Synergistic therapies of cannabidiol with hypothermia for neuroprotection

a technology of cannabidiol and synergistic therapy, applied in the direction of drug composition, contraceptive devices, cardiovascular disorders, etc., can solve the problems of brain development, determining long-term morbidity, toxic increase of intracellular calcium,

Active Publication Date: 2016-08-25
GW RES LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The combination of CBD with hypothermia significantly reduces brain damage and improves neuroprotection in animal models of NHIE, offering a promising treatment option for NHIE and potentially for stroke or cardiac arrest, with CBD showing beneficial effects for up to three days post-injury.

Problems solved by technology

In addition to inflicting direct brain damage, leading to acute brain dysfunction, such an insult can also interfere with brain development, determining long-term morbidity.
After the early energetic fall during hypoxia-ischemia, failure of neuronal ionic pumps lead to a toxic increase of intracellular calcium, activating degrading enzymes.
During reperfusion, re-oxygenation and inflammatory responses start a second wave of damage, which lead to a secondary energetic failure and to DNA damage, activating apoptosis.
However in the majority of cases lack of treatment results in severe brain damage or death.
The immature brain is particularly susceptible to hypoxic-ischemic damage because of a higher sensitivity to glutamate, cytokines and oxidative stress, and the preponderance of pro-apoptotic mechanisms.
Hypoxic-ischemic (HI) damage may affect the fetus at various stages of fetal development, or it can affect the newborn during labour and delivery and in the postnatal period.
Problems during labour and delivery can include umbilical cord occlusion, torsion or prolapse, rupture of the placenta or uterus, excessive bleeding from the placenta, abnormal fetal position such as the breech position, prolonged late stages of labour, or very low blood pressure in the mother.
Problems after delivery can include severe prematurity, severe lung or heart disease, serious infections, trauma to the brain or skull, congenital malformations of the brain, or very low blood pressure in the baby.
Unfortunately, these benefits are partial and only successful in mild cases.
Hypothermia does not completely protect an injured brain; newborns with the most severe forms of HI injury are often not successfully treated.
However it is important to consider that drugs administered during the neonatal period may be toxic to the immature brain.
Excretion of many drugs and their metabolites can be modified by hypothermia, and thus failure of liver and kidney clearance due to HI injury could exacerbate any toxicity.
Thus, CB1 agonists are not suitable for neuroprotection in NHIE.
Currently the lack of useful treatments to augment therapeutic hypothermia mean a considerable financial and lifelong personal burden on society and the affected families of newborns suffering from NHIE.

Method used

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  • Synergistic therapies of cannabidiol with hypothermia for neuroprotection
  • Synergistic therapies of cannabidiol with hypothermia for neuroprotection
  • Synergistic therapies of cannabidiol with hypothermia for neuroprotection

Examples

Experimental program
Comparison scheme
Effect test

example 1

Neuroprotective Properties of Cannabidiol (CBD) Following Hypdxic-Ischemica (HI)

Materials and Methods

[0035]A piglet model of HI was used as described in (Alvarez et al. 2008). Briefly, an HI insult is induced in anesthetized 1-3 day-old piglets by occluding both carotid arteries and decreasing inspired oxygen from 21 to 10% for 30 min.

[0036]Thirty minutes after the recovery of HI the test compound was administered via the i.v. route. The test compounds were: Vehicle;

CBD (1 mg / kg);

CBD (1 mg / kg) plus AM630 which is a CB2 antagonist (1 mg / kg);

CBD (1 mg / kg) plus WAY100635 which is a 5HT1A antagonist (0.1 mg / kg); or

CBD (1 mg / kg) plus Caffeine which is a non-specific adenosine receptor antagonist (10 mg / kg).

[0037]Hemodynamic parameters (cardiac output, blood pressure, heart rate and extravascular lung water content), temperature, respiratory parameters (lung compliance, airway resistance, oxygenation index) were recorded for 6 hours from the end of HI.

[0038]Blood samples were obtained hou...

example 2

Synergistic Administration of Cannabidiol (CBD) with Therapeutic Hypothermia Following Hypdxic-Ischemica (HI)

Materials and Methods

[0055]Sedated and ventilated piglets (1-2 day-old) underwent HI brain damage (hypoxia-FiO2 10%+bilateral carotid artery compression for 30 min).

[0056]Normothermic (NT) piglets were maintained at 37-38° C. using a warmed air blanket.

[0057]Hypothermic (HT) piglets were cooled by a cool water mattress to 33-34° C.

[0058]Thirty min after HI piglets received via the i.v. route either vehicle (VEH) or CBD (1 mg / kg).

[0059]HI brains were obtained for histological studies quantifying the number of neurons (Nissl), astrocytes (GFAP) and microglial cells (mGC) (IBA-1) in parietal cortex 6 hours after HI injury.

[0060]By dividing the area percentage of GFAP- or IBA-1-immunoreactive processes and cell bodies (ImageJ) by the number of cells, a mean size of astrocytes or mGC was obtained.

[0061]Similarly studied animals without HI insult served as controls (Sham, SHM).

Resu...

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Abstract

The present invention relates to the combination of the phytocannabinoid cannabidiol with therapeutic hypothermia for use in the treatment of neuroprotection or astroprotection.

Description

[0001]The present invention relates to the use of the phytocannabinoid cannabidiol (CBD) in combination with other therapies that are useful in neuroprotection. Preferably the other therapy is hypothermia. In a further embodiment the combination treatment of hypothermia and CBD may additionally include further treatments that are useful in neuroprotection. Such therapies include anti-epileptic drugs; xenon; N-acetylcysteine; erthyropoietin, and melatonin. Preferably the neuroprotective therapies are used in the treatment of hypoxic-ischemic encephalopathy (HIE), more preferably the HIE is newborn hypoxic-ischemic encephalopathy (NHIE), stroke or cardiac arrest.BACKGROUND TO THE INVENTION[0002]Perinatal asphyxia resulting in newborn hypoxic-ischemic encephalopathy (NHIE) occurs in between 2 to 9 / 1000 live term newborns. A vastly higher number of preterm babies (60 / 1000 live preterm babies) also suffer from this condition. In addition to inflicting direct brain damage, leading to acut...

Claims

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Application Information

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Patent Type & AuthorityApplications(United States)
IPC IPC(8): A61K31/05A61F7/00A61K36/185
CPCA61K31/05A61F7/00A61F7/02A61F2007/0056A61K36/185A61K2300/00A61P25/00A61P43/00A61P9/10A61K45/06
InventorMARTINEZ-ORGADO, JOSEGUY, GEOFFREY
OwnerGW RES LTD