Clinical Pathology txhais lus hauv dev thiab Nonhuman Primates hauv Preclinical Studies

dev thiabnonhuman primates (NHPs), tshwj xeeb tshaj yog Beagle dev thiab cynomolgus lossis rhesus macaques, yog cov qauv tsiaj loj loj hauv kev txhim kho tshuaj preclinical. Lawv lub cev zoo sib xws rau tib neeg muab kev txhais lus muaj txiaj ntsig rau kev nyab xeeb, tshuaj, thiab kev ntsuas biomarker.

Tsis zoo li cov nas tsuag, cov tsiaj loj tuaj yeem ua rau rov kuaj ntshav thiab cov qauv loj dua, ua rau muaj kev sib txuam.Pharmacokinetic (PK), toxicokinetic (TK), thiab kev soj ntsuam kab mob pathology. Txawm li cas los xij, kev txhais cov ntaub ntawv kho mob pathology hauv cov tsiaj no yog qhov tsis txaus ntseeg los ntawm kev hloov pauv lom neeg, kev tsim qauv, tsiaj keeb kwm, thiab cov txheej txheem sim. Kev paub qhov tseeb ntawm kab lus xeem- cuam tshuam txog toxicity los ntawm lub cev tsis muaj zog lossis cov txheej txheem txheej txheem yuav tsum muaj kev nkag siab zoo ntawm cov kev hloov pauv no.

Hauv kev tshawb fawb tsiaj loj, qhov ntau thiab tsawg ntawm pawg neeg muaj kev txwv vim yog kev coj ncaj ncees thiab kev coj ua. Yog li ntawd, ua ntej- cov ntaub ntawv hauv qab koob tshuaj yog qhov tseem ceeb. Kev ua ntau yam ua ntej- kev ntsuas koob tshuaj tso cai rau cov neeg tshawb xyuas:

• Tsim kom muaj txhua tus tsiaj raws li nws tus kheej longitudinal tswj.
• Quantify tus kheej biological variability.
• Txheeb xyuas thiab tshem tawm cov tsiaj tsis zoo lossis cov tsiaj tsis noj qab haus huv ua ntej randomization.
• Sib txawv ntawm kev tuav- ua rau muaj kev ntxhov siab los ntawm lub hauv paus physiology.

Kev hloov ntawm tus kheej tshwj xeeb tshaj yog nyob rau hauv NHPs piv rau lub hom phiaj -bred nas lossis dev. Cov kab mob hauv nruab nrab feem ntau suav nrog qhov tsis sib xws ntawm erythrocyte tsis sib xws, kev nce siab hauv cov enzymes hepatic, lossis atypical protein profiles. Yog tias cov kev hloov pauv hauv qab no sib tshooj nrog lub hom phiaj xav tau tshuaj tshuaj lossis tshuaj toxicological profile ntawm tsab xov xwm xeem, kev tshuaj xyuas ua ntej - koob tshuaj yog thawj txheej txheem los tiv thaiv qhov tsis tseeb ntawm kev txhais lus zoo.

Feem ntau phlebotomy rau pharmacokinetic profileing tuaj yeem ua rau iatrogenic hematological hloov. High-frequency lossis siab- ntim cov ntshav ntau zaus ua rau poob qis hauv:

• Cov qe ntshav liab (RBC) suav
• Qhov concentration ntawm hemoglobin (Hgb).
• Hematocrit (Hct)
• Tag nrho cov protein thiab albumin (vim hemodilution)

Yog tias cov pob txha ua haujlwm tsis zoo, cov kev hloov microcytic lossis normocytic feem ntau yog nrog los ntawm kev them nyiaj yug reticulocytosis. Yog li ntawd, kev poob qis me me hauv erythron tsis yuav tsum tau hla - hais txog nrog tag nrho cov ntshav ntim thoob plaws txoj kev tshawb no.

NHP cov txheej txheem niaj hnub yuav tsum muaj tshuaj loog rau kev tswj hwm, kev tshuaj xyuas, lossis kev kuaj mob. Kev xaiv thiab lub sijhawm ntawm kev siv tshuaj loog cuam tshuam ncaj qha rau kev kho mob pathology nyeem ntawv. Cov tsiaj uas tsis muaj tshuaj loog feem ntau pom muaj kev hloov pauv ntawm cov leukocyte faib thiab hloov cov ntaub ntawv electrolyte piv rau cov neeg nco qab, tuav tswj cov pab pawg. Tsis tas li ntawd, kev txhaj tshuaj intramuscular thiab intramuscular tshuaj loog tuaj yeem ua rau cov leeg mob subclinical raug mob, ua rau muaj cov kab mob creatine kinase (CK). Cov txheej txheem ua piv txwv zoo ib yam thiab cov txheej txheem tshuaj loog uas tsim nyog yuav tsum tau ua nyob rau txhua theem kev kawm.

Cov kev tshawb fawb ntxiv kev tsim qauv hloov pauv uas xav tau kev tswj hwm nruj xws li:

• Tsiaj hnub nyoog thiab kev loj hlob theem
• Lub sijhawm yoo mov thiab lub sijhawm sib piv rau kev sau
• Order of sampling nyob rau hauv ib cohort
• Txoj kev thiab tus nqi ntawm kev tswj hwm
• Compounding cov txheej txheem kev sim (piv txwv li, phais koob tshuaj, nruam infusions)

Cov dev thiab NHPs muaj erythrocyte lifespans ntev dua li nas, hloov cov kinetics ntawm anemia txoj kev loj hlob thiab pob txha rov qab. Tom qab cov ntshav poob qis, cov tsiaj loj ua rau pom qhov feem pua ​​​​ntawm cov reticulocyte qis dua thiab cov lus teb rov ua dua tshiab.

Nyob rau hauv macaques, cov yam ntxwv ntawm lub hauv paus erythrocyte (xws li txhais tau tias lub cev ntim) cuam tshuam nrog thaj chaw keeb kwm (xws li Suav vs. Cambodian vs. Mauritian cynomolgus liab). Kev siv tsiaj los ntawm ib thaj chaw ib puag ncig txo qis suab nrov. Tsis tas li ntawd, subclinical keeb kwm kab mob (xws li hemoparasites lossis kab mob latent viral) tuaj yeem cuam tshuam erythropoiesis thiab yuav tsum tau tshuaj xyuas thaum lub sijhawm cais tawm.

Leukocyte cov ntaub ntawv yog ntau hom- tshwj xeeb. Cov dev yog neutrophil- tseem ceeb, thaum noj qab haus huv NHPs pom muaj qhov sib npaug ntau dua los yog lymphocyte- feem ntau faib. Cov kev sib txawv hauv paus no qhia cov qauv qhia txawv txawv thaum lub sij hawm ua mob.

Tsis tas li ntawd, kev tswj lub cev, qhov chaw tshiab, lossis kev ntshai ua rau muaj kev tso tawm sai sai ntawm catecholamine thiab glucocorticoid. Cov lus teb kev ntxhov siab no ua rau muaj kev sib koom ua ke ntawm lub pas dej ua ke, nthuav tawm raws li kev hloov pauv ntawm neutrophilia thiab lymphopenia. Vim tias NHPs muaj kev nkag siab zoo rau kev tswj hwm kev ntxhov siab, kev hloov pauv hauv cov qe ntshav dawb suav - tsis tuaj yeem pom cov tsos mob tshwm sim lossis cov pov thawj histopathological ntawm cov nqaij mos o - yuav tsum tau txhais nrog ceev faj.

Coagulation kinetics txawv ntawm hom. Baseline prothrombin lub sij hawm (PT) yog qhov tseem ceeb hauv cov dev luv dua li tib neeg, thiab qhov tsis zoo ntawm cov tshuaj idiosyncratic tuaj yeem ua rau muaj kev sib cais, tsis yog- yeeb tshuaj- cuam tshuam PT ntev hauv ib tus dev. Hauv kev tshawb fawb NHP, activated partial thromboplastin time (APTT) assays are very sensitive to reagent batch variability and sample handling (eg, ib nrab clotting thaum sau). Thaum lub coagulation cascade yog ib lub hom phiaj ntawm qhov kev xeem tsab xov xwm, nruj lub hauv paus sib piv thiab niaj hnub reagent ntau yog qhov tseem ceeb.

Alanine aminotransferase (ALT) yog tus qauv biomarker rau hepatocellular to. Hauv cov tub ntxhais hluas, lub hom phiaj-bred Beagle dev, lub hauv paus kab ALT yog nqaim, tso cai rau kev tshawb pom qhov hloov maj mam, kev kho mob- ntxias cov kab mob siab hloov pauv. Piv txwv li, cov dev laus thiab NHPs nthuav dav kev hloov pauv ntawm lub cev.

Macaques feem ntau nthuav tawm ib ntus, tus kheej - txwv tsis pub ALT spikes vim kev hloov pauv hauv siab tom qab lossis kab mob subclinical flares. Yog li ntawd, ib qho - taw tes nce siab hauv daim siab enzymes xav tau kev pom zoo los ntawm cov khoom siv biomarkers (piv txwv li, aspartate aminotransferase, tag nrho cov kua tsib acids), kev soj ntsuam ua haujlwm, thiab kev soj ntsuam histopathological.

Alkaline phosphatase (ALP) thiab gamma-glutamyl transferase (GGT) yog qhov qhia txog kab mob hepatobiliary lossis cholestatic. Thaum ALP muaj kev nkag siab zoo rau cholestasis hauv cov dev, nws tsis tshua muaj tshwj xeeb hauv NHPs vim yog cov pob txha tseem ceeb thiab plab hnyuv isoenzyme, tshwj xeeb tshaj yog cov menyuam yaus, cov tsiaj loj hlob. GGT feem ntau yog ib qho kev txhim khu kev ntseeg siab dua hauv cov qauv NHP.

Cov ntshav urea nitrogen (BUN) thiab cov ntshav creatinine tseem yog cov qauv ntsuas ntawm glomerular pom, txawm tias lawv tsis nkag siab txog thaum ntxov - lub raum tsis zoo. Cov dev muaj qhov nqaim physiological ntau yam rau cov tshuaj ntsuam xyuas no, ua kom yooj yim rau kev txheeb xyuas qhov hloov ntawm lub raum me me. Hauv qhov sib piv, NHPs nthuav qhia cov kab hauv qab dav dav, ua rau kev hloov pauv hloov nyuaj rau tus yam ntxwv.

Vim tias BUN cuam tshuam los ntawm cov protein catabolism, kev noj zaub mov noj, thiab lub xeev dej, nws yuav tsum tau txhais nrog creatinine. Kev kuaj zis muab cov ntsiab lus tseem ceeb, tab sis kev sau cov qauv hauv cov tsiaj loj- feem ntau cuam tshuam nrog kev sau lub lauj kaub thaum hmo ntuj- qhia txog kev pheej hmoo ntawm evaporation, fecal paug, lossis cellular degradation. Thaum nephrotoxicity yog ib qho kev txhawj xeeb tseem ceeb, sij hawm, ultrasound-copy cystoscopy lossis tshwj xeeb metabolic caging yog pom zoo.

Creatine kinase (CK) nce siab yog muaj nyob rau hauv NHP kev tshawb fawb. Lawv feem ntau tau tsav los ntawm kev ntes lub cev, txwv tsis pub, txhaj tshuaj intramuscular, lossis ncua sijhawm rov qab los ntawm kev siv tshuaj loog es tsis yog cov kab lus kuaj mob toxicity. Txhawm rau tiv thaiv kev txhais lus tsis raug, cais CK spikes yuav tsum raug ntsuas tawm tsam:

• Chronological sib thooj rau cov xwm txheej ntxhov siab lossis txhaj tshuaj
• Cov koob tshuaj meej meej- nyob ntawm cov pab pawg kho mob
• Co- ua kom cov ntaub so ntswg tshwj xeeb
• Concurrent hloov hauv aspartate aminotransferase (AST) thiab lactate dehydrogenase (LDH)

Rau kev ntsuam xyuas cardiotoxicity, cardiac troponins (I lossis T) yuav tsum tau siv, vim tias lawv muab cov cardiospecificity zoo dua li cov cim enzymatic ib txwm nyob hauv ob tus dev thiab NHPs.

Glucose thiab lipid metabolism hauv NHPs muaj kev cuam tshuam rau ib puag ncig kev ntxhov siab thiab kev hloov pauv kev noj haus. Kev tuav -induced epinephrine tso tawm niaj hnub ua rau glycogenolysis sai, ua rau muaj kev hloov pauv hauv hyperglycemia. Cov sijhawm pub mis kuj ua rau muaj kev hloov pauv hauv cov ntshav triglycerides thiab cov roj cholesterol.

NHPs kuj pom muaj ntau dua thiab sib txawv ntawm cov hauv paus hauv cov ntshav cov protein ntau dua cov nas. Kev hloov pauv hauv albumin thiab globulin feem ntau feem ntau cuam tshuam tsis yog - mob tshwj xeeb - cov lus teb rau cov txheej txheem, kab mob subclinical, lossis hloov pauv cov khoom noj khoom haus, es tsis yog lub hom phiaj ncaj qha - lub cev toxicity.

Serum electrolyte concentrations, tshwj xeeb tshaj yog sodium, potassium, thiab chloride, yuav raug hloov pauv sai hauv NHPs vim muaj dej txaus, kua qaub-piv tsis txaus los ntawm kev siv tshuaj loog- mob ua pa nyuaj siab, lossis cov qauv hemolysis.

Tag nrho cov calcium concentrations ncaj qha mus rau cov ntshav albumin. Yog li ntawd, kev hloov pauv hauv tag nrho cov calcium yuav tsum tau ua lej lossis kho lub cev rau qib albumin; Kev hloov pauv hauv tag nrho cov calcium tsis tas yuav qhia txog kev hloov pauv lom neeg hauv kev ua haujlwm, ionized calcium feem.

Kev txhais cov ntaub ntawv kho mob pathology hauv cov dev thiab cov tsiaj tsis yog tib neeg primates txuas ntxiv tshaj li cov qauv kev sib piv ntawm cov tsheb thiab cov pab pawg kho mob. Kev hloov pauv lom neeg lom neeg, kev sib tw hauv paus, phlebotomy artifacts, tshuaj loog, thiab tuav kev ntxhov siab feem ntau qhia cov ntaub ntawv tsis meej pem.

Kev ntsuas kev nyab xeeb kom raug yog nyob ntawm kev sib koom ua ke ntawm cov kab mob pathology nrog kev kawm tsim qauv, kev soj ntsuam tiag tiag - lub sijhawm soj ntsuam, cov ntaub ntawv raug tshuaj pharmacokinetic, thiab cov txiaj ntsig histopathological tseeb. Ib qho nyuaj, hom-txoj hauv kev tshwj xeeb rau cov ntaub ntawv no yog qhov tseem ceeb rau kev txhais cov kev tshawb pom ua ntej mus rau qhov tseeb ntawm tib neeg kev pheej hmoo.

Hu rau Prisys Biotech

Hall, RL, & Everds, NE (2003). Cov xwm txheej cuam tshuam rau kev txhais lus ntawm canine thiab nonhuman primate chaw kho mob pathology.Toxicological pathology, 31(1_suppl), 6-10. PIB: 101080192/01926230390174878