Ignite Creation Date:
2024-05-06 @ 4:44 PM
Last Modification Date:
2024-10-26 @ 2:15 PM
Study NCT ID:
NCT05077813
Status:
UNKNOWN
Last Update Posted:
2021-10-14
First Post:
2021-10-10
Brief Title:
Utilizing the Crosstalk Among Chicoric Acid 13-Cis Retinoic AcidAerosolized Minocycline and Vitamin D as a Potent Quadrate Therapy for Treating Patients With Multidrug-resistant TB and Patient With Both Multidrug-resistant TB and COVID-19
Sponsor:
Kafrelsheikh University
Organization:
Kafrelsheikh University
Study Overview
Official Title:
Utilizing the Crosstalk Among Chicoric Acid 13-Cis Retinoic AcidAerosolized Minocycline and Vitamin D as a Potent Quadrate Therapy for Treating Patients With Multidrug-resistant TB and Patient With Both Multidrug-resistant TB and COVID-19
Status:
UNKNOWN
Status Verified Date:
2021-10
Last Known Status:
NOT_YET_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Utilizing the Crosstalk Among Chicoric Acid 13-Cis Retinoic AcidAerosolized Minocycline and Vitamin D as a Potent Quadrate Therapy for treating patients with Multidrug-resistant TB and patient with both Multidrug-resistant TB and COVID-19 A double-edged sword Clinical Study
IPart of Tuberculosis
Tuberculosis TB is a major infectious disease killer globally It affected 10 million and killed 14 million people in 2019 alone The predicted impact of the COVID-19 pandemic is an additional 190000 TB deaths in 2020 and it is expected in the next 5 y that there will be up to a 20 increase in the global TB disease burden stressing the critical need for new safe and effective drugs against Mycobacterium tuberculosis Mtb In addition controlling multidrug-resistant TB MDR-TB presents a huge public health challenge New drug discovery could require several years with no guarantee but repurposing established may be useful to treat patients with tuberculosis Here we demonstrate that we could utilize the crosstalk among Chicoric Acid 13-Cis Retinoic Acid Minocycline and vitamin D as a novel quadrate therapy against TBDrug-resistant tuberculosis represents a global emergency requiring new drugs Recently Minocycline was found to be highly potent in laboratory strains of Mycobacterium TB and 30 drug-sensitive and multidrugextensively drug-resistant clinical strains were susceptible to clinically attainable dosages The lung concentration-time profiles of a 7 mgkgday human-equivalent minocycline dosage yielded bacterial kill rates comparable to first-line antituberculosis drugs Extracellular bacilli were destroyed directly by minocycline Minocycline also killed intracellular bacilli indirectly through granzyme A-driven apoptosis Furthermore minocycline showed dose-dependent antiinflammatory effect suggesting that it may protect tuberculosis patients against immunopathology A study showed that M tuberculosis induced the expression of indoleamine 23-dioxygenase IDO an enzyme involved in tryptophan catabolism in macrophages and in the lungs of animals mice and macaque with active disease In a macaque model of inhalation TB suppression of IDO activity reduced bacterial burden pathology and clinical signs of TB disease leading to increased host survival This increased protection was accompanied by increased lung T cell proliferation induction of inducible bronchus-associated lymphoid tissue and correlates of bacterial killing A recent study showed that Minocycline-induced significantly inhibition of IDO expression But Minocycline-induced inhibition of IDO expression is retinoid-dependent The combined treatment with minocycline and retinol however resulted in a striking statistically significant decrease in IDO Co-treatment with minocycline and retinol again resulted in decreased TNF-α and IL-6 levels A study showed that IL-6 inhibits IFN-γ induced autophagy in Mycobacterium TB H37Rv infected macrophages As well as neutralization of endogenous IL-6 by anti-IL-6 antibody significantly enhances the IFN-γ mediated killing of the intracellular bacteria Minocyclines anti-inflammatory effects are mediated through RAR signaling Therefore The combined treatment with minocycline and retinol is expected to effectively inhibit TB and its inflammatory complication Fortunately Retinoic Acid significantly inhibits the in vivo growth of M tuberculosis and the development of tuberculosis In addition to 13-Cis RA and Chicoric Acid CA enhanced the cell surface expression of HLA-DR and CD14 molecules on U937 macrophages and prevented the growth of Mtb within macrophages Moreover 13-cis RA and CA have increased NO generation compared to untreated control macrophages significantly Both drugs have a significant inhibitory effect on Mtb growth but CA at the highest concentration was more potent than 13-cis RA Therefore we will use retinoic acid to induce the effect of Minocycline as well as its ability to inhibit tuberculosis in combination with CA Recent data showed that Vitamin D support innate immune responses to Mycobacterium TB and Low vitamin D levels were associated with a 5-fold increased risk for progression to tuberculosis Deficiency of vitamin D has long been implicated in activation of TB Serum vitamin D in TB patients are lower than in healthy controls Vitamin D has been found to speed up the clearance of TB bacteria from the lungs of people with multi-drug resistant TB according to a study of 1850 patients It was showed that Vitamin D receptor VDR must form a heterodimer complex with retinoid X receptor RXR to regulate gene transcription Retinol plays a crucial role in lung development and signaling the vitamin D pathway 9-cis-retinoic acid an active vitamin A metabolite and the ligand of RXR assists VDR signaling and suppresses the degradation of circulating vitamin D
IPart of Tuberculosis
Tuberculosis TB is a major infectious disease killer globally It affected 10 million and killed 14 million people in 2019 alone The predicted impact of the COVID-19 pandemic is an additional 190000 TB deaths in 2020 and it is expected in the next 5 y that there will be up to a 20 increase in the global TB disease burden stressing the critical need for new safe and effective drugs against Mycobacterium tuberculosis Mtb In addition controlling multidrug-resistant TB MDR-TB presents a huge public health challenge New drug discovery could require several years with no guarantee but repurposing established may be useful to treat patients with tuberculosis Here we demonstrate that we could utilize the crosstalk among Chicoric Acid 13-Cis Retinoic Acid Minocycline and vitamin D as a novel quadrate therapy against TBDrug-resistant tuberculosis represents a global emergency requiring new drugs Recently Minocycline was found to be highly potent in laboratory strains of Mycobacterium TB and 30 drug-sensitive and multidrugextensively drug-resistant clinical strains were susceptible to clinically attainable dosages The lung concentration-time profiles of a 7 mgkgday human-equivalent minocycline dosage yielded bacterial kill rates comparable to first-line antituberculosis drugs Extracellular bacilli were destroyed directly by minocycline Minocycline also killed intracellular bacilli indirectly through granzyme A-driven apoptosis Furthermore minocycline showed dose-dependent antiinflammatory effect suggesting that it may protect tuberculosis patients against immunopathology A study showed that M tuberculosis induced the expression of indoleamine 23-dioxygenase IDO an enzyme involved in tryptophan catabolism in macrophages and in the lungs of animals mice and macaque with active disease In a macaque model of inhalation TB suppression of IDO activity reduced bacterial burden pathology and clinical signs of TB disease leading to increased host survival This increased protection was accompanied by increased lung T cell proliferation induction of inducible bronchus-associated lymphoid tissue and correlates of bacterial killing A recent study showed that Minocycline-induced significantly inhibition of IDO expression But Minocycline-induced inhibition of IDO expression is retinoid-dependent The combined treatment with minocycline and retinol however resulted in a striking statistically significant decrease in IDO Co-treatment with minocycline and retinol again resulted in decreased TNF-α and IL-6 levels A study showed that IL-6 inhibits IFN-γ induced autophagy in Mycobacterium TB H37Rv infected macrophages As well as neutralization of endogenous IL-6 by anti-IL-6 antibody significantly enhances the IFN-γ mediated killing of the intracellular bacteria Minocyclines anti-inflammatory effects are mediated through RAR signaling Therefore The combined treatment with minocycline and retinol is expected to effectively inhibit TB and its inflammatory complication Fortunately Retinoic Acid significantly inhibits the in vivo growth of M tuberculosis and the development of tuberculosis In addition to 13-Cis RA and Chicoric Acid CA enhanced the cell surface expression of HLA-DR and CD14 molecules on U937 macrophages and prevented the growth of Mtb within macrophages Moreover 13-cis RA and CA have increased NO generation compared to untreated control macrophages significantly Both drugs have a significant inhibitory effect on Mtb growth but CA at the highest concentration was more potent than 13-cis RA Therefore we will use retinoic acid to induce the effect of Minocycline as well as its ability to inhibit tuberculosis in combination with CA Recent data showed that Vitamin D support innate immune responses to Mycobacterium TB and Low vitamin D levels were associated with a 5-fold increased risk for progression to tuberculosis Deficiency of vitamin D has long been implicated in activation of TB Serum vitamin D in TB patients are lower than in healthy controls Vitamin D has been found to speed up the clearance of TB bacteria from the lungs of people with multi-drug resistant TB according to a study of 1850 patients It was showed that Vitamin D receptor VDR must form a heterodimer complex with retinoid X receptor RXR to regulate gene transcription Retinol plays a crucial role in lung development and signaling the vitamin D pathway 9-cis-retinoic acid an active vitamin A metabolite and the ligand of RXR assists VDR signaling and suppresses the degradation of circulating vitamin D
Detailed Description:
This double blinded randomized placebo controlled trial on the clinical efficacy and antimicrobial mechanisms of quadrate therapyChicoric Acid 13-Cis Retinoic AcidAerosolized Minocycline and Vitamin D as a Potent Quadrate Therapy Against Tuberculosis 200 men and women will be enrolled who are age 18 to 65 years inclusive have at least two positive sputum smears for tuberculosis TB and have given informed consent to participate in the study All of the enrollees will have active TB The effect of the quadrate therapy status will be examined in the context of a randomized trial conducted in Egyptian or Saudi Arabian Subjects will be randomized to receive either the quadrate therapy or placebo from the start of their TB therapy through the 1 months of anti-TB therapy and until the last recruited patient reaches 6 months of follow up Thus the first subject is likely to be followed for 12 months assuming the duration of recruitment is 12 months The endpoints of interest include bacteriologic cure immune response parameters and clinical outcomes The researchers will also examine the utility of these immune response parameters as surrogate markers for treatment efficacy in TB irrespective of the quadrate therapy and other risk factors The study will be carried out as a collaborative effort between Kafr elshiekh university Faculty of Medicine Egypt and First health cluster Ministry of health Saudia Arabia Subjects will be randomly assigned to receive A Minocycline iv 45 mgkg gradual in 2 divided doses increases from 45 mgkg from the first week to 75 and 10 mgkg to the last week In addition to Aerosolized 13 cis retinoic acid or All trans retinoic acid or 9 cis retinoic acid gradual in 2 divided doses increases from 02 mgkgday to 4 mgkgday as inhaled retinoic acid therapy for 30 days Moreover the patients will receive Echinacea Purpurea Extract Capsules Polyphenols Chicoric Acid Chicoric acid also known as cichoric acid and dicaffeoyltar- taric acid is the main phenolic compound found in Echinacea purpurea Echinacea phytochemical profile Each tablet is comprised of the equivalent of 1275 mg of echinacea root as follows A Echinacea purpurea - 675 mg root yields 1125 mg dried extract standardized to contain 21mg alkamides Each batch of tablets Caffeic acid derivative levels are typically as follows caftaric acid 05 to 20 mgtablet cichoric acid 34 to 85 mgtablet chlorogenic acid 05 mgtablet dicaffeoyl quinic acids including cynarin 07 to 20 mgtablet echinacoside 10 to 17 mgtablet Furthermore the patients will receive CholecalciferolVitamin D Intramuscular injection of 600000 units of Cholecalciferol for 2 doses given at week 0 and week 4 b placebo The primary objectives are to 1 determine the efficacy of the quadrate therapy on sputum and culture negativity at one month and two months 2 determine the efficacy of micronutrient supplements on survival between two arms at 8 and 24 months and 3 determine the efficacy of micronutrient supplements on TB relapse and reinfection Secondary study objectives are to 1 compare the treatment arms with respect to absolute change in CD4 counts from 0 to 1 6 12 months 2 compare the treatment arms with respect to weight change from baseline and1 months 6 months and 12 months 3 compare the treatment arms with respect to immunological parameters namely ex vivo lymphocyte proliferation and cytokine production namely IL-2 IL-6 INF-g INF-Alpha IL-12 and TNF-a and Interferon alpha at 1 6 12 months and 4 correlate the above mentioned immunological markers with smear conversion rates at 1 month 2 months cure relapse and death Finally we suggest that this combination therapy will effectively inhibit tuberculosis infection and achieve treatment with significant effect against TB
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None