USE OF ANTAGONISTS AND/OR INVERSE AGONISTS OF CB1 RECEPTORS FOR PREPARING MEDICAMENTS FOR TREATING FATIGUE POST-VIRAL FATIGUE SYNDROME

Abstract

The invention relates to the use of an antagonist and/or inverse agonist of CB1 receptors, in particular Rimonabant, in the treatment of post-viral fatigue syndrome, and more particularly, for the preparation of medicaments useful for treating fatigue after COVID-19. A method of treating post-viral fatigue syndrome in COVID-19 patients comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an antagonist and/or inverse agonist of CB1 receptors.

Claims

1. A method of treating post-viral fatigue syndrome in COVID-19 patients, comprising administering a therapeutically effective amount of an antagonist and/or inverse agonist of CB1 receptors.

2. The method according to claim 1 wherein said antagonist and/or inverse agonist is rimonabant or any of their pharmaceutically acceptable salts.

3. The method according to claim 1 wherein said antagonist and/or inverse agonist is administered in a form of administration selected from oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal, and rectal.

4. A method of treating post-viral fatigue syndrome in COVID-19 patients comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an antagonist and/or inverse agonist of CB1 receptors.

5. The method according to claim 4 wherein antagonist and/or inverse agonist is rimonabant or any of their pharmaceutically acceptable salts.

6. The method according to claim 4 wherein said pharmaceutical composition comprises is administered in a form of administration selected from oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal, and rectal.

7. The method according to claim 4 wherein said pharmaceutical composition contains an effective dose of at least one agonist and/or inverse agonist of CB1 receptors, and at least one pharmaceutically acceptable excipient.

8. The method according to claim 7, wherein the effective daily dose of the antagonist and/or inverse agonist ranges from 1 mg to 50 mg per dose.

Description

DESCRIPTION OF THE DRAWINGS

[0025] FIGS. 1A-1C. General fatigue (FSS), fatigue perception (Borg Scale) and motor system excitability (MEP amplitudes) in a post COVID-19 patient compared to healthy age-matched individuals. FIG. 1A: General fatigue was measured using the fatigue severity score and it was higher in the COVID-19 group (median±S.D. 38±10.8) in comparison with healthy controls (median±S.D. 9.5±0.5; *Mann-Withney Test p<0.001). FIG. 1B: Fatigue perception after a motor effort (1 min isometric task) was measured using the Borg Scale and it was higher in the COVID-19 group (median±S.D. 75±15.6) in comparison with healthy controls (median±S.D. 54.6±9.7; **Unpaired T test, p<0.001). FIG. 1C: Motor system excitability (MEP amplitude) was lower in the COVID-19 group (mean±S.D. 0.8±0.5 mV) in comparison with healthy controls (mean±S.D. 1.9±1.2 mV, **Unpaired T test, p=0.001).

[0026] FIG. 2. In healthy subjects, motor system excitability was increased 24 hours after the administration of Rimonabant 20 mg (baseline: mean±S.D. 1.1±0.6 mV; 24 hours after rimonabant: mean±S.D. 2.1±1.2 mV; ***paired T test, p=0.02).

EXAMPLES

[0027] The following experiments were carried out using Rimonabant, but it is to be understood that in no way the scope of the present invention should be limited by the example below. To the contrary, what is proved for Rimonabant can be extended to other antagonists/inverse agonists of CB1 receptors.

[0028] Material and Methods

[0029] A large number of patients who recover from the acute phase of coronavirus disease 2019 (COVID-19), caused by the novel “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2), manifest a plethora of long-lasting symptoms. Among them, a high proportion of individuals (53.1%) experience fatigue. Fatigue may be related to disorders of the excitability of the motor system.

[0030] The aim of the present experiments was to use transcranial magnetic stimulation to test the motor system excitability in patients with COVID-19 related fatigue.

[0031] Neurophysiological examination was performed with a case control design and 12 COVID-19 patients were compared with 12 control age-matched individuals.

[0032] Using transcranial magnetic stimulation (TMS), we evaluated the MEP amplitude in the first dorsal interosseous muscle (FDI) at rest.

[0033] Subjects

[0034] 12 healthy volunteers (mean age±S.D. 64.3±10.5 years) and 12 COVID 19 patients three months after the COVID-19 (mean age±S.D. 67.0±9.6 years) participated in all experiments. All the subjects gave their written informed consent.

[0035] Description of COVID-19 Group

[0036] General fatigue was measured using the fatigue severity score was higher in the COVID-19 group (median±S.D. 38±10.8) in comparison with healthy controls (median±S.D. 9.5±0.5, p<0.05).

[0037] Fatigue perception after a motor effort (1 min isometric task) was measured using the Borg Scale was higher in the COVID-19 group (median±S.D. 75±15.6) in comparison with healthy controls (median±S.D. 54.6±9.7, p<0.05).

[0038] Motor system excitability (MEP amplitude) was evaluated using transcranial magnetic stimulation in the COVID-19 group in comparison with healthy controls.

[0039] Magnetic stimulation was performed using a high-power Magstim 200 magnetic stimulator (Magstim Co., Whitland, UK). A figure-of-eight coil with external loop diameters of 9 cm was held over the right motor cortex at the optimum scalp position to elicit motor responses in the contralateral first dorsal interosseous (FDI). The induced current flowed in a postero-anterior direction. Resting motor threshold (RMT) was defined as the minimum stimulus intensity that produced a liminal motor evoked response (about 50 μV in 50% of 10 trials) at rest. The main variables we test are the RMT and MEP amplitude in the two groups. MEP amplitude was obtained at 120% RMT. MEP amplitudes were compared using unpaired t test. Motor system excitability was lower in the COVID-19 group (mean±S.D. 0.8±0.5 mV) in comparison with healthy controls (mean±S.D. 1.9±1.2 mV, p=0.008). To summarize, COVID-19 has lower MEP Amplitudes.

[0040] MEP amplitude reflects the excitability of the motor system (Brasil-Neto J P, Pascual-Leone A, Valls-Solé J, Cammarota A, Cohen L G, Hallett M. Postexercise depression of motor evoked potentials: a measure of central nervous system fatigue. Exp Brain Res 1993; 93(1): 181-4). Based on this consideration we demonstrated that the excitability of the human motor system is reduced in COVID-19.

Example 1. Effects of Rimonabant on the Excitability of Motor Cortex and of Spinal Motor Neurons

[0041] As it is previously described, Rimonabant penetrates the blood-brain barrier and, at normally used doses (20 mg per day) to produce psychological effects in healthy humans with a broad range of symptoms.

[0042] The aim of the present experiments was to use transcranial magnetic stimulation to test the effects of a single dose of 20 mg of Rimonabant on the excitability of motor cortex and of spinal motor neurons.

[0043] Neurophysiological examination was performed before and 24 hours after the administration of a single dose of 20 mg of Rimonabant.

[0044] Using transcranial magnetic stimulation (TMS), it was evaluated the thresholds for electromyographic responses in the first dorsal interosseous muscle (FDI) at rest and during voluntary contraction.

[0045] Subjects

[0046] Nine healthy volunteers (mean age±S.D. 32.1±5.8 years) participated in all experiments. All the subjects gave their written informed consent.

[0047] Magnetic stimulation was performed using a high-power Magstim 200 magnetic stimulator (Magstim Co., Whitland, UK). A figure-of-eight coil with external loop diameters of 9 cm was held over the right motor cortex at the optimum scalp position to elicit motor responses in the contralateral first dorsal interosseous (FDI). The induced current flowed in a postero-anterior direction. Resting motor threshold (RMT) was defined as the minimum stimulus intensity that produced a liminal motor evoked response (about 50 μV in 50% of 10 trials) at rest. The main variables we test is the RMT and MEP amplitude before and 24 hours after the Rimonabant 20 mg. MEP amplitude was obtained at 120% RMT.

[0048] Rimonabant effects on vigilance were moderate and did not interfere with subjects' ability to fully comply with the requirements of the experimental protocol. Hitherto, three subjects experienced agitation and anxiety (this effect lasted an average of 6 hours) and one suffered for nausea (for 24 hours).

[0049] MEP amplitudes before and after Rimonabant were compared using paired t test. Administration of Rimonabant significantly increased the mean MEP amplitude (baseline: mean±S.D. 1.1±0.6 mV; 24 hours after rimonabant: mean±S.D. 2.1±1.2 mV; ***paired T test, p=0.02). These results show that Rimonabant increased MEP Amplitude, which reflects the excitability of the motor system (Brasil-Neto J P, Pascual-Leone A, Valls-Solé J, Cammarota A, Cohen L G, Hallett M. Postexercise depression of motor evoked potentials: a measure of central nervous system fatigue. Exp Brain Res 1993; 93(1): 181-4).

[0050] Based on this consideration it is demonstrated that the excitability of the human motor system is facilitated by CB1 antagonist Rimonabant.

[0051] Based on this consideration it is demonstrated that CB1 antagonist Rimonabant facilitates the excitability of the human motor system.