USE OF PHENOL IN THE TREATMENT OF MICROBIAL-INDUCED DYSPNEA

Abstract

This article describes the use of phenol in the treatment of microbially induced dyspnea, specifically viral dyspnea, in a human patient, where the phenol is administered parenterally. The dyspnea is associated, in particular, with Acute Respiratory Distress Syndrome (ARDS). The viral infection is caused, in particular, by a virus selected from the group consisting of coronaviruses, influenza, Ebola, respiratory syncytial virus, HIV, Lassa virus, and rhinovirus. The phenol is administered parenterally, specifically subcutaneously or intravenously.

Description

USE OF PHENOL IN THE TREATMENT OF MICROBIAL-INDUCED DYSPNEA The invention relates to the novel use of phenol in the treatment of microbially induced dyspnea in a patient. Phenol was discovered in 1834 by F.F. Runge through its extraction from coal tar. It was obtained in pure form by A. Laurent in 1841. In the medical field, phenol has been widely used as an antiseptic. Currently, phenol is routinely used in matricectomy. Additionally, phenol is used as a preservative in injectables such as insulin and vaccines. As an active ingredient, phenol is known for treating sore throats. Furthermore, document CN102198091 describes the use of phenol as a therapeutic drug against certain chronic inflammations and herpes zoster, although it does not provide a mechanism of action for phenol in the therapeutic process. The use of phenol has not been further examined. Document EP0707849 describes the use of iodophenolic compounds that can be administered both orally and parenterally for the treatment of a plurality of infections and asthma. When a body is invaded by external pathogens, the immune system needs time to strengthen itself to the level where it can cure the illness again. We all know that after a common cold, for example, resulting from a viral or bacterial infection, most people recover naturally within a week. The microbe (i.e., the virus or bacteria) does not directly damage organs and tissues. The damage is primarily caused by changes in the immune system. Microbial-induced shortness of breath triggers the activation of the innate immune response, leading to a massive cytokine storm and tissue damage from severe oxidation. To eliminate the virus from the body, the body's immune system activity increases, and with it, oxidative activity. This over-oxidation of the body is both a cause and a consequence of the inflammatory storm.This vicious cycle ultimately undermines the possibility of recovery. After infection and the stress caused by illness, the body's oxidation level is high. The concentration of free radicals increases throughout the body. 7.7.07. ίη / ZZOZ / E / YILI higher concentration near the site of infection and the area affected by stress, such as the airways and lungs, with the areas of stress being the neck and head. Both the infection and the area of ​​stress can spread further. As a defense against over-oxidation, the body produces catalase, an enzyme that breaks down hydrogen peroxide (H2O2), before hydroxyl or superoxide radicals are formed. Now, surprisingly, it has been discovered that phenol can be used to treat microbially induced dyspnea in a patient, particularly a human patient, via parenteral administration. While no explanation has been established, it is believed that phenol can be converted in the body into catechol and hydroxyquinone, which have antioxidant properties. The physiological conversion of phenol is catalyzed by glycerol and consumes H₂O₂, as shown in the following reaction scheme: 77Q7 ίη / ΖΖΠΖ / Ε / ΥΙΛΙ glycerol catechol phenol Due to the above reaction, both phenol and phenolic reaction products provide antioxidant activity against the inflammatory storm in infection and, more particularly, when dyspnea is associated with Acute Respiratory Distress Syndrome (ARDS) or pneumonia. In particular, microbial-induced dyspnea is caused by a viral or bacterial infection that can lead to pneumonia. Microbial-induced dyspnea is specifically caused by a virus, selected from the group that includes coronaviruses, influenza, Ebola, respiratory syncytial virus (RSV), HIV, Lassa virus, and rhinovirus, as such viral infections, particularly when acute, become life-threatening due to the resulting dyspnea. Acute Respiratory Distress Syndrome (ARDS) caused by coronavirus disease 2019 (COVID-19) has become the world's number one challenge. The exponential pattern in the number of severe cases has been shown to reach the maximum ICU capacity of nations within weeks, rather than months, after the outbreak, regardless of rigorous population-based preventive measures. The COVID-19 virus (SARS-CoV-2) emerged in December 2019 and became a pandemic. There is still no effective and safe antiviral medication or drug available to treat patients with COVID-19. Given that the provision of targeted vaccines and / or antiviral drugs is complicated and depends on the production of a limited number of suppliers, therapeutic measures that can immediately mitigate the course of COVID-19-related lung damage are potentially needed on a global scale. Parenteral administration has been shown to provide relief and rapid recovery from dyspnea and the underlying infection. The preferred parenteral administration methods are subcutaneous injection or intravenous administration. The patient can be any animal suffering from microbially induced dyspnea, particularly mammals, preferably livestock or companion animals. Preferably, the patients are human. Parenteral administration, particularly subcutaneous or intravenous administration, has been shown to be particularly effective when the patient suffers from dyspnea, particularly induced by a microbial infection, such as a viral infection, such as a coronavirus such as COVID-19, influenza, Ebola, respiratory syncytial virus (RSV), HIV, Lassa virus and rhinovirus, dengue, chikungunya; bacterial infection, such as meningitis, multidrug-resistant Staphylococcus aureus (MRSA); pneumonia, particularly influenza-induced pneumonia; acute respiratory distress syndromes (ARDS). Phenol is preferably in a physiological saline solution, i.e., preferably administered in a composition comprising phenol and physiological saline solution. Physiological saline solution is an isotonic saline solution with the blood of the patient to be treated. The saline solution is preferably a NaCl solution. For humans and most mammals, a 0.9% w / w NaCl solution is isotonic and is preferred as physiological saline solution. However, other pharmaceutically acceptable salts or combinations thereof may be selected to obtain an isotonic solution. Although not required, the composition may comprise additional adjuvants commonly known in the art. 77Q7 ίη / ZZΖηZ / E / YΙΛΙ composition can be combined with usual care, such as antibiotics, and with antiviral agents commonly known in the technique. Advantageously, phenol is available in a lidocaine-free formulation, meaning it is administered without lidocaine in the same solution. While lidocaine has been shown to provide some relief from local discomfort following injections, it is not considered an active ingredient in the treatment of the intended condition and may cause unwanted side effects. Therefore, administering phenol without lidocaine is preferable. The formulation preferably consists of phenol in physiological saline solution. In an advantageous embodiment, the phenol is administered in a liquid composition comprising 0.005 to 0.07% w / w, preferably 0.01 to 0.06% w / w of phenol, more preferably in physiological saline solution. In a particularly advantageous embodiment, phenol is injected subcutaneously, that is, into the soft tissue beneath the skin at a depth of 0.5 to 2.0 cm. Through such injection, the phenol diffuses rapidly to surrounding areas and exerts its antioxidant effect. According to clinical observation, phenol can remain in the body for approximately 24 hours, with an immediate effect lasting about 7 days. Based on studies conducted in diabetic patients injecting insulin containing 0.2 to 1.0 mg of phenol per dose as a preservative, there is no significant accumulation of phenol in the body with daily use. A high dose would harm the body, but too low a dose will have no effect. The dose is preferably 0.4 to 3.0 mg of phenol once daily, more preferably 0.8 to 2 mg of phenol once daily. If symptoms are mild or subsiding, the dosage may be reduced, for example, to every other day or to a once-weekly dose of, for example, the same amounts. The dose is preferably administered in a liquid volume of 0.3 to 5.0 ml, more preferably 0.3 to 3.0 ml, and even more preferably 0.5 to 2.5 ml, preferably of an isotonic saline solution, and more preferably physiological saline solution, i.e., 0.9% w / w NaCl. Although not required, the composition may comprise not only phenol and saline solution, but optionally additional adjuvants commonly known in the technique. If necessary, the composition may include a local anesthetic to prevent any 77Q7 ίη / ZZΖΠZ / E / YΙΛΙ pain effect during injection. As explained above, the presence of lidocaine is not preferable. A single dose is intended to refer to the amount of phenol administered subcutaneously. This administration may be divided into multiple injections at different sites, provided that these injections are given consecutively, one after the other, with no more than 10 minutes, preferably no more than 5 minutes, and even more preferably no more than 3 minutes between each injection. The above dose is preferably divided into two to ten subdoses. In particular, obese patients and those with a high level of oxidative activity, for example, as a result of an immune disorder, are candidates for receiving the dose in 6 to 10 injections. For most patients, four to six subdoses are preferred. Preferably, the dose is divided equally between two and ten subdoses, preferably between four and six subdoses, both in volume and in phenol concentration, so that each of the different locations receives an equal subdose. For the treatment of dyspnea, local administration has proven to be the most effective; in particular, administration to the neck area is preferred, especially near the central nervous system and the airways. The neck area is the most accessible and practical location for depositing phenol as close as possible to the site of dyspnea. The injection points are preferably selected to coordinate the central autonomic nervous system, regulate both the sympathetic and parasympathetic systems, and provide antioxidant signals to the local airways and the lungs at points anterior and posterior to the lungs, as well as to release tension in the neck muscles to facilitate better circulation to the brain. The term “neck area” encompasses the area between the head and shoulders, limited above the 8th cervical vertebra. Preferably, the dose for administration in the neck area is divided into four to ten, more preferably four to six, and even more preferably four injections. Such subdoses preferably comprise 0.4 to 3.0 mg, more preferably 0.8 to 2.0 mg each. The volume of the subdoses is preferably 0.3 to 0.8 ml each, while the concentration of phenol in the composition to be administered is preferably 0.06% w / w. 7.7.07. ίη / ΖΖΠΖ / Ε / ΥΙΛΙ Preferably, the subdoses comprise four 0.5 ml injections containing 0.06% w / w phenol. If a different number of injections is used, the preferred volume per injection is 0.5 ml, with a composition containing 0.06% w / w phenol. For this purpose, the different injection sites in the neck area are preferably selected from the group consisting of: the posterior margin of the sternocleidomastoid muscle at the level of the laryngeal node on both the left and right sides of the body; the upper half of the sternal cavity; and the depression below the spinous process of the first cervical vertebra. In another advantageous embodiment, phenol is administered intravenously. With this method, the phenol diffuses very rapidly throughout the patient's body and exerts its antioxidant effect. With subcutaneous administration, phenols can remain in the body for approximately 24 hours, with an immediate effect lasting from 7 to 14 days. The dose of phenol to be administered intravenously is preferably 0.02 to 0.1 mg per kg of body weight per day, more preferably 0.03 to 0.07 mg per kg of body weight per day. The more severe the dyspnea or the underlying disease, the higher the dose should be. The dose is preferably administered in several consecutive periods until the patient recovers. This period is preferably 3 to 8 consecutive days, weeks, or alternate weeks. However, if the patient is recovering, the dose may be reduced, either in quantity, in the interval between doses, or both. For example, a dose may be administered every two days, every week or alternate week, or monthly, once recovery is observed. Therefore, in a preferred embodiment, starting the day after the last day of administration of said dose, a second dose of 0.005 to 0.2 mg per kg of body weight per day of phenol is administered for 1 to 5 days. Such additional treatment may also comprise one or more daily subcutaneous injections, particularly in the neck area, as described above. To this end, the total dose of said subcutaneous injections is preferably 0.4 to 1.5 mg per day, wherein the injections are preferably divided into multiple injections of 0.8 to 1.5 mg in 0.3 to 0.8 ml each, particularly in four positions in the neck, which are preferably selected from the group consisting of the anterior and posterior margins of the sternocleidomastoid muscle at the level of the laryngeal nodule on both the left and right sides. 77Q7 ίη / ZZΖΠZ / E / YΙΛΙ and as on the right side of the body; the upper half of the cavity of the sternum and the depression below the spinous process of the 1st cervical vertebra. The dose can be administered intravenously as single or multiple bolus injections, but is preferably administered by infusion, particularly by drip infusion, where the phenol concentration is preferably 0.005 to 0.07% w / w. The infusion is preferably administered over a period of 3 minutes to two hours. In particular, when the patient is recovering, the infusion time may be short, for example, from 3 to 30 minutes. The invention also relates to an infusion composition, particularly for drip infusion, comprising 0.005 to 0.07% w / w, preferably 0.01 to 0.06% w / w, of phenol in physiological saline solution. The infusion composition is preferably packaged as such, for example, in a plastic bag, which preferably includes outlets designed for connecting infusion tubing and, for example, suspension means for being suspended from a frame, designed for suspending infusion bags. Example 1 Virus-induced pneumonia Subject 1 is a 60-year-old male, weighing 85 kg, with a pre-existing condition of asthma. Probable viral-induced pneumonia. Medical history prior to treatment: He reported a dry throat, mild headache, and a cough that began three days later, followed by shortness of breath the next day. He initially thought it was a common cold and asthma. On the afternoon of the fourth day, he developed a fever. He self-treated with Ventolin and paracetamol. The fever subsided somewhat, but the cough persisted. By the sixth day, the fever was still present, with a measured temperature of 37.8°C. He also experienced shortness of breath and chest pain, and felt very tired and had insomnia. On the eighth day, he developed a cough with a lot of mucus. The patient believed the problem was serious and contacted his primary care physician. He was diagnosed with viral pneumonia, with a temperature of 38.1°C. The treatment began over 9 consecutive days with four daily subcutaneous injections of 0.06 w / w phenol in physiological saline solution, administered in: 1 and 2) the posterior margin of the sternocleidomastoid muscle at the level of the laryngeal nodule on both the left and right sides of the body, each approximately 1 cm deep; 3) the midpoint of the superior cavity of the sternum at a depth of about 0.5 cm; and 4) the depression below the spinous process of the 77Q7 ίη / ΖΖΠΖ / Ε / ΥΙΛΙ 1- Cervical vertebra, approximately 0.5 cm deep. The first day of treatment is designated as Day 1 Observations: Day 1: Temperature of 38.1 °C. Day 2: Temperature of 37.6 °C. A large amount of clear mucus. Chest pain. Limited sensation of shortness of breath and asthma. Feeling tired. Day 3: Temperature 37.4 °C. Less shortness of breath. Tired. Feels some pain at the injection site during treatment. Mild headache after the injection. Day 4: Temperature of 37.4 °C, cough and tiredness, but less tired than before. Shortness of breath has improved significantly. No chest pain when coughing. Day 5. Temperature of 37.4 °C, cough and less tiredness. Shortness of breath slightly better. Day 6: Temperature 37.0 °C. Sleeped reasonably well. Still has a cough, but less so. Reports feeling well. No longer short of breath. Day 7: No fever. Feels well. Feels energetic again. Still has a mild cough. No pain. Normal breathing. Day 8: No fever. Almost no cough. Day 9: Same as day 8. Last day of injections. Analysis: The patient experienced a mild headache, but no other side effects after the injection. Treatment with Ventolin and paracetamol was discontinued on day 2. Example 2 COVID-19 in its initial phase Subject 2 is a 29-year-old male with early-stage COVID-19. A former professional athlete (soccer), he does not smoke or drink alcohol and weighs 75 kg. Pre-treatment medical history: The patient felt well in the morning. Around midday, he began to experience a sore throat and had trouble sleeping. The following day, he felt tired and started coughing. In the afternoon, he developed a fever and continued to have trouble sleeping. The next day, his cough worsened, accompanied by severe chest pain when coughing, shortness of breath, a feeling of fever, and difficulty sleeping. The following day, his chest pain and difficulty breathing increased. 77Q7 ίη / ZZΖΠZ / E / YΙΛΙ for breathing. See your doctor for treatment. You have a fever of 38.4 °C. Treatment for four consecutive days with four subcutaneous injections as described for patient 1. The first day of treatment is designated as Day 1. Observations: Day 1: Temperature of 38.4 °C. Day 2: After treatment, the patient experienced a mild headache that lasted for about four hours. He slept reasonably well, with his rest interrupted only by coughing. He coughed less frequently and experienced almost no chest pain when coughing. He still feels weak. His temperature was 37.2°C. Day 3: The cough has subsided even further; there is no longer chest pain when coughing. Temperature is 36.8 °C. The patient feels normal and is no longer weak. He is sleeping well. Day 4: Normal temperature. Mild cough. Day 5: Normal temperature. The mild cough persisted for 5 more days and then disappeared completely. No further injections were administered. Analysis: No headache, except after the first treatment. Slight pain at the injection site during the injection. No other side effects observed. Example 3 Treatment in critical phase of Covid-19, treatment of diffuse intravascular coagulation. Patient cured with this injection. Clinical observations: over 69 years old, obese, with fever and cough for 10 days, fluctuating fever for 7 days. R / R 41, SpO2 91%, intubated, D-dimer test was 1.1 pg / ml on infusion (sodium glucose). Treated with 0.01% phenol in 60 ml, drip infusion over 20 minutes, once daily. After the fever subsided, treatment was continued with a 15-minute drip infusion once daily, using 30 ml of 0.01% phenol infusion medium. Treatment continued until 3 days of normal body temperature, R / R 20, SpO2 97%. Recovery process: improvement in respiratory rate and SpO2 measured 6 hours after the start of treatment, with normal temperature, respiratory rate, and SpO2 by day 6. On day 6, the dose was reduced to a concentration of 0.01% in 30 ml. Treatment was discontinued after day 9. The patient recovered. See Table 1. 77Q7 ίη / ΖΖΩΖ / Ε / ΥΙΛΙ Example 4 MRSA lung infection following prostate cancer surgery. A 72-year-old male, weighing 88 kg, presented with dyspnea, cough, chest pain, and fever, and had a urinary catheter. He had taken various antibiotics before and after prostate cancer surgery and for a pulmonary infection. The fever was persistent. MRSA culture was positive. Treatment consisted of an infusion of 30 ml of 0.02% phenol over approximately 15 minutes, once daily for 3 consecutive days. After the fever subsided from 38.0 to 37.4 °C, the phenol was reduced to 15 ml of 0.02% over 10 minutes for a further 5 days. The temperature remained stable below 37 °C. On day 18, a chest X-ray showed that the pneumonia was almost completely resolved. Example 5 Pneumonia due to influenza. An 84-year-old woman, weighing 72 kg, presented with fever, chest pain, headache, and a cough with gray mucus for two weeks, along with dyspnea. She was unresponsive to antibiotics. The patient developed diarrhea and became increasingly weak. Her heart rate was 120 bpm and irregular. Her respiratory rate was 29 bpm. Her temperature ranged from 37.5 to 38.6 °C. A chest X-ray showed pulmonary infiltrates in the right middle and lower lobes and the left lower lobe. She was treated with 0.02% phenol 30 ml intravenously, administered over 10 minutes once daily for 5 consecutive days. On day 5, her breathing was quiet, and her heart rate was approximately 90 bpm. Her fever was 36.8 to 37.5 °C. She received additional treatment with four local subcutaneous injections in the neck and one between the third and fourth thoracic vertebrae for another 6 days. At each location, 0.5 ml of 0.06% subcutaneous injection was administered. The patient is physically recovering, with some coughing. On day 14, the chest x-ray shows much-improved pulmonary infiltrate. 77Q7 ίη / ΖΖΠΖ / Ε / ΥΙΛΙ 7.7.07. ίη / ΖΖΠΖ / Ε / ΥΙΛΙ Table 1: Treatment and recovery of the patient in example 3

Claims

1. Phenol for use in the treatment of dyspnea in a patient, the dyspnea being associated with Acute Respiratory Distress Syndrome (ARDS) and being caused by a virus, wherein the phenol is in a lidocaine-free composition and is administered parenterally.

2. Phenol for use according to claim 1, wherein the phenol is administered by subcutaneous injection or intravenous administration.

3. Phenol for use according to claim 1 or 2, wherein the patient is a human being.

4. Phenol for use according to claim 1, wherein dyspnea is caused by a virus selected from the group consisting of coronavirus, influenza, Ebola, respiratory syncytial virus (RSV), HIV, Lassa virus and rhinovirus.

5. Phenol for use according to claim 4, wherein dyspnea is caused by COVID-19.

6. Phenol for use according to any one of the preceding claims, wherein the phenol is in a physiological saline composition.

7. Phenol for use according to any one of the preceding claims, wherein the phenol is administered in a liquid composition comprising from 0.005 to 0.07% w / w of phenol.

8. Phenol for use according to claim 7, wherein the liquid composition comprises 0.01 - 0.06% w / w phenol.

9. Phenol for use according to any one of the preceding claims, wherein the phenol is administered by subcutaneous injection. 77Q7 ίη / ZZOZ / E / YILI 10. Phenol for use according to claim 9, wherein the dose is 0.4 to 3.0 mg once a day, preferably 0.8 to 2.0 mg once a day.

11. Phenol for use according to claim 9, wherein the dose is 0.4 to 3.0 mg once a week, preferably 0.8 to 2.0 mg once a week.

12. Phenol for use according to any one of claims 9 to 11, wherein the dose is from 0.3 to 3.0 ml of physiological saline solution, preferably from 0.3 to 0.8 ml of physiological saline solution.

13. Phenol for use according to any one of claims 9 to 12, wherein the dose is divided into 2 to 10 subdoses, preferably 4 to 6 subdoses.

14. Phenol for use according to claim 13, wherein the dose is divided equally between two and ten subdoses.

15. Phenol for use according to claim 13 or 14, wherein the volume of the subdoses is 0.3 to 0.8 ml each.

16. Phenol for use according to any one of claims 9 to 15, wherein the phenol is administered in the neck area.

17. Phenol for use according to claim 16, wherein the dose is divided into two to ten subdoses for administration in different positions in the neck area.

18. Phenol for use according to claim 16 or 17, wherein the different positions in the neck area are selected from the group consisting of the posterior margin of the sternocleidomastoid muscle at the level of the laryngeal node on both the left and right sides of the body; the upper half of the sternal cavity; and the depression below the spinous process of the first cervical vertebra. 77Q7 ίη / ZZΖΠZ / E / YΙΛΙ 19. Phenol for use according to claim 2, wherein the phenol is administered intravenously.

20. Phenol for use according to claim 19, wherein the dose is 0.02 to 0.1 mg per kg of body weight per day.

21. Phenol for use according to claim 19 or 20, wherein the dose is administered daily for 3 to 8 consecutive days.

22. Phenol for use according to claim 21, wherein, starting from the day after the last day of administration of said dose, a second dose of 0.005 to 0.3, in particular 0.005 to 0.2 mg per kg of body weight per day of phenol is administered for a period of 1 to 5 days.

23. Phenol for use according to any one of claims 19 to 22, wherein the dose is administered by infusion, in particular by drip infusion.

24. Phenol for use according to claim 23, wherein the phenol is administered for a period of 10 minutes to 2 hours.