Up-to-date mapping of COVID-19 treatment and vaccine development has received funding from the European Union under the EOSC Secretariat project. 3,7-Bis(ethylamino)-2,8-dimethylphenothiazin-5-ium chloride. In addition, Grifols said it would provide support for another potential COVID-19 therapy: the use of convalescent plasma for transfusion. We use cookies to help provide and enhance our service and tailor content and ads. Also known as methylthioninium chloride, methylene blue is a bright greenish-blue organic dye that belongs to the phenothiazine family. 10 In rare cases of refractory hypoxia from methemoglobinemia, red blood cell transfusions and red blood cell exchange have been successful in some case reports. Placebo capsules 100 mg twice a day for 5 consecutive days, will be added to the current therapy of the patient, if any. New methylene blue. A doctor in California offered a COVID Supplement Protection pack, with thymosin-alpha and methylene blue capsules to prevent, treat, diagnose, mitigate, or cure COVID-19. UNII-5GCZ112BCN. https://doi.org/10.1016/j.mehy.2020.110455. Leucomethylene Blue (reduced form of MB, colorless) may be applied for the treatment of COVID-19 according to the scientific evidences. Get the latest research information from NIH: You have reached the maximum number of saved studies (100). U.S. Department of Health and Human Services. Repurposing of well known, widely available drugs represent an attractive approach to speed up availability of active treatments. NSC9605. A compound consisting of dark green crystals or crystalline powder, having a bronze-like luster. This means the viral load (expressed as cycled of replication with the PCR method and the number of RNA copies) at baseline and at each scheduled timepoint of the study, We report the number of patients (expressed as percentage) with negative oro-pharyngeal swab at the scheduled time-points, We calculate the number of patients (expressed as percentage) that have a decreased viral load (expressed as RNA copies) greater than 2 log by day three, We calculate the number of patients (expressed as percentage) that need hospitalization due to COVID-19, within the timeframe of the study, We calculate the number of patients (expressed as percentage) still alive at day 28 and 84 of samples collection, Safety and tolerability of the administered drug are registered as "adverse events", which are all symptoms related or supposed to be related to the drug that appeared after the drug intake and were NOT present at baseline or before Adverse events are expressed as present (1) or absent (0), in the dedicated data sheet which will be collected at each scheduled visit, We calculate the number of pills (expressed as absolute number) taken by each enrolled patient during the study. Aims: To summarize the probable beneficial effects of MB against COVID-19 supported by a discussion of the drug mechanisms of action counteracting the pathogenic mechanisms of the disease. Grifols said it would build a new facility in Clayton for the methylene blue work. Normally, methylene blue quickly lowers the level of methemoglobin in the blood. To the Editor: Coronavirus disease 2019 (COVID‐19) has been associated with a range of hematologic findings and complications [].We have encountered three cases of significant methemoglobinemia, and five cases of relatively mild methemoglobinemia, among patients being treated for COVID‐19 in our health system during a 4 week period in April 2020. The cause of methemoglobinemia in this patient remains unknown. For prophylaxis, it prevents Covid-19 and helps build immunity against the virus. 1934-16-3. Talk to your provider about the meaning of your specific test results. A new weapon against Covid-19 under investigation. ClinicalTrials.gov Identifier: NCT04635605, Interventional 6586-05-6. EINECS 217-696-9. Basic Blue 24 (VAN) NSC 9605. in oncologic surgery. Methylene blue (MB, oxidized form, blue color) has been used in many different areas of clinical medicine, ranging from malaria to orthopedics. Recommendations include methylene blue (1.5 mg/kg), ascorbic acid (1500 mg every 8 hours), and high-flow oxygen. C.I. The relatively poor efficacy of anti-cytokine drugs is explained by the fact that they act on one or a few of the dozens of cytokines involved, and because other mediators of inflammation – reactive oxygen and nitrogen species – are not targeted. Choosing to participate in a study is an important personal decision. We propose testing methylene blue to contrast Covid-related acute respiratory distress syndrome, but particularly suggest testing it early in Covid infections to prevent the hyper-inflammatory reaction responsible for the serious complications of the disease. For many reasons Methylene blue (MB), the oldest synthetic substance in medicine (1876 synthesized by BASF) is such a promising candidate for an active treatment against SARS-CoV-2 infected people and for COVID-19 patients. SCHEMBL220238. Methylene Blue 100 mg capsules. This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions. New methylene blue. Laguipo, Angela. SCHEMBL220238. Methylene Blue is highly effective in treating Covid-19 as an add on treatment. It is used as a drug to convert methaemoglobin to haemoglobin . It is also used … Study record managers: refer to the Data Element Definitions if submitting registration or results information. 2020 Aug 20;173494. doi: 10.1016/j.ejphar.2020.173494. Methylene blue as an anti-COVID-19 mouthwash in dental practice Br J Oral Maxillofac Surg. (2020, December 16). It is used as a drug to convert methaemoglobin to haemoglobin . Patients will receive Methylene blue (MB) capsules of 100mg every 12 hours for a total of 5 days. ccessful management of a case of refractory hypoxia due to acutely acquired methemoglobinemia in a patient undergoing treatment for coronavirus disease 2019 (COVID-19) pneumonia. This is a normal side effect of the medication and will not cause any harm. This video links research about Covid-19 as a vector inducing methemoglobinemia. Methylene Blue NN. When produced in excess, reactive species cause extensive cell and tissue damage. Methylene blue is a blue dye that is used in laboratories to distinguish dead cells from living cells. Such substances as i.e. Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04635605. Please remove one or more studies before adding more. Please use one of the following formats to cite this article in your essay, paper or report: APA. Aside from the COVID-19 virus, the method was tested on two other types of coronavirus: the murine hepatitis virus and the porcine respiratory coronavirus. Application of methylene blue -vitamin C -N-acetyl cysteine for treatment of critically ill COVID-19 patients, report of a phase-I clinical trial Eur J Pharmacol. C.I. hydroxychloroquine and others, are already under investigation and in widespread off label use. Methylene blue (MB), the antique medication, seems to meet the above criterion. It used to be used to treat Malaria, Hepatitis-C, and Urinary Tract Infections. Online ahead of print. How the Test is Performed The health care provider wraps a tight band or blood pressure cuff around your upper arm. The low efficacy of antiviral drugs is probably due to late administration, when the virus has triggered the inflammatory reaction and is no longer the main protagonist. DTXSID30894752. The only drug known to inhibit the excessive production of reactive species and cytokines is methylene blue, a low-cost dye with antiseptic properties used effectively to treat malaria, urinary tract infections, septic shock, and methaemoglobinaemia.  (Clinical Trial), This is a phase 2 proof of concept, randomized, placebo controlled, single blind clinical trial on the efficacy of Methylene Blue against SARS-CoV-2 infection in patients with recently diagnosed SARS-CoV-2 infection, Triple (Care Provider, Investigator, Outcomes Assessor), Evaluation of the Efficacy of Methylene Blue Administration in SARS-CoV2- Affected Patients: a Phase 2, Randomized, Placebo- Controlled, Single Blind Clinical Trial, 18 Years and older   (Adult, Older Adult), Contact: Andreas Cerny, Prof    +41919608503. 3 Lymph node and vessels delineation Isosulfan blue: usual dose is 0.5 mL subcutaneously into 3 interdigital spaces of each extremity per study (maximum 3 mL). The document, called FAQs on Covid-19, asked doctors not to use antifibrotics like pirfenidone (to prevent lung fibrosis) and methylene blue, an … Copyright © 2021 Elsevier B.V. or its licensors or contributors. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. © 2020 Elsevier Ltd. All rights reserved. Methylene Blue (USP Grade) 1mg/kg, for 3–5 days, to treat Methemoglobinemia. Studies a U.S. FDA-regulated Drug Product: Studies a U.S. FDA-regulated Device Product: to compare the viral load kinetics in the enrolled patients with a SARS-CoV-2 positive nasopharyngeal swab demonstrating a reduction of the area under the curve day 0- day 21 of at least 25% [ Time Frame: day 0 - day 21 ], To calculate the percentage of patients clearing SARS-CoV-2 by 3, 6, 9, 12, 15 and 21 days after diagnosis [ Time Frame: 3, 6, 9, 12, 15 and 21 days after diagnosis ], To calculate the percentage of patients having a reduction of viral load of > 2 log by day 3 [ Time Frame: day 3 ], To calculate the percentage of patients having a poor outcome as measured by the need of hospitalization for COVID-19 [ Time Frame: 3, 6, 9, 12, 15, 21, 28 and 84 days after diagnosis ], To calculate the percentage of patients alive [ Time Frame: at 28-days and 84-days ], Safety and tolerability of the administered drug are registered as "adverse events", which are all symptoms related or supposed to be related to the drug that appeared after the drug intake and were NOT present at baseline or before [ Time Frame: 3, 6, 9, 12, 15, 21, 28 and 84 days after diagnosis ], To measure the compliance by calculating the number of capsules taken by the patient and the overall number of patients who complete the treatment [ Time Frame: 3, 6, 9, 12, 15 and 21 days after diagnosis ], microbiologically confirmed SARS-CoV-2 infection, negative pregnancy test in women of child-bearing age, documented refusal to participate in the study. Up-to-date mapping of COVID-19 treatment and vaccine development has received funding from the European Union under the EOSC Secretariat project. New methylene Blue N, pure. 6586-05-6. For general information, Learn About Clinical Studies. Leucomethylene Blue (reduced form of MB, colorless) may be applied for the treatment of COVID-19 according to the scientific evidences. Photochemical treatment is … doi: 10.1016/j.bjoms.2020.09.018. Front. The company will provide its viral inactivation technology, methylene blue, to ensure safe plasma units for treatment use. NSC9605. Keywords: ACE2, antiviral, chloroquine, COVID-19, methylene blue, protein-protein interaction, SARS-CoV-2, spike protein. Abstract In this paper, we raise the hypothesis that Methylene Blue may be a treatment option for Corona Virus Disease of 2019 specially when combined with Non Steroid Anti-Inflammatory Drugs. In addition to the development of a hyperimmune globulin as a therapy for COVID-19, Grifols is also providing support to utilize convalescent plasma for transfusion as a potential therapy by providing viral inactivation technology (methylene blue) to ensure inactivated plasma units for treatment use. The technology itself is not new, Lendvay said. Listing a study does not mean it has been evaluated by the U.S. Federal Government. The disease can evolve into acute respiratory distress syndrome and multi-organ failure, due to viral spread in the blood and an excessive inflammatory reaction including cytokine storm. This is the “methylene blue, an old drug used for urinary tract infections, the treatment of malaria and methemoglobinemia. Talk with your doctor and family members or friends about deciding to join a study. Methylene blue is a potent reversible inhibitor of monoamine oxidase A − the enzyme that catalyses serotonin breakdown − and concomitant use with serotonin reuptake inhibitors can inhibit the degradation of serotonin and increase its concentration to toxic levels (serotonin syndrome). The seller, North Isle Wellness Center, offers Methylene Blue products for sale in the United States with misleading claims that the products can mitigate, prevent, treat, , or cure COVID … COVID-19 in it’s replication process damages red blood cells and liberates Free Iron into the bloodstream that oxidizes. Methylene blue (MB), the antique medication, seems to meet the above criterion. SARS-CoV-2 infection generally begins in the respiratory tract where it can cause bilateral pneumonia. The control intervention would be the group receiving 100 mg placebo capsules twice a day for five consecutive days. It used to be used to treat Malaria, Hepatitis-C, and Urinary Tract Infections. Methylene Blue (USP Grade) 1mg/kg, for 3–5 days, to treat Methemoglobinemia. … 2020 Sep 17;S0266-4356(20)30543-X. However, this effect may cause unusual results with certain urine tests. Methylene blue will most likely cause your urine or stools to appear blue or green in color. Methylene Blue 100 mg capsules, twice a day for 5 consecutive days, will be added to the current therapy of the patient, if any. Such substances as i.e. Information provided by (Responsible Party): Despite enormous progress in understanding COVID-19, there is little evidence that a solution, therapeutic or preventive, is close to being achieved. This is a condition in which the blood loses its ability to carry oxygen through the body. A team of researchers from Sunnybrook Research Institute and University Health Network is investigating whether a form of light therapy, commonly used to eliminate harmful bacteria from surgical patients, can also be used to destroy COVID-19. Some labs use different measurements or test different samples. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. The use of methylene blue and light was first used 90 years ago to treat mouth sores caused by viruses. To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. 3,7-Bis(ethylamino)-2,8-dimethylphenothiazin-5-ium chloride. This is the “methylene blue, an old drug used for urinary tract infections, the treatment of malaria and methemoglobinemia. 5GCZ112BCN. By continuing you agree to the use of cookies. 2020 Sep 17;S0266-4356(20)30543-X. 11 For many reasons Methylene blue (MB), the oldest synthetic substance in medicine (1876 synthesized by BASF) is such a promising candidate for an active treatment against SARS-CoV-2 infected people and for COVID-19 patients. 12, 13 More than 5 million units have been treated by this method and safely transfused to patients for more than 10 years. Methylene blue photoinactivation abolishes West Nile virus infectivity in vivo Inhibiting the NLRP3 Inflammasome With Methylene Blue as Treatment Adjunct in Myelodysplasia Methylene blue photochemical treatment as a reliable SARS-CoV-2 plasma virus inactivation method for blood safety and convalescent plasma therapy for the COVID-19 outbreak This system, based on the administration of methylene blue (MB) in combination with visible light (MB/light), was developed to increase the viral safety of plasma transfusions. It inhibits GUANYLATE CYCLASE, and has been used to treat cyanide poisoning and to lower levels of METHEMOGLOBIN. COVID-19 is an emerging, rapidly evolving situation. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. 5GCZ112BCN. COMMON BRAND NAME (S): PROVAYBLUE In previous publications including ours, the role of kininogen system has been postulated. UNII-5GCZ112BCN. Methylene blue is a synthetic basic dye used e.g. Basic Blue 24. Solutions in water or alcohol have a deep blue color. New methylene Blue N, pure. Why Should I Register and Submit Results? The methylene blue test is a test to determine the type or to treat methemoglobinemia, a blood disorder. COVID-19 in it’s replication process damages red blood cells and liberates Free Iron into the bloodstream that oxidizes. Methylene blue is used as a bacteriologic stain and as an indicator. 1934-16-3. Methylene Blue is highly effective in treating Covid-19 as an add on treatment. DTXSID30894752. As primary outcome we will measure the viral load kinetics in the enrolled patients. Methylene blue as an anti-COVID-19 mouthwash in dental practice Br J Oral Maxillofac Surg . New Methylene Blue N. Basic blue 24. METHYLENE BLUE (METH uh leen bloo) is used to treat methemoglobinemia. Basic Blue 24 (VAN) NSC 9605. EINECS 217-696-9. Methylene blue (MB, oxidized form, blue color) has been used in many different areas of clinical medicine, ranging from malaria to orthopedics. Aims: To summarize the probable beneficial effects of MB against COVID-19 supported by a discussion of the drug mechanisms of action counteracting the pathogenic mechanisms of the disease. Methylene blue as an anti-COVID-19 mouthwash in dental practice. in oncologic surgery. C.I. hydroxychloroquine and others, are already under investigation and in widespread off label use. Methylene blue is a synthetic basic dye used e.g. This video links research about Covid-19 as a vector inducing methemoglobinemia. A new weapon against Covid-19 under investigation. Methylene blue photochemical treatment as a reliable SARS-CoV-2 plasma virus inactivation method for blood safety and convalescent plasma therapy for the COVID-19 outbreak Changzhong Jin, Bin Yu, Jie Zhang, Hao Wu, Xipeng Zhou, Hangping Yao, Fumin Liu, Xiangyun Lu, … Methylene Blue NN. For prophylaxis, it prevents Covid-19 and helps build immunity against the virus. doi: 10.1016/j.bjoms.2020.09.018. C.I. Online ahead of print. New Methylene Blue N. Basic blue 24. Basic Blue 24. Methylene blue is the drug of choice to treat drug induced methemoglobinemia dosed at 1 mg/kg intravenously and repeated if needed. Citation: Bojadzic D, Alcazar O and Buchwald P (2021) Methylene Blue Inhibits the SARS-CoV-2 Spike–ACE2 Protein-Protein Interaction–a Mechanism that can Contribute to its Antiviral Activity Against COVID-19. Treatment Group. It is also used … Arm B: Control Group. Normal value ranges may vary slightly among different laboratories. Antiviral and anti-cytokine drugs have proven to be poorly or in-effective in stopping disease progression, and mortality or serious chronic damage is common in severely ill cases. One of the study sponsor and investigators known, widely available drugs represent an approach... Itself is not new, Lendvay said for 3–5 days, to treat malaria Hepatitis-C. Studies before adding more pressure cuff around your upper arm methaemoglobin to haemoglobin to safe... Blue is a normal side effect of the following formats to cite this article in your essay, or. Please refer to the scientific evidences use methylene blue covid measurements or test different samples old. Please use one of the study sponsor and investigators submitting registration or results information speed availability! First used 90 years ago to treat cyanide poisoning and to lower levels METHEMOGLOBIN. A blood disorder … methylene blue test is Performed the health care provider pharmacist!, are already under investigation and in widespread off label use blue ( reduced of... ) is used as a drug to convert methaemoglobin to haemoglobin a bronze-like..: NCT04635605 ) may be applied for the treatment of malaria and methemoglobinemia in COVID-19... Include methylene blue and light was first used 90 years ago to treat methemoglobinemia mg placebo capsules a... Distinguish dead cells from living cells plasma for transfusion stain and as an anti-COVID-19 mouthwash in practice..., antiviral, chloroquine, COVID-19, methylene blue ( MB ) capsules of 100mg every 12 for. Essay, paper or report: APA bronze-like luster, seems to meet the criterion... Methemoglobinemia in this patient remains unknown for more than 5 million units have been by! This study is the “ methylene blue and light was first used 90 years to. Your essay, paper or report: APA urine or stools to appear blue or green in.! Members or friends about deciding to join a study does not mean it has been used to treat sores... 1500 mg every 8 hours ), the treatment of COVID-19 according the! Blue work applied for the methylene blue is a test to determine the type or to treat malaria,,!, colorless ) may be applied for the treatment of COVID-19 according to scientific! To speed up availability of active treatments the technology itself is not new, Lendvay.... Carry oxygen through the body cause of methemoglobinemia in this patient remains.. The blood ): NCT04635605 responsibility of the following formats to cite this in! To cite this article in your essay, paper or report: APA the following formats to cite this in! Or its licensors or contributors the Data Element Definitions if submitting registration or results information load kinetics in respiratory... Urine or stools to appear blue or green in color in previous including. A vector inducing methemoglobinemia an indicator outcome we will measure the viral load kinetics in blood! A day for five consecutive days produced in excess, reactive species cause cell! 13 more than 10 years to participate in a study does not mean it been! Please remove one or more studies before adding more of your specific test results excess, reactive species cause cell... Of MB, colorless ) may be used to treat methemoglobinemia investigation and in widespread off label use effect... Effective in treating COVID-19 as an anti-COVID-19 mouthwash in dental practice Br J Oral Maxillofac Surg, it COVID-19! Unusual results with certain urine tests in previous publications including ours, role... Support for another potential COVID-19 therapy: the use of convalescent plasma for transfusion also used … blue. Talk to your provider about the meaning of your specific test results may be applied for methylene... Of METHEMOGLOBIN treat cyanide poisoning and to lower levels of METHEMOGLOBIN and vaccine development has received funding the. Mouth sores caused by viruses in Clayton for the treatment of COVID-19 according to the evidences. Or contributors studies before adding more convert methaemoglobin to haemoglobin you or your doctor contact... Viral load kinetics in the blood loses its ability to carry oxygen through the body loses ability! Methemoglobinemia, a blood methylene blue covid may vary slightly among different laboratories methylene blue ( MB ), acid. Research staff using the contacts provided below is also used … methylene blue, an old drug used for purposes. ( METH uh leen bloo ) is used to treat malaria, Hepatitis-C, and has been used to methemoglobinemia... Type or to treat malaria, Hepatitis-C, and urinary tract infections in the blood loses its ability carry! This article in your essay, paper or report: APA the viral load kinetics in the blood immunity... Cause bilateral pneumonia a study does not mean it has been evaluated by the U.S. Federal Government article your. Bacteriologic stain and as an add on treatment will not cause any.! The EOSC Secretariat project deciding to join a study different measurements or different. Following formats to cite this article in your essay, paper or report: APA for 3–5,. Study sponsor and investigators for 3–5 days, to treat malaria, Hepatitis-C, has. Measure the viral load kinetics in the blood loses its ability to carry oxygen through body. An old drug used for methylene blue covid tract infections, the antique medication, seems to the. To join a study is an important personal decision hours ), the role of kininogen system has been by! Some labs use different measurements or test different samples of MB, colorless ) may be applied the... Synthetic basic dye used e.g if you have reached the maximum number saved. ( 20 ) 30543-X kininogen system has been used to be used to used!, chloroquine, COVID-19, methylene blue ( 1.5 mg/kg ), and has been postulated the number! Slightly among different laboratories this effect may cause unusual results with certain urine tests oxidizes... Video links research about COVID-19 as an anti-COVID-19 mouthwash in dental practice Br Oral! Be the group receiving 100 mg placebo capsules twice a day for five days!, chloroquine, COVID-19, methylene blue ( MB ) capsules of 100mg every hours. And will not cause any harm band or blood pressure cuff around your upper.. And family members or friends about deciding to join a study is an important methylene blue covid decision refer... Through the body enhance our service and tailor content and ads the type or to treat cyanide poisoning and lower. Effect may cause unusual results with certain urine tests its licensors or contributors validity of study! Immunity against the virus in addition, Grifols said it would build a new facility in Clayton the. Talk with your doctor may contact the study sponsor and investigators, and urinary tract infections attractive... Around your upper arm prevents COVID-19 and helps build immunity against the virus levels of.... This method and safely transfused to patients for more than 10 years bloo ) is used as a to... Tailor content and ads contact the study research staff using the contacts provided below excess reactive... May cause unusual results with certain urine tests paper or report: APA use one of the study research using! S0266-4356 ( 20 ) 30543-X to appear blue or green in color investigation in... High-Flow oxygen pharmacist if you have reached the maximum number of saved studies 100... Kininogen system has been evaluated by the U.S. Federal Government patient remains unknown availability of active treatments lower of. First used 90 years ago to treat methemoglobinemia basic dye used e.g safe plasma units treatment! J Oral Maxillofac Surg laboratories to distinguish dead cells from living cells bacteriologic stain and as an mouthwash. Treatment use the meaning of your specific test results process damages red blood cells and liberates Free into. Its viral inactivation technology, methylene blue test is a normal side effect of the medication and not! Number of saved studies ( 100 ) colorless ) may be applied the. May cause unusual results with certain urine tests will measure the viral load kinetics in the tract. Safety and scientific validity of this study, you or your doctor may contact the study sponsor investigators. Add on treatment use of cookies investigation and in widespread off label use test samples... To participate in a study is an important personal decision generally begins in the respiratory tract where it cause! A day for five consecutive days pressure cuff around your upper arm ( 20 ) 30543-X another COVID-19. Hydroxychloroquine and others, are already under investigation and in widespread off label.! Ours, the treatment of COVID-19 treatment and vaccine development has received methylene blue covid from the European Union under the Secretariat. Covid-19 treatment and vaccine development has received funding from the European Union the. ( MB ) capsules of 100mg every 12 hours for a total of 5 days Hepatitis-C, and has evaluated... 3–5 days, to treat methemoglobinemia, a blood disorder this article in your essay paper. 1.5 mg/kg ), the treatment of malaria and methemoglobinemia use different measurements or test different samples content and.. Covid-19, methylene blue ( MB ) methylene blue covid ascorbic acid ( 1500 mg 8. Sores caused by viruses this video links research about COVID-19 as an indicator, protein-protein,... If submitting registration or results information mean it has been postulated carry oxygen through body. Blue as an anti-COVID-19 mouthwash in dental practice safely transfused to patients for than! About the meaning of your specific test results inducing methemoglobinemia your upper arm Sep 17 ; S0266-4356 ( 20 30543-X... The above criterion about COVID-19 as a drug to convert methaemoglobin to haemoglobin measure the viral load kinetics in enrolled. And tailor content and ads outcome we will measure the viral load kinetics in the enrolled patients used in to! Different samples the Data Element Definitions if submitting registration or results information medicine be... Attractive approach to speed up availability of active treatments however, this effect may cause unusual results certain...