democratic controls and involved tens of millions of dollars ruled over by career bureaucrats.     Every American who is prescribed a drug by a physician has the belief that the pill has undergone rigorous trials to scrutinize its safety and will be effective. And when there are known potential adverse effects, we blindly assume the attending physician knows these dangers. However, this is a myth perpetuated not only by drug makers but also by our own federal health agencies.   As we have reported on many occasions, iatrogenic deaths, deaths caused by medical error and prescribed medications is now the third leading cause of mortality in the US. The Institute of Medicine has warned about “the nation’s epidemic of medical errors.” A large percent of these errors are related to adverse drug events (ADEs). The FDA states, “ADRs are one of the leading causes of morbidity and mortality in healthcare.” Dr. Curt Furburg published an article in the Archives of Internal Medicine proposing sweeping changes throughout the FDA.  Furburg and his colleagues wrote, “We see eight major problems with the current system of assessment and assurance of drug safety at the FDA.” A fundamental problem is the FDA’s initial review for drug approval that often fails to detect serious ADRs: “A study by the US General Accountability Office (GAO) concluded that 51% of all approved drugs had at least one serious ADR that was not recognized during the approval process.”   A 2003 investigation published in The Independent in the UK reported “under pressure from the pharmaceutical industry, the FDA routinely conceals information it considers commercially sensitive, leaving medical specialists unable to assess the true risks [of approved drugs].” One case involved a very popular over-the-counter drug, the painkiller ibuprofen. The investigators’ search uncovered concealed data showing that ibuprofen increased heart attack risks by 25 percent. Even Freedom of Information (FOI) filings to the FDA do not produce all the information being requested. For example, a group of Swiss investigators filed an FOI to procure trial data about the musculoskeletal pain drug Celecoxib and received back only 16 of the 27 trials conducted on it. A separate FOI concerning a similar drug, Valdecoxib, had pages and paragraphs deleted because sections of the document were marked as “trade secrets.” An even worse case involving a leaked report concerning internal memos and secret FDA reports provided detailed evidence that the FDA approved 9 different antidepressants, representing a total of 22 studies enrolling 4,250 children, while knowing full well that the risk of “suicide-related events” was twice as high as children taking a placebo. These are just several examples among numerous others, which may best be summarized by a Forbes article entitled “The FDA is Basically Approving Everything.”   Isn't it time for real truth telling? The FDA, which was budgeted for $5.9 billion in FY 2019, is ruled and governed by a small group of political scientists who have abdicated their ethical responsibilities as physicians and medical professionals. With all the controversy and debate over the efficacy and safety of new mRNA vaccines and the aggressive emergency approval of the ineffective anti-Covid drug remdesivir, we may consider a Harvard University article published in the Journal of Law, Medicine and Ethics entitled “Institutional Corruption of Pharmaceuticals and the Myth of Safe and Effective Drugs.”  For the past four decades, the paper states,    “patients have suffered from a largely hidden epidemic of side effects from drugs that usually have few offsetting benefits. The pharmaceutical industry has corrupted the practice of medicine through its influence over what drugs are developed, how they are tested, and how medical knowledge is created. Since 1906, heavy commercial influence has compromised Congressional legislation to protect the public from unsafe drugs. The authorization of user fees in 1992 has turned drug companies into the FDA’s prime clients, deepening the regulatory and cultural capture of the agency.”     We are witnessing the pharmaceutical industry increasing its demands for shorter than average times for the FDA to review new drug submissions; alternatively they have an option to pay the FDA costly fees to have these drugs fast-tracked under its Accelerated Approval Program, thereby jumping over many regulatory hurdles to bring their products to market more quickly. According to a 2019 review of the Program, conducted by the University of Nebraska’s Institute for Operations Research, “from 1992 to 2008, 36% of post-market studies had not been completed, and 50% of the uncompleted studies took on average of 5 years to even begin.”  Yet throughout the duration of years, these drugs continued to be prescribed and reap enormous profits for the companies benefiting from the FDA’s loopholes.    As a consequence, the FDA’s entire regulatory protocol has consistently deteriorated with each passing year. From a system originally mandated to function as a guardian to protect patients from dubious industry commercial interests, it has been transformed into an anti-preventative pipeline favoring drug companies’ bottom line and their shareholders.    In 2013, the Union of Concerned Scientists released its investigative report, four years after the Obama administration launched a process to increase transparency in the federal sciences agencies --- another well-meaning Obama initiative that failed to make any fundamental change. The Union concluded that the  FDA had created a culture lacking scientific integrity, including no formal procedures for investigating scientific misconduct.    The FDA’s serious failures to carry out its duties to monitor and regulate drug companies are well exemplified in the case of the North Carolina outsourcing firm Cetero.  After several years of gross negligence to thoroughly review pharmaceutical drugs, mostly generic knock-offs submitted for licensure, the agency finally uncovered Cetero’s five-year history of faking documents and data or early clinical trials and bioanalytics.  While we expect contractors who carry out clinical trials for large drug companies to be busy at work conducting research on the recorded trial data, on over 1,900 occasions there were no personnel in the Cetero facilities. Approximately 1,400 trials for roughly 100 drugs were faked. Whereas the FDA did little to conduct a thorough investigation, the European Medicines Agency on the other hand discovered that Cetero and its Big Pharm partners, including Roche and Genentech, failed to submit 80,000 reports on American approved drugs that killed over 15,000 Europeans. We need to consider that the Mayo Clinic is on record stating that the last ten years of cancer research are utterly useless due to systemic fraud,    To understand the systemic rot eating away the FDA, we may take note of the research of Dr. Charles Seife and his students at New York University. Seife and his team undertook the task to investigate and analyze the extent to which the FDA covers up evidence of fraud and corruption in medical drug trials. They reviewed FDA documents for about 600 clinical trials. One of Seife’s primary questions was the frequency that FDA officials discover flagrant and intentional misconduct and subsequently decide to bury the evidence and prevent it from becoming public to the medical community.  He discovered such actions to be an official pattern within the agency. Given the high rate of content deleted or blacked out from the documents the FDA provided, the investigators could only determine which pharmaceutical company or drug was involved in 1 of 6 of the reviewed trials. For one trial alone, where FDA inspectors found significant fraud and misconduct, 78 different medical publications printed articles based upon that single study.  In an article for Slate, Seife writes,    "Nobody ever finds out which data is bogus, which experiments are tainted, and which drugs might be on the market under false pretenses. The FDA has repeatedly hidden evidence of scientific fraud not just from the public, but also from its most trusted scientific advisers, even as they were deciding whether or not a new drug should be allowed on the market. Even a congressional panel investigating a case of fraud regarding a dangerous drug couldn't get forthright answers."   In one case, a new anti-blood clotting drug, rivaroxaban, involved four large trials recruiting thousands of patients in clinical sites in over a dozen countries. According to Seife, one of the trials "was a fiasco."  In half of the sixteen clinical sites, the FDA discovered "misconduct, fraud, fishy behavior or other practices so objectionable that the data had to be thrown out." One Colorado site falsified data. At the Mexican site, there was "systematic discarding of medical records." Despite these overwhelming problems, the drug trial was published favorably in the prestigious British journal The Lancet. The FDA found similar problems in the three other trials; in one the data was ruled "worthless." The FDA advisory committee of "expert" reviewers were only informed that inspectors discovered only "significant issues" at two sites in one of the trials. Rivaroxaban was nevertheless approved in 2011. Since then lawsuits for wrongful death from the drug continue to increase.    One of the deeper flaws within the FDA’s mode of operations is that it solely relies on the studies and clinical trials conducted by drug makers without conducting any studies of its own. Consequently these private firms have complete control over the clinical data and can provide such data or not at their own discretion. For example, if a company conducts 20 clinical trials on a potential new drug and15 trials conclude it is absolutely useless or results in serious reactions and deaths, the company is only required to submit documentation for the 5 trials that are favorable.    Over the years, Congressional subcommittees have voiced warnings to FDA officials to clean up their act. A House Government Reform Committee reported that both the CDC’s and FDA’s advisory committees for vaccines were thoroughly compromised with pharmaceutical conflicts of interest.     One of the most glaring examples of FDA misconduct, deceit and cover-up to protect pharmaceutical interests in the agency’s history was the federal case against Merck and its anti-inflammatory drug Vioxx. Dr. David Graham, a former Associate Director for Science and Medicine in the FDA’s Office of Drug Safety, testified before the US Senate. Dr. Graham has impeccable credentials qualifying him as an expert on the failures of pharmaceutical drugs. He graduated from the Johns Hopkins University School of Medicine, and trained in Internal Medicine at Yale and in adult Neurology at the University of Pennsylvania.    Dr. Graham told the Senate:   “During my career, I believe I have made a real difference for the cause of patient safety. My research and efforts within the FDA led to the withdrawal from the US market of Omniflox, an antibiotic that caused hemolytic anemia; Rezulin, a diabetes drug that caused acute liver failure; Fen-Phen and Redux, weight loss drugs that caused heart valve injury; and PPA (phenylpropanolamine), an over- the-counter decongestant and weight loss product that caused hemorrhagic stroke in young women.   “My research also led to the withdrawal from outpatient use of Trovan, an antibiotic that caused acute liver failure and death. I also contributed to the team effort that led to the withdrawal of Lotronex, a drug for irritable bowel syndrome that causes ischemic colitis; Baycol, a cholesterol-lowering drug that caused severe muscle injury, kidney failure and death; Seldane, an antihistamine that caused heart arrhythmias and death; and Propulsid, a drug for night-time heartburn that caused heart arrhythmias and death. . . .   “I have done extensive work concerning the issue of pregnancy exposure to Accutane, a drug that is used to treat acne but can cause birth defects in some children who are exposed in utero if their mothers take the drug during the first trimester. During my career, I have recommended the market withdrawal of twelve drugs. Only two of these remain on the market today—Accutane and Arava, a drug for the treatment of rheumatoid arthritis that I and a co-worker believe causes an unacceptably high risk of acute liver failure and death.”   The Los Angeles Times reported that witnesses told the Senate panel that Merck and the FDA knowingly had data well before the approval and licensure of Merck’s Vioxx painkiller that proved the drug’s serious cardiovascular health risks. Nevertheless, the FDA granted it approval without resolving the risks, and Vioxx was aggressively marketed.   Testifying about Merck’s Vioxx, Dr. Graham states:   "Today . . . you, we, are faced with what may be the single greatest drug safety catastrophe in the history of this country or the history of the world. We are talking about a catastrophe that I strongly believe could have, should have been largely or completely avoided. But it wasn’t, and over 100,000 Americans have paid dearly for this failure. In my opinion, the FDA has let the American people down, and sadly, betrayed a public trust."   According to Dr. Graham. “Not only did the FDA ignore known risks from Vioxx and related drugs but . . . it tried to prevent Graham and others from publicizing their own research that proved the extent of these risks.”   Members of Congress have echoed Graham’s concerns. Charles Grassley (R–Iowa) said he was concerned that the FDA “has a relationship with drug companies that is too cozy.”  Sen. Jeff Bingaman (D–New Mexico) said the problem was within the FDA’s own culture.“ This culture is one whereby the pharmaceutical industry, which the FDA is mandated to regulate, is the FDA’s most favored and lucrative client.   Sixteen years have passed since Dr. Graham’s public statements exposing the life-threatening policies and corruption that infest the FDA. It’s difficult to comprehend why the agency has been unable to clean up its act. Instead the FDA’s culture of deceit has only worsened. Nevertheless, the evidence clearly shows that our government health officials would rather support pharmaceutical profiteering than the health and safety and American citizens. In fact, 45 percent or $2.7 billion of its budget derives from private pharmaceutical “user fees.”   The disturbing data suggest that the FDA’s evaluation of pharmaceuticals for safety and efficacy may be so flawed that only 4% of all trial results are identified as such. As a result, FDA scientists and officials responsible for approving drugs to the market are kept largely uninformed about the egregious scientific misconduct involved in obtaining study data. Further, these erroneous and fraudulent studies are published in peer-reviewed scientific literature and accepted as valid science. The American public is ‘virtually defenseless’ if another medication proves to be unsafe after it is approved.   But it gets worse.  The agency has been warning against highly effective off-patent drugs to treat early SARS-CoV-2 infections such as hydroxychloroquine (HCQ) and ivermectin.  Shortly after the pandemic was formally announced, and with no promising treatment in sight, the FDA recommended HCQ but then reversed its decision in June after Anthony Fauci publicly announced the coming arrival of Gilead’s novel drug remdesivir. The FDA’s approval of remdesivir baffled many scientists, according to the journal Science, who were keeping a close watch on the drug’s clinical reports, which showed a “disproportionally high number of reports of liver and kidney problems”Nor did remdesivir lessen hospital stays or lower mortality rates.   Two months ago the agency issued a warning statement against the use of ivermectin. “The very next day,” reported the Alliance for Natural Health, “Merck announced positive results from a clinical trial on a new drug called molnupiravir in eliminating the virus in infected patients.”  Again, the FDA had been working in concert with the pharmaceutical industry to advance expensive experimental drugs rather than cheaper and proven drugs with decades of research to back their safety records.    In addition, the FDA has waged a war against alternative medical systems for many decades, including natural supplements. Last September, the agency attempted to ban N-acetylcysteine (NAC) after it showed promise to reduce cytokine storms associated with SARS-CoV-2 infection. The supplement had already been shown to improve lung problems due to respiratory infections such as pneumonia and acute respiratory distress symptom. Three years ago, an FDA advisory committee met to consider banning five supplements made by specialized compounding pharmacies: alpha lipoic acid, CoQ10, pyridoxal-5-phosphate, creatine monohydrate  and quercetin dehydrate. Earlier the FDA had banned curcumin, boswellia and aloe vera from pharmacologic compounding. One of the key executors of the agency’s revitalized assault against supplements and the natural health industry was Trump’s appointment of Scott Gottlieb as FDA Commissioner. Following his two years at the FDA’s helm, Gottlieb quit and joined Pfizer’s Board of Directors.   The FDA’s argument is rather straightforward, albeit dubious; since supplements, including Vitamin C and D, Omega-3 fatty acids, and even minerals such as magnesium and zinc have not been formally submitted to the FDA for evaluation to be registered as “approved drugs,” it is against the law to make any health claims about their health benefits.  This is despite the thousands of peer-reviewed studies in the National Library of Medicine to support their efficacy. The average median cost to conduct clinical trials to meet FDA standards for approval, according to a Johns Hopkins University evaluation, is $19 million and upwards to $2-3 billion. In other words to get Vitamin D officially recommended as a viable preventative defense against Covid-19 would require a minimum of $19 million in addition to numerous fees and other legal costs prior to and after submission. And that doesn’t even address the problem of ownership since Vitamin D is a natural substance and excluded from patenting. In the meantime, supplement manufacturers are prohibited from stating the vitamin’s benefit to the public thereby contributing to a gross disservice.    “Clearly these are the actions of an agency looking to restrict the supplement market,” according to the Alliance for Natural Health, “and remove as many products as possible in as many ways as possible.”  One reason is that if a vitamin or supplement were to go through the FDA licensure treadmill, the agency could potentially require a supplement’s access by prescription only. It would no longer be available over the counter. And this in turn would be another boon for the drug industry, which is already developing synthetic supplemental knock-offs that are patentable.    Much of the blame lies on the shoulders of politicians on both sides of the aisle and the mainstream media who have enabled the FDA and CDC to run amok and then propagate the pharmaceutical industry’s nonsense. A recent Harvard University and Robert Wood Johnson Foundation survey reported that public trust in America’s health care system has rapidly fallen during the pandemic to 34 percent. Only 37 percent stated they had much trust in the FDA.    This trend may very likely continue as a growing number of physicians and medical experts are sounding alarms over the flagrant incompetence of our federal officials leading the national efforts against Covid-19 and the approval vaccines with highly questionable safety records and expensive novel drugs that fail to warrant use. Worldwide, tens of thousands of otherwise orthodox medical professionals are charging Anthony Fauci, the CDC, FDA and the World Health Organization with gross mishandling of the pandemic.  Lawsuits are underway against national health ministries around the world for deceiving their populations with fraudulent PCR testing, fake mortality rates and unwarranted public health policies that have produced extreme harm and suffering.  As the situation deteriorates more suits will be anticipated.    Sadly there is no reason to expect the FDA to undergo a structural change. For decades Congressional committees have warned the agency about it’s ignoring the public health of Americans and its revolving door policies with drug makers. Yet matters continue to worsen. A complete overhaul by adopting policies similar to the European Medicines Agency such as independent leadership divorced from the pharmaceutical complex and full public funding, would be a decent start. Another  solution could be the creation of separate and independent National Drug Safety Board without ties to private industry or overlapping conflicts of interest with the existing health agencies in dire need of reform. However that tipping point has not been reached to expect any of our politicians to switch sides and for once serve the public’s health interests  

Editor's Summary by Gregory Curfman, MD, Deputy Editor of JAMA, the Journal of the American Medical Association, for the April 6, 2021 issue

(Club de Revista 034) En el club de revista de hoy comentaremos artículo que compara diacereína con celecoxib para osteoartritis de rodilla. ENLACE: http://bit.ly/3rBGQlI

In this week's episode of the Spine & Nerve podcast Dr. Nicolas Karvelas and Dr. Brian Joves discuss one of the most commonly utilized medications, non-steroidal anti-inflammatory drugs (NSAIDs).   NSAIDs are medications with anti-inflammatory, analgesic, and anti-pyretic properties.  The mechanism of action of NSAIDs is predominantly through inhibition of cylo-oxygenase, but there are multiple other pathways by which NSAIDs exert their therapeutic effect including but not limited to modulation of neutrophil function and cell membrane function.  It is important to understand that there are multiple different classes of NSAIDs, and each NSAID has its own unique properties resulting in differences in regards to safety and efficacy.     Listen as the doctors discuss important topics including: -drug-drug interactions concerning NSAIDs including NSAIDs interaction with aspirin and SSRI medications.   -research including the PRECISION trial addressing the question of whether or not Celecoxib (a selective COX-2 inhibitor) has increased cardiovascular risk relative to relatively non-selective NSAIDs. -optimal utilization of NSAIDs in the setting of acute musculoskeletal injuries. This podcast is for information and educational purposes only, it is not meant to be medical or career advice. If anything discussed may pertain to you, please seek council with your healthcare provider. The views expressed are those of the individuals expressing them, they may not represent the views of Spine & Nerve.   References: 1. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. N Engl J Med;  2016. 2. Pharmacology of Nonsteroidal Antiinflammatory Drugs and Opioids. Pharmacology in Interventional Radiology; 2010. 3. New insights into the use of currently available non-steroidal anti-inflammatory drugs. Journal of Pain Research; 2014. 4. Cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib. Ann Rheum Dis;  2007. 5. Efficacy and safety of oral NSAIDs and analgesics in the management of osteoarthritis: Evidence from real-life setting trials and surveys. Seminars in Arthritis and Rheumatism; 2016. 6. COX-2 inhibition impairs mechanical stimulation of early tendon healing in rats by reducing the response to microdamage. Journal of Applied Physiology; 2015.

This week we cover the the risk of antihypertensive med use during the pandemic; The Emergency Use Authorization for remdesivir in hospitalized patients with suspected or confirmed COVID-19; The addition of a Boxed Warning to Montelukast; A new Farxiga indication; And a novel treatment for acute migraines.

Celecoxib is easy to remember as its mechanism of action is "COX"-2 Inhibition. This can result in result in reduced prostaglandin formation and help with pain and inflammation. Kidney function is important to monitor in our patient on celecoxib. It is especially important in patients taking ACE inhibitors, ARBs, and/or diuretics. While GI bleed may be less likely with celecoxib compared to traditional NSAIDs like indomethacin and ibuprofen, it still needs to be monitored for. Digoxin concentrations may be increased with the use of celecoxib. Celecoxib is generally dosed twice per day as the half-life of the drug is in the ballpark of 10-12 hours.

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.                                                 Is there a unique lipoprotein profile for incident peripheral artery disease as opposed to coronary or cerebral vascular disease? Well, you're just gonna have to wait for our feature discussion to find out. That's coming right up after these summaries.                                                 Our first original paper this week tells us that gene variance known to be associated with idiopathic and peripartum cardiomyopathy are also associated with preeclampsia. First and corresponding author Dr Gammill from University of Washington and colleagues studied 181 participants with confirmed preeclampsia from the Preeclampsia Registry in BioBank. Saliva samples were collected for DNA isolation and whole exome sequencing was performed to detect rare variants in 43 genes known to be associated with cardiomyopathy.                                                 Results were compared with data from two controlled groups, unrelated women with a gynecological disorder, sequence using the same methods and instruments, as well as published variant data from 33,000 subjects in the Exome Aggregation Consortium.                                                 The results showed that women who developed preeclampsia are more likely to carry protein altering mutations in genes associated with cardiomyopathy, particularly, the TTN gene which encodes the sarcomeric protein titin. Thus, detecting these gene variants may allow more specific diagnosis, classification, counseling and management of women at risk.                                                 Prior trials have shown that nonsteroidal anti-inflammatory drugs or NSAIDS confer cardiovascular risk. Now this has been postulated to be due to enhanced formation of methyl arginines in the kidney that would limit the action of nitric oxide throughout the vasculature. However, the next original paper in this week's journal suggests that this may not be correct. First author, Dr Ricciotti, corresponding author, Dr FitzGerald from University of Pennsylvania Perelman School of Medicine and colleagues, used multiple genetic and pharmacological approaches to disrupt the COX 2 pathway in mice and analyze plasma from patients taking NSAIDS.                                                 However, they did not observe an increase in methyl arginines. In contrast, they did observe an increase in plasma asymmetric dimethylarginine or EDMA in mice-rendered hypertensive by infusion of angiotensin II at a dose that also caused renal impairment. After a four week washout period following the infusion of angiotensin II, blood pressure, creatinine, and ADMA levels all fell back to normal levels.                                                 Celecoxib-treated mice also exhibited increased ADMA and plasma creatinine in response to infusion of angiotensin II and their levels also returned to normal thereafter. Thus, it seems likely that the previous reported elevations in ADMA reflected renal dysfunction rather than a direct consequence of COX 2 deletion or inhibition. The authors end by suggesting that the most plausible mechanism by which NSAIDS confer a cardiovascular risk, is by suppression of COX 2 derived cardioprotective prostaglandins such as Prostacyclin rather than by enhanced formation of methyl arginines.                                                 The next original paper identifies new targets with the potential to prevent vascular malformations in patients with hereditary hemorrhagic telangiectasia. Co-corresponding authors, Dr Ola and Eichmann from Yale University School of Medicine and colleagues looked at SMAD4, which is a downstream effector of transforming growth factor-beta/bone morphogenetic protein family ligands that signal via activin-like kinase receptors.                                                 The authors generated a tamoxifen inducible postnatal endo-fetal specific SMAD for a mutant mouse and showed that SMAD4 prevented flow-induced arterial venous malformations by inhibiting casein kinase II. The uncovered pathways provided novel targets for the treatment of vascular lesions in hereditary hemorrhagic telangiectasia related juvenile polyposis patients carrying SMAD4 mutations.                                                 The next original paper provides important data for the accurate diagnosis of long QT syndrome. Long QT syndrome can be a challenging diagnosis partly because the optimal method for QT assessment is not unequivocally established. QT experts advocate manual measurements with a tangent or threshold method.                                                 In today's paper, first and corresponding author, Dr Vink from Academic Medical Center University of Amsterdam and colleagues, aimed to assess similarities and differences between these two methods of QT interval analysis among 1,484 patients with a confirmed pathogenic variant in either KCNQ1, KCNH2 or SNC5A genes from 265 families. Both QT measurement methods yielded a high inter and intra reader validity and a high diagnostic accuracy.                                                 Using the same current guideline cutoff of QTC interval 480 milliseconds, both methods had similar specificity but yielded a different sensitivity. QTC interval cutoff values for the QT measured by the tangent method was lower compared to that measured by the threshold method. Plus, values were different depending on the correction for heart rate, age, and sex.                                                 The authors provided an adjusted cutoff values specified for method, correction formula, age, and sex. In addition, a freely accessible online probability calculator for long QT syndrome at www.QTcalculator.org has been made available as an aid in the interpretation of the QT interval.                                                 The next original paper demonstrates for the first time that thrombin mediated signaling may play a role in diet-induced atherogenesis. Co-first authors, Dr Raghavan and Singh, corresponding author Dr Rao from University of Tennessee Health Science Center and colleagues, used a mouse model of diet-induced atherosclerosis and molecular biological approaches and explored the role of thrombin and its G protein coupled receptor signaling in diet-induced atherosclerosis.                                                 They found that thrombin-induced CD36 expression and foam cell formation required protease activated receptor 1, G alpha 12, Pyk2, GAB 1, and protein kinase C theta dependent activating transcription factor 2 activation. Thus, inhibition of thrombin G protein coupled receptor signaling could be a promising target for the development of new drugs in reducing the risk of diet-induced atherogenesis.                                                 The next study provides insights into the long- term association of LDL cholesterol with coronary heart disease mortality in individuals at low tenure risks of atherosclerotic cardiovascular disease. First and corresponding author, Dr Abdullah, from VA North Texas Medical Center and UT Southwestern Medical Center and colleagues studied more than 36,000 subjects in the Cooper Clinic Longitudinal Study cohort who are at low tenure estimated risk of atherosclerotic cardiovascular disease. In other words, a low tenure risk of less than 7.5%. They've followed these patients for more than two decades.                                                 Results showed that LDL cholesterol and non-HDL cholesterol at or above 160 milligrams per deciliter were independently associated with a 50 to 80% increased relative risk of cardiovascular disease mortality. The associations between LDL cholesterol and cardiovascular disease mortality were more robust when follow up was extended beyond the traditional 10 year estimated risk period.                                                 The associations remain significant in those with an estimated tenure atherosclerotic cardiovascular disease risk of less than 5%. These data suggests that LDL cholesterol levels at or above 160 milligrams per deciliter in individuals deemed to be at low tenure atherosclerotic cardiovascular risk are associated with worse long term cardiovascular disease mortality. These findings, along with other observational data and data extrapolated from clinical trials, support further consideration of appropriate LDL cholesterol thresholds for lipid lowering interventions in individuals categorized as low short-term risk.                                                 The final paper this week uncovers a novel therapeutic target for the prevention and treatment of thoracic aortic aneurysms. First author, Dr Nogi, corresponding author Dr Shimokawa from Tohoku University Graduate School of Medicine and colleagues, used genetically modified mice to show a pathogenic role of the small GTP binding protein, GDP dissociation stimulator in the development of angiotensin 2 induced thoracic aortic aneurysms and dissection. Down regulation of this protein contributed to dysfunction of aortic smooth muscle cells and hence oxidative stress, and matrix metalloproteinase activities in the pathogenesis of thoracic aortic aneurysms and dissection.                                                 Local over expression of this small GTB binding protein GDP dissociation stimulator around the thoracic aorta inhibited aortic dilatation and rupture in deficient mice. And that wraps it up for this week's summaries. Now for our feature discussion.                                                 Atherosclerosis has been considered a systemic process, meaning that when we see a disease in one vascular bed, we assume that that's a risk marker for disease in other vascular territories, and that they share pathophysiology, they share risk factors. However, if we think about it, the prior studies have all been sort of focusing on coronary and cerebral vascular disease, but today's feature paper changes that a bit because it addresses a key knowledge gap in peripheral artery disease risk, and interestingly suggests that there may be a unique lipid profile that's related to peripheral artery disease.                                                 This is gonna be an exciting discussion and I have the first author, Dr Aaron Aday from Vanderbilt University Medical Center currently. We have our editorialist, Dr Parag Joshi from UT Southwestern, and our associate editor, Dr Anand Rohatgi from UT Southwestern. Welcome gentlemen and Aaron, could we start with you sharing about your study? Dr Aaron Aday:                 So, as you mentioned, a lot of the previous epidemiologic data on atherosclerosis have been primarily in coronary artery disease and stroke, and when we looked at peripheral artery disease or PAD, there seemed to be some subtle differences. So for instance, total cholesterol on HTL cholesterol seemed to be the strongest risk factors for future peripheral artery disease and in terms of LDL cholesterol, the data are somewhat mixed. Some have found a weak association, some have actually found no association. And so building on that, we wanted to see if using nuclear magnetic resonance spectroscopy, we could elucidate more details about the litho protein pathways associated with peripheral artery disease.                                                 And we did this in the women's health study which is a prospective cohort study of women free of cardiovascular disease, the baseline, they were aged 45 and older. And what we've found in terms of the standards with their profiles, we again found that there was no association between LDL cholesterol and future peripheral artery disease, whereas certain standard lipid measures like HDL cholesterol were strongly associated with PAD, and then using the Endemol spectroscopy tool, we found that actually, small LDL particles and total LDL particles were concentrations of both of those markers, were strong risk factors for future PAD and other measures like total HDL particle concentration were even more strongly associated with future PAD than coronary artery disease.                                                 So essentially the signature associated with future peripheral artery disease, had some important differences than that for a composite of coronary artery disease and stroke. Dr Carolyn Lam:                Aaron thanks for that. That's beautifully described and just so intriguing. Parag, could you tell us how should we be thinking about results like this? Dr Parag Joshi:                   It's a great paper and it really highlights a new and unique approach in that we ... Peripheral artery disease as an isolated incident event is fairly understudied I guess we could say and so, this is a really nice paper to start choosing out some of the risk factors for that. I think overall, when we think of peripheral arterial disease in general, I think historically, we've thought of it as similar pathophysiology, you know LDL particles and perhaps other particles depositing in the arterial space. But this does highlight some important differences that might exist and I think one of those seems to be that maybe this is more a signature of elevated remnant lipoproteins or triglyceride rich remnant lipoproteins, small dent LDL particles, low HDL, that sort of metabolic syndrome type patterns that we look at as a high risk factor that may be more contributory to peripheral artery disease than coronary disease, or at least more specific to peripheral artery disease.                                                 I guess one of my main questions about that from your work Aaron is, how can we be sure this isn't just a pre-clinical marker of diabetic patients which we know have this type of pattern? Dr Aaron Aday:                 Sure, it's certainly a possibility. I think what's notable in the cohort, at least a time enrollment. And there was a very little diabetes and actually there was a much greater prevalent of metabolic syndrome. So in my mind, it may be more of a metabolic syndrome specific marker rather than necessarily down the diabetes pathway, but it's certainly something that needs to be explored further. Dr Parag Joshi:                   I wonder whether women's health studies such a healthy cohort that I wonder if this is picking up some signal before the answer to diabetes or as you said, metabolic syndrome, you know which certainly suggests an insulin resistance pattern and we know the association of diabetes with peripheral artery disease is stronger and so I wonder if this may be a sort of earlier way of picking that up. Dr Aaron Aday:                 It may be. I think one thing to notice is the outcome of peripheral artery disease that we're using. So it is symptomatic disease. So, we're not picking up a lot of ulcers that are developing in the future, it's more the claudication and then people who've undergone revascularization. Certainly diabetics have both of those as well but I think that may suggest it's not fully unexplained by developing diabetes than peripheral artery disease further down the line. Dr Parag Joshi:                   Yeah that's a great point. Dr Carolyn Lam:                Yeah great questions, great thoughts. Anand, what about you? Did you have questions too? Dr Anand Rohatgi:            I think from my perspective and thinking about it for circulation and its readership, we found this really interesting for several reasons. Number one, I think is, as you all have discussed, peripheral arterial disease just is not as well characterized and you can see that here in over 25,000 people, add about a 100 a bed, so I think in younger folk, it takes a lot of people to study, to be able to really understand kind of the pathophysiology of peripheral arterial disease.                                                 The other thing that they think they really shed some light on is how this is happening in women in particular and in women, of course as we know have been understudied in all cardiovascular diseases, but in particular, diseases like this which are less common. It's really insightful to see that these lipid abnormalities in women are contributing to peripheral arterial disease more so than your typical LDL cholesterol management and interestingly enough, most of the women who had PAD events in this study, did not have other cardiovascular events.                                                 They really just had PAD events exclusively and I thought that was really intriguing, and the use of this advanced lipoprotein testing, this NMR modality has been very useful in terms of biology and research, and I think that's the case here where we really go under the hood Carolyn, as you said, and get kind of deep dive, the lipid metalobles on abnormalities. And I think Parag and Aaron hit the nail in the head that this is really capturing an insulin resistance of phenotype and what I really liked about this is, instead of studying people who are 70, 80 years old and a lot of things are sort of clustering, a lot of diseases are clustering and they're manifesting all at the same time, it's very hard to tease apart the effective age.                                                 Here, we captured women in their 50s and middle aged, just as they have kind of gone through menopause and this adverse metabolite's phenotype starts to rise in women. And then we could follow them over time and see what the natural history of that is, and the women who have this phenotype go on to have this devastating consequence, this peripheral arterial disease. One of the questions I had then, Aaron for you is, what do you think the implications are from these findings? Does it mean that in terms of diagnostics, we should be doing more advanced testings looking at LDL and HDL type particles with NMR or some other mortality? Does it change therapies with new therapies beings studies right now? What do you think the implications are from your work? Dr Aaron Aday:                 That's important right. I think you mentioned this and I see the inter marked tool in this study, is really a way to try to dig further into the biology of peripheral artery disease as a form of atherosclerosis. I think that we already know patients who are extremely high risk or PAD, those are patients with diabetes, smoking history, metabolic syndrome et cetera., and as you can see in a patient population in 28,000 middle aged women who are pretty healthy, we only had just over a 100 PAD events.                                                 So, I think even if you were to scale this up in terms of cost, I'm not sure that that would necessarily be a viable option for patients, but I think it does suggest that truly focusing on LDL in a very high-risk patient population, meaning patients with PAD, or we may not be fully addressing their risk. And so I think this is a need to highlight that important gap, think about other therapeutic options and we'll soon have ongoing trials, triglyceride low in therapy that may be particularly beneficial in this patient population and so that's how I see this being used. Dr Anand Rohatgi:            That makes a lot of sense and particular because in middle aged women like this, your standard risk score algorithms will not really capture that they're at increased risk, even if they smoke, just because they're women and they're younger and so, I think this really is a call to arms to more refined risk assessment in these women. Dr Parag Joshi:                   Aaron, do you think there's actually a difference in the biology in the peripheral arteries compared to the coronary and cerebral vascular beds, or is there data to kind of look at that or maybe histopathological data to look at that? Dr Aaron Aday:                 We know there's a lot of overlaps, so I don't wanna suggest that PAD is not a former atherosclerosis. I think one limitation is that the primary animal model for PAD is the hyperCKemia model. That doesn't fully recapitulate what's happening in a limb with PAD and so I think that has been one limitation in understanding the biology. But I think what we're starting to see in some clinical trials that have come out in the last couple of years or starting to see a somewhat different signal for therapies in patients with PAD so for instance, in 48, we actually saw that there was a greater benefit to LDL lower [inaudible 00:21:00] inhibitors than for coronary disease. We now have the compass trial results, again, more events, higher risk among these patients but for their benefit, add on River Oxodine therapy, we've seen lymph events or lymph signals in the SGLP2 inhibitor trials. So, I think we're starting to get a sense that there may be something else on top of the traditional ascariasis biology that may be a potential target on down the road. Dr Parag Joshi:                   I think it's really a fascinating biological question of how these different territories might actually differ in their pathophysiology. I think it's a really a nice time to look at this. Also I think, Anand and Aaron both mentioned ongoing trials. The omega 3 fatty acid trials I think reduce it, will be soon to be presented and hopefully published in the next month or so. It would be nice to see if they evaluate peripheral events in that group, I'm sure they will. Dr Carolyn Lam:                Indeed, these have been just such great thoughts and discussion. Nothing really much to add there. I suppose I could say something cheeky like for the first time, and I never thought I'd say it on the podcast, I feel kind of bad that there are no men included in this trial but anyway, I just learnt so much from this. I just wanna thank you gentlemen for a great discussion.                                                 Thank you, listeners, for joining us today and don't forget to tune in again next week to Circulation on the Run.

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Commentary by Dr. Valentin Fuster

On this week's News & Views we cover: NSAIDs like Ibuprofen, Celebrex, and Naproxen; new research that suggests high HDL is not heart protective; and how worrying about health can actually affect your health. The food for thought continues in the Moment of Paleo segment, which explores the things we cannot do when we must do them. After the Bell features a talk by Alan Watts on the topic of Double Binds. Links for this episode:Why & How to Support Latest in PaleoRecommended Food & Other ProductsRecommended Books & Audio BooksComment on this Episode or Share a News LinkCardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis — NEJMCelebrex arthritis drug just as safe as NSAIDs for pain relief, with fewer side effects, study finds - CBS NewsSurprise! Arthritis Drug Celebrex Shown As Safe As Ibuprofen And NaproxenIbuprofen May Not Be As Safe As You Think | TIMENew Study Reveals Ibuprofen and Naproxen Health RisksHigh-Density Lipoprotein Cholesterol and Cause-Specific Mortality in Individuals Without Previous Cardiovascular Conditions: The CANHEART Study | Journal of the American College of Cardiology | American College of Cardiology FoundationDoes 'Good' Cholesterol Matter in Heart Disease Risk?: MedlinePlus Health NewsWhat you need to know about "good" HDL cholesterol - CBS NewsLow levels of HDL (the “good” cholesterol) appear connected to many health risks, not just heart disease - Harvard Health Blog - Harvard Health PublicationsBombshell health study: Raising HDL "good" cholesterol does not help prevent heart disease | Genetic Literacy ProjectHealth anxiety and risk of ischaemic heart disease: a prospective cohort study linking the Hordaland Health Study (HUSK) with the Cardiovascular Diseases in Norway (CVDNOR) project -- Berge et al. 6 (11) -- BMJ OpenWorrying about health increases heart disease risk - Medical News TodayCan worrying about your health make you ill? | Life and style | The GuardianWorried sick? Stressing that you'll get an illness can make you sick, study says - NBC NewsAlan Watts: The Double Bind - YouTubeVisit PuraKai to shop for eco-friendly clothing and stand-up paddle boards. Be sure to use coupon code "latest in paleo" for 15% off all clothing purchases.

[intro music] Host – Dan Keller Hello, and welcome to Episode Eight-two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Depression affects as many as 50 percent of people with MS during their lifetimes. But according to Dr. Adam Kaplin, a psychiatrist in the Johns Hopkins MS Center in Baltimore, it is treatable to a large extent, and with good results. Dr. Kaplin studies the immune basis of depression and cognitive impairment, specifically in MS and central nervous system-related autoimmune diseases. We met in Baltimore. Interviewer – Dan Keller Let’s talk about depression in multiple sclerosis. Is it a reaction to someone having a chronic disease, or is there something more going on because of the disease? Interviewee – Adam Kaplin It’s a great question, and what I will tell you is one of my patients says to me that you’re either stressed, or you’re dead. We all have stress going on, and it’s always possible to look at something in our life and say, ah, that’s what caused the trouble. But we know now, in multiple sclerosis, the depression is due primarily and dramatically significantly to the inflammation going on in the brain that causes all of the symptoms that you see in MS, such as cognitive impairment, or weakness/numbness/tingling, autonomic nervous system dysfunction; all of those are effects of the MS on the CNS. And in the case of depression, it is similar. It’s not a character flaw. It’s not a personal weakness. And just to, you know, clarify, one of the best pieces of evidence we have for that is, number 1, that people who are depressed with MS, it does not correlate with their EDSS scores. It doesn’t correlate with their level of disabilities. So if it was you know, gee, it’s just a matter of stress, then those people who are in wheel chairs or on ventilators should be depressed, and those people who are upright and walking around shouldn’t. But in fact, I think the key element is that this is one of the, as they often say, silent symptoms of MS. It occurs to 50% of patients across their lifetime. And it is important you know for people to understand that this is not something that people aren’t rising to the occasion, or those kinds of things. MSDF Is depression accompanying MS more prevalent than in the general population, and how serious is it? Dr. Kaplin You know people often ask why, as a neuropsychiatrist, why study MS? And I say, you know, why did Willie Sutton rob banks? That’s where the money is. MS has the highest rate of clinical depression of any medical neurological or surgical disease. Again, 50% of people, following the diagnosis of MS, will have a clinical depression. We can talk about what that is. And it turns out that that’s in any clinic you go into – neurology clinic – that’s one in four patients. If you go out to the waiting room, one in four patients will be suffering from a clinical depression. MSDF How serious a problem is it? What aspects of life does it affect? Does it affect everything, and how serious is it? Dr. Kaplin I think what is often misunderstood about the depression in MS is, I would argue, that it has the highest morbidity and mortality of any of the symptoms of MS, in the sense that it is the third leading cause of death in the largest study that looked at, across the lifespan, what causes death in people with MS, [found] a study out of Canada, where it’s more prevalent because of the higher elevation and the lower vitamin D levels, probably. And it is absolutely the case that seven-and-a-half times the rate – the suicide rate in MS – to the general population. And in fact, in the studies that were done, 30% of people with multiple sclerosis will have thoughts of suicide at some point during their life. Ten percent – fully 10% will attempt suicide. And that lethality is profound. But if it doesn’t kill you, it is important to understand that it has significant, significant morbidity associated with it. Just to begin with, the number one correlate of quality of life of patients—more important than their pain, or more important than their cognitive impairment, or weakness, or other symptoms—the number one correlate of the quality of life of the patient is their depression or whether they are depressed or not. And it’s similarly the number one quality of life of the care givers—not whether they have to push them around in a wheelchair, it is whether their loved one is suffering from a clinical depression. So it has significant morbidity and mortality associated with it. MSDF Are there aspects of serious depression in MS that are very characteristic? Any different from other severe depression? Or can it be recognized in the same way with the same diagnostic criteria? Dr. Kaplin There actually are some specifics to MS, although that hasn’t been well-published. I can be clear about things that are well-supported by the literature, and then those that are my clinical experiences. What I can tell you is that the way we diagnose depression in MS is the same way we diagnose depression in people without MS, which is you have to have 5 of 9 symptoms greater than two weeks, one of which must be either decreased mood or decreased interest. And we remember it by SIG-EM-CAPS, the nine symptoms. Trouble with sleep, where people are often having early morning awakenings or hypersomnia where they just sleep all day. Loss of interest, people’s get up and go has gotten up and gone. Feelings of guilt or worthlessness – and that’s a big problem, because patients who are depressed as a result of that often won’t seek help. You have to ask about it. They won’t volunteer it. And loss of energy or fatigue; low mood – that’s the sadness part; concentration problem; appetite changes, either increased or decreased weight; and psychomotor retardation, they’re not their normal bubbly self; and thoughts of death or suicide. With MS, what I will tell you, I find that patients with MS often, rather than sadness, have very frequently irritability. That tends to be more common. And sleep is usually decreased, not increased, so I see very frequently increased early morning awakening and those kinds of things. One pearl, though, to keep in mind is – or two pearls – if you’re trying to make the diagnosis of depression in somebody with MS, the first thing to do, because there are overlapped symptoms like fatigue, like concentration problems between depression and MS, so there is frequently, in up to 80% of people, will have diurnal variations in their moods; so usually worst in the morning and better at night. Sometimes it’s reversed, but you know that person has the same life circumstance, the same disease circumstance in the evening that they did in the morning, but their mood has changed dramatically, often, with MS with these cyclical changes. And that’s a good indication that it’s not demoralization; it’s depression. The other thing is ask the loved one. Get an outside informant, because nobody gets the brunt of it quite like the family. And they know that person, and if the family member says the one thing I hear so often, this is not the person I married, then you’re pretty much on the right track if you’re thinking about depression. MSDF How amenable to treatment is depression in MS? Dr. Kaplin I think that that is probably one of the key aspects is to understand that it is very treatable. So my expectation when patients come to me and I diagnose them with depression is that I will get them a hundred percent well with respect to those SIG-EM-CAPS symptoms, back to their baseline. And it’s very hard to get patients a hundred percent well from their gait problems; a hundred percent well from their cognitive problems. And, again, what I tell people is, look, I can’t tell you whether your cognitive impairment is due to the depression or due to the MS, or maybe it’s 10% depression/90% MS or 90% depression/10% MS. But I can promise you this: treating the depression, the depression is much more amenable to treatment. We don’t have good treatments for cognitive impairment in MS to reverse the cognitive impairment, but boy, we can reverse it if it’s a symptom of depression. What’s really exciting now is that we are now understanding more and more that many of the treatments you use for depression end up being good nerve tonics. So, there was a double-blind placebo-controlled study of fluoxetine demonstrating that, in patients who weren’t depressed with MS, they had fewer gadolinium-enhancing lesions over 24 weeks. And then there was the FLAME study in a related kind of way looking at fluoxetine as a way of significantly enhancing the recovery of hemiplegic stroke patients. So it turns out that I wasn’t so misguided in thinking that studying the immune basis of depression would be important, because as it turns out, our treatments actually do have an effect on the nervous system and the immune system for general types of depression as well. MSDF That sort of covers the SSRI class. What about tricyclic antidepressants? What about SNRIs? Do those fit in? Dr. Kaplin Yes, so absolutely. So the topic of how to choose and select the right treatment for patients with MS is … we could spend an hour and just sort of get only the highlights done there. But generally there’re sort of two strategies. One is to use a medication that has the fewest side effects, so that you won’t have drug-drug interactions with the patient if they’re on a numerous medicines for other concerns—their other symptoms and syndromes—that the antidepressant won’t interfere with it. And so along those lines, escitalopram and sertraline have the fewest drug-drug interactions. You essentially don’t need to look up drug-drug interactions if your patient is on one of those two medicines. The other approach is to say let’s choose a medicine that will have favorability with respect to the side effects, will be beneficial for the problems that the patient has. So a classic example is duloxetine is FDA-approved, not just for depression, not just for anxiety, but also for neuropathic and musculoskeletal pain. So here you’re talking about one treatment that will help you with the fact that your patient, their depression will get better; their neuropathic pain will get better if they have migraines—which are often a comorbidity—that will also benefit the neuropathic pain from that as well. And you know you will get two birds with one stone, as it were. And then the tricyclics, as you had asked about, we’ve had a lot of experience with them. They also will benefit in terms of the urinary incontinence problem. They are strongly anticholinergic, and so you can also benefit in terms of preventing the urinary/bowel problems. So really Cymbalta as just sort of son-of-tricyclics, has some fewer side effects, but doesn’t, therefore, cover some of the things that the tricyclics will. MSDF As you alluded to earlier, the depression in MS may largely be a result of immune processes going on—inflammation, cytokines, things like that. So how well do the disease-modifying therapies of MS attack the depression? Dr. Kaplin You know you mentioned cytokines. So that is another way that we know that this is due to the inflammation—the depression in MS—and not just other things, because for instance, interferon-alpha used to treat patients with hepatitis C will cause depression in upwards of 20 to 25% of people who take it, not when they first start it, but within you know a week to two weeks after starting it, you know, then up to eight weeks. So that’s just one cytokine, and in MS, all of the cytokines get activated. And similarly, interferon-beta that’s used, or Copaxone, you know, the ABCR drugs that we’ve used to try to—you know, with great effect since 1993—to slow the exacerbations down in MS; they don’t stop the inflammation, they just alter it. And so not surprisingly, they do not have antidepressant properties. But when you look at something like Tysabri, we actually have not published this yet. We did present it at a MS conference but working in collaboration with Biogen. We are going to publish shortly data that shows that, in a double-blind placebo-controlled study of adding natalizumab to Avonex, or adding placebo to Avonex, those patients who were depressed to begin with show a dramatic and statistically significantly decrease in their depression as a result of the natalizumab. So natalizumab is actually quite a good antidepressant—we have data for it—because that really does shut the inflammation down in the brain, and since that’s causing the depression in MS, that’s what benefits them. MSDF Just to clarify, natalizumab is a good antidepressant in MS. Dr. Kaplin Exactly right. That’s exactly right. Although, you know, it’s good that you clarified that. What’s interesting is that now that people are beginning to appreciate the role of the immune system in idiopathic depression, people are beginning to say, hmm, maybe we should be looking at these anti-inflammatories and seeing if the anti-inflammatories benefit patients with depression. Now, nobody has tried natalizumab, but TNF-alpha inhibitors have actually been tried. There was a study out of Emory looking at using TNF-alpha inhibitors for refractory depression. And I think coming down the road there will be more and more studies that begin to show the role of anti-inflammatories for not all, but some people with refractory depression. MSDF Yes, I’ve seen some studies on anti-inflammatories—traditional ones, NSAIDS sort of things—presented a German study at a neurology conference. Didn’t do too much. Dr. Kaplin Yes. What I can tell you is that not all NSAIDs are created equal. Celecoxib actually now has five studies that are placebo-controlled that have shown its benefit for depression or bipolar disorder. And so when added to antidepressant by itself: No. But when added to fluoxetine or—I can’t remember what other; it might have been sertraline—it clearly had a statistically significant improvement in the depression response, celecoxib. But not all NSAIDs are created the same. MSDF What about non-drug therapies, cognitive behavioral therapy, even just physical activity? And, if someone’s depressed, isn’t it hard to get them up and do physical activity? Dr. Kaplin Well, I’m so glad brought that up, because I’d be remiss to forget that. So all of the data says, look, therapies like cognitive behavioral therapy are effective for mild and moderate depression. Antidepressants are effective as well. The data shows that the antidepressants work quicker, but that the combination of antidepressants and psychotherapy is much better than either one alone. So that’s a crucial issue. And to make sense of what has happened—and often when people are depressed, they’ve been depressed, and that’s caused damage to their professional life and personal life, and having someone help them sort of, depending how long the depression’s been going on, sort of talk them through, coach them through, how to get back up and going. However, in severe depression, you can talk till the cows come home. If your patient is so depressed that basically they have this tunnel vision, and all of the options that are in front of them, the kind of mental flexibility that you need for CBT to work, for instance, it will not work if you patient is really severely depressed. You have to get them started with the antidepressant, which really then serves as a catalyst for the psychotherapy to kick in. And then the aspect of exercise, you can’t really pick a topic related to MS where the answer isn’t exercise. Cognitive impairment, absolutely exercise is beneficial. Depression, exercise is beneficial. It stimulates growth hormones that have positive neurological effects on the CNS, as well as on the peripheral nervous system and body. What I tell people, again, is that if your patient is severely depressed, they’re not going just go back out and start running. So you’ve got to begin to have a plan where you say, look, we’re going to begin this medicine. As you start to be able to have the ability to you know maybe push yourself more than you might usually and just sort of walk down the block, and then you know walk for a mile and then start jogging for a mile and sort of build up to it, that’s very beneficial. MSDF Are there barriers to recognizing and/or treating depression both on the patient’s side and on the physician’s side? Dr. Kaplin The big barrier on the physician’s side is, you know, don’t ask, don’t tell. So if you don’t think of depression, or worse, if the neurologist says, well, I went into neurology not psychiatry, you know, this whole depression thing, that’s not my bailiwick, that’s not my responsibility, you’re missing the fact that this is —first of all, this is very rewarding. There’s nothing else that you could treat that gets a patient from being non-functional, sitting at home, not taking care of the family, not working, in a bed to fully functional, taking care of the family, back at work, like treating the depression can. But also it is. It affects all aspects. It affects the patient’s compliance with all your other medicines. It affects their ability to exercise, etc., etc. So, you know, you’ve got to think of it. And then you have to know something about treating it. One of the big problems with neurologists when they treat depression is that they don’t appreciate the fact that the goal is to get that patient a hundred percent well, because you sort of have this sigma curve where, if you get them 50% well, they’re still in that sort of steep portion of the curve where something comes along—an MS attack or you even a viral infection—and they will slip right down that curve. Whereas, if you can push them way out into the hundred percent well, that’s great. Now you can’t always do it with one medicine. You take the dose as high as the patient can tolerate, where the side effects don’t become worse than the depression you’re trying to treat. But then you might need to add another medicine, an augmenting agent or something, so you’ve got to make sure you recognize it and treat it. And then, what I always tell my colleagues—and my colleagues at Hopkins are wonderful; they do appreciate you know you’re treating the whole patient, not just you know their reflex arcs and that kind of stuff—and what they are very good at is, if the patient is depressed and suicidal, that is the psychiatric equivalent of a heart attack. So then they will get in touch with me and we’ll work together. So if you’ve got someone who’s suicidal, you really want to get in touch. Unless you have the utmost experience and confidence in treating the worst cases of depression, you probably want to get a psychiatrist involved, or mental health professional involved, to help coordinate the care for someone like them. MSDF Very good! I appreciate it. [transition music] MSDF Thank you for listening to Episode Eighty-two of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. [outro music] We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.

Prof James (University of Warwick, Warwick, UK) and Prof Efstathiou (MD Anderson Cancer Center, Houston, USA) discuss survival results from the STAMPEDE randomised controlled trial for ecancertv at ASCO GU 2016. Celecoxib was investigated with or without zoledronic acid for hormone-naïve prostate cancer. The data showed no survival advantage for the addition of celecoxib alone for men starting long-term hormone therapy for the first time. However, the addition of celecoxib combined with zoledronic acid demonstrated a survival advantage for men with metastatic disease, in a pre-planned analysis, and requires further investigation.

Background To evaluate the in vivo response by detecting the anti-angiogenic and invasion-inhibiting effects of a triple-combination-therapy in an experimental-small-animal-squamous-cell-carcinoma-model using the “flash-replenishment” (FR) method to assess tissue hemodynamics via contrast-enhanced-ultrasound (CEUS). Methods Human hypopharynx-carcinoma-cells were subcutaneously injected into the left flank of 22-female-athymic-nude-rats. After seven days of subcutaneous tumor growth, FR-measurements were performed on each rat. Treatment-group and control-group were treated every day for a period of one week, with the treatment-group receiving solvents containing a triple therapy of Upamostat®, Celecoxib® and Ilomastat® and the control-group solvents only. On day seven, follow-up measurements were performed using the same measurement protocol to assess the effects of the triple therapy. VueBox® was used to quantify the kinetic parameters and additional immunohistochemistry analyses were performed for comparison with and validation of the CEUS results against established methods (Proliferation/Ki-67, vascularization/CD31, apoptosis/caspase3). Results Compared to the control-group, the treatment-group that received the triple-therapy resulted in a reduction of tumor growth by 48.6% in size. Likewise, the immunohistochemistry results showed significant decreases in tumor proliferation and vascularization in the treatment-group in comparison to the control-group of 26%(p≤0.05) and 32.2%(p≤0.05) respectively. Correspondingly, between the baseline and follow-up measurements, the therapy-group was associated with a significant(p ≤ 0.01) decrease in the relative-Blood-Volume(rBV) in both the whole tumor(wt) and hypervascular tumor(ht) areas (p≤0.01), while the control-group was associated with a significant (p≤0.01) increase of the rBV in the wt area and a non-significant increase (p≤0.16) in the ht area. The mean-transit-time (mTT) of the wt and the ht areas showed a significant increase (p≤0.01) in the follow-up measurements in the therapy group. Conclusion The triple-therapy is feasible and effective in reducing both tumor growth and vascularization. In particular, compared with the placebo-group, the triple-therapy-group resulted in a reduction in tumor growth of 48.6% in size when assessed by CEUS and a significant reduction in the number of vessels in the tumor of 32% as assessed by immunohistochemistry. As the immunohistochemistry supports the CEUS findings, CEUS using the “flash replenishment”(FR) method appears to provide a useful assessment of the anti-angiogenic and invasion-inhibiting effects of a triple combination therapy.

Einflüsse der Therapie mit Risperidon und Celecoxib auf das zelluläre Immunsystem schizophrener Patienten

Thu, 27 Oct 2005 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/4953/ https://edoc.ub.uni-muenchen.de/4953/1/Ulmschneider_Markus.pdf Ulmschneider, Markus