作者: Vermudez, Sheryl Anne D. ; Eastman, Cliff ; Vermudez, Sheryl Anne D ; Hameed, Mustafa Q ; D'Ambrosio, Raimondo ; Rundfeldt, Chris ; D’Ambrosio, Raimondo ; Liebhardt, Amanda ; Hui, Benjamin ; Choe, Yongho ; Klein, Pavel ; Lin, Rui ; Hameed, Mustafa Q. ; Löscher, Wolfgang ; Rotenberg, Alexander

Post-traumatic epilepsy (PTE) is a recurrent and often drug-refractory seizure disorder caused by traumatic brain injury (TBI). No single drug treatment prevents PTE, but preventive drug combinations that may prophylax against PTE have not been studied. Based on a systematic evaluation of rationally chosen drug combinations in the intrahippocampal kainate (IHK) mouse model of acquired epilepsy, we identified two multi-targeted drug cocktails that exert strong antiepileptogenic effects. The first, a combination of levetiracetam (LEV) and topiramate, only partially prevented spontaneous recurrent seizures in the model. We therefore added atorvastatin (ATV) to the therapeutic cocktail (TC) to increase efficacy, forming "TC-001". The second cocktail - a combination of LEV, ATV, and ceftriaxone, termed "TC-002" - completely prevented epilepsy in the mouse IHK model. In the present proof-of-concept study, we tested whether the two drug cocktails prevent epilepsy in a rat PTE model in which recurrent electrographic seizures develop after severe rostral parasagittal fluid percussion injury (FPI). Following FPI, rats were either treated over 3-4 weeks with vehicle or drug cocktails, starting either 1 or 4-6 h after the injury. Using mouse doses of TC-001 and TC-002, no significant antiepileptogenic effect was obtained in the rat PTE model. However, when using allometric scaling of drug doses to consider the differences in body surface area between mice and rats, PTE was prevented by TC-002. Furthermore, the latter drug cocktail partially prevented the loss of perilesional cortical parvalbumin-positive GABAergic interneurons. Plasma and brain drug analysis showed that these effects of TC-002 occurred at clinically relevant levels of the individual TC-002 drug components. In silico analysis of drug-drug brain protein interactions by the STITCH database indicated that TC-002 impacts a larger functional network of epilepsy-relevant brain proteins than each drug alone, providing a potential network pharmacology explanation for the observed antiepileptogenic and neuroprotective effects observed with this combination.

2023-11-01·Journal of Ocular Pharmacology and Therapeutics

Pharmacokinetic and Ocular Toxicity Evaluation of Latanoprost Ophthalmic Solution, 0.005%, with Preservative Level Reduced to Below the Limit of Quantitation

Article

作者: Venkatesh, Srini ; Richardson, Mary

Purpose: The systemic and ocular pharmacokinetics (PK), and ocular toxicity of benzalkonium chloride (BAK)-free TearClear latanoprost ophthalmic solution, 0.005% formulation (TC-002) were evaluated. TC-002 is designed to selectively capture BAK at the time of drug administration; therefore, the dose delivered to the eye contains no quantifiable level of preservative. Methods: The systemic and ocular PK of TC-002 were compared to a BAK containing reference listed drug (RLD, Xalatan™) over a 24-h period, after a single topical ocular dose to 1 eye of male Dutch Belted (DB) rabbits (n = 3/timepoint). Latanoprost acid concentrations were measured in plasma and ocular tissues. The ocular toxicity was evaluated in a separate study and included toxicokinetic evaluation of TC-002 after once daily topical ocular dosing into each eye of DB rabbits (n = 8/group) for at least 28 days. Toxicity endpoints included ophthalmic and clinical evaluations, necropsy, and microscopic evaluation of ocular tissues. Results: Average ratios of C_max values for TC-002/RLD ranged from 0.6 to 1.6, and C_max and area under the concentration-time curve of last observed concentration (AUC_last) exposures to latanoprost acid were similar (<2-fold) between the 2 treatments. In the 28-day study, the T_max was achieved in both groups in <0.5 h. There were no abnormal ocular findings. Conclusions: TC-002 with no quantifiable preservative or BAK-containing RLD exhibited similar ocular and systemic PK profiles. TC-002 was well tolerated and comparable to RLD. TC-002 retains the safety and PK characteristics of RLD without the added concern of long-term exposure of the eye to preservatives.

2023-04-18·Analytical chemistry

Bifunctional Single-Molecular Fluorescent Probe: Visual Detection of Mitochondrial SO₂ and Membrane Potential.

Article

作者: Deng, Yu ; Bu, Yingcui ; Yu, Zhi-Peng ; Wang, Sen ; Ren, Mengjuan ; Zhu, Yicai ; Huang, Houshi ; Ai, Wenming ; Zhou, Hongping ; Wang, Junjun

Mitochondrial membrane potential (MMP) and sulfur dioxide (SO₂) significantly affect the mitochondrial state. In this work, TC-2 and TC-8 were constructed through side-chain engineering, in which TC-2 bearing the poorer hydrophobicity could localize on mitochondria better. Interestingly, short-wave emission was captured due to the sensitive response of TC-2 to SO₂ (LOD = 13.8 nM). Meanwhile, the probe could bind with DNA, presenting enhanced long-wave emission. Encouragingly, TC-2 could migrate from mitochondria to the nucleus when MMP was decreased, accompanied by the increase of fluorescence lifetime (9-fold). Hence, TC-2 could be used for dual-channel monitoring of mitochondrial SO₂ and MMP, which showed a completely different pathway from the commercial MMP detectors JC-1/JC-10. The cellular experiments showed that MMP was gradually decreased due to reactive oxygen species-triggered oxidative stress, and the SO₂ level was up-regulated simultaneously. Overall, this work proposed a new method to investigate and diagnose the mitochondrial-related diseases.

项与 TC-002 相关的新闻（医药）

2022-09-29

·BioSpace

TearClear Announces Positive Topline Results from CLEAR Phase 3 Study for the Treatment of Glaucoma with TC-002 (latanoprost ophthalmic solution 0.005%)

Successfully met the primary and all secondary endpoints On track for New Drug Application (NDA) filing, with the FDA in Q1 2023 TC-002 is the first of four proprietary glaucoma drugs in the TearClear near term pipeline CHICAGO, Sept. 29, 2022 (GLOBE NEWSWIRE) -- TearClear, an ophthalmic pharmaceutical company that transforms trusted drugs into branded best-in-class therapies, announced today that the company’s lead product, TC-002 (latanoprost ophthalmic solution 0.005%) met the primary and all secondary endpoints in the CLEAR Phase 3 pivotal trial. With these results, TearClear plans to New Drug Application (NDA) with the US Food and Drug Administration (FDA) in the first quarter of 2023. Upon approval, TC-002 will offer patients the first and only means of delivering preservative-free doses of latanoprost from conventional multi-dose bottles. “TearClear is responding to an important unmet need. Many patients on preserved glaucoma medications experience moderate to severe signs and symptoms of ocular surface disease (OSD)1. This causes discomfort for patients, frustration for physicians and drives additional costs for payers,” said Stuart Raetzman, CEO of TearClear. “Switching from preserved to unpreserved glaucoma medications significantly reduces the prevalence of signs and symptoms of OSD2. In these cases, physicians want to keep well controlled glaucoma patients on the same drug, payers want to reduce the additional costs related to OSD treatment and patients want to keep multi-dose bottles. Only TearClear addresses the needs of all stakeholders.” Developed from a platform of interconnected and proprietary technologies, TC-002 contains the preservative benzalkonium chloride (BAK) while in the bottle, but delivers pristine, preservative free drops to the eye. In the bottle, BAK maintains sterility, increases stability and aids in solubility. Because the BAK is removed from the drops as they are dispensed to the eye, the prevalence of OSD signs and symptoms can be reduced compared to the prevalence caused by drops that contain BAK. “In glaucoma, my field of specialty, we treat the disease, in many instances with eyedrops and in many cases, multiple eye drops. And while it's essential to get these pharmaceuticals to the surface of the eye, pristine and sterile, the BAK formulas in many cases are delivering a high dose of benzalkonium chloride,” says Thomas Samuelson, MD, a founding partner of Minnesota Eye Consultants. “If we can keep the BAK in the bottle, but once the eyedrop hits the surface of the eye, it's BAK-free, that's really the best of both worlds.” “CLEAR is a Phase 3 prospective, double masked, randomized, multi-center, active-controlled, parallel group, three-month trial evaluating the efficacy and safety of TC-002 in patients with elevated intraocular pressure (IOP),” says Srini Venkatesh, Ph.D., President, R&D and Technical Operations. “We achieved the primary efficacy endpoint, which is the difference in mean change from baseline in IOP at weeks two, six and twelve at 8:00 am, 10:00 am and 4:00 pm. We also achieved all of the secondary efficacy endpoints, which includes diurnal (average of 8:00am, 10:00 am and 4:00 pm measurements) IOP at weeks two, six and twelve.” In the near term, TearClear is using its proprietary platform to develop a portfolio of four glaucoma drugs. In addition to TC-002 (latanoprost 0.005%), TearClear also filed an investigational new drug (IND) application for TC-003 (brimonidine/timolol) in June 2022, which the FDA has cleared for initiating the TC-003 clinical trial. TearClear plans to IND applications for TC-001 (timolol) and for TC-004 (brimonidine). In the mid- and longer-term, TearClear can use the proprietary platform to develop products to treat dry eye, allergy, inflammation, presbyopia, myopia and other ophthalmic conditions. Contacts: Media Contact Patrick Crowley TearClear 859-462-4245 pcrowley@strategicadvisersllc.com Other Inquiries Kevin Hershfield TearClear Chief Operating Officer khershfield@TearClear.com Baudouin, Christophe, Detrimental effect of preservatives in eye drops: Implications for the treatment of glaucoma. Acta Ophthalmologica 2008: 86: 716-726 Jaenen, N., Baudouin, C, Pouliquen, P., Manni, Figueiredo, A., Zeyen, T. Ocular symptoms and signs with preserved and preservative-free glaucoma medications. European Journal of Ophthalmology, Vol. 17 no. d, 2007/ pp. 341 -349.

100 项与 TC-002 相关的药物交易

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