NL2025295B1 - Use of phenol in treatment of microbially induced dyspnoea - Google Patents

Abstract

Described is the use of phenol for the treatment of microbially, in particular virally, induced dyspnoea in a patient, in particular a human patient. The dyspnoea is in particular associated with Acute Respiratory Distress Syndrome (ARDS). The viral infection is particularly caused by a virus, chosen from the group, consisting of corona, influenza, Ebola, respiratory syncytial virus, HIV. Phenol is administered parenterally, in particular subcutaneously.

Description

Use of phenol in treatment of microbially induced dyspnoea The invention relates to the novel use of phenal treatment of microbially induced dyspnoea in a patient.

Phenol was discovered in 1834 by F.F. Runge by extraction from coal tar. It was obtained in pure form by A. Laurent in 1841. In the medical world, phenol has widely been used as antiseptic. Presently, phenol is commonly used in matrixectomy. Also, phenol is used a preservative in injectables such as insulin and vaccines.

As active ingredient, phenol is known for treatment of sore throat. Further, CN102198091 describes the use of phenol as therapeutic drug against some chronical inflammations and herpes zoster, however without providing a mechanism of action of phenol in the therapeutic process. The use of phenol has not been further explored. When a body is invaded by external pathological factors, the immune system needs time to build up till the level which can cure the illness again. We all know that after a common cold, e.g. as a result from a viral of bacterial infection, most people naturally get better within a week. The microbe (i.e. the virus or bacterium) does not damage the organs and tissues directly. The damage is caused mostly by changes of the immune system. Microbially induced dyspnea triggers the activation of the pro- inflammatory response of the innate immunity causing a massive cytokine storm and tissue damage by strong oxidation. In order to remove the virus from the bady, the body’s immune system activity increases, and therewith the oxidation activity. Over- oxidation in the body is both cause and consequence of the inflammatory storm. This vicious circle ultimately undermines the recover possibility. After infection and stress due to illness, the oxidation level of the body is high. The concentration of free radicals increases throughout the body with higher concentration near the infection location and stress affected area such as the airway and lungs, the stress areas being the neck and head. Both infection and stress area may spread further. As defense against over-oxidation, the body produces catalase, an enzyme that decomposes hydrogen peroxide (H202)}), before hydroxyl or superoxide radicals are formed. It has now surprisingly been found that phenol can be used in the treatment of microbially induced dyspnoea in a patient, in particular in a human patient. Without the wish to be bound to any explanation it is believed that phenol can be converted in the body into catechol and hydroxyquinone that have antioxidant function. The physiological conversion of phenol is catalysed by glycerol and consumes H20O: as depicted in the reaction scheme below: 9g “given LJ ® > pheno cabmubh bydroguinane By the above reaction, both phenol and the reaction products phenolic provide antioxidant activity against the inflammatory storm in the infection and more in particular when the dyspnoea is associated with Acute Respiratory Distress Syndrome (ARDS) or pneumonia.

In particular the microbially induced dyspnoea is caused by a viral or bacterial infection that can cause pneumonia. The microbially induced dyspnoea is in particular caused by a virus, chosen from the group, consisting of corona, influenza, Ebola, respiratory syncytial virus (RSV), HIV, lassa and rhinovirus, as such viral infections, in particular when acute, become life threatening for the patient as a result of dyspnoea.

The Acute Respiratory Distress Syndrome (ARDS) caused by coronavirus disease 2019 (CoViD-19) has now become the world’s number 1 challenge. The exponential pattern in the number of severe cases has shown to reach nations’ maximum ICU capacities in weeks rather than months after outbreak of the disease irrespective of rigorous population based preventive measures. The CoVid-19 (SARS- CoV-2) virus emerged in December 2019 and turned pandemic. No antiviral medication or effective and safe drug is available yet to treat CoVid-19 patients.

As vaccine development and/or targeted anti-viral medication will require several months at least, therapeutic measures that can immediately attenuate the course of CoViD-19-related lung damage potentially are directly needed on a global scale.

It has been found that parenteral administration, in particular when administered by subcutaneous injection relief of the dyspnoea is observed.

When phenol is injected subcutaneously, i.e. in the soft tissue below the skin with a depth of up to 0.5 — 2.0 cm, it will diffuse fast to the neighboring locations and exert its antioxidant action.

According to the clinical observation, phenol may remain about 24 hours in the body, with an immediate effect of about 7 days.

Based on studies done on diabetic patients that inject insulin comprising 0.2 to 0.7 mg per dose phenol as preservative, there is no significant accumulation of phenol in the body by daily use.

A high dose would damage the body, but too low will show no effect.

The dose is preferably 0.4 — 3.0 mg phenol once daily, more preferably 0.8 — 2 mg phenol once daily.

If the symptoms are mild or decreasing, the dose can be lowered to e.g. every other day or a dose once weekly of e.g. the same amounts.

The dose is preferably provided in a liquid volume of 0.3 — 5.0 ml, more preferably of 0.3 — 3.0 ml, even more preferably 0.5 — 2.5 ml, preferably of an isotonic saline solution, more preferably physiological saline, i.e. 0.9 w/w% NaCl.

Although not necessary, the composition can comprise not only phenol and saline, but optionally additional adjuvants that are commonly known in the art.

If necessary, the composition can comprise a local anaesthetic in order to avoid any pain effect upon injection.

Local administration is found to be most effective; therefore, the administration is preferably in the neck area, in particular close to the central nerve systems and cicse to the airways.

The neck area is most accessible and practical location to deposit the phenol as close as possible at the location of the dyspnoea.

A single dose is intended to relate to the amount of phenol administered, wherein the administration can be divided over a plurality of injections at different locations, as long as these injections are performed together, i.e. one after the other, not more than 10 minutes, preferably not more than 5 minutes, even more preferably not more than 3 minutes being between each injection.

The above dose is preferably divided over two to ten subdoses.

In particular for obese patients and patient having a high level of oxidative activity, e.g. as a result of an immune disorder are candidates for receiving the dose in 6 to 10 injections.

For the majority of patients, four to six subdoses are preferred.

In particular subcutaneous injections are preferred, to be administered on different positions in the neck area.

The locations of injection points are preferably chosen with the objective to coordinate the central autonomic nerve,

and regulate both sympathetic and parasympathetic system and to provide the antioxidant signals to the local airway and entry of the lungs at the points before and behind the entry of lungs, and to release tension of the neck muscles to provide better circulation to the brain. The term ‘neck area’ encompasses the area between the head and the shoulders, limited to above the 8" vertebra.

The dose is preferably equally divided over the two to ten subdoses, preferably four to six subdoses, in particular subcutaneous injections, both in volume and phenol concentration, so that the above locations each receive an equal subdose. Preferably, a dose of 0.4 — 3.0 mg, more preferably of 0.8 — 2.0 mg is divided over four to ten, more preferably over four to six, even more preferably over four injections of 0.3 — 0.8 ml each, and most preferably to 4 injections of 0.5 ml comprising 0.06 w/w% phenol. In case of a different number of injections, the preferred volume per injection is 0.5 ml, with a composition comprising 0.06 w/w% phenol. To this end, the different positions in the neck area are preferably chosen from the group, consisting of: the posterior margin of the sternocleidomastoid muscle on the level of the larynx knot at both left and right side of the body; the middle of the upper socket of the sternum, and the depression below the spinous process of the 7! cervical vertebra.

Example 1 Subject 1 was a male, 60 years old, weight 85 kg, pre-condition asthma. Probably virus induced pneumonia. Pretreatment history: Suffering from dry throat, slight headache, started coughing after three days, next day short breath. thought it was a common cold and asthma. In the evening of fourth day fever. Self-treatment with Ventolin and paracetamol. Fever reduced slightly, but still coughing. Sixth day. Still fever. Measured temperature 37.8°C. Short of breath, and pain in the chest. Felt very tired. Insomnia. Eighth day: Cough with lot of mucus. Patient thinks that the problem is serious, and contacts GP. Diagnosis probably virus induced pneumonia. Temperature 38.1°C.

Treatment started for 9 consecutive days by four subcutaneous injections of a

0.06 w/w®% phenol in physiological saline daily administered in: 1 and 2) the posterior margin of the sternocleidomastoid muscle on the level of the larynx knot at both left and right side of the body, each about 1 cm deep; 3) the middle of the upper socket of the sternum about 0.5 cm deep, and 4) the depression below the spinous process of the 7!" cervical vertebra, about 0.5 cm deep. First day of treatment is set as ‘Day

1. Observations: Day 1: Temperature 38.1°C. 5 Day 2: Temperature 37.6°C. A lot of transparent slime. Chest pain. Limited feeling of short breath and asthma. Tired feeling. Day 3: Temperature 37.4°C. Less short breath. Tired. Feels some pain at injection point during treatment. Slight headache after injection. Day 4: Temperature 37.4°C, coughing, tired but less tired than before. Short breath much better. No chest pain by coughing. Day 5. Temperature 37.4°C. coughing, less tired. Short breath slightly better. Day 6: Temperature 37.0°C. Slept reasonable. Still coughing, but less. Says feels good. No more short breath. Day 7: No fever. Feels good. Feeling energy back. Still light coughing. No pain. Breathing normal. Day 8: No fever. Almost no cough. Day 9: As Day 8. Last day of injections. Analysis: Patient experienced a slight headache, no other side effect after injection. Patient stopped with Ventolin and paracetamol on treatment Day 2.

Example 2 Subject 2 male, 29 years, suffering early stage CoViD-19. Former professional sportsman (soccer), doesn’t smoke, no alcohol, weight 75 kg. Pre-treatment history. Patient felt good in the morning. Around noon started irritation of the throat, problems sleeping. Next day felt tired, started coughing, in the afternoon feeling feverish, problems sleeping. Next Day: Coughing increased, strong pain in the chest when coughing. Feels to have fever. Sleeping problems. Next day pain in the chest increases. Shortness of breath increases. Came to GP for treatment. Fever 38.4°C. Treatment for four consecutive days of four subcutaneous injections as described for patient 1. First day of treatment is set as ‘Day 1. Observations: Day 1: Temperature 38.4°C.

Day 2: After treatment the patient felt a slight headache which remained for about four hours. Slept reasonable, only interrupted by coughing. Coughing less, almost no more pain in the breast when coughing. Still feels weak. Temperature 37.2°C.

Day 3: Coughing lessened further, no more pain in the chest when coughing. Temperature 36.8°C. Patient feels normal, not weak anymore. Slept well.

Day 4: Temperature normal. Slight cough. Day 5: Temperature normal. the slight cough remained for 5 more days and then is fully gone. No further injections administered. Analysis: No headache except after first treatment. Injection location slight pain at injection. No other side effects noted.

Claims (15)

CONCLUSIONS A phenol for use in treating microbe-induced dyspnea in a patient. A phenol for use according to claim 1, wherein the subject is a human. A phenol for use according to claim 1 or 2, wherein the dyspnea is associated with Acute Respiratory Distress Syndrome (ARDS) or pneumonia. The phenol for use according to claim 3, wherein the dyspnea is caused by a virus, in particular selected from the group consisting of corona, influenza, Ebola, respiratory syncytial virus (RSV), HIV, lassa and rhinovirus. The phenol for use according to claim 4, wherein the virus is COVID-19. A phenol for use according to any preceding claim, wherein the phenol is administered parenterally. The phenol for use according to claim 8, wherein the phenol is administered by subcutaneous injection. Phenol for use according to claim 6 or 7, wherein the dose is 0.4-3.0 mg, preferably 0.8-2.0 mg once a day. Phenol for use according to claim 6 or 7, wherein the dose is 0.4-3.0 mg once weekly, preferably 0.8-2.0 mg. A phenol for use according to any one of claims 6-8, wherein the dose is contained in 0.3-3.0 ml physiological saline solution. The phenol for use according to any one of claims 6 to 10, wherein the phenol is administered in the neck region. A phenol for use according to any one of claims 6 to 11, wherein the dose is divided into two to ten doses, to be administered to different sites in the neck region, in particular by subcutaneous injection. The phenol for use according to claim 12, wherein the dose is divided equally among the two to ten doses. A phenol for use according to any one of claims 6 to 13, wherein the dose is from 0.4 to 3.0 mg. Preferably from 08.-2.0 mg is divided into 2 to 10 sub-doses, preferably into 4 to 6 sub-doses of 0.3-0.8 ml each. A phenol for use according to any one of claims 12 to 14, wherein the different sites in the neck region are selected from the group consisting of the posterior edge of the sternocleidomastoid muscle at the level of the larynx node on both the left and right sides of the body , the center of the upper cavity of the sternum, and the intervertebral space between the 7° and 8° vertebral spina.