====== NicaPlant ======

//J.Sales-Llopis//

//Neurosurgery Service, Alicante University General Hospital, Spain.//
----
see also [[Nicardipine for aneurysmal subarachnoid hemorrhage]].

To obtain sufficient [[nicardipine]] drug concentration at the site of action without observing the systemic [[side effect]]s the [[drug]] needs to be delivered in close proximity to the place where it should be active.

This can be obtained by placing it in close contact with the wall of the [[cerebral artery]] at the time of [[aneurysm]] [[clipping]], in this way circumventing the [[blood-brain barrier]]. The selection of the calcium channel blocker nicardipine, contained in NicaPlant® is based on its chemical-physical characteristics and a [[prospective]] [[randomized]] multicenter [[Phase 2b trial]], Vajkoczy et al. could demonstrate the [[safety]] and [[efficacy]] of NicaPlant® implants in preventing CV in patients with SAH
((Vajkoczy, Peter MD; Thomé, Claudius; Kerschbaumer, Johannes; Meyer, Bernhard MD; Wostrack, Maria; Adage, Tiziana; Breitenbach, Jörg; Bavinzski, Gerhard; Hirschmann, Dorian; Bendszus, Martin; Rohde, Veit; Mielke, Dorothee; Wessels, Lars. 104 A Safety and Efficacy Study of NicaPlant® in Aneurysmal Subarachnoid Haemorrhage Patients Undergoing Aneurysm Clipping. Neurosurgery 69(Supplement_1):p 23, April 2023. | DOI: 10.1227/neu.0000000000002375_104)).

[[https://www.ema.europa.eu/en/documents/orphan-designation/eu/3/19/2240-public-summary-opinion-orphan-designation-nicardipine-treatment-non-traumatic-subarachnoid_en.pdf|Orphan designation]]

===== Developer =====

https://www.bit-pharma.com/product/

===== Trials =====

The trial was performed as an international [[randomized]], [[controlled study]], [[single-blinded study]] [[multicenter study]]. 40 Patients with [[World Federation of Neurosurgical Societies grading for subarachnoid hemorrhage]] 3 and 4 undergoing surgical repair of their [[ruptured aneurysm]] were [[random]]ized to receive ten pellets of NicaPlant® (40 mg) plus standard of care or standard of care alone. The [[implant]]s were administered immediately following [[clip]] ligation of the ruptured aneurysm in proximity to all the exposed cerebral [[blood vessel]]s. The [[primary endpoint]] was the incidence of moderate to severe [[cerebral vasospasm]] (day 8 ± 1). A blinded independent outcome accessor analyzed all imaging data.

In the implant group, 20% (4/20) of patients reached the [[primary endpoint]], compared to 58% (11/19) of patients in the control group (p = 0.024). Including mild CV, 75% of all patients in the control group developed CV compared to 30% in the implant group (p = 0.0129). 32% (6/19) of the patients in the control group developed new cerebral infarction, compared to 10% (2/20) in the implant group (p = 0.1273). Endovascular rescue therapy was performed in 10% of the patients in the implant group compared to 58% in the control group (p = 0.002). 4 subjects (20%) in the control group experienced Treatment-emergent adverse events (TEAE), compared with none in the active group
((Vajkoczy, Peter MD; Thomé, Claudius; Kerschbaumer, Johannes; Meyer, Bernhard MD; Wostrack, Maria; Adage, Tiziana; Breitenbach, Jörg; Bavinzski, Gerhard; Hirschmann, Dorian; Bendszus, Martin; Rohde, Veit; Mielke, Dorothee; Wessels, Lars. 104 A Safety and Efficacy Study of NicaPlant® in Aneurysmal Subarachnoid Haemorrhage Patients Undergoing Aneurysm Clipping. Neurosurgery 69(Supplement_1):p 23, April 2023. | DOI: 10.1227/neu.0000000000002375_104)).

https://clinicaltrials.gov/ct2/show/NCT04269408

===== Animal Studies =====

Bayerl et al. tested in vitro the release dynamics of a novel formulation of the [[calcium channel blocker]] [[nicardipine]] and in vivo local tolerance and tissue [[reaction]] using a chronic cranial window model in [[mice]].
To characterize the release kinetics [[in vitro]], dissolution experiments were performed using [[artificial cerebrospinal fluid]] over a time period of 21 days. The [[excipient]]s used in this formulation ([[NicaPlant]]) for sustained nicardipine release are a mixture of two completely degradable [[polymer]]s. A chronic cranial window in [[C57BL/6 mice]] was prepared, and NicaPlant slices were placed in proximity to the exposed cerebral [[vasculature]]. Epifluorescence video microscopy was performed right after implantation and on days 3 and 7 after surgery. The vessel diameter of the arteries and veins, vessel permeability, vessel configuration, and leukocyte-endothelial cell interaction were quantified by computer-assisted analysis. Immunofluorescence staining was performed to analyze inflammatory reactions and neuronal alterations.

In vitro, the nicardipine release profile showed an almost linear curve with about 80% release on day 15 and full release on day 21. In vivo, epifluorescence video microscopy showed a significantly higher arterial vessel diameter in the NicaPlant group due to vessel dilatation (21.6 ± 2.6 µm vs 17.8 ± 1.5 µm in controls, p < 0.01) confirming vasoactivity of the implant, whereas the venous diameter was not affected. Vessel dilatation did not have any influence on the vessel permeability measured by contrast extravasation of the fluorescent dye in epifluorescence microscopy. Further, an increased leukocyte-endothelial cell interaction due to the implant could not be detected. Histological analysis did not show any microglial activation or accumulation. No structural neuronal changes were observed
((Bayerl SH, Ghori A, Nieminen-Kelhä M, Adage T, Breitenbach J, Vajkoczy P, Prinz V. In vitro and in vivo testing of a novel local nicardipine delivery system to the brain: a preclinical study. J Neurosurg. 2019 Jan 25;132(2):465-472. doi: 10.3171/2018.9.JNS173085. PMID: 30684943.)).