Nivadil (nilvadipine) / Cortice Biosci - LARVOL DELTA

Toward a personalized chronotherapy of blood pressure. (PubMed, Biomed J) - "Personalized optimization of treatment timing to best match a healthy circadian BP pattern is recommended, guided by chronobiological analyses of ABPM data collected over several days in view of the large day-to-day variability in all features of the 24-hour BP rhythm."

Journal

Cholesterol-27α-hydroxylase inhibitor nilvadipine can effectively treat cholestatic liver injury in adult offspring induced by prenatal dexamethasone exposure. (PubMed, MedComm (2020)) - "Finally, nilvadipine effectively reversed cholestatic liver injury induced by PDE. This study confirmed PDE could cause cholestatic liver injury, and innovatively proposed its early intervention target (CYP27A1) and effective drug (nilvadipine), providing a theoretical and experimental basis for guiding rational drug use during pregnancy, and preventing and treating the fetal-originated cholestatic liver injury."

Journal • Hepatology • Liver Failure • CYP27A1

Adrenal High-Expressional CYP27A1 Mediates Bile Acid Increase and Functional Impairment in Adult Male Offspring by Prenatal Dexamethasone Exposure. (PubMed, Adv Sci (Weinh)) - "Finally, administration of nilvadipine (CYP27A1 inhibitor) to male offspring for 4 weeks after birth resulted in the reversal of PDE-induced adrenal morphological and functional damage. In conclusion, PDE induces fetal adrenal corticosteroid dysfunction in adult male offspring by upregulating CYP27A1 promoter region H3K27ac levels and expression in the adrenal gland through the GR/SETBP1 signaling pathway. This effect persists beyond birth, leading to bile acids local increase and subsequent enhancement of ERS, ultimately inducing cellular dysfunction in adult adrenal glands."

Journal • CYP27A1 • SETBP1

Advancements in autophagy perturbations in Alzheimer's disease: Molecular aspects and therapeutics. (PubMed, Brain Res) - "These drugs include metformin that has been found to modulate the expression of TRIB3 for autophagy regulation. BACE1 and mTOR inhibitors like arctigenin, nilvadipine and dapagliflozin were also found to restore autophagy. This study elaborates recent advances in signaling and molecular pathways and discusses current and emerging therapeutic interventions targeting autophagy dysfunction in AD."

Journal • Review • Alzheimer's Disease • CNS Disorders • Inflammation • Metabolic Disorders • TRIB3

Carvedilol increases seizure resistance in a mouse model of SCN8A-derived epilepsy. (PubMed, Front Pharmacol) - "The top compounds that emerged from this screen included amitriptyline, carvedilol, and nilvadipine. In the current study, we evaluated the ability of these three compounds to increase resistance to 6 Hz or pentylenetetrazole (PTZ)-induced seizures in wild-type CF1 mice and in a mouse line expressing the human SCN8A R1620L mutation...While amitriptyline, carvedilol, and fenfluramine provided robust protection against induced seizures in CF1 mice, only carvedilol was able to significantly increase resistance to 6 Hz- and PTZ-induced seizures in RL/+ mutants. These results provide support for further evaluation of carvedilol as a potential treatment for patients with SCN8A mutations."

Journal • Preclinical • Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Mental Retardation • SCN8A

Ginseng root extract-mediated synthesis of monodisperse silver nanoparticles as a fluorescent probe for the spectrofluorometric determination of nilvadipine; Evaluation of remarkable anti-bacterial, anti-fungal and in-vitro cytotoxic activities. (PubMed, Spectrochim Acta A Mol Biomol Spectrosc) - "Finally, in-vitro cytotoxicity assay of Ag-NPs against normal and cancerous human cell lines was studied using MTT assay. The results proved the potential use of the produced Ag-NPs as an adjunct to anticancer treatment or for drug delivery without significantly harming healthy human cells."

Journal • Preclinical • Oncology

Long-term antipsychotic use, orthostatic hypotension and falls in older adults with Alzheimer's disease. (PubMed, Eur Geriatr Med) - "Even in mild-to-moderate AD, long-term antipsychotic use was associated with ssOH. Both antipsychotic use and ssOH were associated with a greater risk of incident falls/syncope over 18 months. Further attention to optimal prescribing interventions in this cohort is warranted and may involve screening older adults with AD prescribed antipsychotics for both orthostatic symptoms and falls."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Dementia • Geriatric Disorders • Hypotension

Neuroprotective effect of the calcium channel blocker nilvadipine on retinal ganglion cell death in a mouse ocular hypertension model. (PubMed, Heliyon) - "Nilvadipine was a potent neuroprotective agent for RGCs in our mouse model of OH and may have potential for protection against glaucoma. This model is useful as a screening tool for drugs with retinal protective effects."

Journal • Preclinical • Cardiovascular • Glaucoma • Ophthalmology • THY1

Hydroxychloroquine induces endothelium-dependent and endothelium-independent relaxation of rat aorta. (PubMed, Turk J Med Sci) - "HCQ produced relaxation of RA rings. The relaxation mechanism differs according to the concentration of HCQ. At con-centrations of 10-6 and 10-5 M, the relaxation is endothelium-dependent and mediated by NO. We strongly suggest that Ca2+ channel inhibition is involved at concentrations of 10-5 and 10-4 M, as well as NO."

Journal • Preclinical • Immunology • Infectious Disease • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology

Combination of Lanosterol and Nilvadipine Nanosuspensions Rescues Lens Opacification in Selenite-Induced Cataractic Rats. (PubMed, Pharmaceutics) - "Moreover, the opacity levels in the cataractic rats were reduced after treatment with the combination of LAN-ONSs and NIL-ONSs. It is possible that the combination of LAN and NIL will be useful for the treatment of lens opacification in the future."

Journal • Preclinical • Cataract • Ophthalmology

Instillation of Ophthalmic Formulation Containing Nilvadipine Nanocrystals Attenuates Lens Opacification in Shumiya Cataract Rats. (PubMed, Pharmaceutics) - "In addition, the anti-cataract effect in the lens of rats instilled with NIL-NP dispersions was also significantly higher than that in NIL-MP dispersions. NIL-NPs could be used to prevent lens opacification."

Journal • Preclinical • Cataract • Ophthalmology

Recent Advances in Molecular Pathways and Therapeutic Implications Targeting Mitochondrial Dysfunction for Alzheimer's Disease. (PubMed, Mol Neurobiol) - "Excessive calcium release also impairs mitochondrial functions; to overcome this, calcium channel blockers like nilvadipine are used. Modulations in AMPK, SIRT1 and Akt pathways can also come out to be better therapeutic strategies as these pathways regulate functions of mitochondria. Oxidative phosphorylation is major generator of Reactive Oxygen Species (ROS) leading to mitochondrial damage; therefore reduction in production of ROS by using antioxidants like MitoQ, Curcumin and Vitamin Eis quiteeffective."

Journal • Review • Alzheimer's Disease • CNS Disorders • Metabolic Disorders • APP

The Expanding Role of Pyridine and Dihydropyridine Scaffolds in Drug Design. (PubMed, Drug Des Devel Ther) - "In the US FDA database, there are 95 approved pharmaceuticals that stem from pyridine or dihydropyridine, including isoniazid and ethionamide (tuberculosis), delavirdine (HIV/AIDS), abiraterone acetate (prostate cancer), tacrine (Alzheimer's), ciclopirox (ringworm and athlete's foot), crizotinib (cancer), nifedipine (Raynaud's syndrome and premature birth), piroxicam (NSAID for arthritis), nilvadipine (hypertension), roflumilast (COPD), pyridostigmine (myasthenia gravis), and many more. This review examines the prospects of highly potent bioactive molecules to emphasize the advantages of using pyridine and dihydropyridine in drug design. We cover the most recent developments from 2010 to date, highlighting the ever-expanding role of both scaffolds in the field of medicinal chemistry and drug development."

Journal • Review • Alzheimer's Disease • Cardiovascular • Chronic Obstructive Pulmonary Disease • CNS Disorders • Genito-urinary Cancer • Human Immunodeficiency Virus • Hypertension • Immunology • Infectious Disease • Myasthenia Gravis • Oncology • Prostate Cancer • Pulmonary Disease • Respiratory Diseases • Rheumatology • Solid Tumor • Tuberculosis

Nilvadipine suppresses inflammation via inhibition of P-SYK and restores spatial memory deficits in a mouse model of repetitive mild TBI. (PubMed, Acta Neuropathol Commun) - "Treatment with racemic nilvadipine mitigated the TBI-induced inflammatory response and significantly improved spatial memory, whereas (-)-enantiomer decreased microgliosis and improved spatial memory but failed to reduce the astroglial response to as much as the racemate. These results suggest the therapeutic potential of SYK inhibition that is enhanced when combined with the CCB effect, which indicate a therapeutic advantage of multi-action drugs for r-mTBI."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Immunology • Inflammation • Vascular Neurology • SYK

Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension. (PubMed, J Am Heart Assoc) - P3 | "Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02017340."

Clinical • Journal • Alzheimer's Disease • CNS Disorders • Hypertension • Hypotension • Musculoskeletal Diseases • Orthopedics

Some calcium-channel blockers: kinetic and in silico studies on paraoxonase-I. (PubMed, J Biomol Struct Dyn) - "IC values were found as 41.00, 48.00, and 180 µM for nimodipine, cinnarizine, and nilvadipine, respectively. Therefore, further biological studies such as gene expression and in vivo experiments should be done for these drugs. Communicated by Ramaswamy H. Sarma."

Journal • PON1

Congruent release of drug and polymer: A "sweet spot" in the dissolution of amorphous solid dispersions. (PubMed, J Control Release) - "Specifically, the effect of drug log P, phase behavior of the hydrated but undissolved ASD matrix and the relative dissolution rates of drug and polymer were studied as a function of drug loading, using nilvadipine (Nil) (ClogP = 3.04) and cilnidipine (Cil) (ClogP = 5.54) as model drugs...These most likely arise due to faster polymer release in comparison to drug, whereby the drug-rich composition around these pits was confirmed by energy-dispersive X-ray (EDX) analysis and the surface drug enrichment on the compacts was confirmed by X-ray photoelectron spectroscopy (XPS). This study demonstrates two important findings, firstly, a link between congruent release of drug and polymer and the occurrence of LLPS and secondly, the switch between congruent and incongruent release of drug and polymer is a result of competitive kinetics between phase separation and the release rate of ASD components with minimal influence from drug hydrophobicity for two structural analogues."

Journal

Major human drug trial underway for Alzheimer's (Medical Xpress) - "A potentially ground-breaking human drug trial is currently underway...whether blood pressure medication can slow or halt the progression of Alzheimer's Disease (AD)...This major 18-month study is NILVAD ('Nilvadipine in Alzheimer's disease')..."

Anticipated trial initiation date • Alzheimer's Disease

Therapeutic Effect of Ophthalmic Formulation containing Nilvadipine Nanoparticles on Retinal Dysfunction in Rats Injected with Streptozotocin (ARVO 2018) - "These findings provide significant information that can be used to design further studies aimed at therapeutic treatment of retinopathy. We designed the novel ophthalmic formulation containing nilvadipine nanoparticles, and the ophthalmic formulation may lead the effective therapy for retinopathy."

Preclinical • Biosimilar • Ophthalmology

Effects of wet-granulation process parameters on the dissolution and physical stability of a solid dispersion. (PubMed) - Int J Pharm - "...SDs of nilvadipine (NIL) and hypromellose prepared by spray-drying were wet-granulated and dried under various conditions...A statistical analysis revealed that the amount of granulation liquid (w/w%) and the ratio of water to ethanol in the liquid (v/v%) significantly affected the dissolution property, and that the drying temperature had a significant effect on the physical stability. Although exposure to water makes the wet-granulation process seem less suitable for granulating a SD, the results indicated that the process can be used to develop SD granules by selecting appropriate conditions, such as a lower proportion of granulation liquid, a higher water to ethanol ratio in the liquid, and a higher drying temperature."

Journal • Biosimilar

Gait speed, cognition and falls in people living with mild-to-moderate Alzheimer disease: data from NILVAD. (PubMed, BMC Geriatr) - P3 | "Poorer baseline cognition was associated with both baseline and incident slow gait speed. Slow gait speed was associated with a significantly increased risk of falls over the study period. Our study adds further evidence to the complex relationship between gait and cognition in this vulnerable group and highlights increased falls risk in older adults with AD and slow gait speed."

Journal

The Influence of Baseline Alzheimer's Disease Severity on Cognitive Decline and CSF Biomarkers in the NILVAD Trial. (PubMed, Front Neurol) - P3 | "These studies suggest that baseline AD severity influenced the treatment outcome in the NILVAD trial and that future clinical trials of nilvadipine should be restricted to mild and very mild AD patients. Trial Registration: NCT02017340 Registered 20 December 2013, https://clinicaltrials.gov/ct2/show/NCT02017340 EUDRACT Reference Number 2012-002764-27 Registered 04 February 2013, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-002764-27."

Biomarker • Journal

Nilvadipine and related drugs could slow Alzheimer’s progression (European Pharmaceutical Review) - "A clinical trial testing the efficacy of Nilvadipine in Alzheimer’s disease patients has shown that the drug can slow cognitive decline in very early- and early-stage Alzheimer’s disease....The institute has been awarded funding by the National Institutes of Health to develop a second generation of drugs with Nilvadipine’s benefits minus the unwanted side effects, such as lowered blood pressure."

Clinical data • Grant

Calcium Channel Blockers: Molecular Docking and Inhibition Studies on Carbonic Anhydrase I and II Isoenzymes. (PubMed, J Biomol Struct Dyn) - "It was found that calcium channel blockers (nimodipine, nilvadipine, nitrendipine, isradipine, and nifedipine) exhibit potential inhibitor properties for hCA I and hCA II. Among these drugs, nitrendipine was found to be the most potent inhibitor for hCA I and nimodipine for hCA II. These compounds may be useful for CA inhibitors."

Journal

Alzheimer’s drug trial begins this week (The Irish Times) - "A major 18-month human drug trial gets under way this...blood pressure medication can slow or halt the progression of Alzheimer’s disease symptoms. An Irish medical researcher, Prof Brian Lawlor, is co-ordinating the international trial, Nilvad (nilvadipine in Alzheimer’s disease), which involves nine countries and has funding worth €6 Million...European Community’s seventh framework programme research budget."

Anticipated new trial • Financing