STRESS MANAGEMENT IN HUMAN SUBJECTS IN NEED THEREOF

Abstract

The present invention discloses uses of hexadecanal in managing stress.

Claims

1. A composition comprising hexadecanal (HEX) for use in managing stress in a human subject.

2. The composition according to claim 1, comprising HEX as the sole active material.

3. The composition according to claim 1, wherein the stress is human perceived stress.

4. The composition according to claim 1, for preventing stress, for reducing or relieving symptoms associated with perceived stress, or for reducing reoccurrence of stress.

5. The composition according to claim 1, wherein the HEX is administered by inhalation, smelling or sniffing.

6. The composition according to claim 1, comprising an odorless solvent.

7. The composition according to claim 6, wherein the odorless solvent is a mineral oil.

8. The composition according to claim 1, wherein the amount of HEX is between 0.2 and 2 wt %.

9. The composition according to claim 1 being in a form of a solid composition, a liquid composition or a solution.

10. The composition according to claim 1, being in a form of an aerosol formulation.

11. The composition according to claim 10, comprising a propellant.

12. The composition according to claim 1, being in a form of a nebulizer composition or an atomizer composition.

13. The composition according to claim 1, being a cosmetic formulation.

14. The composition according to claim 13, for application onto a subject's skin region.

15. The composition according to claim 14, wherein the composition is adapted for entering a subject's lung via smelling of said skin region.

16. The composition according to claim 1, being in a form of a lotion, a crème, a spray, a scented cloth, a perfume, a cologne, a scratch-and-sniff odor patch, a blister pack, a solid air freshener, an air-conditioning potpourri, an incense, a lightbulb ring, or a candle.

17. A kit comprising hexadecanal (HEX) and instructions of use in managing stress.

18-19. (canceled)

20. A method for managing stress in a human subject, the method comprising administering to the subject an effective amount of hexadecanal (HEX) to thereby manage stress in the subject.

21. The method according to claim 20, wherein the stress is human perceived stress.

22. The method according to claim 21, wherein administration is by inhalation, smelling or sniffing.

Description

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

[0090] Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

[0091] In the drawings:

[0092] FIG. 1 is a graph showing stress levels of Hexadecanal (named “Blue”) treated group vs placebo group.

[0093] FIG. 2 is a bar graph showing attention measures by Stroop testing as a measure for cognitive performance in the OB treated group vs placebo group.

[0094] FIG. 3 is a bar graph showing memory parameters as a measure for cognitive performance in the OB treated group vs placebo group.

[0095] FIGS. 4A-B depict the following: The upper FIG. 4A depicts stress results along the experiment for men. The columns represent p values. The lower FIG. 4B depicts stress results for women.

[0096] FIG. 5 depicts the average HR along an experiment. The difference across all subject between the conditions is remarkable and statistically significant (p<0.0001).

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

[0097] According to the World Health Organization, stress is a significant problem of our times and affects both physical as well as the mental health of people. Stress coping methods are the cognitive, behavioral and psychological efforts to deal with stress, including, but not limited to, medication, aromatherapy, meditation, psychotherapy and others. The disadvantages in using medication for reducing stress are many and mostly related to side effects, e.g. impaired cognitive ability, addiction and abuse. Aromatherapy and meditation require specific environments e.g. a closed room, a quiet area and the like; and psychotherapy requires prolonged treatment and the effectiveness can vary between subjects. Therefore, there is a need for a stress management method and composition which overcomes the disadvantages of the known methods and compositions, i.e. can be administered easily, does not require a specific environment, almost immediate effect and has no known side effects.

[0098] Whilst conceiving embodiments of the present invention, the present inventors have uncovered that hexadecanal can be used effectively in stress amelioration without affecting cognitive parameters as assayed by memory tests and Stroop assays.

[0099] The ability to manage stress without affecting cognition is central to the development of stress treatment modalities, rendering hexadecanal a promising clinical tool.

[0100] As used herein the term “about” refers to ±10%

EXAMPLES

[0101] Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non-limiting fashion.

[0102] Generally, the nomenclature used herein and the laboratory procedures utilized in the present invention include molecular, biochemical, microbiological and recombinant DNA techniques. Such techniques are thoroughly explained in the literature. See, for example, “Molecular Cloning: A laboratory Manual” Sambrook et al., (1989); “Current Protocols in Molecular Biology” Volumes I-III Ausubel, R. M., ed. (1994); Ausubel et al., “Current Protocols in Molecular Biology”, John Wiley and Sons, Baltimore, Md. (1989); Perbal, “A Practical Guide to Molecular Cloning”, John Wiley & Sons, New York (1988); Watson et al., “Recombinant DNA”, Scientific American Books, New York; Birren et al. (eds) “Genome Analysis: A Laboratory Manual Series”, Vols. 1-4, Cold Spring Harbor Laboratory Press, New York (1998); methodologies as set forth in U.S. Pat. Nos. 4,666,828; 4,683,202; 4,801,531; 5,192,659 and 5,272,057; “Cell Biology: A Laboratory Handbook”, Volumes I-III Cellis, J. E., ed. (1994); “Culture of Animal Cells—A Manual of Basic Technique” by Freshney, Wiley-Liss, N.Y. (1994), Third Edition; “Current Protocols in Immunology” Volumes I-III Coligan J. E., ed. (1994); Stites et al. (eds), “Basic and Clinical Immunology” (8th Edition), Appleton & Lange, Norwalk, Conn. (1994); Mishell and Shiigi (eds), “Selected Methods in Cellular Immunology”, W. H. Freeman and Co., New York (1980); available immunoassays are extensively described in the patent and scientific literature, see, for example, U.S. Pat. Nos. 3,791,932; 3,839,153; 3,850,752; 3,850,578; 3,853,987; 3,867,517; 3,879,262; 3,901,654; 3,935,074; 3,984,533; 3,996,345; 4,034,074; 4,098,876; 4,879,219; 5,011,771 and 5,281,521; “Oligonucleotide Synthesis” Gait, M. J., ed. (1984); “Nucleic Acid Hybridization” Hames, B. D., and Higgins S. J., eds. (1985); “Transcription and Translation” Hames, B. D., and Higgins S. J., eds. (1984); “Animal Cell Culture” Freshney, R. I., ed. (1986); “Immobilized Cells and Enzymes” IRL Press, (1986); “A Practical Guide to Molecular Cloning” Perbal, B., (1984) and “Methods in Enzymology” Vol. 1-317, Academic Press; “PCR Protocols: A Guide To Methods And Applications”, Academic Press, San Diego, Calif. (1990); Marshak et al., “Strategies for Protein Purification and Characterization—A Laboratory Course Manual” CSHL Press (1996); all of which are incorporated by reference as if fully set forth herein. Other general references are provided throughout this document. The procedures therein are believed to be well known in the art and are provided for the convenience of the reader. All the information contained therein is incorporated herein by reference.

Example 1

Olfactory Blue (Hexadecanal) Test Protocol

Hexadecanal

[0103] All three chemicals (Penta-, Hexa- and Heptadecanal) were purchased from TCI Europe. Penta-, Hexa- and Heptadecanal both from TCI were from Caymen (CAS #629-80-1).

[0104] As specified by the distributor, Hexadecanal was stored in the freezer at −20° C. For Pentadecanal and Heptadecanal this is not indicated, so they were stored in the fridge at +4° C. The chemicals (in the closed bottle) were transferred to room temperature for 20-30 min for better handling before use. The chemicals were used it either as powder or diluted in 1,2-Propandiol (dissolved at 37° C. with shaking). After use, the chemicals were overlayed in the bottle with N2 to avoid oxidation, sealed in the bottle with parafilm and store at the indicated temperatures.

[0105] For experiments 0.083M of Hexadecanal (HEX) dissolved in propylene glycol was used. Heating it for a few minutes eases the process (37° C. is sufficient). The mixture was aliquoted into daily portions, such that we thawed a daily serving prior to experiments. Participants were exposed to 100 ul of 0.083M HEX in 10 consecutive sniffs from a jar, and then taped a band aid with 30 ul on the upper lip. The band aid stayed to assure exposure throughout the experiment. Since propylene glycol has an odor, we used a masking odor.

[0106] Another possible diluent is mineral oil that has no perceived odor, so there is no need for a masking odor. The dilution is the same (0.083M).

Protocol for Initial Efficacy Testing

Settings

[0107] 30 male subjects, 15 using Olfactory Blue (OB—Hexadecanal) and 15 with placebo. Participants were randomly assigned either the OB or placebo conditions (a double blind, between subject designs). [0108] 2 experimenters—main experimenter and assistant (to facilitate double blind experiments) [0109] Subjects are exposed to controlled cognitive stressors (manipulations) to raise their stress [0110] OB/Placebo is presented to subject to smell before actual test starts. [0111] Double blind experiments—experimenter and subject do not differentiate between OB and placebo. [0112] Experiments conducted in office environment, subject sits in front of computer—all tests are conducted on the computer. [0113] Stress level is monitored through physiological sensors (HR, facial parameters) [0114] Cognitive performance measured through standard cognitive tests—Memory test and Stroop test [0115] In addition, subjective feedback is recorded in questionnaire throughout the test—before and after each step. [0116] The entire experiment is video recorded for reference.

Equipment

[0117] Computer/laptop with test script and cognitive tests [0118] HR wrist monitor and Central unit [0119] Video camera [0120] 2×50 ml identical bottles—one with OB (solvent+Hexadecanal) and one only with dipropylene glycol (DPG)

Goals and KPIs.

[0121] The goal of these trials is to validate the efficacy of the Olfactory Blue (OB) in reducing stress without impairing cognitive performance.

KPIs

[0122] 1. Significant differences between groups in subjective reported stress—lower subjective stress for the OB group.
2. No differences between groups in performance in both tests:
a. Memory test—no difference in number of words recalled between both conditions
b. Stroop test—Comparable Stroop effects in both conditions

Test Setup

[0123] Subjects—men only [mean age: 24.97 (SD=1.92)]. [0124] An isolated office space (to avoid subject distraction) is prepared with a table and chair. [0125] The computer, Modify standalone and the video recording are positioned and prepared.

Test Running

[0126] Subject is introduced and asked to take place in front of computer [0127] Experimenter briefs the subject on the test procedure in general [0128] Subject fills in a consent form (including GDPR consent) and signs the receipt for the money (see form in annex) [0129] Subject fills in personal data on the computer [0130] Experimenter presents the scent bottle (OB or Placebo) given to him by an assistant (who records which bottle has been given) to the subject to smell five sniffs within one minute (2% in the bottle). [0131] Subject is asked about his subjective stress level on a scale between 0 (no stress at all) to 10 (extreme stress)—questionnaire on the computer [0132] Experimenter completes the briefing and introduce 3 assignments to the participants: a memory task, a Stroop task and the stress manipulation—subject will have to give a 5 min lecture to an audience on one of three given topics—stressor. [0133] Subject starts the experiment by following instructions on the computer:
1. Subjective stress level
2. Memory test with time limitation—cognitive test #1
3. Subjective stress level
4. Stroop test—cognitive test #2
5. Subjective stress level
6. Subject is given 5 min to prepare lecture
7. Subjective stress level
8. End of experiment [0134] Experimenter debriefs subject—asks for general comments and feeling [0135] Subjective stress level [0136] End of test

Measurements

[0137] The following physiological measurements are recorded:
1. HR—heart rate; through a standalone measurement and a HR wrist monitor. The following psychological/subjective measurements are recorded:
2. Memory test—the ability to remember a series of words seen one after the other and after conducting several simple mathematical tasks; scored by counting number of words correctly remembered.
3. Stroop test—the ability to correctly press the colored key corresponding to the colour of the text [Rosenbaum, D., Mama, Y., & Algom, D. (2017). Stand by your Stroop: Standing up enhances selective attention and cognitive control. Psychological science, 28(12), 1864-1867].
4. Subjective stress level—the stress level the subject feels at that moment; recorded on the computer.

[0138] All data is recorded with clear assignment to the subject, for later analysis. An experimenter assistant confidentially records for each subject the type of scent—OB or Placebo.

[0139] Data analysis is performed to result in comparison between the OB group and the Placebo group on the following parameters:

1. HR measurement
2. Score of memory test
3. Score of Stroop test
4. Reported subjective stress level and evolution

OB Experiment—First Results

[0140] FIG. 1 presents subjective stress reports along the experiment and across all participants. The blue columns represent the Blue condition (OB) and the orange columns represent the Placebo condition. Stress scores were from 0 (no stress) to 10 (extreme stress). The asterisks depict significant difference (p<0.01).

*—significant difference (p<0.01)

[0141] The X-axis represent five subjective stress reports in different stages of the experiment:

stress0—baseline
stress1—after getting assignments (inducing stress) and smelling the substance
stress2—after memory test
stress3—after Stroop test (just before the lecture)
stress4—end (after being told there will be no lecture)

[0142] The results in FIG. 1 show that there was no difference in stress0 (baseline) and stress4 (end) between groups. Blue=DPG (solvent)+hexadecanal. Placebo=DPG (solvent). However, all other reports show highly significant differences between conditions. In all three reports, the Blue group exhibited stress to a significantly lower degree than the Placebo group.

[0143] Cognitive Performance:

[0144] The use of Hexadecanal does not affect cognitive performance relative to placebo, as evidenced by the Stroop test (FIG. 2). Stroop is the gold standard of attention measurement. No differences were found between blue and placebo conditions, either in reaction time or in number of errors.

[0145] In a free recall assignment, no differences were found between the conditions (see FIG. 3).

[0146] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0147] All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting. In addition, any priority document(s) of this application is/are hereby incorporated herein by reference in its/their entirety.

Example 2

[0148] The aim of the study was to test the effect of HEX, previously tested on men, on women subjects.

[0149] HEX was found to reduce stress among men, and in the current experiment the study carried out on male subjects was reproduced on women participants.

[0150] Sixty-four participants (35 women) with an average age of 27.34 (SD 4.65), half participated in the HEX group and the other half in the PLACEBO group. The study was conducted in Ra'anana, Israel in a rented office using a laptop computer.

[0151] Participants came in separately into the Ra'anana office, a research assistant (RA) welcomed them. After a short brief, participants were introduced with a bottle of liquid and were required to smell the bottle for 1 minute (with the instruction to breath normally). After being exposed to the smell, the RA explained about the three tasks (memory, attention, public speaking—the stressor). Participants reported their stress level before and after each assignment (7 times). Just before the last task, participants were informed that this task was canceled and then were asked to report their stress level for the last time.

Results

[0152] The first stress report was given pre-manipulation; therefore, it may shed light upon the general stress level of the participants. Mean score for first stress report was 3.32 (SD 1.68) for men and 2.59 (SD 1.76) for women. Four participants (2 women) were excluded from the analysis due to outlier responses: 1 reported she suffers from extreme stage fright, 1 reported she loves to speak in public, 2 reported they were not stressed yet—their stress level reports did not match and were 9-10 throughout the experiment.

[0153] A two-way ANOVA was conducted with average stress (measures 2-6) as a dependent variable and gender and fragrance condition as the independent variables. The results show significant main effect for gender as women were significantly less stressed than men (3.61 and 4.44 respectively), F(1,56)=4.63, p=0.03. Main effect for fragrance was also significant, F(1,56)=5.1, p=0.03. No interaction was found (F<0.1). FIG. 4 shows the stress levels along the experiment. The results clearly support the positive physiological effect of the HEX on stress levels, both for men and women.

[0154] FIG. 5 depicts average HR data (for men and women together) which clearly show a difference between the two groups with average HR in HEX group lower than the HR in the placebo group. Both cognitive tests, memory (free recall) and attention (Stroop test) did not differ between the groups.

[0155] It seems that the HEX fragrance had a continuous and steady effect on stress both physically (HR) and psychologically (self-repot). The effect seemed to be comparable for both men and women. A decrease in the stress reports after the cognitive tests attest to the importance of the results.