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| Name | Class |
|---|---|
| University of Sao Paulo | OTHER |
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This study aims to evaluate the influence of age and sepsis on in vivo activity of OATP1A2 using rocuronium (ROC) as a probe and evaluating the pharmacokinetics and pharmacodynamics in ASA I-III surgical patients. Thus, adult patients without sepsis (control group, n= 12), adult patients with sepsis (sepsis group, n= 12) and elderly patients without sepsis (elderly group, n= 12), all submitted to small to medium-sized surgeries who were induced with individual doses of rocuronium, fentanyl and propofol are being investigated.
Rocuronium (ROC), a neuromuscular blocking agent used in surgical procedures, is primarily eliminated by biliary excretion. Its distribution to the liver, mediated the organic anion transporting polypeptide 1A2 (OATP1A2), is a determining factor for the duration of neuromuscular blockade. Age and release of cytokines during inflammation and infection processes of sepsis can alter expression of SLCO1A2 gene, encoding OATP1A2. The objective of this study is to evaluate the influence of age and sepsis on in vivo activity of OATP1A2 using ROC as a probe and evaluating the pharmacokinetics and pharmacodynamics in ASA I-III surgical patients. Adult patients without sepsis (control group, n=12), adult patients with sepsis (sepsis group, n=12) and elderly patients without sepsis (elderly group, n=12), all submitted to small to medium-sized surgeries are being investigated. All patients are being induced with individual doses of rocuronium, fentanyl and propofol. Serial blood samples are being collected up to 360 minutes after administration of ROC. Neuromuscular blockade induced by ROC is monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same times of blood sampling. The plasma concentration of ROC will be analyzed by liquid chromatography coupled to mass spectrometry with electrospray ionization using positive ion mode.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control group | Active Comparator | Adult patients(18-50 years old) ASA I-II without sepsis submitted to small to medium sized surgery under general anesthesia are being recruited. All patients are being induced with individualized doses of rocuronium, midazolam, propofol and fentanyl. Serial blood sampling are being collected up to 6 h after administration of the drug for pharmacokinetic study. Neuromuscular blockade is being monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same time as blood sampling. All patients are being submitted to blood testing for liver and renal function (creatinine, urea, albumin, aspartate aminotransferase and alanine aminotransferase). |
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| Sepsis group | Experimental | Adult patients (18-50 years old) ASAII and III with sepsis, systemic inflammatory response syndrome or septic shock submitted to small to medium sized surgery under general anesthesia are being recruited. All patients are being induced with individualized doses of rocuronium, midazolam, propofol and fentanyl. Serial blood sampling are being collected up to 6 h after administration of the drug for pharmacokinetic study. Neuromuscular blockade is being monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same time as blood sampling. All patients are being submitted to blood testing for liver and renal function (creatinine, urea, albumin, aspartate aminotransferase and alanine aminotransferase). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Serial blood sampling | Procedure | Serial blood samples are being collected at times 0, 2, 5, 10, 15, 20, 30, 60, 120, 180, 240 and 360 minutes after rocuronium administration. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Determination of AUC/dose | Determination of area under the plasma concentration versus time curve (AUC)/dose of rocuronium will be estimated for pharmacokinetic analysis. | Up to 6h after rocuronium administration |
| Measure | Description | Time Frame |
|---|---|---|
| Determination of total clearance | Determination of total clearance of rocuronium will be estimated for pharmacokinetic analysis. | Up to 6h after rocuronium administration |
| Determination of volume of distribution |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Natalia V. de Moraes, Prof. | Universidade Estadual Paulista Júlio de Mesquita Filho | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Universidade Estadual Paulista Júlio de Mesquita Filho | Araraquara | São Paulo | 14801902 | Brazil |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24370612 | Result | de Moraes NV, Lauretti GR, Filgueira GC, Lopes BC, Lanchote VL. Analysis of rocuronium in human plasma by liquid chromatography-tandem mass spectrometry with application in clinical pharmacokinetics. J Pharm Biomed Anal. 2014 Mar;90:180-5. doi: 10.1016/j.jpba.2013.11.032. Epub 2013 Dec 7. | |
| 28409297 | Derived | Costa ACC, Coelho EB, Lanchote VL, Correia BV, Abumansur JT, Lauretti GR, de Moraes NV. The SLCO1A2 -189_-188InsA polymorphism reduces clearance of rocuronium in patients submitted to elective surgeries. Eur J Clin Pharmacol. 2017 Aug;73(8):957-963. doi: 10.1007/s00228-017-2243-1. Epub 2017 Apr 14. |
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| Elderly group |
| Experimental |
Elderly patients (> 65 years old) ASA I-II without sepsis submitted to small to medium sized surgery under general anesthesia are being recruited. All patients are being induced with individualized doses of rocuronium, midazolam, propofol and fentanyl. Serial blood sampling are being collected up to 6 h after administration of the drug for pharmacokinetic study. Neuromuscular blockade is being monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same time as blood sampling. All patients are being submitted to blood testing for liver and renal function (creatinine, urea, albumin, aspartate aminotransferase and alanine aminotransferase). |
|
| Train of four monitoring | Procedure | Neuromuscular blockade is being evaluated at the same time of blood sampling by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF). |
|
|
| Blood testing for liver and renal function | Procedure | Blood testing: urea, creatinine, aspartate aminotransferase, alanine aminotransferase, albumin, glycemia |
|
| General anesthesia | Drug | All patients were induced with individual intravenous doses of midazolam, rocuronium, fentanyl and propofol. |
|
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| Small to medium sized surgery under general anesthesia | Procedure | Patients classified according American Society of Anesthesiologists (ASA) as ASA I-III and submitted to small-medium sized surgery under general anesthesia were recruited for the present investigation. |
|
Determination of volume of distribution of rocuronium will be estimated for pharmacokinetic analysis.
| Up to 6h after rocuronium administration |
| Determination of mean residence time | Determination of mean residence time of rocuronium will be estimated for pharmacokinetic analysis. | Up to 6h after rocuronium administration |
| OATP1A2 genotyping using Real Time-PCR | The single nucleotide polymorphisms of SLCO1A2 gene (404A>T, 559G>A, 833delA at coding sequence and -1105G>A, -1032G>A, -715T>C, -361G>A e -189_-188insA at the non-coding sequence of SLCO1A2) are being evaluated in all included patients, using Real Time PCR. | Up to 5 minutes before rocuronium administration |
| Analysis of cytokine IL-1α in plasma | Plasma cytokine Interleukin-1α (IL-1α) will be evaluated in each patient. | Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration |
| Analysis of cytokine IL-1β in plasma | Plasma cytokine IL-1β will be evaluated in each patient. | Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration |
| Analysis of cytokine IL-6 in plasma | Plasma cytokine IL-6 will be evaluated in each patient. | Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration |
| Analysis of cytokine TNF-α in plasma | Plasma cytokine Tumor Necrosis Factor-α (TNF-α) will be evaluated in each patient. | Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration |
| Pharmacokinetic-Pharmacodynamic analysis: relationship between rocuronium plasma concentration and the neuromuscular blockade | The relationship between rocuronium plasma concentration and the neuromuscular blockade will be described by a sigmoid maximum effect model for each patient | Up to 6h after rocuronium administration |
| ID | Term |
|---|---|
| D018805 | Sepsis |
| D018746 | Systemic Inflammatory Response Syndrome |
| D012772 | Shock, Septic |
| ID | Term |
|---|---|
| D007239 | Infections |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012769 | Shock |
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| ID | Term |
|---|---|
| D006403 | Hematologic Tests |
| D008110 | Liver Extracts |
| D000768 | Anesthesia, General |
| D008874 | Midazolam |
| D000077123 | Rocuronium |
| D005283 | Fentanyl |
| D015742 | Propofol |
| ID | Term |
|---|---|
| D019411 | Clinical Laboratory Techniques |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D008919 | Investigative Techniques |
| D014020 | Tissue Extracts |
| D045424 | Complex Mixtures |
| D000758 | Anesthesia |
| D000760 | Anesthesia and Analgesia |
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D000732 | Androstanols |
| D000731 | Androstanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D010880 | Piperidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
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