Evaluation of Transcutaneous Posterior Tibial Nerve Electro Stimulation With or Without Low Dose Trospium Chloride in the Management of Overactive Bladder in Females
This study was done to verify whether the combination of transcutaneous posterior tibial nerve stimulation (TPTNS) with low dose trospium chloride in the treatment of females with overactive bladder (OAB) would be more effective than TPTNS alone after failure of behavioral therapy.
Microtubule defects are a common feature in several neurodegenerative disorders, including the hereditary spastic paraplegia. The most frequent form of hereditary spastic paraplegia is caused by mutations in the SPG4/SPAST gene, encoding the microtubule severing enzyme spastin. To date, there is no effective therapy available but spastin-enhancing therapeutic approaches are emerging, thus prognostic and predictive biomarkers are urgently required.
We developed an automated, simple, fast, and non-invasive cell imaging-based method to quantify microtubule cytoskeleton organization changes in lymphoblastoid cells and peripheral blood mononuclear cells.
We observed that lymphoblastoid cells and peripheral blood mononuclear cells from individuals affected by SPG4-hereditary spastic paraplegia show a polarized microtubule cytoskeleton organization. In a pilot study on freshly isolated peripheral blood mononuclear cells, our method discriminates SPG4-hereditary spastic paraplegia from healthy donors and other hereditary spastic paraplegia subtypes. In addition, we show that our method can detect the effects of spastin protein level changes.
These findings open the possibility of a rapid, non-invasive, inexpensive test useful to recognize SPG4-hereditary spastic paraplegia subtype and evaluate the effects of spastin-enhancing drug in non-neuronal cells.
2019-01-01·Current Organic Synthesis4区 · 化学
Synthesis of Novel Fluorine Compounds Substituted-4-thiazolidinones Derived from Rhodanine Drug as Highly Bioactive Probes
4区 · 化学
作者: Makki, Mohammad S. T. ; Abdel-Rahman, Reda M. ; Alshammari, Nawaa A. H.
AIM AND OBJECTIVE:
It is known that rhodanine drug has various biocidal activities. The aim of this work was to improve the structure of rhodanine drug via alkylation at N, S, and O- centers in addition to the introduction of fluorine atoms. The new fluorinated modified rhodanines 2-16 were evaluated as enzymatic probes for cellobiase activity produced by fungi and as CDK2 inhibitors of tumor cells.
MATERIALS AND METHODS:
Novel fluorine substituted N-alkyl, S-alkyl and amino-rhodanines were obtained via Hydroxy methylation, Mannich reactions, chlorination and amination of 5-(4'-fluorophenylene)-2-thioxothiazolidin- 4-one, and the enzymatic effects of cellobiase produced by fungi and /or CDK2 inhibition of tumor cells were evaluated.
Most of the targets were obtained in high yield and in the form of very pure crystals with characteristic colors. Only compounds 5, 8, 10, 13, and 14 exhibited a higher activity as cellobiase while compounds 2 and 5 showed a highly enzymatic effect on tumor cells. In addition, compounds 2 and 10 can be used as Olomoucine (standard referees).
Various N, S and O-alkyl derivatives of fluorine-substituted rhodanines were prepared via a simple method and used as enzymatic probes for cellobiase activity produced by fungi and CDK2 inhibitors for tumor cells. The more bioactive compounds had rich fluorine atoms as p-fluorophenyl and p-fluorobenzoyl bearing N, S, O-alkyl rhodanine. The highly active compounds may be used as enzymatic materials for various biological transformations in the future.
1993-08-01·Clinical neuropharmacology4区 · 医学
Bruxism secondary to chronic antidopaminergic drug exposure.
4区 · 医学
作者: F Micheli ; M Fernandez Pardal ; M Gatto ; J Asconapé ; R Giannaula ; I C Parera
Eight cases of diurnal bruxism (DB) secondary to long-term antidopaminergic drug exposure are reported. Five exhibited a grinding pattern, one a clenching form, and two a mixed type. An odontological etiology was absent throughout. EMG recordings disclosed two distinct patterns of muscle activity, one with brief rhythmic, forceful contractions and the other featuring sustained prolonged contractions. Surface EMG and EEG monitoring during a 24-h period confirmed the absence of bruxism during sleep. Several drug trials failed to provide relief. Our findings support DB as a focal tardive dystonia syndrome.
In the topical treatment of atopic dermatitis, Incyte's Opzelura cream will likely have to compete with Roivant Sciences's Vtama and Arcutis' Zoryve.
Fighting for a place in the competitive atopic dermatitis market, Incyte hopes to reach younger patients with its JAK inhibitor cream Opzelura. A new pivotal trial win may help the company reach that goal, but safety concerns may present a challenge in a forthcoming market clash.
In a phase 3 trial in children ages 2 to 11 with atopic dermatitis, Opzelura cleared skin in significantly more patients than a nonmedicated topical control did, Incyte said Tuesday. The drug, a topical version of the ruxolitinib ingredient used in Jakafi, is currently approved in eczema patients 12 and older.
The trial, called TRuE-AD3, showed that Opzelura takers had a better chance at achieving clear or almost clear skin with at least a two-point improvement on the Investigators’ Global Assessment Treatment Success (IGA-TS) score at the eighth week. The trial, therefore, hit its primary endpoint.
The readout comes a few weeks after Roivant Sciences’ Dermavant said its rival cream Vtama hit the goals of two phase 3 atopic dermatitis trials in patients as young as 2. Arcutis Biotherapeutics also recently touted a win for its Zoryve cream in two phase 3 trials in eczema patients 6 years of age and older, with a separate study in children ages 2 to 5 expected to report topline data later this year.
In Opzelura’s case, a JAK classwide box warning could be a heavy cross to bear.
When approving Opzelura for eczema in 2021, the FDA slapped a box warning on the topical drug’s label. The warning discusses increased cardiovascular disease risks, serious infections and other side effects that were observed in studies of oral JAK inhibitors.
For the original approval in patients 12 years and above, Opzelura is made of 1.5% ruxolitinib and given twice daily. For the TRuE-AD3 trial in younger patients, Incyte tested both that dose and a lower 0.75% strength.
The company didn’t share specific efficacy or safety data but said the drug’s overall safety profile is “consistent with previous data” with no new safety signals observed. The trial remains ongoing to collect long-term safety data.
Incyte will discuss the data with regulatory agencies to determine the next steps, Jim Lee, M.D., Incyte’s VP for inflammation & autoimmunity, said in a statement Wednesday. By the company’s estimates, eczema affects about 2 million to 3 million children ages 2 to 11 and more than 21 million people 12 years and older.
Meanwhile, Incyte's Opzelura could use a market expansion. The drug’s sales disappointed in the first quarter, coming in at $57 million, or an 8% sequential decline. At that time, Leerink Partners analysts noted that Vtama and Zoryve are expected to enter the eczema market by the second half of 2024. These two drugs don’t have box warnings in their approved plaque psoriasis uses.
Incyte has also been suffering from a high discount rate for Opzelura at around 50% to 60% as of the first quarter. Payers could leverage the potential competition to push for bigger discounts, the Leerink team said in a May note.
Opzelura at the 1.5% strength currently boasts the strongest efficacy data among the three agents, although cross-trial comparisons can be problematic, the Leerink team noted in a May report. Vtama’s data across a wider age group looked comparable to Opzelura at the 0.75% strength in the previous TRuE-AD trials in older patients.
After Vtama’s readout, Leerink analysts put the Dermavant drug’s peak U.S. sales at above $1.5 billion. By comparison, the team figured Opzelura could reach global peak sales of $721 million.
Chinook Therapeutics has stopped testing of a liver disease therapy after a healthy patient in an early-stage study developed an unexpected complication believed to be a reaction to the experimental drug.
The serious adverse event prompted investigators to halt dosing of the drug, CHK-336. Chinook, a Seattle-based biotech, said it is voluntarily pausing the study to further investigate the matter. The FDA has been notified via a suspected unexpected severe adverse reaction report.
CHK-336 is in development for treating primary hyperoxaluria, a rare disease that leads to the buildup of oxalate in the body. Oxalate is a compound produced by the liver and also found in some foods. Primary hyperoxaluria stems from an inherited deficiency of an enzyme needed to break down oxalate so it can be filtered by the kidneys and then excreted in urine. The resulting oxalate buildup develops into kidney stones, which can in turn lead to chronic kidney disease that progresses to kidney failure. The Chinook drug is a small molecule designed to block lactate hydrogenase, or LDHA. This enzyme is key to the final step in oxalate production in the liver.
The Phase 1 study was designed to evaluate single and multiple-ascending doses of CHK-366. According to Chinook, the drug was generally well tolerated by 62 study participants at single doses up to 500 mg and multiple doses up to 60 mg taken daily for 14 days. The reported adverse event occurred in a patient given a 125 mg dose. The event had a rapid onset followed by rapid recovery, the company said. The complication is being investigated as potential hypersensitivity to the drug or its excipients, the inactive ingredients that make up the pill formulation.
CHK-336 is the third drug candidate that Chinook has advanced into human testing. The company’s lead program is atrasentan, a small molecule currently in Phase 3 testing in the rare kidney disease immunoglobulin A nephropathy. Another program, an antibody drug called BION-1301, is in Phase 2 testing in the same disorder.
In a research note, William Blair analyst Matt Phipps said that while the prospects for CHK-336 as a treatment for hyperoxaluria are intriguing, the drug is not a value driver for the company given its early stage of development. Instead, investor interest is centered on atresantan’s pivotal study, which is expected to post preliminary data in the fourth quarter of this year.
HI-Bio Eyes Pivotal Test of Antibody Drug Licensed From MorphoSys
In other kidney disease news, Human Immunology Biosciences (HI-Bio) reported positive results Tuesday from two separate Phase 2 tests of an antibody drug in development for treating primary membranous nephropathy (PMN), a rare disorder with no FDA-approved therapies.
The drug, felzartamab, is an antibody designed to target CD38, a protein abundant on plasma cells. These cells produce autoantibodies that cause autoimmune problems and they are believed to drive PMN. The HI-Bio drug is designed to deplete CD38-positive plasma cells.
South San Francisco-based HI-Bio reported data for an open-label Phase 1b/2a study that enrolled 31 patients who were given nine doses of the study drug over five months. A separate two-arm, open-label Phase 2 study enrolled 24 patients to evaluate two doses over two weeks and five doses over two months. Hi-Bio said the most durable reductions in an autoantibody called aPLA2R were observed in the Phase 1b/2a study. Results showed “early and substantial reductions” of aPLA2R levels as early as one week, where the median reduction was 45%. Most of those who responded to the treatment showed maintenance or a deepening of their response through 12 months.
Based on the mid-stage results, HI-Bio said it plans to advance felzartamab to Phase 3 testing after discussions with regulators. HI-Bio licensed felzartamab from MorphoSys last June. Last November, the biotech revealed $120 million in financing to support a pipeline of other drugs in development for treating autoimmune diseases. One of them is immunoglobulin A nephropathy—the same target Chinook is pursuing with its lead program.
Aptinyx’s approach of treating neurological disorders by targeting a key receptor in the brain has fallen short again, this time in Parkinson’s disease. With its third clinical trial failure in less than a year, the biotech said it will end the Parkinson’s program as well as a separate one in post-traumatic stress disorder.
The drug candidate for Parkinson’s, NYX-458, was in testing as a potential treatment for mild cognitive impairment or mild dementia associated with that disease or a closely related neurological disorder called dementia with Lewy bodies. The once-daily pill was being evaluated in a 99-patient, placebo-controlled study. According to preliminary results released after Monday’s market close, the Aptinyx drug did not show clinically meaningful improvement as assessed using tests to evaluate function and cognition in Parkinson’s patients.
“The results overall do not support further advancement of the development program by Aptinyx,” the company said in its announcement.
Evanston, Illinois-based Aptinyx develops small molecule drugs that target and modulate N-methyl-D-asparate (NMDA) receptors. These receptors are important to normal function of the brain and central nervous system. Aptinyx’s drugs stem from its platform technology for discovering molecules that can modulate NMDA receptors.
The Aptinyx technology has yielded drug candidates for chronic pain, Parkinson’s, and PTSD. Last April, Aptinyx reported that chronic pain drug NYX-2925 failed to distance itself from a placebo in a Phase 2 study enrolling patients with diabetic peripheral neuropathy. The company continued a mid-stage test assessing the drug in fibromyalgia. Last August, the chronic pain drug failed that study as well.
After the Parkinson’s failure, Aptinyx isn’t waiting to see the results for drug candidate NYX-783 in PTSD. The company said it will terminate that study and analyze the data to determine its next steps for that program. Aptinyx also said it will implement cost-cutting measures and explore “strategic alternatives,” which could mean a sale of the company or its assets, or perhaps a merger with a privately held biotech looking for way to enter the public markets.
Aptinyx’s drug discovery technology came from Naurex, a psychiatric drugmaker that was acquired by Allergan in 2015. That year, Aptinyx launched to develop its NMDA receptor-targeting drugs. The company went public in 2018, pricing its shares at $16 each and raising nearly $118 million. Shares of Aptinyx opened Tuesday at 20 cents apiece.
Image: Dr_Microbe, Getty Images