作者: Wang, Hongtao ; Dai, Feibiao ; Hu, Chengyun ; Zhang, Zhetao ; Li, Xue ; Tang, Chaoliang ; Dong, Yongfei ; Wang, Jiawu ; Zhou, Wanjun ; Geng, Qingtian

JOURNAL/nrgr/04.03/01300535-202411000-00028/figure1/v/2024-04-10T160327Z/r/image-tiff Calcium influx into neurons triggers neuronal death during cerebral ischemia/reperfusion injury. Various calcium channels are involved in cerebral ischemia/reperfusion injury. Cav3.2 channel is a main subtype of T-type calcium channels. T-type calcium channel blockers, such as pimozide and mibefradil, have been shown to prevent cerebral ischemia/reperfusion injury-induced brain injury. However, the role of Cav3.2 channels in cerebral ischemia/reperfusion injury remains unclear. Here, in vitro and in vivo models of cerebral ischemia/reperfusion injury were established using middle cerebral artery occlusion in mice and high glucose hypoxia/reoxygenation exposure in primary hippocampal neurons. The results showed that Cav3.2 expression was significantly upregulated in injured hippocampal tissue and primary hippocampal neurons. We further established a Cav3.2 gene-knockout mouse model of cerebral ischemia/reperfusion injury. Cav3.2 knockout markedly reduced infarct volume and brain water content, and alleviated neurological dysfunction after cerebral ischemia/reperfusion injury. Additionally, Cav3.2 knockout attenuated cerebral ischemia/reperfusion injury-induced oxidative stress, inflammatory response, and neuronal apoptosis. In the hippocampus of Cav3.2-knockout mice, calcineurin overexpression offset the beneficial effect of Cav3.2 knockout after cerebral ischemia/reperfusion injury. These findings suggest that the neuroprotective function of Cav3.2 knockout is mediated by calcineurin/nuclear factor of activated T cells 3 signaling. Findings from this study suggest that Cav3.2 could be a promising target for treatment of cerebral ischemia/reperfusion injury.

2024-10-31·ALTERNATIVE THERAPIES IN HEALTH AND MEDICINE

Protective Efficacy of T-type, Calcium Channel Antagonist on Auditory Function in Cdh23 Erl/Erl Mice.

Article

作者: Gao, Ying ; Zhang, Xiaotong ; Li, Heng ; Hu, Juan ; Ma, Weijun ; Cheng, Ying ; Xu, Min

Context:

In normal physiological conditions, calcium ions (Ca2+) have an important effect in terms of the regulation of hair cell (HC) functions, and T-type calcium antagonists may be protective against hearing loss. However, no studies have occurred related to a T-type calcium-channel antagonist with regard to otoprotection in a Cdh23 mouse model.

Objective:

The study intended to examine the protective efficacy of ethosuximide-a T-type calcium-channel antagonist-against age-related hearing loss in a Cadherin 23 (Cdh23) erl/erl mouse model, to potentially offer an insight and foundation for therapy in the near future for patients in clinical practice who suffer from age-related hearing loss.

Design:

The research team conducted an animal study.

Animals:

The animals were 12 male and 12 female, Cdh23 erl/erl mice.

Intervention:

The research team randomly divided the mice into two groups, with 12 mice in each group: (1) the control group, the saline group, which received saline at 10 mL/kg of body weight, and (2) the intervention group, the ethosuximide group, which received ethosuximide at 10 mL/kg of body weight. Both groups received the treatments intraperitoneally every other day, beginning postnatally at 7 days until the mice were 8 weeks old.

Outcome Measures:

For both groups, the research team: (1) measured auditory brainstem response (ABR); (2) measured distortion product otoacoustic emission (DPOAE) at 4, 6, and 8 weeks of age; (3) separated the basilar membrane from the modiolus and lateral tissues and determined the percentage of inner-and-outer hair-cell (IHC and OHC) loss; (4) investigated relative levels of apoptosis-related gene mRNA using reverse transcription polymerase chain reaction (PCR); and (5) examined relative levels of apoptosis-related protein, using immunofluorescent (IF) staining.

Results:

Compared to the saline group, the ethosuximide group: (1) had significantly lower ABR thresholds for click at 8 weeks, for 8 KHz at 6 and 8 weeks, and for 16 KHz and 32 KHz (all P < .01); (2) had significantly higher DPOAE amplitudes at 4 weeks at 15.4 KHz and 17.7 KHz (both P < .01); at 6 weeks at 8.8 KHz (P < .05), 10.1 KHz (P < .01), 11.7 KHz (P < .01), 13.4 KHz (P < .01), 15.4 KHz (P < .01), and 17.7 KHz (P < .01); and at 8 weeks at 6.7 KHz (P < .05), 7.7 KHz (P < .05), 10.1 KHz (P < .01), 11.7 KHz (P < .01), 13.4 KHz (P < .01), 15.4 KHz (P < .01), and 17.7 KHz (P < .01); (3) had significantly lower OHC loss in the middle and basal turns of the cochlea's surface (both P < .05); (4) at the age of 2 months, had significantly lower mRNA relative levels of apoptosis-related genes, including caspase-3, caspase-9, caspase-12, m-calpain and u-calpain, as found using a polymerase chain reaction (PCR); and (5) had weaker protein levels of caspase-3 and caspase-9 in the inner ears, as found using immunofluorescent (IF) staining.

Conclusions:

T-type calcium-channel antagonists can exert protective efficacy in terms of the hearing function among cdh23 erl/erl mouse.

2024-01-01·JOURNAL OF CARDIOVASCULAR PHARMACOLOGY AND THERAPEUTICS

MARRIAGE: A Randomized Trial of Moxonidine Versus Ramipril or in Combination With Ramipril in Overweight Patients With Hypertension and Impaired Fasting Glucose or Diabetes Mellitus. Impact on Blood Pressure, Heart Rate and Metabolic Parameters

Article

作者: Jambart, Selim ; Valensi, Paul

Background:

Moxonidine, an imidazoline I1 receptor agonist, is an effective antihypertensive drug that was shown to improve insulin sensitivity. RAAS-blockers are recommended as first-line therapy in patients with diabetes, alone or in combination with a calcium-channel antagonist or a diuretic.

Aims:

This study compared the effects of moxonidine and ramipril on blood pressure (BP) and glucose metabolism in overweight patients with mild-to-moderate hypertension and impaired fasting glucose or type 2 diabetes.

Methods:

Treatment-naïve patients for hypertension and dysglycemia were randomized to 12 weeks of double-blind moxonidine 0.4 mg or ramipril 5 mg once-daily treatment. At 12 weeks, for a further 12 weeks non-responders received combination of mox/ram, while responders continued blinded treatment.

Results:

Moxonidine and ramipril were equivalent in lowering SiDBP and SiSBP at the end of the first 12 weeks. The responder rate was approximately 50% in both groups, with a mean SiDBP and SiSBP decrease of 10 and 15 mm Hg in the responders, respectively. The normalization rate (SiDBP < 85 mm Hg) was non significantly different between treatments groups. Moxonidine reduced heart rate (HR) (average −3.5 bpm, p = 0.017) during monotherapy, and when added to ramipril. HbA1c decreased significantly at Week 12 in both groups. Neither drug affected glucose or insulin response to the oral glucose tolerance test. In non-responders, moxonidine/ramipril combination further reduced BP without compromising metabolic parameters.

Conclusion:

Moxonidine 0.4 mg and ramipril 5 mg were equally effective on BP lowering and were well tolerated and mostly metabolically neutral either as monotherapies or in combination. HR was lowered on moxonidine treatment.

项与 T-type calcium channel antagonist(Diakron Pharmaceuticals) 相关的新闻（医药）

2018-10-04

·businesswire.com

Cavion to Announce Results of its Phase 2 Essential Tremor Clinical Trial

CHARLOTTESVILLE, Va. & CAMBRIDGE, Mass.--(BUSINESS WIRE)--Cavion, Inc., a leading clinical stage biotechnology company committed to developing novel therapeutics for people with neurological diseases, announced today that results of the Phase 2 study of its lead compound for essential tremor will be presented as a late-breaking poster at the International Congress of Parkinson’s Disease and Movement Disorders® in Hong Kong October 5-9, 2018. Phase 2 data from @CavionPharma in #essentialtremor will be highlighted in #latebreaker at #MDSCongress in Hong Kong on October 8 with three additional posters on its first-in-class T-Type calcium channel modulator CX-8998 Cavion’s team of experts is developing oral small molecules designed to selectively modulate T-type calcium channel activity in the central nervous system, acting as a biological “pacemaker” to help restore the brain’s natural rhythms. The company’s lead compound, CX-8998, was evaluated in the T-CALM study, a Phase 2, double-blind, placebo controlled clinical trial of 95 patients with essential tremor conducted at 25 sites across the United States. Patients were randomized to receive either placebo or CX-8998 titrated up to 10mg dosed twice daily (BID). A majority of subjects (64 percent) added study drug to their existing standard of care anti-tremor medication. “Cavion is dedicated to developing first-in-class T-type calcium channel therapies aimed at improving function for people with movement disorders and rare neurological diseases, using state-of-the-art clinical development methodologies,” said Spyros Papapetropoulos, MD, PhD, Cavion’s Executive Vice President of Research & Development and Chief Medical Officer. “Our T-CALM study is one of the largest Phase 2 essential tremor clinical trials ever conducted, and CX-8998 is the only late-stage essential tremor small molecule in development for this disease. We look forward to presenting these results as we grow the body of clinical evidence supporting our ground-breaking approach in essential tremor, a disorder that has not seen any new approved drug therapies in more than 30 years.” The T-CALM study abstract was selected for a late-breaking poster presentation on Monday, October 8: “Proof-of-Concept, Double-Blind, Placebo-Controlled Study for CX-8998 a State-Dependent T-Type Calcium (Cav3) Channel Antagonist in Essential Tremor Patients (T-CALM): Efficacy and Safety Results.” Additional Cavion research to be presented at the Congress includes: Proof-of-Principle Quantitative EEG Study Of CX-8998, An Oral, Potent and Selective T-Type Calcium Antagonist in Development for Symptomatic Treatment of Essential Tremor and Parkinson’s Disease Tremor A Phase 2 Efficacy Study of CX-8998, A Potent and Selective T-Type Calcium (Cav3) Modulator in Parkinson’s Disease Tremor (PDT) Patients: Design and Dose-Selection Rationale Therapeutic Exposures of CX-8998, A Potent, Selective and State Dependent Cav3 Channel Antagonist in Development for Essential Tremor and Parkinson’s Disease Tremor in Cav3 Driven Neurological Models About Cavion, Inc. Cavion, Inc. is a privately held clinical stage biotechnology company creating therapies aimed at modulating the T-type calcium channel for the treatment of chronic and rare neurological diseases. Cavion’s portfolio of T-type calcium channel modulators is being developed to restore the brain’s natural rhythms in a variety of neurological diseases such as essential tremor, Parkinson’s disease tremor, neuropathic pain, and epilepsy with absence seizures. About Essential Tremor About 10 million Americans and 42 million people worldwide are affected by essential tremor (ET), the most common movement disorder. ET is a progressive neurodegenerative disease that ranges from mild to fully debilitating, with significant effects on people’s quality of life and activities of daily living, such as eating and drinking, dressing, writing and typing. The condition can lead to social embarrassment, phobia, anxiety, and depression. With no new drugs approved for more than three decades, there is an incredible need for new and effective options for patients with ET (Haubenberger and Hallett. 2018. Essential Tremor. New England Journal of Medicine. 378:19). Forward-Looking Statement This press release contains forward-looking statements that are subject to risks and uncertainties and includes statements that are not historical facts. Actual results could differ significantly from results discussed. Cavion, Inc. disclaims any intent or obligation to update forward-looking statements, except as required by law.

临床2期临床结果

100 项与 T-type calcium channel antagonist(Diakron Pharmaceuticals) 相关的药物交易

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