BACKGROUNDAcute respiratory distress syndrome (ARDS) is a life-threatening condition caused by direct or indirect injury to the lungs. Despite improvements in clinical management (for example, lung protection strategies), mortality in this patient group is at approximately 40%. This is an update of a previous version of this review, last published in 2004.OBJECTIVESTo evaluate the effectiveness of pharmacological agents in adults with ARDS on mortality, mechanical ventilation, and fitness to return to work at 12 months.SEARCH METHODSWe searched CENTRAL, MEDLINE, Embase, and CINAHL on 10 December 2018. We searched clinical trials registers and grey literature, and handsearched reference lists of included studies and related reviews.SELECTION CRITERIAWe included randomized controlled trials (RCTs) comparing pharmacological agents with control (placebo or standard therapy) to treat adults with established ARDS. We excluded trials of nitric oxide, inhaled prostacyclins, partial liquid ventilation, neuromuscular blocking agents, fluid and nutritional interventions and medical oxygen. We excluded studies published earlier than 2000, because of changes to lung protection strategies for people with ARDS since this date.DATA COLLECTION AND ANALYSISTwo review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of evidence with GRADE.MAIN RESULTSWe included 48 RCTs with 6299 participants who had ARDS; two included only participants with mild ARDS (also called acute lung injury). Most studies included causes of ARDS that were both direct and indirect injuries. We noted differences between studies, for example the time of administration or the size of dose, and because of unclear reporting we were uncertain whether all studies had used equivalent lung protection strategies.We included five types of agents as the primary comparisons in the review: corticosteroids, surfactants, N-acetylcysteine, statins, and beta-agonists. We included 15 additional agents (sivelestat, mesenchymal stem cells, ulinastatin, anisodimine, angiotensin-converting enzyme (ACE) inhibitor, recombinant human ACE2 (palifermin), AP301, granulocyte-macrophage colony stimulating factor (GM-CSF), levosimendan, prostacyclins, lisofylline, ketaconazole, nitroglycerins, L-2-oxothiazolidine-4-carboxylic acid (OTZ), and penehyclidine hydrochloride).We used GRADE to downgrade outcomes for imprecision (because of few studies and few participants), for study limitations (e.g. high risks of bias) and for inconsistency (e.g. differences between study data).Corticosteroids versus placebo or standard therapyCorticosteroids may reduce all-cause mortality within three months by 86 per 1000 patients (with as many as 161 fewer to 19 more deaths); however, the 95% confidence interval (CI) includes the possibility of both increased and reduced deaths (risk ratio (RR) 0.77, 95% CI 0.57 to 1.05; 6 studies, 574 participants; low-certainty evidence). Due to the very low-certainty evidence, we are uncertain whether corticosteroids make little or no difference to late all-cause mortality (later than three months) (RR 0.99, 95% CI 0.64 to 1.52; 1 study, 180 participants), or to the duration of mechanical ventilation (mean difference (MD) -4.30, 95% CI -9.72 to 1.12; 3 studies, 277 participants). We found that ventilator-free days up to day 28 (VFD) may be improved with corticosteroids (MD 4.09, 95% CI 1.74 to 6.44; 4 studies, 494 participants; low-certainty evidence). No studies reported adverse events leading to discontinuation of study medication, or fitness to return to work at 12 months (FTR).Surfactants versus placebo or standard therapyWe are uncertain whether surfactants make little or no difference to early mortality (RR 1.08, 95% CI 0.91 to 1.29; 9 studies, 1338 participants), or whether they reduce late all-cause mortality (RR 1.28, 95% CI 1.01 to 1.61; 1 study, 418 participants). Similarly, we are uncertain whether surfactants reduce the duration of mechanical ventilation (MD -2.50, 95% CI -4.95 to -0.05; 1 study, 16 participants), make little or no difference to VFD (MD -0.39, 95% CI -2.49 to 1.72; 2 studies, 344 participants), or to adverse events leading to discontinuation of study medication (RR 0.50, 95% CI 0.17 to 1.44; 2 studies, 88 participants). We are uncertain of these effects because we assessed them as very low-certainty. No studies reported FTR.N-aceytylcysteine versus placeboWe are uncertain whether N-acetylcysteine makes little or no difference to early mortality, because we assessed this as very low-certainty evidence (RR 0.64, 95% CI 0.32 to 1.30; 1 study, 36 participants). No studies reported late all-cause mortality, duration of mechanical ventilation, VFD, adverse events leading to study drug discontinuation, or FTR.Statins versus placeboStatins probably make little or no difference to early mortality (RR 0.99, 95% CI 0.78 to 1.26; 3 studies, 1344 participants; moderate-certainty evidence) or to VFD (MD 0.40, 95% CI -0.71 to 1.52; 3 studies, 1342 participants; moderate-certainty evidence). Statins may make little or no difference to duration of mechanical ventilation (MD 2.70, 95% CI -3.55 to 8.95; 1 study, 60 participants; low-certainty evidence). We could not include data for adverse events leading to study drug discontinuation in one study because it was unclearly reported. No studies reported late all-cause mortality or FTR.Beta-agonists versus placebo controlBeta-blockers probably slightly increase early mortality by 40 per 1000 patients (with as many as 119 more or 25 fewer deaths); however, the 95% CI includes the possibility of an increase as well as a reduction in mortality (RR 1.14, 95% CI 0.91 to 1.42; 3 studies, 646 participants; moderate-certainty evidence). Due to the very low-certainty evidence, we are uncertain whether beta-agonists increase VFD (MD -2.20, 95% CI -3.68 to -0.71; 3 studies, 646 participants), or make little or no difference to adverse events leading to study drug discontinuation (one study reported little or no difference between groups, and one study reported more events in the beta-agonist group). No studies reported late all-cause mortality, duration of mechanical ventilation, or FTR.AUTHORS' CONCLUSIONSWe found insufficient evidence to determine with certainty whether corticosteroids, surfactants, N-acetylcysteine, statins, or beta-agonists were effective at reducing mortality in people with ARDS, or duration of mechanical ventilation, or increasing ventilator-free days. Three studies awaiting classification may alter the conclusions of this review. As the potential long-term consequences of ARDS are important to survivors, future research should incorporate a longer follow-up to measure the impacts on quality of life.

News (Medical) associated with Mesenchymal stem cells (Therapeutic Solutions International)

13 Mar 2023

·www.biospace.com

Therapeutic Solutions International Advances Chronic Obstructive Pulmonary Disease Program by Identifying Novel B Regulatory Cell Mechanism of Action for JadiCell Universal Donor Adult Stem Cell

Company Builds on Previous Observations Correlating Clinical Responses to Stem Cells with Unique B Cell Population ELK CITY, Idaho--(BUSINESS WIRE)-- Therapeutic Solutions International (TSOI) announced today new data and filing of a patent covering the discovery that JadiCell therapeutic activity in a model of Chronic Obstructive Pulmonary Disease (COPD) can be transferred to naïve animals by a specialized type of B cell. These findings build upon previous discoveries of the company that specialized B cells, called “B regulatory cells”, correlate with patient response to stem cell therapy1. In a series of experiments the Company found that B cell depletion abrogated therapeutic effects of JadiCell in a COPD model, and that transfer of a unique population of B cells to naïve mice was able to induce a protective effect. Furthermore, antibody mediated blockade of the cytokine interleukin-35, was able to block therapeutic activity. “Today’s findings provide further scientific basis for clinical use of JadiCells in not only acute pulmonary conditions such as COVID-19 ARDS, but also in more chronic degenerative conditions such as COPD,” said Dr. James Veltmeyer, co-inventor, and Chief Medical Officer of the Company. “By identifying the critical role of interleukin-35 in therapeutic mechanisms, we are one step closer to further increasing the already potent therapeutic effects we observe with these unique cells.” In addition to the patent licensed from JadiCell, LLC (#9,803,176 B2), for respiratory indications, Therapeutic Solutions International has several patent applications pending and published covering the whole family of umbilical cord mesenchymal stem cells, to which JadiCell belongs to, for treatment of COPD2, as well as means of selecting for cells with enhanced activity3. “The discovery announced today supports not only expansion of our intellectual property portfolio covering this terrible condition, but also adds to the wealth of scientific knowledge which one day will hopefully lead to a cure for COPD,” said Timothy Dixon, President, and CEO of the Company and co-inventor. “We understand that all medical advances sit on the shoulder of other advances, and we are proud to contribute to taking steps towards ending this disease.” About Therapeutic Solutions International, Inc. Therapeutic Solutions International is focused on immune modulation for the treatment of several specific diseases. The Company's corporate website is . 1 Therapeutic Solutions International Identifies Novel Cellular Marker Associated with Therapeutic Response to JadiCell Stem Cell Treatment 2 20230057957 (uspto.gov) 3 20230057356 (uspto.gov)

Cell Therapy

14 Nov 2022

·www.biospace.com

Therapeutic Solutions Announces Universal Donor Myeloid Derived Suppressor Therapy Platform for Treatment of Chronic Obstructive Pulmonary Disease (COPD)

Breathe Biologics Inc., a Pulmonary Regenerative Medicine Subsidiary of TSOI, Discloses Allogeneic Pulmonary Myeloid Suppressor Cell Based Product ELK CITY, Idaho--(BUSINESS WIRE)-- Therapeutic Solutions International (TSOI) announced today new data, licensing, and patent filing on a novel cellular therapy for treatment of Chronic Obstructive Pulmonary Disease (COPD) by its Spin-Off Company Breathe Biologics. The Company disclosed that administration of monocytic progenitors derived from umbilical cord blood treated under proprietary conditions were able to reduce inflammation and preserve lung function in the elastase mediated animal model of COPD. The cellular product possessed characteristics of pulmonary progenitor cells combined with immune regulatory myeloid suppressor cells. Furthermore, it was demonstrated that blockade of the cytokine’s interleukin-10 and/or interleukin-17 negated the therapeutic effect of the cells, thus suggesting a possible mechanism of action for this novel cellular therapy. “As a physician who has witnessed firsthand the dismal lack of options in treatment of advanced COPD, and based on our preclinical animal data, I am eager to work with regulators in accelerating translation from the bench to the clinic,” said Dr. James Veltmeyer, Chief Medical Officer and co-inventor of the patent. Breathe Biologics is developing the use of JadiCells, a stem cell product in Phase III for COVID ARDS, for the treatment of COPD under IND# 28508. Breathe Biologics has acquired the IND from Therapeutic Solutions International as part of its initial licensing. “The beauty of running a biotechnology company in the USA is that we have access to brilliant minds, we have access to a patent system that respects innovation, we have access to collaborators who can perform experiments for us in a rapid and efficient manner, and we have investors and regulators who assess our work in real-time,” said Timothy Dixon, President, and CEO of Therapeutic Solutions International and co-inventor. About Therapeutic Solutions International, Inc. Therapeutic Solutions International is focused on immune modulation for the treatment of several specific diseases. The Company's corporate website is .

Cell TherapyPhase 3License out/in

09 Nov 2022

·www.biospace.com

Therapeutic Solutions International Launches Spin-Off Breathe Biologics Aimed at Curing Chronic Obstructive Pulmonary Disease (COPD)

Phase III Clinical Trial Stem Cell Company Aims to Fast Forward Regenerative Solutions to Dreaded Lung Disease ELK CITY, Idaho--(BUSINESS WIRE)-- Therapeutic Solutions International (TSOI) announced today the launching of a spin-off company, Breathe Biologics, Inc., to commercialize technologies in the area of COPD. Therapeutic Solutions International has licensed to Breathe Biologics assets in the COPD space including the Investigational New Drug Application (IND) which has been granted FDA number 28508. With the IND, the FDA assigned the stem cell therapy the new name of “Allogeneic Umbilical Cord Mesenchymal Stem Cells, JadiCell; Intravenous injection.” COPD is marked by lung inflammation and damage to alveoli — the tiny air sacs in the lungs responsible for gas exchange. The precursor cells that line the alveoli, called alveolar epithelial progenitor cells, cannot adequately respond to this damage by generating enough new alveoli. JadiCells are mesenchymal stem cells (MSCs) — a type of adult stem cell found in several tissues that can give rise to many different cell types. MSCs possess anti-inflammatory, neuroprotective, and regenerative properties that have made them increasingly popular as potential therapeutic avenues for some conditions. “The effects of JadiCell on numerous types of inflammatory disease are profound. In my personal experience, in patients with COVID-19 under Right to Try and Emergency Use IND, the results are nothing short of miraculous,” said Dr. James Veltmeyer, Chief Medical Officer of the Company. “To date regenerative medicine has not been truly applied to the problem of COPD, I am excited to assist Breathe Biologics in accelerating this novel technology to address a significant unmet medical need.” “Through selecting opinion leaders in science and business and providing them with new and clinically applicable technologies I believe that we can extract significant value from our Innovation Factory at Therapeutic Solutions International,” said Timothy Dixon, President, and CEO of the Company. “I look forward to the rapid commercialization of the JadiCell for COPD which we believe will have a significant impact on patients.” About Therapeutic Solutions International, Inc. Therapeutic Solutions International is focused on immune modulation for the treatment of several specific diseases. The Company's corporate website is .

Cell Therapy

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Indication	Highest Phase	Country/Location	Organization	Date
COVID-19	Phase 3	US	Therapeutic Solutions International, Inc.	-
Chronic Traumatic Encephalopathy	Phase 1	US	Therapeutic Solutions International, Inc.	-
Pulmonary Disease, Chronic Obstructive	Phase 1	US	Therapeutic Solutions International, Inc.	-
Epilepsy	Preclinical	US	Therapeutic Solutions International, Inc.	24 Oct 2022
Idiopathic Pulmonary Fibrosis	Preclinical	US	Therapeutic Solutions International, Inc.	18 Jul 2022
Schizophrenia	Preclinical	US	Therapeutic Solutions International, Inc.	-

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