Tramadol Linked to Increased Hip Fracture Risk in Adults Aged ≥50

In continuation of my update on Tramadol

For older adults, initiation of tramadol is associated with an increased risk for hip fracture compared with initiation of codeine, ibuprofen, and other commonly used nonsteroidal anti-inflammatory drugs, according to a study published online Feb. 5 in the Journal of Bone and Mineral Research.

Jie Wei, Ph.D., from Central South University in Changsha, China, and colleagues examined the association between tramadol and the risk for hip fracture among individuals aged 50 years or older without a history of hip fracture, cancer, or opioid use disorder. Five sequential propensity score-matched cohort studies were assembled, including participants initiating tramadol (146,956 participants) or one of the following: codeine (146,956 participants), naproxen (115,109 participants), ibuprofen (107,438 participants), celecoxib (43,130 participants), or etoricoxib (27,689 participants).

The researchers identified 518 hip fractures in the tramadol cohort and 401 in the codeine cohort (3.7 versus 2.9/1,000 person-years) during one-year follow-up (hazard ratio, 1.28 for tramadol versus codeine). Hip fracture risk was higher in the tramadol cohort compared with the naproxen (2.9 versus 1.7/1,000 person-years; hazard ratio, 1.69), ibuprofen (3.4 versus 2.0/1,000 person-years; hazard ratio, 1.65), celecoxib (3.4 versus 1.8/1,000 person-years; hazard ratio, 1.85), and etoricoxib (2.9 versus 1.5/1,000 person-years; hazard ratio, 1.96) cohorts.

"Considering the significant impact of hip fracture on morbidity, mortality, and health care cost, our results point to the need to consider tramadol's associated risk of fracture in clinical practice and treatment guidelines," the authors write.

https://asbmr.onlinelibrary.wiley.com/doi/10.1002/jbmr.3933

https://en.wikipedia.org/wiki/Tramadol












Tramadol Linked to Increased Hip Fracture Risk in Adults Aged ≥50 

Combination of COX-2-selective NSAID with PPI can reduce risk of stomach, intestinal ulcers

Non-steroidal anti-inflammatory drugs (NSAIDs)—including ibuprofen, diclofenac, naproxen and others—are commonly used pain medications that are generally safe but may increase the risk of developing stomach and intestinal ulcers.

After researchers analyzed a large number of clinical trials that compared different ways of reducing these risks of NSAIDs, they found that the best strategy with the lowest overall risk was to combine a certain type of NSAID, known as a COX-2-selective NSAID, with a proton pump inhibitor (PPI). PPIs are most often used to treat heartburn and gastro-oesophageal reflux disease.

"The combination of a COX-2-selective NSAID with a PPI will be expensive and is not recommended for all patients who need to be on a NSAID; however, it is the safest and most effective treatment strategy for those at high risk of ulcer bleeding from NSAID treatment," said Prof. Jin Ling Tang, co-author of the Alimentary Pharmacology and Therapeutics study.

FDA Approves Onzetra Xsail (sumatriptan nasal powder) for the Acute Treatment of Migraine

Sumatriptan is a medication used for the treatment of migraine headaches.It is a synthetic drug belonging to the triptan class. Structurally, it is an analog of the naturally occurring neuro-active alkaloidsdimethyltryptamine (DMT), bufotenine, and 5-methoxy-dimethyltryptamine, with an N-methyl sulfonamidomethyl- group at position C-5 on theindole ring.

Sumatriptan is produced and marketed by various drug manufacturers with many different trade names such as Imitrex, Imigran, and Treximetas a combination product with naproxen.

Avanir Pharmaceuticals, Inc. today announced that the U.S. Food and Drug Administration (FDA) has approved Onzetra Xsail (sumatriptan nasal powder), formerly known as AVP-825, for the acute treatment of migraine with or without aura in adults. Onzetra Xsail is an intranasal medication delivery system consisting of a low-dose (22mg) of sumatriptan powder that is delivered utilizing the novel Xsail™ Breath Powered Delivery Device. Onzetra Xsail is a fast-acting dry powder formulation of sumatriptan, the most commonly prescribed migraine medication.

“While there are many acute migraine treatment options available, more than 70% of patients are not fully satisfied with their current migraine treatment. Given this high dissatisfaction, there remains an unmet need to provide patients with fast-acting, well tolerated therapies that deliver consistent relief,” said Stewart Tepper, M.D., professor of neurology at the Geisel School of Medicine at Dartmouth.

“Onzetra Xsail provides a new and much needed treatment option for what can be a debilitating condition for millions of people,” said Roger K. Cady, M.D., director of the Headache Care Center and associate executive chairman of the National Headache Foundation. “The Xsail Breath Powered Delivery Device allows the medication to be deposited deep into the nose, an area that is rich with blood vessels. By delivering the medication here, Onzetra Xsail provides targeted and efficient delivery with the potential for fast, consistent relief, while also limiting the amount of medicine that goes down the back of the throat.”

“We are excited about this major milestone for Avanir as the approval of Onzetra Xsail represents our second approved product. We expect to make Onzetra Xsail available to patients in the coming months,” said Rohan Palekar, president and CEO of Avanir. “We continue to be focused on building a leading CNS biopharmaceutical company and the addition of Onzetra Xsail to our product portfolio takes us closer to achieving that goal.”

FDA Approves Onzetra Xsail (sumatriptan nasal powder) for the Acute Treatment of Migraine

Naproxen and omeprazole combination effective in preventing bladder cancer

The anti-inflammatory class of drugs NSAIDs have shown great promise in preventing cancers including colon, esophagus and skin. However, they can increase the risks of heart attacks, ulcers and rare but potentially life-threatening bleeds.

A new study suggests there may be ways to reduce these dangerous side effects. Collaborators from the University of Michigan, the National Cancer Institute and the University of Alabama looked at naproxen, which is known to have a lower cardiovascular risk than other NSAIDs. Naproxen, like most NSAIDs and aspirin, does increase the risk for gastric ulcers or bleeding. Here, the researchers used the proton pump inhibitor omeprazole, a commonly used acid inhibitor, in combination with naproxen and tested its effects on cancer prevention in a rat model of bladder cancer.

They found that naproxen reduced the incidence of bladder cancer by 75 percent in rats. Omeprazole by itself did not affect the development of cancer but it also did not interfere with the effect of naproxen at preventing tumors. The rats who received naproxen alone or naproxen with omeprazole developed cancer at similarly low rates, while all rats receiving omeprazole alone or no treatment developed bladder cancer.

Clinical data in humans has previously shown combining omeprazole plus naproxen reduced gastric toxicity roughly 70 percent.

The authors also found that intermittent dosing with naproxen (three weeks on the drugs, followed by three weeks off) was highly effective and likely to reduce gastric toxicity. However, it does not have the clear clinical data supporting reduced gastric toxicity associated with naproxen and omeprazole.

"Our study shows that naproxen works just as well with a proton pump inhibitor as without. This provides proof of principle that this could be a valuable cancer prevention strategy and one hopes it can advance quickly to a clinical trial for those at high risk of colon, esophageal, squamous cell skin cancer or potentially other cancers," says lead study author Ronald A. Lubet, Ph.D., a scientist with the Chemopreventive Agent Development Research Group at the National Cancer Institute.

Naproxen and omeprazole combination effective in preventing bladder cancer

Pain reliever shows anti-viral activity against flu

In continuation of my update on naproxen

New influenza vaccines must be developed annually, because the surface proteins they target mutate rapidly, the way cars used to get a whole new look every year. The researchers, led by Anny Slama-Schwok of the Institut National de la Recherche Agronomique, Jouy en Josas, France, found a much more stable, reliable target for anti-influenza activity. The so-called ribonucleoprotein complexes are necessary for replication, and the researchers realized they could target the nucleoprotein, preventing assembly of the complexes. Because of its vital function, the nucleoprotein is highly conserved, making it a good potential target for antiviral drugs.

The nucleoprotein's three dimensional structure, solved in 2006, provided the basis for searching for new drugs that could interfere with its action. The researchers did a virtual screening within the Sigma-Aldrich online catalog of biochemicals. That screening identified Naproxen, better known as the over-the-counter pain reliever Aleve, and as expected, it bound to the nucleoprotein, and impeded RNA binding, says Slama-Schwok. In further testing, it reduced the viral load in cells infected with H1N1 and H3N2 influenza A virus, and in mice it demonstrated a therapeutic index against influenza A that was superior to that of any other anti-inflammatory drug.

Specifically, naproxen blocks the RNA binding groove of the nucleoprotein, preventing formation of the ribonucleoprotein complex, thus taking the vital nucleoproteins out of circulation. The researchers write that naproxen is a lead compound for drug development that could be improved by tweaking the molecule to boost its ability to bind to nucleoprotein.

As an already approved drug, naproxen could become a treatment against influenza relatively quickly, the researchers write. Its status as a non-steroidal anti-inflammatory drug (NSAID), which inhibits the COX-2 pathway, as well as an antiviral would boost its efficacy.

Ref : http://aac.asm.org/content/early/2013/02/26/AAC.02335-12.abstract?sid=e3391873-6ffe-4f2e-8737-685e5f2ca15f

Pain reliever shows anti-viral activity against flu

Two-Drug Combo (naproxen and sumatriptan) Helps Teens With Migraines

A two-drug combination that relieves migraines in adults also works well in adolescents, new research indicates.

Because the combination of Imitrex (sumatriptan see structure left) and naproxen (structure right) sodium (Aleve and other brand names) isn't approved for use by the U.S. Food and Drug Administration for this age group, doctors must prescribe it "off label" to adolescents.

"There are no FDA-approved abortive [migraine] treatments for children," said Dr. Noah Rosen, director of the Headache Center at the Cushing Neuroscience Institute in Great Neck, N.Y. "This is the first really large-scale abortive treatment study for adolescents."

Migraines in children and adolescents are physiologically no different from migraines in adults, said Drexler, although migraines in younger people tend not to last as long.

The class of drugs known as triptans are the most studied, but none of those trials have shown a great benefit, possibly because of a large placebo response, the study authors wrote.

Scientists Spot How Cox-2 Painkillers Raise Heart Risks

In continuation of my update on COX-II inhibitors....

New research has uncovered how some cox-2 painkillers increase the risk for both heart attacks and stroke. The once popular cox-2 drugs, Vioxx and Bextra, were pulled off the market in 2004 and 2005, respectively, after research showed that both raised the chances of cardiovascular trouble. Meanwhile, Celebrex, a painkiller in the same drug class that remains on the market, carries a "black box" warning alerting patients to potential heart risks.

Now, a team of scientists from the University of Pennsylvania in Philadelphia say that, although cox-2 inhibitors are very good at inhibiting the workings of the cox-2 enzyme -- and thereby easing pain -- they also throw off the cardiovascular system's delicate balance by inhibiting an enzyme that relaxes blood vessels and guards against clotting.

"It's really about a rock and a hard place," said Dr. Christopher Cannon, a cardiologist at Brigham and Women's Hospital in Boston. "There's a balance in the bloodstream of clotting and vasoconstriction, as well as protection against clotting and vasodilation, which means that there's a constant balance of clotting and preventing clotting, and constricting arteries and dilating arteries."

"But with cox-2 inhibitors, they have found that you knock the protective side of that balance off," Cannon said. "And then you're left only with the constrictive part, which means the drugs up the risk for clotting and arterial constriction."

"This problem is bigger than just Vioxx, which no longer exists," he added. "It applies to every single NSAID (non-steroidal anti-inflammatory drug), because with all NSAIDs -- including Celebrex and ibuprofen, which zillions of people take -- the same issue exists. You block out the good stuff and leave the bad stuff unchecked. The one exception is Naproxen, which has an anti-platelet effect that seems to work against stroke and heart attack risk."

"Sometimes you have to take a cox-2 because you have really bad daily pain," said Cannon. "But this is a dose-dependent problem, with the more cox-2 you take the greater the cardiovascular risk. So you have to limit the dose and take the least amount you can get away with, so you can try to control crippling pain but also try not to poison your blood vessels and predispose yourself to clotting and high blood pressure."

Ref : http://stm.sciencemag.org/content/4/132/132ra54.abstract?sid=25c1e6c3-e6ee-449c-ae09-b83f14efc9f2

New anti-inflammatory drug shows promise for treating inflammatory disorders

In one of my earlier blog, I  did mention about the antiinflammatory activity of H₂S gas. Now interestingly John Wallace, a pharmacologist and director of the Farncombe Family Digestive Health Research Institute at McMaster University, compared naproxen, a commonly used NSAID, to a novel anti-inflammatory drug, ATB-346 (ATB-346 is a derivative of naproxen which releases hydrogen sulfide), which he developed in collaboration with a team of Italian chemists and is now commercializing through his company, Antibe Therapeutics Inc. The basis for this research is by the fact that hydrogen sulphide is an important mediator of gastric mucosal defence. As we all know the ulcerogenecity associated with NSAIDs, there is a need to have NSAIDs with least or no ulcerogenecity.

As per the claim by the researchers, ATB-346, [above, structure : 2-(6-methoxy-napthalen-2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester] acts by inhibiting cyclooxygenase-1 and 2 and  reduces inflammation (in vivo). More interesting out come from their research is  that ATB-346 suppressed gastric prostaglandin E₂ synthesis as effectively as naproxen, but produced negligible damage in the stomach and intestine. 

ATB-346 did not cause significant damage, where as naproxen rendered significant  gastric mucosa damage (e.g. ablation of sensory afferent nerves, inhibition of endogenous nitric oxide or hydrogen sulphide synthesis, co-administration with aspirin, antagonism of K_IR6.x channels). Unlike naproxen and celecoxib, ATB-346 accelerated healing of pre-existing gastric ulcers. In a mouse airpouch model, ATB-346 suppressed cyclooxygenase-2 activity and inhibited leukocyte infiltration more effectively than naproxen. ATB-346 was as effective as naproxen in adjuvant-induced arthritis in rats, with a more rapid onset of activity, but with substantially reduced gastrointestinal toxicity (100 times safer than naproxen). Unlike naproxen, ATB-346 did not elevate blood pressure in hypertensive rats.

The researchers concluded that H2S-releasing NSAIDs appear to represent a promising alternative to existing therapies for the treatment of inflammation and pain. Future research will focus on the potential cardiovascular benefits of these drugs. .....

Ref : John L Wallace et. al., British Journal of Pharmacology, 159(6),  1236 - 1246

Naproxcinod a better NSAID.....

I knew  about Naproxen, because my first job was with Rallis India  Limited and the pharma division (sold to Shreya Group) was selling it as  a gel. It works by inhibiting both the COX-1 and COX-2 enzymes and that is the reason, why it has side effects. It has  been established already that the selective inhibitors of  COX-2 & 5 -LO will be the best drugs with least or no ulcerogenecity. We have  some drug like Celecoxib with selective inhibition of COX-2 (cyclo oxygenase enzyme), still we need to have selective inhibitors of both COX-2 & 5 -LO, so that  there will not be any cases like Rofecoxib withdrawal.

Naproxcinod, is a nitroxybutyl ester of naproxen. The ester group allow it to also act as a nitric oxide donor. Interestingly, this second mechanism of action makes naproxcinod the first of a new class of drugs, the cyclooxygenase inhibiting nitric oxide donators (CINODs), that are expected to produce similar analgesic efficacy to traditional NSAIDs, but with less gastrointestinal and cardiovascular side effects.  Now NicOx S.A announced that European Medicines Agency (EMEA) has validated the Marketing Authorization Application (MAA) for naproxcinod. NicOx is seeking approval for an indication for the relief of the signs and symptoms of primary osteoarthritis. This follows the acceptance for filing of a New Drug Application (NDA) by the US Food and Drug Administration (FDA) in November 2009.

More interestingly, in addition to naproxcinod, NicOx's pipeline includes several nitric oxide- donating NCEs, which are in development internally and with partners, including Merck & Co., Inc., for the treatment of widespread eye diseases, cardiometabolic diseases, hypertension and dermatological disease.

Details of the press release, one can read at the link....