Drug Used to Treat Rheumatoid Arthritis May Also Help Prevent It

A clinical trial  showed that the  drug abatacept (Orencia) – which is already used to treat diagnosed rheumatoid arthritis – also can prevent people from progressing to the painful inflammatory disease.

Abatacept eases symptoms and prevents joint damage in rheumatoid arthritis patients by dampening the immune system, researchers said.

About 1.3 million Americans live with rheumatoid arthritis, which occurs when the body’s immune system starts attacking tissues in the joints, causing inflammation, pain and swelling.

Day’s clinical trial showed that abatacept also is effective in preventing the onset of rheumatoid arthritis.

About 6% of patients treated with abatacept developed arthritis compared to 29% given a placebo following a year of treatment, according to clinical trial results published Feb. 13 in The Lancet.

“This is the largest rheumatoid arthritis prevention trial to date and the first to show that a therapy licensed for use in treating established rheumatoid arthritis is also effective in preventing the onset of disease in people at risk,” researcher Andrew Cope, head of the King’s College London Center for Rheumatic Diseases, said in a news release.

“These initial results could be good news for people at risk of arthritis, as we show that the drug not only prevents disease onset during the treatment phase but can also ease symptoms such as pain and fatigue,” he continued.

For the clinical trial, researchers recruited 213 patients older than 18 at high risk of rheumatoid arthritis. They all had early symptoms like joint pain, but no swelling that would lead to a formal diagnosis.

Rheumatoid arthritis most often begins in middle age, but also can affect much younger adults, researchers said.

“Enrolling in the trial was a no-brainer; it was a ray of hope at a dark time,” Day said.

Half of the participants were treated with abatacept and the other half with a placebo every week for a year. The drug is given by weekly injections at home or in a hospital via an IV drip.

After a year of treatment, the drug was stopped and patients were monitored to see how many would develop rheumatoid arthritis.

After the full two years, 25% of abatacept patients had progressed to rheumatoid arthritis compared with 37% of those on a placebo.

“The results clearly show that during the treatment period almost all individuals receiving the biologic drug showed no symptoms or signs of RA compared with the control population,” Ravinder Maini, an emeritus professor of rheumatology at Imperial College London who was not involved in the research, said of the clinical trial.

Drug Used to Treat Rheumatoid Arthritis May Also Help Prevent It 

FDA Approves Aurlumyn (iloprost) as the First Medication to Treat Severe Frostbite

The U.S. Food and Drug Administration approved Aurlumyn (iloprost) injection to treat severe frostbite in adults to reduce the risk of finger or toe amputation.

"This approval provides patients with the first-ever treatment option for severe frostbite,” said Norman Stockbridge, M.D., Ph.D., director of the Division of Cardiology and Nephrology in the FDA’s Center for Drug Evaluation and Research. “Having this new option provides physicians with a tool that will help prevent the lifechanging amputation of one’s frostbitten fingers or toes."

Frostbite can occur in several stages, ranging from mild frostbite that does not require medical intervention and does not cause permanent skin damage, to severe frostbite when both the skin and underlying tissue are frozen and blood flow is stopped, sometimes requiring amputation. Iloprost, the active ingredient in Aurlumyn, is a vasodilator (a drug that opens blood vessels) and prevents blood from clotting.

Iloprost’s efficacy in treating severe frostbite was primarily established in an open-label, controlled trial that randomized 47 adults with severe frostbite, who all received aspirin by vein and standard of care, into one of three treatment groups. One of these groups (Group 1) received iloprost by vein (intravenously) for 6 hours daily for up to 8 days. The two other groups received other medications that are unapproved for frostbite, given with iloprost (Group 2) or without iloprost (Group 3). The primary measure of efficacy was a bone scan obtained 7 days after initial frostbite that was used to predict the need for amputation of at least one finger or toe.

On day 7, the bone scan finding predictive of needing amputation was observed in 0% (0 of 16) patients receiving iloprost alone (Group 1) compared to 19% (3 of 16) patients in Group 2 and 60% (9 of 15) patients in Group 3. The presence of the bone scan abnormality was significantly lower in the two groups receiving iloprost. Most patients had follow-up information on whether they subsequently underwent at least one finger or toe amputation. The need for amputation was consistent with the bone scan findings.

The most common side effects of Aurlumyn include headache, flushing, heart palpitations, fast heart rate, nausea, vomiting, dizziness, and hypotension (blood pressure that is too low). Aurlumyn also has a warning and precaution noting that it may cause symptomatic hypotension.

Aurlumyn received Priority Review and Orphan Drug designations for this indication.

Iloprost was originally approved in 2004 for the treatment of pulmonary arterial hypertension.  The FDA granted the approval of Aurlumyn to Eicos Sciences Inc.

Ref; https://en.wikipedia.org/wiki/Iloprost.

FDA Approves Aurlumyn (iloprost) as the First Medication to Treat Severe Frostbite

FDA Approves Xelpros (latanoprost ophthalmic emulsion) to Treat Open-angle Glaucoma or Ocular Hypertension

In continuation of my update on latanoprost

Sun Pharmaceutical Industries Ltd. and Sun Pharma Advanced Research Company Ltd. (SPARC) announced U.S. Food and Drug Administration (USFDA) approval for the New Drug Application (NDA) of Xelpros (latanoprost ophthalmic emulsion) 0.005% for the reduction of elevated intraocular pressure (IOP, or pressure inside the eye) in patients with open-angle glaucoma or ocular hypertension. This approval is from Sun Pharma’s Halol (Gujarat, India) facility.

Sun Pharma in-licensed Xelpros from SPARC in June 2015 and this approval will trigger a milestone payment to SPARC. SPARC is also eligible for milestone payments and royalties on commercialization of Xelpros in the US.

Xelpros is the first and only form of latanoprost that is not formulated with benzalkonium chloride (BAK), a preservative commonly used in topical ocular preparations. Xelpros is developed using SPARC’s proprietary Swollen Micelle Microemulsion (SMM) technology.

“As the only BAK-free version of latanoprost, Xelpros will be an important and alternative treatment option for individuals with open-angle glaucoma or ocular hypertension,” said Abhay Gandhi, CEO, North America, Sun Pharma. “This approval, coming less than one month following the approval of CEQUA™ (cyclosporine ophthalmic solution) 0.09%, reaffirms the strength of Sun Pharma’s fast-growing Ophthalmics division and its commitment to serving the needs of patients with ocular disorders.”

Anil Raghavan, CEO, SPARC said, “Approval of Xelpros by USFDA is a significant milestone for SPARC. It is also a validation of our SMM technology which helps to solubilize drugs that have limited or no solubility thus eliminating the need for benzalkonium chloride (BAK).”

In randomized, controlled clinical trials of patients with open-angle glaucoma or ocular hypertension with a mean baseline Intraocular pressure (IOP) of 23-26 mmHg, Xelpros lowered IOP by a mean of up to 6-8 mmHg.

Xelpros will be commercialized in the U.S. by Sun Ophthalmics, the branded ophthalmic division of Sun Pharmaceutical Industries Ltd.’s wholly owned subsidiary.

Drug used to treat amoebic dysentery may block journey of rabies virus in nerves

In continuation of my update on Emetine

To successfully infect its host, the rabies virus must move from the nerve ending to the nerve cell body where it can replicate.

In a study published July 20 in the journal PLoS Pathogens, researchers from Princeton University reveal that the rabies virus moves differently compared to other neuron-invading viruses and that its journey can be blocked by a drug commonly used to treat amoebic dysentery.

Most viruses only infect the nervous system accidentally when the immune system is compromised. But some "neurotropic" viruses have evolved to target neurons as part of their normal infectious cycle. The rabies virus, for example, is transmitted when an infected animal bites into a host's muscle. It then spreads into the end terminals of motor neurons innervating the muscle and travels along the neurons' long axon fibers to the neuronal cell bodies. From there, the virus can spread throughout the central nervous system and into the salivary glands, where it can be readily transmitted to other hosts. Though rabies infections in humans are rare in the United States, the virus kills more than 59,000 people annually, according to the Centers for Disease Control and Prevention.

Alpha herpesviruses, such as herpes simplex viruses, also enter peripheral nerve terminals and move along axons to the neuronal cell body, where they can lie dormant for the life of the host.

"Transport to the neuronal cell body is not a passive process, but an active one relying on the neuron's own motor proteins and microtubule tracks," said Lynn Enquist, Princeton's Henry L. Hillman Professor in Molecular Biology, a professor of molecular biology and the Princeton Neuroscience Institute, and the study's senior author. "Virus particles must engage this machinery for efficient transport in axons, otherwise infection cannot start."

Enquist and colleagues previously found that alpha herpesviruses engage the neuronal transport machinery by stimulating protein synthesis at infected nerve terminals. Viral transport to the cell body can therefore be blocked by drugs that inhibit protein synthesis, as well as by cellular antiviral proteins called interferons.

In the current study, Enquist and colleagues investigated how the rabies virus engages the neuronal transport machinery. The researchers infected neurons with a virulent strain of the virus tagged with a red fluorescent protein, allowing the researchers to observe viral transport in real time by live-cell fluorescence microscopy.

The study was led by Margaret MacGibeny, who earned her Ph.D. in 2018, and associate research scholar Orkide Koyuncu, at Princeton, with contributions from research associate Christoph Wirblich and Matthias Schnell, professor and chair of microbiology and immunology at Thomas Jefferson University.

In contrast to alpha herpesvirus infections, the team found that interferons had no effect on rabies virus transport, perhaps because, until it reaches the neuronal cell body, the rabies virus hides out inside cellular structures called endosomes.

"We also couldn't detect increased protein synthesis in axons upon rabies virus infection," MacGibeny said. "But, to our surprise, we saw that a protein synthesis inhibitor called emetine efficiently blocked rabies virus transport to the cell body."

Emetine had no effect on the transport of endosomes devoid of the rabies virus. But endosomes carrying the virus were either completely immobilized, or were only able to move short distances at slower-than-normal speeds.

Other protein synthesis inhibitors did not block rabies virus transport, however, suggesting that emetine works by inhibiting a different process in infected neurons.

"Emetine has been used to treat amoebic dysentery," Koyuncu said. "In the laboratory it is widely used to inhibit protein synthesis but there are recent reports indicating that emetine has anti-viral effects that are independent of protein synthesis inhibition. Our study shows that this drug can inhibit rabies virus invasion of the nervous system through a novel mechanism that hasn't been reported before."

"The manuscript by MacGibeny et al. both advances and complicates our understanding of how neurotropic viruses make their way from the axon terminus to the cell body," said Professor Glenn Rall, an expert in neurotropic virus infections at Fox Chase Cancer Center, who was not involved in the study. "Revealing variations in the axonal transport of neurotropic viruses, coupled with intriguing insights into new roles for well-known drugs, has both mechanistic and clinical implications for these life-threatening infections.

"Our next step is to figure out how emetine disrupts rabies virus transport in axons," Enquist says. "Does it inhibit cell signaling pathways after rabies virus entry, or does it directly block the recruitment of motor proteins to virus-carrying endosomes?"

Ref : https://molbio.princeton.edu/news/enquist-lab-researchers-uncover-new-details-rabies-virus-movement