<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03278730</url>
  </required_header>
  <id_info>
    <org_study_id>PTE-2015-02</org_study_id>
    <nct_id>NCT03278730</nct_id>
  </id_info>
  <brief_title>Efficacy of Para-Tyrosine Supplementation on the Survival and Clinical Outcome in Patients With Sepsis</brief_title>
  <official_title>Phase 2 Single Center, Randomized, Placebo-controlled, Double-blind, Parallel Group Study to Evaluate Efficacy of Para-Tyrosine Supplementation on the Survival and Clinical Outcome in Patients With Sepsis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Pecs</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Pecs</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Meta-and ortho-Tyrosine are known markers of oxidative stress, while the physiological&#xD;
      isomer, para-Tyrosine is suggested the antagonize the effects of meta- and ortho-Tyrosine.&#xD;
      The changes in the serum levels of meta- and ortho-Tyrosine have been found to be paralel to&#xD;
      that of the common sepsis markers. The hypothesis of the study is, that supplementation of&#xD;
      para-Tyrosine (p-Tyr) in the early phase of sepsis may diminish some specific inflammatory&#xD;
      procedures and thus may have a favourable impact on the disease progress, and consequently on&#xD;
      the mortality.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Data suggest, that among the amino acids, the meta- and ortho- isomers of tyrosine are&#xD;
      potential markers of oxydative stress. The changes in their serum levels (and urinary&#xD;
      excretion) in sepsis were found to be parallel to the changes of the common inflammatory&#xD;
      markers, i.e. C-reactive protein (CRP) and pro-calcitonin (PCT). However, para-Tyrosine,&#xD;
      which is the isomer physiologically present, seemed to have different kinetics. Furthermore,&#xD;
      according to the observations, pathological processes linked to the inflammation could be&#xD;
      attenuated or partially or completely reversed by para-tyrosine.&#xD;
&#xD;
      The hypothesis of the study is, that supplementation of para-Tyrosine (p-Tyr) in the early&#xD;
      phase of sepsis may diminish some specific inflammatory procedures and thus may have a&#xD;
      favourable impact on the disease progress, and consequently on the mortality.&#xD;
&#xD;
      The primary objective of the study is to evaluate, whether oral P-Tyr supplementation reduces&#xD;
      mortality compared to placebo group during the ICU stay in patients with sepsis.&#xD;
&#xD;
      The primary endpoint is the comparison of mortality starting from randomization and start of&#xD;
      treatment (which should be on the same day) during the period of ICU stay between the active&#xD;
      treatment group and placebo group. The secondary objectives of the study are:&#xD;
&#xD;
      to evaluate whether supplementation of p-Tyr has effect on clinical outcome of sepsis&#xD;
      compared to placebo in patients receiving appropriate standard care; to evaluate the effect&#xD;
      of p-Tyr supplementation on 28-day survival of patients with sepsis; to evaluate, whether the&#xD;
      treatment can reduce the time of the ICU stay, to evaluate the effect on overall mortality of&#xD;
      patients with sepsis during their hospitalization, to evaluate the effect of p-Tyr&#xD;
      supplemetation on the overall hospitalization time, to evaluate the safety of the&#xD;
      investigational product. The investigators wish to explore To explore whether serum level of&#xD;
      p-Tyr can be maintained with the oral supplementation; dynamics and interrelation of the&#xD;
      levels of oxidative stress markers (o- and m-Tyr) and the physiologic isomer of Tyr (p-Tyr)&#xD;
      and Phenylalanine (Phe) and the correlation of o-Tyr and m-Tyr serum levels and other&#xD;
      parameters of inflammation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">February 1, 2024</start_date>
  <completion_date type="Anticipated">February 28, 2025</completion_date>
  <primary_completion_date type="Anticipated">February 1, 2025</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>The objective is to evaluate, whether p-Tyr supplementation reduces the ICU mortality of the patients with sepsis comparing to placebo group</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Mortality</measure>
    <time_frame>30 days</time_frame>
    <description>Comparison of mortality starting from randomization and start of treatment (which should be on the same day) during the period of ICU stay between the active treatment group and placebo group.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Effect of para-Tyrosine supplementation on the clinical outcome of sepsis</measure>
    <time_frame>30 days</time_frame>
    <description>The investigators wish to evaluate whether supplementation of p-Tyr has effect on clinical outcome (appearance of organ failures due to sepsis: renal failure, respiratory failure, coagulation disorders, hepatic failure, cardiac failure, need for vasopressors, CH balance, nitrogen-balance) of sepsis compared to placebo in patients receiving appropriate standard care. The investigators wish to assess wether para-Tyrosine supplementation can ameliroate the time course and severity of sepsis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Long term effects of para-Tyrosine supplementation on survival</measure>
    <time_frame>28 days</time_frame>
    <description>The investigators would like to evaluate the effect of p-Tyr supplementation on 28-day survival of patients with sepsis based on the patients' electronic documentation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reduction in the time of ICU stay</measure>
    <time_frame>30 days</time_frame>
    <description>The investigators shall evaluate, whether the treatment can reduce the time of the ICU stay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall mortality</measure>
    <time_frame>60 days</time_frame>
    <description>The investigators will evaluate the effect on overall mortality of patients with sepsis during their hospitalization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospitalization time</measure>
    <time_frame>60 days</time_frame>
    <description>The investigators will evaluate the effect of p-Tyr supplemetation on the overall hospitalization time</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability of para-Tyrosine supplementation (Incidence of Treatment-Emergent Adverse Events)</measure>
    <time_frame>60 days</time_frame>
    <description>The investigators wish to evaluate the safety of the investigational product: Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events shall be recorded, using physiological parameters such as impairment in renal and hepatic function, bone marrow toxicity, severe blood pressure changes, tachycardia etc.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Effect of supplementation on the maintanance of the serum level of para-Tyrosine</measure>
    <time_frame>30 days</time_frame>
    <description>The investigators will explore using high performance liquid cromatography (HPLC) whether serum level of p-Tyr can be maintained with the oral supplementation</description>
  </other_outcome>
  <other_outcome>
    <measure>Assessment of pharmacodynamics</measure>
    <time_frame>10 days</time_frame>
    <description>Exploration of the dynamics and interrelation of the levels of oxidative stress markers (o- and m-Tyr) and the physiologic isomer of Tyr (p-Tyr) and Phenylalanine (Phe)</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation of o-Tyr and m-Tyr serum levels and other parameters of inflammation</measure>
    <time_frame>10 days</time_frame>
    <description>The investigators will assess the correlation of o-Tyr and m-Tyr serum levels and other parameters of inflammation</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">296</enrollment>
  <condition>Sepsis</condition>
  <arm_group>
    <arm_group_label>Para-Tyrosine intervention</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The patients will receive the study drug during their stay at the ICU but for a maximum of 7 days.&#xD;
Study drug will be dispensed by a nominated member of the study team and administered to the patients by the ICU staff via nasogastric tube in form of oral suspension. The content of the hard capsules will be dissolved in 20 ml of tap water before the dosing.&#xD;
Drug name: Tyrosine. Strength 500 mg. Oral dose form: hard capsule. Number of Dispensed at frequency of 3x2 g daily. Duration of administration: 4 to 7 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>The patients will receive the study drug during their stay at the ICU but for a maximum of 7 days.&#xD;
Study drug will be dispensed by a nominated member of the study team and administered to the patients by the ICU staff via nasogastric tube in form of oral suspension. The content of the hard capsules will be dissolved in 20 ml of tap water before the dosing.&#xD;
Drug name: Placebo.. Strength N/A. Oral dose form: capsule matching to Tyrosine capsule. Number of Dispnsed an frequency 3x2 g daily. Duration of administration: 4 to 7 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Para-Tyrosine supplementation</intervention_name>
    <description>Patients will recieve the study drug during their stay at the ICU, but for a maximum of 7 days. The study drug is 3x2 gramms of para-Tyrosine, which will be dispensed and administered in a form of oral suspension via a nasogastric tube.</description>
    <arm_group_label>Para-Tyrosine intervention</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo solution</intervention_name>
    <description>Patients will recieveplacebo during their stay at the ICU, but for a maximum of 7 days. The study drug is 3x2 gramms of placebo, which will be dispensed and administered in a form of oral suspension via a nasogastric tube.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Subjects must meet the following inclusion criteria to be eligible for the study:&#xD;
&#xD;
          1. Are able to provide written informed consent (either the patient or the person&#xD;
             entitled by legislation to consent on behalf of the patient)&#xD;
&#xD;
          2. Male and female patients ≥ 18 years&#xD;
&#xD;
          3. Have a current primary diagnosis of sepsis based on the the third international&#xD;
             consensus definitions for sepsis and septic shock (Sepsis-3)Willing and able to comply&#xD;
             with all aspects of the protocol&#xD;
&#xD;
          4. Females of childbearing potential must have negtive serum pregnancy test az screening.&#xD;
             (All females will be considered to be of childbearing potential unless they are&#xD;
             postmenopausal i.e. amenorrheic for at least 12 consecutive months, in the appropriate&#xD;
             age group and without other known or suspected cause or have been sterilized&#xD;
             surgically i.e. bilateral tubal ligation, total hysterectomy, or bilateral&#xD;
             oophorectomy, all with surgery at least 1 month before dosing)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Subjects must not have any of the following criteria to be eligible for the study:&#xD;
&#xD;
          1. Females who are pregnant (positive β-hCG test at screening) or breastfeeding&#xD;
&#xD;
          2. chronic use of steroids or immunosuppressive drugs within the past 3 months&#xD;
&#xD;
          3. other therapy influencing the immune system within the past 3 months (radiotherapy,&#xD;
             chemotherapy etc.)&#xD;
&#xD;
          4. malignant hematologic disease&#xD;
&#xD;
          5. jejunal tube feeding&#xD;
&#xD;
          6. any other significant illness in the medical history ongoing in the preceeding 1&#xD;
             month, which may have an influence on the survival and clinical outcome of the&#xD;
             patients (e.g severe chronic heart failure NYHA III-IV., AMI, stroke, major surgery,&#xD;
             COPD, renal failure, hepatic failure, hepatic cirrhosis etc.)&#xD;
&#xD;
          7. Life expectancy less, than 1 months according to the judgement of the Investigator&#xD;
             (even without significant illness, due to age or general status of the patient)&#xD;
&#xD;
          8. Hypersensitivity to any of the excipients of the study product&#xD;
&#xD;
          9. Known to be human immunodeficiency virus (HIV) positive&#xD;
&#xD;
         10. Active viral hepatitis (B or C) as demonstrated by positive serology&#xD;
&#xD;
         11. History of drug or alcohol dependency or abuse within approximately the last 2 years&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>István Wittmann, MD,PhD,DSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pecs</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>István Wittmann, MD,PhD,DSc</last_name>
    <phone>+3672536050</phone>
    <email>istvan.wittmann@aok.pte.hu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Gergő A Molnár, MD, PhD</last_name>
    <phone>+3672536050</phone>
    <email>molnargergo1@yahoo.de</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>2nd Department of Medicine and Nephrological Center</name>
      <address>
        <city>Pécs</city>
        <state>Baranya</state>
        <zip>7624</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Anaesthesiology and Intensive Care</name>
      <address>
        <city>Pécs</city>
        <state>Baranya</state>
        <zip>7624</zip>
        <country>Hungary</country>
      </address>
    </facility>
    <contact>
      <last_name>Lajos Bogar, MD, PhD, DSc</last_name>
      <phone>+3672536000</phone>
      <email>bogar.lajos@pte.hu</email>
    </contact>
    <contact_backup>
      <last_name>Csaba Csontos, MD, PhD</last_name>
      <phone>+3672536000</phone>
      <email>csaba.csontos@pte.hu</email>
    </contact_backup>
    <investigator>
      <last_name>Diána Mühl, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Lívia Szélig, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Hungary</country>
  </location_countries>
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  </reference>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>September 1, 2017</study_first_submitted>
  <study_first_submitted_qc>September 7, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 12, 2017</study_first_posted>
  <last_update_submitted>May 18, 2022</last_update_submitted>
  <last_update_submitted_qc>May 18, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 19, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Pecs</investigator_affiliation>
    <investigator_full_name>István Wittmann</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>sepsis</keyword>
  <keyword>para-Tyrosine</keyword>
  <keyword>ortho-Tyrosine</keyword>
  <keyword>meta-Tyrosine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sepsis</mesh_term>
    <mesh_term>Toxemia</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03278730
org study id: PTE-2015-02
nct id: NCT03278730
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Meta-and ortho-Tyrosine are known markers of oxidative stress, while the physiological
      isomer, para-Tyrosine is suggested the antagonize the effects of meta- and ortho-Tyrosine.
      The changes in the serum levels of meta- and ortho-Tyrosine have been found to be paralel to
      that of the common sepsis markers. The hypothesis of the study is, that supplementation of
      para-Tyrosine (p-Tyr) in the early phase of sepsis may diminish some specific inflammatory
      procedures and thus may have a favourable impact on the disease progress, and consequently on
      the mortality.
Data suggest, that among the amino acids, the meta- and ortho- isomers of tyrosine are
      potential markers of oxydative stress. The changes in their serum levels (and urinary
      excretion) in sepsis were found to be parallel to the changes of the common inflammatory
      markers, i.e. C-reactive protein (CRP) and pro-calcitonin (PCT). However, para-Tyrosine,
      which is the isomer physiologically present, seemed to have different kinetics. Furthermore,
      according to the observations, pathological processes linked to the inflammation could be
      attenuated or partially or completely reversed by para-tyrosine.

      The hypothesis of the study is, that supplementation of para-Tyrosine (p-Tyr) in the early
      phase of sepsis may diminish some specific inflammatory procedures and thus may have a
      favourable impact on the disease progress, and consequently on the mortality.

      The primary objective of the study is to evaluate, whether oral P-Tyr supplementation reduces
      mortality compared to placebo group during the ICU stay in patients with sepsis.

      The primary endpoint is the comparison of mortality starting from randomization and start of
      treatment (which should be on the same day) during the period of ICU stay between the active
      treatment group and placebo group. The secondary objectives of the study are:

      to evaluate whether supplementation of p-Tyr has effect on clinical outcome of sepsis
      compared to placebo in patients receiving appropriate standard care; to evaluate the effect
      of p-Tyr supplementation on 28-day survival of patients with sepsis; to evaluate, whether the
      treatment can reduce the time of the ICU stay, to evaluate the effect on overall mortality of
      patients with sepsis during their hospitalization, to evaluate the effect of p-Tyr
      supplemetation on the overall hospitalization time, to evaluate the safety of the
      investigational product. The investigators wish to explore To explore whether serum level of
      p-Tyr can be maintained with the oral supplementation; dynamics and interrelation of the
      levels of oxidative stress markers (o- and m-Tyr) and the physiologic isomer of Tyr (p-Tyr)
      and Phenylalanine (Phe) and the correlation of o-Tyr and m-Tyr serum levels and other
      parameters of inflammation.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: The objective is to evaluate, whether p-Tyr supplementation reduces the ICU mortality of the patients with sepsis comparing to placebo group
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Mortality
time frame: 30 days
description: Comparison of mortality starting from randomization and start of treatment (which should be on the same day) during the period of ICU stay between the active treatment group and placebo group.
measure: Effect of para-Tyrosine supplementation on the clinical outcome of sepsis
time frame: 30 days
description: The investigators wish to evaluate whether supplementation of p-Tyr has effect on clinical outcome (appearance of organ failures due to sepsis: renal failure, respiratory failure, coagulation disorders, hepatic failure, cardiac failure, need for vasopressors, CH balance, nitrogen-balance) of sepsis compared to placebo in patients receiving appropriate standard care. The investigators wish to assess wether para-Tyrosine supplementation can ameliroate the time course and severity of sepsis
measure: Long term effects of para-Tyrosine supplementation on survival
time frame: 28 days
description: The investigators would like to evaluate the effect of p-Tyr supplementation on 28-day survival of patients with sepsis based on the patients' electronic documentation
measure: Reduction in the time of ICU stay
time frame: 30 days
description: The investigators shall evaluate, whether the treatment can reduce the time of the ICU stay
measure: Overall mortality
time frame: 60 days
description: The investigators will evaluate the effect on overall mortality of patients with sepsis during their hospitalization
measure: Hospitalization time
time frame: 60 days
description: The investigators will evaluate the effect of p-Tyr supplemetation on the overall hospitalization time
measure: Safety and tolerability of para-Tyrosine supplementation (Incidence of Treatment-Emergent Adverse Events)
time frame: 60 days
description: The investigators wish to evaluate the safety of the investigational product: Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events shall be recorded, using physiological parameters such as impairment in renal and hepatic function, bone marrow toxicity, severe blood pressure changes, tachycardia etc.
measure: Effect of supplementation on the maintanance of the serum level of para-Tyrosine
time frame: 30 days
description: The investigators will explore using high performance liquid cromatography (HPLC) whether serum level of p-Tyr can be maintained with the oral supplementation
measure: Assessment of pharmacodynamics
time frame: 10 days
description: Exploration of the dynamics and interrelation of the levels of oxidative stress markers (o- and m-Tyr) and the physiologic isomer of Tyr (p-Tyr) and Phenylalanine (Phe)
measure: Correlation of o-Tyr and m-Tyr serum levels and other parameters of inflammation
time frame: 10 days
description: The investigators will assess the correlation of o-Tyr and m-Tyr serum levels and other parameters of inflammation
arm group label: Para-Tyrosine intervention
arm group type: Active Comparator
description: The patients will receive the study drug during their stay at the ICU but for a maximum of 7 days.
Study drug will be dispensed by a nominated member of the study team and administered to the patients by the ICU staff via nasogastric tube in form of oral suspension. The content of the hard capsules will be dissolved in 20 ml of tap water before the dosing.
Drug name: Tyrosine. Strength 500 mg. Oral dose form: hard capsule. Number of Dispensed at frequency of 3x2 g daily. Duration of administration: 4 to 7 days.
arm group label: Placebo
arm group type: Placebo Comparator
description: The patients will receive the study drug during their stay at the ICU but for a maximum of 7 days.
Study drug will be dispensed by a nominated member of the study team and administered to the patients by the ICU staff via nasogastric tube in form of oral suspension. The content of the hard capsules will be dissolved in 20 ml of tap water before the dosing.
Drug name: Placebo.. Strength N/A. Oral dose form: capsule matching to Tyrosine capsule. Number of Dispnsed an frequency 3x2 g daily. Duration of administration: 4 to 7 days.
intervention type: Drug
intervention name: Para-Tyrosine supplementation
description: Patients will recieve the study drug during their stay at the ICU, but for a maximum of 7 days. The study drug is 3x2 gramms of para-Tyrosine, which will be dispensed and administered in a form of oral suspension via a nasogastric tube.
arm group label: Para-Tyrosine intervention
intervention type: Drug
intervention name: Placebo solution
description: Patients will recieveplacebo during their stay at the ICU, but for a maximum of 7 days. The study drug is 3x2 gramms of placebo, which will be dispensed and administered in a form of oral suspension via a nasogastric tube.
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: István Wittmann, MD,PhD,DSc
role: Principal Investigator
affiliation: University of Pecs
last name: István Wittmann, MD,PhD,DSc
phone: +3672536050
email: istvan.wittmann@aok.pte.hu
last name: Gergő A Molnár, MD, PhD
phone: +3672536050
email: molnargergo1@yahoo.de
facility: 
facility: 
contact: 
contact backup: 
investigator: 
investigator: 
country: Hungary
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PMID: 21385509
citation: Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christman BW, Dupont WD, Higgins SB, Swindell BB. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med. 1997 Mar 27;336(13):912-8. doi: 10.1056/NEJM199703273361303.
PMID: 9070471
citation: Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992 Jun;101(6):1644-55. doi: 10.1378/chest.101.6.1644.
PMID: 1303622
citation: Dandona P, Mohanty P, Hamouda W, Ghanim H, Aljada A, Garg R, Kumar V. Inhibitory effect of a two day fast on reactive oxygen species (ROS) generation by leucocytes and plasma ortho-tyrosine and meta-tyrosine concentrations. J Clin Endocrinol Metab. 2001 Jun;86(6):2899-902. doi: 10.1210/jcem.86.6.7745.
PMID: 11397907
citation: Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013 Feb;39(2):165-228. doi: 10.1007/s00134-012-2769-8. Epub 2013 Jan 30.
PMID: 23361625
citation: Druml W, Heinzel G, Kleinberger G. Amino acid kinetics in patients with sepsis. Am J Clin Nutr. 2001 May;73(5):908-13. doi: 10.1093/ajcn/73.5.908.
PMID: 11333844
citation: Hirose T, Shimizu K, Ogura H, Tasaki O, Hamasaki T, Yamano S, Ohnishi M, Kuwagata Y, Shimazu T. Altered balance of the aminogram in patients with sepsis - the relation to mortality. Clin Nutr. 2014 Feb;33(1):179-82. doi: 10.1016/j.clnu.2013.11.017. Epub 2013 Dec 14.
PMID: 24377412
citation: Jensen GL, Miller RH, Talabiska DG, Fish J, Gianferante L. A double-blind, prospective, randomized study of glutamine-enriched compared with standard peptide-based feeding in critically ill patients. Am J Clin Nutr. 1996 Oct;64(4):615-21. doi: 10.1093/ajcn/64.4.615.
PMID: 8839508
citation: Jorres RA, Holz O, Zachgo W, Timm P, Koschyk S, Muller B, Grimminger F, Seeger W, Kelly FJ, Dunster C, Frischer T, Lubec G, Waschewski M, Niendorf A, Magnussen H. The effect of repeated ozone exposures on inflammatory markers in bronchoalveolar lavage fluid and mucosal biopsies. Am J Respir Crit Care Med. 2000 Jun;161(6):1855-61. doi: 10.1164/ajrccm.161.6.9908102.
PMID: 10852757
citation: Kun S, Mikolas E, Molnar GA, Selley E, Laczy B, Csiky B, Kovacs T, Wittmann I. Association of plasma ortho-tyrosine/para-tyrosine ratio with responsiveness of erythropoiesis-stimulating agent in dialyzed patients. Redox Rep. 2014 Sep;19(5):190-8. doi: 10.1179/1351000214Y.0000000090. Epub 2014 Apr 3.
PMID: 24693974
citation: Kun S, Molnar GA, Selley E, Szelig L, Bogar L, Csontos C, Miseta A, Wittmann I. Insulin Therapy of Nondiabetic Septic Patients Is Predicted by para-Tyrosine/Phenylalanine Ratio and by Hydroxyl Radical-Derived Products of Phenylalanine. Oxid Med Cell Longev. 2015;2015:839748. doi: 10.1155/2015/839748. Epub 2015 Oct 20.
PMID: 26576228
citation: Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287.
PMID: 26903338
citation: Liebau F, Sundstrom M, van Loon LJ, Wernerman J, Rooyackers O. Short-term amino acid infusion improves protein balance in critically ill patients. Crit Care. 2015 Mar 12;19(1):106. doi: 10.1186/s13054-015-0844-6.
PMID: 25882298
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PMID: 8818637
citation: Mikolas E, Kun S, Laczy B, Molnar GA, Selley E, Koszegi T, Wittmann I. Incorporation of ortho- and meta-tyrosine into cellular proteins leads to erythropoietin-resistance in an erythroid cell line. Kidney Blood Press Res. 2013;38(2-3):217-25. doi: 10.1159/000355770. Epub 2014 Apr 9.
PMID: 24751667
citation: Molnar GA, Nemes V, Biro Z, Ludany A, Wagner Z, Wittmann I. Accumulation of the hydroxyl free radical markers meta-, ortho-tyrosine and DOPA in cataractous lenses is accompanied by a lower protein and phenylalanine content of the water-soluble phase. Free Radic Res. 2005 Dec;39(12):1359-66. doi: 10.1080/10715760500307107.
PMID: 16298866
citation: Molnar GA, Wagner Z, Marko L, Ko Szegi T, Mohas M, Kocsis B, Matus Z, Wagner L, Tamasko M, Mazak I, Laczy B, Nagy J, Wittmann I. Urinary ortho-tyrosine excretion in diabetes mellitus and renal failure: evidence for hydroxyl radical production. Kidney Int. 2005 Nov;68(5):2281-7. doi: 10.1111/j.1523-1755.2005.00687.x.
PMID: 16221230
citation: Szijarto IA, Molnar GA, Mikolas E, Fisi V, Cseh J, Laczy B, Kovacs T, Boddi K, Takatsy A, Gollasch M, Koller A, Wittmann I. Elevated vascular level of ortho-tyrosine contributes to the impairment of insulin-induced arterial relaxation. Horm Metab Res. 2014 Oct;46(11):749-52. doi: 10.1055/s-0034-1387701. Epub 2014 Sep 10.
PMID: 25208272
citation: Molnar GA, Mikolas EZ, Szijarto IA, Kun S, Selley E, Wittmann I. Tyrosine isomers and hormonal signaling: A possible role for the hydroxyl free radical in insulin resistance. World J Diabetes. 2015 Apr 15;6(3):500-7. doi: 10.4239/wjd.v6.i3.500.
PMID: 25897359
citation: Molnar GA, Kun S, Selley E, Kertesz M, Szelig L, Csontos C, Boddi K, Bogar L, Miseta A, Wittmann I. Role of Tyrosine Isomers in Acute and Chronic Diseases Leading to Oxidative Stress - A Review. Curr Med Chem. 2016;23(7):667-85. doi: 10.2174/0929867323666160119094516.
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PMID: 3103555
citation: Selley E, Kun S, Kurthy M, Kovacs T, Wittmann I, Molnar GA. Para-Tyrosine Supplementation Improves Insulin- and Liraglutide- Induced Vasorelaxation in Cholesterol-Fed Rats. Protein Pept Lett. 2015;22(8):736-42. doi: 10.2174/0929866522666150610093039.
PMID: 26202368
responsible party type: Principal Investigator
investigator affiliation: University of Pecs
investigator full name: István Wittmann
investigator title: Professor
mesh term: Sepsis
mesh term: Toxemia
sharing ipd: No