Axsome Therapeutics Announces FDA Acceptance of New Drug Application for AXS-07 (meloxicam-rizatriptan) for the Acute Treatment of Migraine

 

In continuation of my update on meloxicam, 

Axsome Therapeutics, Inc.   that the U.S. Food and Drug Administration (FDA) has accepted for filing the Company’s New Drug Application (NDA) for AXS-07 for the acute treatment of migraine, and has set a Prescription Drug User Fee Act (PDUFA) target action date of April 30, 2022 for the NDA. AXS-07 (MoSEIC™ meloxicam-rizatriptan) is a novel, oral, rapidly absorbed, multi-mechanistic, investigational medicine for migraine.

  

meloxicam

 

Rizatriptan

  “The FDA’s acceptance of the NDA for AXS-07 is an important milestone for Axsome as it brings us closer to potentially making this multi-mechanistic treatment available to migraine patients in need,” said Herriot Tabuteau, MD, Chief Executive Officer of Axsome. “We look forward to continued interactions with the FDA during the review process.”

The NDA is supported by results from two Phase 3 randomized, double-blind, controlled trials of AXS-07 in the acute treatment of migraine, the MOMENTUM and INTERCEPT trials, which demonstrated statistically significant elimination of migraine pain with AXS-07 compared to placebo and active controls.

AXS-07 is a novel, oral, rapidly absorbed, multi-mechanistic investigational medicine for the acute treatment of migraine, consisting of MoSEIC™ meloxicam and rizatriptan. Meloxicam is a new molecular entity for migraine enabled by Axsome’s MoSEIC (Molecular Solubility Enhanced Inclusion Complex) technology, which results in rapid absorption of meloxicam while maintaining a long plasma half-life. Meloxicam is a COX-2 preferential non-steroidal anti-inflammatory drug and rizatriptan is a 5-HT1B/1D agonist. AXS-07 is designed to provide rapid, enhanced and consistent relief of migraine, with reduced symptom recurrence. AXS-07 is covered by more than 80 issued U.S. and international patents which provide protection out to 2036. AXS-07 is not approved by the FDA.

https://pubchem.ncbi.nlm.nih.gov/compound/Rizatriptan

https://pubchem.ncbi.nlm.nih.gov/compound/Meloxicam#section=2D-Structure

Rubraca (rucaparib) Approved in the U.S. as Maintenance Treatment of Recurrent Ovarian Cancer

In continuation of my update on Rucaparib

Clovis Oncology, Inc. announced that the U.S. Food and Drug Administration (FDA) has approved Rubraca (rucaparib) tablets for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. FDA granted regular approval for Rubraca in this second, broader and earlier-line indication on a priority review timeline based on positive data from the phase 3 ARIEL3 clinical trial. Biomarker testing is not required for patients to be prescribed Rubraca in this maintenance treatment indication. Warnings and precautions include Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), and embryo-fetal toxicity.

In addition to granting Rubraca approval in this second indication, the FDA converted the approval of the initial treatment indication from accelerated to regular approval.

“Rubraca provided statistically-significant improvement in PFS versus placebo to all patients, regardless of BRCA mutation status,” said Robert L. Coleman, MD, Professor & Executive Director, Cancer Network Research, Ann Rife Cox Chair in Gynecology, Department of Gynecologic Oncology and Reproductive Medicine at University of Texas MD Anderson Cancer Center in Houston and one of the Principal Investigators in the ARIEL3 clinical trial program. “Both the efficacy and safety results from the ARIEL3 study reinforce the important role of Rubraca in the treatment of recurrent ovarian cancer and expands the treatment options for patients and physicians battling this disease.”

“This FDA approval provides a meaningful advancement for the treatment of women with recurrent ovarian cancer, offering them the potential to reduce their risk of disease progression following platinum-based chemotherapy,” said Patrick J. Mahaffy, CEO and President of Clovis Oncology. “We are grateful that the FDA expedited review of this maintenance treatment indication, so that physicians can begin offering it to appropriate patients beginning today.”

On February 28, 2018, Rubraca was added to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology Ovarian Cancer, as maintenance therapy for patients with platinum-sensitive epithelial ovarian, fallopian tube and primary peritoneal cancer who are in partial or complete response after completion of two or more lines of platinum-based therapy. The NCCN designated Rubraca as a category 2A treatment.

NCCN is a not-for-profit alliance that includes 27 of the world’s leading cancer institutions. The NCCN Guidelines document evidence-based, consensus-driven management to ensure that all patients receive preventive, diagnostic, treatment, and supportive services that are most likely to lead to optimal outcomes.[1]

In December 2017, FDA accepted the Rubraca supplemental New Drug Application (sNDA) application and granted priority review status. Priority review designation is granted to proposed medicines that FDA has determined have the potential, if approved, to offer a significant improvement in the safety or effectiveness for the treatment, prevention or diagnosis of a serious condition when compared to standard applications. The Rubraca maintenance treatment approval is based on positive results from the ARIEL3 study, which evaluated Rubraca in the ovarian cancer maintenance-treatment setting among three populations: 1) BRCA mutant (BRCAmut+) 2) HRD positive inclusive of BRCAmut+ and, 3) all patients treated in ARIEL3. The study enrolled a total of 564 patients.

ARIEL3 successfully achieved both its primary and key secondary endpoints, extending investigator assessed progression-free survival (PFS) versus placebo in all patients treated, regardless of BRCA status.

Clovis announced topline results from the ARIEL3 clinical trial in June 2017. Additional data from the trial were presented at the 2017 European Society for Medical Oncology (ESMO) Annual Conference in Madrid, Spain, and subsequently published in The Lancet.

“The FDA approval of Rubraca in the maintenance treatment setting is an important milestone for physicians and their patients with recurrent ovarian cancer because it offers them greater flexibility to use this novel PARP inhibitor, which has demonstrated significant clinical efficacy and has been well received in practice,” said Professor Jonathan Ledermann, MD, Professor of Medical Oncology, Clinical Director, UCL Cancer Institute, and European and the rest of world Principal Investigator for the ARIEL3 study. “This will enable physicians to offer Rubraca to more women with platinum-sensitive, recurrent ovarian cancer.”

"Tens of thousands of women will battle ovarian cancer every year,” said David Barley, Chief Executive Officer, National Ovarian Cancer Coalition. “We need therapies that provide clinically meaningful improvements in reducing the risk of disease progression, among women with recurrent disease."

The safety evaluation of Rubraca 600 mg twice daily as monotherapy for maintenance treatment is based on data from 561 patients with recurrent ovarian cancer treated in the ARIEL3 trial. The safety and tolerability of Rubraca observed in this study was consistent with the previous Rubraca studies. The most common adverse reactions (greater than or equal to 20% of patients; CTCAE Grade 1-4) were nausea, fatigue/asthenia, abdominal pain/distention, rash, dysgeusia, anemia, AST/ALT elevation, constipation, vomiting, diarrhea, thrombocytopenia, nasopharyngitis/upper respiratory tract infection, stomatitis, decreased appetite and neutropenia. The most common laboratory abnormalities (greater than or equal to 25% of patients; CTCAE Grade 1-4) were increase in creatinine, decrease in hemoglobin, increase in cholesterol, increase in alanine aminotransferase (ALT), increase in increase in aspartate aminotransferase (AST), decrease in platelets, decrease in leukocytes, decrease in neutrophils, increase in alkaline phosphatase and decrease in lymphocytes. The majority of adverse reactions and laboratory abnormalities were Grade 1-2.

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.

New combination drug controls tumor growth, metastasis in mice...

Researchers at UC Davis, University of      Massachusetts  and Harvard  Medical  School  have
created a combination drug that controls both tumor growth and metastasis. By combining a COX-2 inhibitor, similar to Celebrex, and an epoxide hydrolase (sEH) inhibitor, the drug controls angiogenesis (blood vessel formation), limiting a tumor's ability to grow and spread. The study appears today in the journal Proceedings of the National Academy of Sciences.

"We've   been   studying  the  effects of  COX  and  sEH  inhibitors, both    by themselves  and in combination, for several years," said senior author and UC Davis Distinguished Professor Bruce Hammock. "We were surprised to find that the dual inhibitor was more active than higher doses of each compound, either individually or together. By combining the two molecules into one we got much greater potency against several diseases and completely unique effects in terms of blocking tumor growth and metastasis."

Both COX and sEH enzymes control lipid signaling, which has long been associated with inflammation, cell migration, proliferation, hypertension and other processes. COX inhibitors block production of inflammatory and pain-inducing lipids, while sEH inhibitors preserve anti-hypertensive, anti-inflammatory and analgesic compounds. Separate COX and sEH inhibitors were previously found to work together in reducing inflammation and neuropathic pain.

After testing individual COX-2 and sEH inhibitors, the team synthesized the drug (PTUTB), the first combined COX-2/sEH inhibitor. They then tested the dual inhibitor against human lung and breast tumors, both in vitro and in mice. They found that PTUTB blocked angiogenesis, inhibiting the proliferation of endothelial cells, which are critical to blood vessel formation. This in turn limited tumor growth and metastasis, reducing lung and breast tumor growth by 70 to 83 percent. 

In breast and lung cancers, the dual inhibitor blocked angiogenesis, which blocked the growth of solid tumors," said Hammock. "This represents a new mechanism to control blood vessel and tumor growth."

Robert Weiss, a co-author and professor of nephrology at UC Davis, added that the combination drug achieved the results with minimal side effects and no cardiovascular or gastrointestinal effects.

"This is particularly important when administering COX-2 inhibitors, which have well-known cardiovascular risks," he said. "However, the added sEH  inhibitor appears to block COX-2's side effects."

The research was initiated by first author Guodong Zhang when he was a postdoctoral fellow in the Hammock laboratory. Zhang previously demonstrated that sEH inhibitors improve the power of omega-3 fatty acid (fish oil) diets to reduce tumor growth and metastasis, and implicated epoxides of the dietary supplement DHA as the causative agent.

New combination drug controls tumor growth, metastasis in mice  

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

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

Etoricoxib better than tramadol for postoperative pain.....

In continuation of my update on Etoricoxib...

Researchers lead by Dr. Metha Brattwall of University Hospital Möndal in Gothenburg, Sweden, have come up with an  interesting finding, i.e., for patients with moderate pain after foot surgery, the cyclo-oxygenase 2 (COX-2) inhibitor drug etoricoxib provides better pain relief with fewer side effects than the opioid drug tramadol. The study also helps to alleviate concerns that COX-2 inhibitors and other nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with bone healing after surgery.  The researchers compared two different pain-relieving drugs in 100 women undergoing surgery for bunions (hallux valgus). One group received the COX-2 inhibitor etoricoxib, while the other group received tramadol, an opioid (narcotic-like) drug similar to codeine.

Although both drugs were effective in controlling pain in the week after surgery, pain scores were significantly lower in the etoricoxib group. Women assigned to etoricoxib had an average pain score of 12.5 (on a 100-point scale), compared to 17 in those receiving tramadol.  As per the claim by  the researchers, patients in the etoricoxib group had lower maximum pain scores throughout the week after surgery. They also had better pain relief on the second and third days after surgery, when pain scores were highest.

"Etoricoxib was also associated with fewer side effects and thus overall patient satisfaction with pain medication," the researchers write...

Interesting results from this study are that, no evidence of impaired healing in patients taking NSAIDs, at least after a relatively minor operation like bunion surgery. Etoricoxib is not currently approved for use in the United States, but is available in other countries. NSAIDs are generally considered much safer than opioid drugs.And this research further substantiate this.

"The results suggest that NSAIDs can provide superior analgesia for patients with moderate pain after bone surgery, with reduced risk," Dr. Shafer adds...

Ref : Metha Brattwall,  Ibrahim Turan, and Jan Jakobsson, Anesthesia & Analgesia

Sulindac inhibits tumor growth !...

We know that, Sulindac(structure), is useful in the treatment of acute or  chronic inflammatory conditions. Sulindac is a prodrug, derived from sulfinylindene, that is converted in the body to the active NSAID. More specifically, the agent is converted by liver enzymes to a sulfide that is excreted in the bile and then reabsorbed from the intestine. This is thought to help maintain constant blood levels with reduced gastrointestinal side effects. Some studies have shown sulindac to be relatively less irritating to the stomach than other NSAID's except for drugs of the COX-2 inhibitor class. The exact mechanism of its NSAID properties is unknown, but it is thought to act on enzymes COX-1 and COX-2, inhibiting prostaglandin synthesis.

Now researchers from Sanford-Burnham Medical Research Institute (Sanford-Burnham) and their colleagues have figured out how  Sulindac, inhibits tumor growth. The study reveals that Sulindac shuts down cancer cell growth and initiates cell death by binding to nuclear receptor RXRα, a protein that receives a signal and carries it into the nucleus to turn genes on or off. 

As per the claim by the researchers, RXRα normally suppresses tumors, but many types of cancer cells produce a truncated form of this nuclear receptor that does just the opposite. This study showed that shortened RXRα enhances tumor growth by stimulating other proteins that help cancer cells survive. Luckily, the researchers also found that Sulindac can be used to combat this deviant RXRα by switching off its pro-survival function and turning on apoptosis, a process that tells cells to self-destruct.  The interesting part of their research lies in the fact that, they were able to overcome the limitation (cardiovascular side effects associated with Sulindac and other NSAIDs), the researchers tweaked Sulindac, creating a new version of the drug now called K-80003 that both decreases negative consequences and increases binding to truncated RXRα..

"Depending on the conditions, the same protein, such as RXRα, can either kill cancer cells or promote their growth," Dr. Zhang said. "The addition of K-80003 shifts that balance by blocking survival pathways and sensitizing cancer cells to triggers of apoptosis."

Ref :  http://www.cell.com/cancer-cell/retrieve/pii/S1535610810001595

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....

Celecoxib reduces the risk of common skin cancer in humans.....

We know that Celecoxib   is a non-steroidal anti-inflammatory drug (NSAID)  used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce numbers of colon and rectum polyps in patients with familial adenomatous polyposis. It is marketed by Pfizer. It is known under the brand name Celebrex or Celebra for arthritis and Onsenal for polyps. Celecoxib is available by prescription in capsule form.

Researchers from UC-San Francisco and Children's Hospital Oakland,  (Dr. Tang was was an assistant professor at UC-San Francisco and Children’s Hospital Oakland  when the trial was conducted) have come up with very interesting results for the same drug. The drug can reduce the risk of a common skin cancer in humans. Though celecoxib, is associated with an increased risk of heart attack and stroke in some people, it's possible that topical application could have a safer, protective effect for people prone to developing the cancers, called basal cell carcinomas, the researcher believes.

For the current research, Tang and her colleagues capitalized on a previous finding suggesting that celecoxib, a NSAID, can inhibit the development of a different kind of skin cancer, squamous cell carcinoma, in mice. They wondered if the drug, sold by the pharmaceutical company Pfizer under the brand names Celebrex and Onsenal, would have a similar effect on the more common basal cell carcinoma.

Celecoxib is thought to work to prevent or slow cancer growth by interfering with the action of an enzyme called Cox-2, which causes tissue inflammation (pro inflammator). Celecoxib has both pain-killing (analgesic) and anti-inflammatory properties. Chronic inflammation has long been associated with the development of many types of cancer, and celecoxib has been shown in clinical trials to reduce the incidence of colon cancer in people with a genetic predisposition to the disease.

Interestingly, researchers stopped the clinical trials in 2003 (from 2001) when the study lead to high risk  of heart attack and stroke in patients taking a different NSAID. (Rofecoxib,  Vioxx by  Merck & Co. was withdrawn from the market by Merck in 2004  and Tang's trial was discontinued that year in response to ongoing concerns about long-term treatment with Cox-2 inhibitors). At that time, most participants had received about two years of drug treatment. No patient died or suffered adverse cardiovascular events due to their participation in the trial. Although drug treatment had been discontinued, the researchers continued to monitor basal cell carcinoma formation in people who had received the drug or placebo for an additional year to complete the three-year study. They found that, although both groups continued to develop new cancers during the study, oral celecoxib treatment decreased the growth of skin tumors by about 50 percent as compared to placebo in participants who entered the trial with 15 or fewer basal cell carcinomas. Celecoxib treatment also reduced the overall tumor burden in the  group of patients (where in the carcinomas are removed upon diagnosis in most people).

Now the lead researcher Dr. Tang is continuing her focus on skin cancer prevention at Stanford. She's currently investigating whether it's possible to develop a topical formulation of the drug that can be applied directly to the skin to achieve a similar protective effect without associated cardiovascular risk. Hope she will get positive results via topical formulation .....

In my opinion  its really a great achievement.We know that compounds with selective inhibitors of 5-LO (Lipoxygenase) and COX (Cyclooxegenase, that too COX-II) will be  the best NSAIDs without any ulcerogenecity, its good see that the  same compounds can be used to treat skin cancer....

Ref : http://med.stanford.edu/ism/2010/january/tang.html

Explanation for the side effect of COX-2 inhibitors !....

When I read this article, went back to my research days (1993-1998). We did prepare some triazoles, oxadiazoles, thiadiazoles and their derivatives. The parent triazoles and oxadiazoles were tested for thier antiinflammatory activity by Carrageenan induced rat paw edema, Cotton pellet induced granuloma tissue formation methods and the results were encouraging and were even better tolerated than the standards (Diclofenac and Ibuprofen). We had many research papers that time claiming that, the selective inhibitors of COX-2 and 5-LO are the best NSAIDs. After few years there were three COX-2 inhibitors in the market (namely-Vioxx (rofecoxib), Bextra (valdecoxib) and Celebrex (celecoxib) and we were happy that atleast the ulcerogenecity of NSAIDS has been taken care of. But the days were countable and the first two drugs were withdrawn from the market, because of the cardiovascular toxicity and only celecoxib is available in the market. Now thanx to Dr. Andrew J. Dannenberg (Director of the Weill Cornell Cancer Center) and group, who have come up with a novel explanation for the cardiovascular toxicity of the COX-2 inhibitors. I would say one more "serendipity" to the drug discovery, because the trial was originally designed to identify biomarkers in urine which could indicate the presence of incipient, smoking-related lung disease. The researchers had hypothesized that early-stage lung injury could "turn on" the COX-2 gene, increasing levels of the major prostaglandin metabolite PGE-M in the urine. In addition to determining PGE-M levels, the investigators also looked at levels of the biomarker leukotriene E4 (LTE4), formed by the 5-lipoxygenase (5-LO) pathway. Both biomarkers, representing these two different pathways, are synthesized from arachidonic acid. The 5-LO pathway has also been implicated in inflammation, cancer and cardiovascular problems. The authors found that Celebrex treatment led to increases in urinary LTE4 levels, primarily among individuals who had started out with high PGE-M levels, which indicated that Celebrex 'shunted' or redirected arachidonic acid into the 5-LO pathway from the COX pathway. When one went down, the other went up." This is important because other studies have suggested an important role for the 5-LO pathway in atherosclerosis, heart attacks and stroke. And it is this increased shunting of arachidonic acid into the 5-LO pathway that may help explain why COX-2 inhibitors contribute to cardiovascular problems, the researchers say. Though further studies are essential to substantiate the claims, is a good beginning and hope with selective inhibitors of both COX-2 (cyclooxygenase) and 5-LO (lipoxygenase) are the need of today's world (I did mention in the beginning about that..)...

Ref: http://news.med.cornell.edu/wcmc/wcmc_2009/04_29_09.shtml

Non ulcerogenic new antiinflammatory drugs ?

When we see the presently available NSAIDs, most of them have ulcerogenicity as one of the common side effect. Ulcerogenicity can be explained by the metabolism of Arachidonic acid into various metabolites. Most of the drugs (NSAIDs) act by inhibiting the prostaglandins. But some of the prostaglandins are essential as cytoprotective layer and hence selective inhibitors of Cyclooxygenase –II (COX-II) and 5-LO (Lipoxygenase) are better tolerable and hence we can call these drugs as non ulcerogenic NSAIDs. Though these 2 enzymes (COX-II and 5-LO) were the targets of many drug discovers (as for as my knowledge goes, 1996-98 there were many papers regarding the selective inhibitors).

Now Oliver Werz and co workers have come with some new compounds 2-(4-(biphenyl-4-ylmethylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (with some structural variations like α substitution with extended n-alkyl or bulky aryl substituents and concomitant replacement of the 2,3-dimethylaniline by a biphenyl-4-yl-methane-amino residue) a derivative of pirinixic acid [PA, 2-(4-chloro-6-(2,3-dimethylphenylamino) pyrimidin-2-ylthio)acetic acid.

Significance of this research is the, less pronounced inhibition of cyclooxygenases-1/2. Taken together, these pirinixic acid derivatives constitute a novel class of dual mPGES-1/5-LO inhibitors with a promising pharmacologial profile and a potential for therapeutic use. More……