FDA Approves Seglentis (celecoxib and tramadol hydrochloride) for the Management of Acute Pain

In continuation of my update on celecoxib and tramadol

The U.S. Food and Drug Administration (FDA) has approved Seglentis (celecoxib and tramadol hydrochloride), a proprietary product developed by Esteve Pharmaceuticals' R&D team. It is an innovative first-in-class product comprised of a co-crystal form of celecoxib (an anti-inflammatory) and tramadol (an analgesic) for the treatment of acute pain in adults. This is Esteve's first proprietary research product to enter the United States market.

In words of Dr. Carlos Plata-Salamán, Chief Scientific Officer and Chief Medical Officer of Esteve "This innovation is the result of applying a crystallization technology to improve the physicochemical properties and pharmacokinetic characteristics of its active pharmaceutical ingredients.1,2,4,7,9 The FDA approval means that clinicians and adult patients in the U.S. now have a new treatment option for acute pain management."

Seglentis is the trade name for tablets that contain a co-crystal7 composed of celecoxib and tramadol hydrochloride. It is a new analgesic designed for acute pain management in a multimodal treatment approach3,5,6 targeting four complementary pain relief mechanisms.5,6 It offers a new treatment option for acute pain management aligned with the multimodal analgesia now considered standard of care. 

The novel co-crystal structure produces a unique pharmacokinetic profile of its active pharmaceutical ingredients compared to their individual or combined administration.1,2,4,9 The New Drug Application (NDA) was approved by the U.S. FDA on October 15, 2021.

Staffan Schüberg, Chief Executive Officer of Esteve, said: "We are proud of this milestone as we understand it as a recognition of our daily efforts to meet patient’s needs and to address the challenges the pain community is facing nowadays".

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 

FDA Approves Consensi (amlodipine and celecoxib) for Treatment of Hypertension and Osteoarthritis Pain

  

In continuation of my update on amlodipine and celecoxib

Kitov Pharma Ltd. an innovative bio pharmaceutical      co.,  announced  that the U.S. Food and Drug Administration (FDA) has approved Consensi (amlodipine and celecoxib) oral tablets for marketing.                               amlodipine                                                     celecoxib      

Consensi is a patent-protected combination of celecoxib, a non-steroidal anti-inflammatory drug (NSAID), and amlodipine besylate, an antihypertensive calcium channel blocker. Consensi was approved for once daily use in three dosage forms, corresponding to the current approved dosages of amlodipine (2.5, 5, and 10 mg) for hypertension and a 200 mg dose of celecoxib for the treatment of osteoarthritis pain.

“We are very pleased with Consensi’s approval and would like to thank the members of Kitov’s team, consultants and investigators, as well as the FDA’s Division of Cardiovascular and Renal Products, for all of their support and assistance,” said Dr. J. Paul Waymack, Chairman of Kitov's Board and Chief Medical Officer. “Consensi provides a safe and effective combination treatment option for the millions of Americans who suffer from osteoarthritis pain and hypertension.

“Now that Consensi has been approved for marketing, our clinical and regulatory teams will focus on leveraging their drug development expertise to advance NT219, an exciting investigational new drug candidate currently in development for various oncology indications.”

Isaac Israel, Kitov’s CEO, added: “This approval demonstrates the Kitov team’s ability and experience in expertly guiding Consensi through clinical trials and regulatory review, from Investigational New Drug (IND) submission to FDA approval in less than four years.

“Over 50 million Americans suffer from osteoarthritis. About 1 of 3 U.S. adults or about 75 million people have high blood pressure*, known as the “silent killer” due to the absence of noticeable symptoms. As a result, patients’ adherence to the hypertension treatment regimen is low. We believe that Consensi, as a single pill combination treatment for osteoarthritis and hypertension, presents a unique value proposition of potentially increasing treatment adherence.

“We recently expanded our commercialization network for Consensi by securing a second licensing agreement in Asia with a major Chinese pharmaceutical company. The FDA approval of Consensi puts us in a stronger position towards securing commercial partnerships for the U.S. and other key territories.”

The FDA-approved Consensi New Drug Application included the positive results from the Company’s Phase III clinical trial. These data demonstrated that the study met its primary endpoint of showing that the drug lowers daytime systolic blood pressure by at least 50% of the reduction in blood pressure achieved in patients treated with amlodipine besylate only, with statistical significance of p=0.001. Kitov also submitted the positive results from its randomized double-blind, placebo-controlled renal function Phase III/IV clinical trial of Consensi. Data from this study validated the primary efficacy endpoint achieved in the completed Phase III clinical trial. This study also demonstrated that treatment with Consensi led to a statistically significant reduction of serum creatinine, a marker of renal function, from its baseline value (p=0.0005), demonstrating improved renal function in patients treated with the combination. In contrast, neither amlodipine besylate nor placebo lowered creatinine to a statistically significant level.

Arthritis drug increases effectiveness of antidepressants in bipolar patients

In continuation of my updates on celecoxib

Giving severely depressed patients the arthritis drug celecoxib (Celebrex®) dramatically boosted the effectiveness of their antidepressant medication, a Loyola study has found. 

Loyola Medicine psychiatrist Angelos Halaris, MD, PhD, presented the study at the Fifth International Congress on Psychiatry and the Neurosciences in Athens, Greece. Dr. Halaris is a professor in the Department of Psychiatry and Behavioral Neurosciences of Loyola University Chicago Stritch School of Medicine. 

 The eight-week study enrolled bipolar adults, aged 18 to 65, who were in the depressive phase of their disease and had not benefitted from an antidepressant. (Bipolar disorder is marked by alternating periods of elation and depression, with depression typically lasting longer.) Patients were randomly assigned to receive the antidepressant escitalopram (Lexapro®) plus celecoxib or Lexapro plus a placebo. 

Seventy-eight percent of the patients in the celecoxib group experienced at least a 50 percent reduction in their depression scores, with 63 percent reporting their depression had gone away completely. By comparison, only 45 percent of the placebo group recorded a 50 percent or more reduction in depression, with only 10 percent reporting their depression had lifted completely.

It typically takes four to six weeks before an antidepressant begins working. In the Loyola study, patients who took celecoxib began seeing a benefit from their antidepressant within a week.
Fifty-five patients completed the study: 31 in the Lexapro plus celecoxib group and 24 in the Lexapro plus placebo group. 

Previous studies have found that depression revs up the immune system, resulting in chronic inflammation. This inflammatory response affects the normal balance of chemical messengers in the brain called neurotransmitters. Inflammation hinders the function of antidepressants that are designed to restore normal chemical balance. By fighting inflammation, celecoxib appears to make antidepressants more effective, Dr. Halaris said. 

 Celecoxib is used to treat pain, redness, swelling and inflammation from arthritis. It also can manage acute pain and menstrual cramps. By itself, it does not treat depression.

 The study's findings support the hypothesis that inflammation plays a critical role in depression. Reducing inflammation with a drug such as celecoxib "reverses treatment resistance and enhances overall antidepressant response," Dr. Halaris wrote in the study. "Such an intervention, if implemented relatively early in the course of the disease, may arrest the neuroprogressive course of bipolar disorder." 

Osteoarthritis: pivotal Phase III trial successfully meets primary efficacy endpoint - Medical News Today

Celecoxib/amlodipine besylate (KIT-302)

  

itov Pharmaceuticals, an innovative biopharmaceutical company focused on late-stage drug development, announced today that the Phase III, double-blind, placebo-controlled clinical trial for its leading drug candidate, KIT-302, successfully met the primary efficacy endpoint of the trial protocol as approved by the U.S. Food & Drug Administration (FDA). Data from the trial further revealed that KIT-302 was more efficacious at reducing hypertension than the widely used hypertension drug amlodipine besylate. Kitov plans to file its New Drug Application (NDA) for marketing approval of KIT-302 with the FDA in the second half of 2016.

A combination drug, KIT-302, simultaneously treats pain caused by osteoarthritis and treats hypertension, which is a common side effect of stand-alone drugs that treat osteoarthritis pain. KIT-302 is comprised of two FDA approved drugs, celecoxib (Celebrex®) for the treatment of pain caused by osteoarthritis and amlodipine besylate, a drug designed to treat hypertension.

The trial protocol, approved by the FDA through the Special Protocol Assessment process, was designed to quantify the decrease of hypertension in patients receiving KIT-302. The trial was performed in the U.K. in four groups of twenty-six (26) to forty-nine (49) patients, with a total of 152 patients. Each patient was treated over a total period of two weeks. Group One was treated with KIT-302, comprised of celecoxib and amlodipine besylate. Group Two was treated with amlodipine besylate only, one of the components of KIT-302. Group Three was treated with celecoxib only, the other component of KIT-302. Group Four was treated with a double placebo. The trial began in June 2014 and was completed in November 2015.

Osteoarthritis: pivotal Phase III trial successfully meets primary efficacy endpoint - Medical News Today

Viagra can have anti-cancer, anti-Alzheimer's disease effects if used with new drugs

Chaperone proteins play an important role in protein folding in human cells and in bacteria and are promising new targets for drugs to treat cancer and Alzheimer's disease and for novel antiviral drugs and antibiotics. How existing drugs such as Viagra or Cialis and a derivative of the drug Celebrex, for example, can reduce the activity of a specific chaperone protein, with the potential for anti-tumor and anti-Alzheimer's disease effects, is described in a Review article in DNA and Cell Biology, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The article is available free on the DNA and Cell Biology website until April 9, 2015.

In the article "HSPA5/Dna K May Be a Useful Target for Human Disease Therapies", Laurence Booth, Jane Roberts, and Paul Dent, Virginia Commonwealth University, Richmond, provide a comprehensive discussion of the HSPA5/Dna K chaperone protein and the published evidence for its role in various human diseases. The authors describe how OSU-03012, an experimental compound derived from the drug celecoxib (Celebrex) interacts with Viagra or Cialis to reduce levels of chaperone proteins. Reduced levels of HSPA5 and Dna K can interfere with virus replication, promote bacterial cell death, and even make drug-resistant "superbugs" susceptible to existing antibiotics.

"Drugs like Celebrex and Viagra are readily available and generally recognized as safe. This study by Booth and colleagues may lead to new applications of these relatively new medicines," says Carol Shoshkes Reiss, PhD, Editor-in-Chief, of DNA and Cell Biology and Professor, Departments of Biology and Neural Science, New York University, NY. "The potential impact, if the experiments described are translatable to human disease, could be paradigm-shifting. The potential applications are serious antibiotic resistant infections, chemotherapy-resistant cancers, and neurodegenerative disease ranging from Parkinson's disease to Huntington's or Alzheimer's disease."

Viagra can have anti-cancer, anti-Alzheimer's disease effects if used with new drugs

Mylan announces U.S. launch of Celecoxib Capsules

In continuation of my update celecoxib

Mylan Inc. (Nasdaq: MYL)      announced the U.S. launch of its Celecoxib Capsules,   50 mg,  100 mg,  200 mg, and 400 mg,  one  of the  first  available  generic  versions        of   Pfizer's elebrex®       Capsules,     which    is   indicated for  the  relief  of the  signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, and for the management of acute pain in adults.

Celecoxib Capsules, 50 mg, 100 mg, 200 mg, and 400 mg, had U.S. sales of approximately $2.5 billion for the 12 months ending September 30, 2014, according to IMS Health.

Currently, Mylan has 286 ANDAs pending FDA approval representing $111.6 billion in annual brand sales, according to IMS Health. Forty-five of these pending ANDAs are potential first-to-file opportunities, representing $29.5 billion in annual brand sales, for the 12 months ending June 30, 2014, according to IMS Health.

Mylan announces U.S. launch of Celecoxib Capsules

Clinical study: Celecoxib drug may treat breast cancer

In continuation of m update on Celecoxib

Clinical study: Celecoxib drug may treat breast cancer

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....

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