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1. WO2020193693 - UTILISATIONS MÉDICALES DE BENZODIAZÉPINES AVEC UN MOTIF D'ÉLECTROENCÉPHALOGRAMME PARTICULIER

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

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Claims

1. A benzodiazepine or pharmaceutically acceptable salt thereof for use in inducing and/or maintaining a MOAA/S score of £ 1 in a human patient selected from an infant, a child and a patient with a cognitive impairment that is at least mild cognitive impairment,

wherein the benzodiazepine or salt is defined by having the property of leading to one or more of the following characteristics of an electroencephalogram of a human reference subject in case said benzodiazepine or salt is administered to said reference subject to induce and/or maintain a MOAA/S score of £ 1 :

(a) the absolute power in a frequency region selected within the range from 0.5 to < 8 Hz reaches its maximum after the first 5 min in which the MOAA/S score is £ 1 ,

(b) after the point in time when a MOAA/S score of £ 1 is first reached, the absolute power in a frequency region selected within the range from 0.5 to < 8 Hz reaches its maximum after that in the range from 8 to < 13 Hz, that in the range from 7.5 to 12.5 Hz or that in the range from 13 to < 30 Hz,

(c) the absolute power in a frequency region selected within the range from 0.5 to < 8 Hz is lower than that in the range from 7.5 to 12.5 Hz, that in the range from 8 to < 13 Hz, that in the range of > 12.5 Hz or that in the range from 13 to < 30 Hz during the first 5 min in which the MOAA/S score is £ 1 ,

(d) during the first 5 min in which the MOAA/S score is £ 1 , the relative power in a frequency region selected within the range from 0.5 to < 8 Hz is not higher than

140% of that immediately before the point in time when a MOAA/S score of £ 1 is first reached, wherein the relative power in said frequency region indicates the absolute power in said frequency region in relation to the absolute power summed over the range from 0.5 to < 30 Hz,

(e) when the MOAA/S score returns to a value of > 1 , the absolute power in a frequency region selected within the range from 0.5 to < 8 Hz has not yet returned to that immediately before the point in time when a MOAA/S score of £ 1 is first reached.

2. The benzodiazepine or salt for use according to claim 1 , wherein the patient is further characterised as follows:

(i) the infant is up to 9 months of age,

(ii) the child is 1 to 9 years of age, and/or

(iii) the patient with the cognitive impairment is at least 65 years of age.

3. A benzodiazepine or pharmaceutically acceptable salt thereof for use in inducing and/or maintaining a MOAA/S score of £ 1 in a patient without causing brain damage,

wherein the benzodiazepine or salt is defined by having the property of leading to one or more of the following characteristics of an electroencephalogram of a human reference subject in case said benzodiazepine or salt is administered to said reference subject to induce and/or maintain a MOAA/S score of £ 1 :

(a) the absolute power in a frequency region selected within the range from 0.5 to < 8 Hz reaches its maximum after the first 5 min in which the MOAA/S score is £ 1 ,

(b) after the point in time when a MOAA/S score of £ 1 is first reached, the absolute power in a frequency region selected within the range from 0.5 to < 8 Hz reaches its maximum after that in the range from 8 to < 13 Hz, that in the range from 7.5 to 12.5 Hz or that in the range from 13 to < 30 Hz,

(c) the absolute power in a frequency region selected within the range from 0.5 to < 8 Hz is lower than that in the range from 7.5 to 12.5 Hz, that in the range from 8 to < 13 Hz, that in the range of > 12.5 Hz or that in the range from 13 to < 30 Hz during the first 5 min in which the MOAA/S score is £ 1 ,

(d) during the first 5 min in which the MOAA/S score is £ 1 , the relative power in a frequency region selected within the range from 0.5 to < 8 Hz is not higher than 140% of that immediately before the point in time when a MOAA/S score of £ 1 is first reached, wherein the relative power in said frequency region indicates the absolute power in said frequency region in relation to the absolute power summed over the range from 0.5 to < 30 Hz,

(e) when the MOAA/S score returns to a value of > 1 , the absolute power in a frequency region selected within the range from 0.5 to < 8 Hz has not yet returned to that immediately before the point in time when a MOAA/S score of £ 1 is first reached.

4. The benzodiazepine or salt for use according to any of the preceding claims, which is defined by having said property in case said benzodiazepine or salt is administered to said reference subject under one or more of the following conditions:

(I) continuous intravenous administration of the benzodiazepine or salt,

(II) administration of the benzodiazepine or salt at a rate of 5 mg/min for 5 min, followed by a rate of 3 mg/min for 15 min and of 1 mg / min for another 15 min,

(III) electrode placement on the reference subject’s scalp according to the international 10/20 system; frontal lead F3-Cz and Fp1 as ground,

(IV) recording the electroencephalogram with a Nicolet v32 amplifier and NeuroWorks 8 software,

(V) continuous recording of the electroencephalogram, digitisation at a sampling rate of 500 Hz with a gain of 0.1525902 pV/unit, first low-pass filtered via a finite impulse response FIR at 47 Hz, down sampled to 125 Hz, and

subsequently high-pass filtered with a FIR filter at 0.5 Hz and segmented into EEG epochs of 8.192 s (210 data points) length,

(VI) placement of three EEG electrodes on the reference subject’s forehead with a distance of at least 8 cm between the two signal electrodes,

(VII) recording the electroencephalogram with a Narcotrend-Compact M monitor, (VIII) reference subject’s age of 20 to 38 years,

(IX) reference subject’s body weight of 64 to 99 kg,

(X) reference subject’s body mass index of 21 to 29 kg/m2,

(XI) reference subject’s height of 169 to 197 cm,

(XII) reference subject is a male.

5. The benzodiazepine or salt for use according to any of the preceding claims, which is further defined by having the additional property of leading to the following characteristic of the electroencephalogram of said reference subject when administered as defined in claim 1 : during the first 5 min in which the MOAA/S score is £ 1 , the absolute power in the range from 13 to < 30 Hz, in the range of > 12.5 Hz, or in the range from 30 to 50 Hz is not lower than that immediately before the point in time when a MOAA/S score of £ 1 is first reached.

6. The benzodiazepine or salt for use according to any of the preceding claims, wherein said use involves

administration to the patient by intravenous infusion or

intrapulmonary and/or intranasal administration to the patient.

7. The benzodiazepine or salt for use according to any of the preceding claims, wherein

in characteristic (a), (b), (c), (d) and (f) the absolute power is a time-average over 10 s and in characteristic (e) the relative power is a time-average over 10 s , and/or

the frequency region selected within the range from 0.5 to < 8 Hz is 0.5 to 3.5 Hz, 3.5 to 7.5 Hz, 0.5 to < 2 Hz, 0.5 to 2 Hz, 2 to < 5 Hz, 2 to 5 Hz, 5 to < 8 Hz, 2 to < 8 Hz, 0.5 to < 3 Hz or 0.5 to 5 Hz.

8. The benzodiazepine or salt for use according to any of the preceding claims, wherein the benzodiazepine is according to formula (I)


wherein

R1 is CHs, CH2CH3, CH2CH2CH3, CH(CH3)2 or CH2CH(CH3)2;

R2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl;

R3 is Cl or Br;

R8 is hydrogen, Ci_4 alkyl or C1.3 hydroxyalkyl; and

R9 is H, Ci_4 alkyl, C1.3 hydroxyalkyl or Ci_4 alkoxy.

9. The benzodiazepine or salt for use according to claim 8, which is methyl 3-[(4S)-8- bromo-1-methyl-6-(pyridin-2-yl)-4H-imidazo[1 ,2-a][1 ,4]benzodiazepin-4- yl]propanoate.

10. The benzodiazepine or salt for use according to claim 9, wherein the use involves administration

at a dose of 0.3 to 40 mg/h/kg or

at a fixed dose irrespective of the patient’s body weight.

11. The benzodiazepine or salt for use according to any of the preceding claims, wherein the salt is selected from the group consisting of halogenides, sulfate, organic sulfates, sulfonate, organic sulfonates, nitrate, phosphate, salicylate, tartrate, citrate, maleate, formiate, malonate, succinate, isethionate, lactobionate and sulfamate.

12. The benzodiazepine or salt for use according to any of the preceding claims, which is used together with a further active ingredient or an excipient.

13. The benzodiazepine or salt for use according to claim 12, wherein

the further active ingredient is an opioid or

the excipient is a disaccharide and/or a dextran.