DK171745B1 - Method for determining the elimination of labeled hCG in humans, agent for use in the method, and its use for determining pathophysiologically formed hCG elimination or for determining organ function - Google Patents
Method for determining the elimination of labeled hCG in humans, agent for use in the method, and its use for determining pathophysiologically formed hCG elimination or for determining organ function Download PDFInfo
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Description
DK 171745 B1DK 171745 B1
Den foreliggende opfindelse angår en fremgangsmåde til fastlæggelse af eliminationen af mærket hCG (human Chorion Gonadotropin) i mennesker, et middel til anvendelse ved fremgangsmåden samt anvendelsen heraf til fastlæggelse af pato-5 fysiologisk dannet hCG's elimination eller til fastlæggelse af organfunktion.The present invention relates to a method for determining the elimination of labeled hCG (human Chorion Gonadotropin) in humans, an agent for use in the method, and its use for determining the pathophysiologically formed hCG elimination or for determining organ function.
hCG er et glycoprotein med en molekylvægt på ca. 36.700 daltons. Proteinet består af en alfa- og en beta-kæde. hCG har et carbohydratindhold på ca. 30%. hCG er på grund af dets 10 mange sialsyresidekæder negativt ladet, hvilket formodentlig også er årsagen til, at hCG ved størrelseskromatografi elue-res med en tilsyneladende molekylvægt på ca. 60.000 daltons^·.hCG is a glycoprotein with a molecular weight of approx. 36,700 daltons. The protein consists of an alpha and a beta chain. hCG has a carbohydrate content of approx. 30%. hCG is negatively charged due to its 10 many sialic acid side chains, which is probably also the reason why the hCG is eluted by size chromatography with an apparent molecular weight of approx. 60,000 daltons ^ ·.
hCG benyttes som lægemiddel i forbindelse med ovulationsstimulation og udskilles i nogen grad uomdannet i urinen. Der er 15 ikke fastlagt andre eliminations- og metaboliseringsorganer hos mennesket end nyrerne^.hCG is used as a drug for ovulation stimulation and is excreted to some extent unchanged in the urine. No elimination and metabolizing organs have been established in man other than the kidneys.
Hos kvinder ses hCG under normale fysiologiske omstændigheder under graviditet. hCG secerneres fra syncytiotrophoblast-cellelaget under graviditet og har en overvejende luteinise-20 rende virkning. Allerede få dage efter befrugtningen af ovum kan der måles hCG i blod og urin. hCG-niveauet stiger indtil ca. 10.-12. graviditetsuge, hvorefter niveauet er konstant indtil fødslen. Efter fødslen forsvinder hCG hurtigt fra blod og urin^"^.In women, hCG is seen under normal physiological conditions during pregnancy. hCG is secreted from the syncytiotrophoblast cell layer during pregnancy and has a predominantly luteinizing effect. Just a few days after fertilization of the ovum, hCG can be measured in blood and urine. hCG level rises until approx. 10th-12th pregnancy week, after which the level is constant until birth. After birth, hCG quickly disappears from blood and urine ^ "^.
25 Under normale fysiologiske omstændigheder forekommer hCG ikke ved sædvanlige målemetoder i målbare mængder hos mænd. hCG er således ved sin tilstedeværelse i målbare mængder hos mænd tegn på sygdomsaktivitet.25 Under normal physiological circumstances, hCG does not occur by usual measurement methods in measurable amounts in men. Thus, in its presence in measurable quantities in men, hCG is indicative of disease activity.
Eksempler på lidelser, hvor der er observeret forhøjelse af 30 hCG-niveau i plasma, er: DK 171745 B1 2 Mænd: testiscancerpatienter, hvor ca. 30%-50% af disse patienter har forhøjet hCG-niveau,Examples of disorders where an elevation of 30 hCG levels in plasma have been observed are: DK 171745 B1 2 Men: testicular cancer patients, where approx. 30% -50% of these patients have elevated hCG levels,
Kvinder: mola, choriocarcinom.Women: mola, choriocarcinoma.
Endvidere ses ved ekstrauterin graviditet forhøjelse af hCG-5 niveauet som led i den normale graviditetsfysiologi.Furthermore, during extrauterine pregnancy, elevation of hCG-5 levels is seen as part of normal pregnancy physiology.
Yderligere ses sporadisk forhøjelse af hCG-niveauet ved en lang række andre maligne tilstande, såsom cancer udgået fra lunge, pancreas, ventrikel, hepar, prostata, uterus, mamma og blære.Furthermore, sporadic elevation of hCG levels is seen in a variety of other malignant conditions, such as lung, pancreatic, ventricular, heparin, prostate, uterus, mammary and bladder cancers.
10 Når patienter behandles for en lidelse, som er ledsaget af unormal hCG-produktion, har man hidtil benyttet gentagne målinger af hCG-niveauet til at vurdere behandlingseffekten. hCG produceres hos cancerpatienter i tumorceller, og et faldende hCG-niveau er således blevet tolket som en nedsat eller 15 ophævet hCG-produktion og dermed positiv effekt af den foretagne behandling7. På nuværende tidspunkt benyttes kun målinger af hCG-niveauet ved immunologiske teknikker til at vurdere faldet af hCG-niveau hos patienter med en lidelse ledsaget af en unormal produktion af hCG8-18.10 When patients are treated for a disorder that is accompanied by abnormal hCG production, repeated measurements of the hCG level have so far been used to assess the treatment effect. hCG is produced in cancer patients in tumor cells, and a declining hCG level has thus been interpreted as a decreased or 15 hCG production and thus a positive effect of the treatment undertaken7. At present, only hCG level measurements are used by immunological techniques to assess the decrease of hCG level in patients with a disorder accompanied by abnormal production of hCG8-18.
20 Det fundne fald i hCG-plasmaniveau sammenholdes med normalværdier fremkommet ved undersøgelser af hCG-omsætningsforhold hos raske personer efter injektion af hCG og måling af hCG i plasma ved immunologisk teknik16,17. Forsvindings- eller eliminationshastigheden for hCG, målt som halveringstiden, er 25 for raske personer fundet at være i gennemsnit ca. 1,5 døgn.20 The observed decrease in hCG plasma level is compared with normal values obtained from studies of hCG turnover ratios in healthy subjects after injection of hCG and measurement of hCG in plasma by immunological technique16,17. The disappearance or elimination rate of hCG, measured as the half-life, is 25 for healthy individuals, found to be on average approx. 1.5 days.
Ved adskillige kliniske målinger hos patienter med testiscancer efter orchiektomi og senere under kemoterapi har man imidlertid ikke kunnet reproducere disse halveringstider9,18-20. Således er der hos patienter med testiscancer 30 fundet halveringstider mellem 1,4 og 3,2 døgn efter qrchiek-tomi som eneste behandling, og disse patienter er blevet helbredt. Der er beskrevet halveringstider på helt op til 34 DK 171745 Bl 3 døgn. I dag betragtes halveringstider for hCG på mere end 3 døgn som forlængede.However, several clinical measurements in patients with testicular cancer after orchiectomy and later during chemotherapy have not been able to reproduce these half-lives9,18-20. Thus, in patients with testicular cancer 30, half-lives between 1.4 and 3.2 days after qrchiek-tomi have been found as the sole treatment, and these patients have been cured. Half-lives of up to 34 DK 171745 Bl 3 days have been described. Today, half-lives of hCG of more than 3 days are considered extended.
Da halveringstiderne for hCG, bestemt hos raske mænd og kvinder efter injektion af oprenset hCG fra gravide kvinder 5 samt fra kvinder post partum, således ikke umiddelbart kan benyttes som reference for halveringstider fundet hos patienter med testiscancer i kemoterapi, er der et behov for et middel, hvormed man pålideligt og med sikkerhed kan fastslå, hvorvidt der finder en fortsat hCG-produktion sted, eller om 10 opretholdelsen af en høj hCG-koncentration skyldes eliminationsforhold. Hidtil har man således udelukkende tolket en forlænget halveringstid (længere end 3 døgn) som udtryk for en fortsat produktion af hCG og dermed tilstedeværelse af vitale tumorceller.As the half-lives of hCG, determined in healthy men and women after injection of purified hCG from pregnant women 5 and from postpartum women, cannot thus be used directly as a reference for half-lives found in patients with test cancer in chemotherapy, there is a need for a remedy which can reliably and confidently determine whether continued hCG production is taking place or whether the maintenance of a high hCG concentration is due to elimination conditions. Thus far, only a prolonged half-life (longer than 3 days) has been interpreted as an expression of continued production of hCG and thus the presence of vital tumor cells.
15 Det har imidlertid nu overraskende vist sig, at man ved at anvende mærket hCG som markørstof med stor sikkerhed kan fastslå, hvorvidt der hos patienter med initialt unormale plasma-hCG-niveauer finder en fortsat hCG-produktion sted.15 However, it has now surprisingly been found that using the labeled hCG as a marker substance can be determined with great certainty whether patients with initially abnormal plasma hCG levels continue to produce hCG.
Opfindelsen angår således en fremgangsmåde til fastlæggelse 20 af eliminationen af mærket hCG i mennesker, hvilken fremgangsmåde er ejendommelig ved, at man 1) indgiver mærket hCG i et menneske, 2) måler koncentrationen af mærket hCG i prøver herfra, udtaget på forskellige tidspunkter, 25 hvorefter man enten 3a) måler koncentrationen af den samlede mængde hCG i prøver fra dette menneske, fortrinsvis udtaget på samme tidspunkter som de under 2) nævnte prøver, og DK 171745 B1 4 4a) sammenligner kurveforløbene for de under 2) og 3a) målte værdier som funktion af tiden til fastlæggelse af eventuel tilstedeværelse af patofysiologisk hCG-produktion, eller 5 3b) måler koncentrationen af mærket hCG i prøver fra en rask forsøgsperson, udtaget på forskellige tidspunkter, og 4b) sammenligner kurve forløbene for de under 2) og 3b) målte værdier som funktion af tiden til fastlæggelse af organ-10 funktion.The invention thus relates to a method for determining the elimination of labeled hCG in humans, which is characterized in that 1) administering labeled hCG in a human, 2) measuring the concentration of labeled hCG in samples thereof, taken at various times, whereupon either 3a) measures the concentration of the total amount of hCG in samples from this human, preferably taken at the same times as the samples mentioned in 2) and DK 171745 B1 4 4a) compares the curve processes for the values measured under 2) and 3a) as a function of time to determine possible presence of pathophysiological hCG production, or 5 3b) measures the concentration of labeled hCG in samples from a fast subject sampled at different times, and 4b) compares the curve paths for those under 2) and 3b) measured values as a function of time for determining organ-10 function.
Opfindelsen angår endvidere et middel til anvendelse ved fremgangsmåden, hvilket middel er ejendommeligt ved, at det som aktiv bestanddel indeholder sterilt fremstillet, mærket hCG, fortrinsvis 125I-hCG.The invention further relates to an agent for use in the process, which is characterized in that it contains as active ingredient sterile labeled hCG, preferably 125 I-hCG.
15 125I-hCG er velkendt fra laboratorieanalyser, hvor det indgår som reagens i radioimmunoassays. Ioderingsteknik og steril-fremstilling af lægemidler er velkendte teknikker.15 125 I-hCG is well known from laboratory assays where it is included as a reagent in radioimmunoassays. Eoding technique and sterile preparation of drugs are well known techniques.
Prøven kan være en plasmaprøve, en fuldblodsprøve eller en anden vævsprøve, fortrinsvis en plasmaprøve.The sample may be a plasma sample, a whole blood sample or another tissue sample, preferably a plasma sample.
20 Der indgives 0,5-50 MBq, fortrinsvis ca. 5 MBq ^2^I-hCG med en specifik aktivitet på 1-100 MBq/mg, fortrinsvis ca. 50 MBq/mg (1 mg - ca. 3000 IU hCG). Herefter følges plasmaforsvindingskurven for 125I-hCG ved at udtage blodprøver på 0,5-100 ml, fortrinsvis ca. 5 ml 1 til 20 gange ugentligt, 25 fortrinsvis 2 til 5 gange ugentligt. Disse blodprøver tælles for aktivitet i spektret 0 til 1 MeV, fortrinsvis 15-75 KeV i brøndtæller. Fra de fremkomne tælletal trækkes baggrunds-aktiviteten beregnet som et gennemsnit af aktiviteten fundet ved tælling på et tomt glas, et glas med plasma og et glas DK 171745 B1 5 vand. Såfremt patienten tidligere har modtaget 12^I-hCG-injektion, kan tælling på den initiale plasmaprøve ikke benyttes til baggrundskorrektion. Da benyttes gennemsnit af tælletal fra tom prøve og prøve med H20.0.5-50 MBq is administered, preferably approx. 5 MBq ^ 2 ^ I-hCG with a specific activity of 1-100 MBq / mg, preferably approx. 50 MBq / mg (1 mg - about 3000 IU hCG). Next, the plasma disappearance curve of 125 I-hCG is followed by taking blood samples of 0.5-100 ml, preferably approx. 5 ml 1 to 20 times a week, preferably 2 to 5 times a week. These blood samples are counted for activity in the spectrum 0 to 1 MeV, preferably 15-75 KeV in the well counter. The background activity calculated as an average of the activity found by counting on an empty glass, a glass with plasma and a glass of water is deducted from the obtained count numbers. If the patient has previously received 12 µl hCG injection, counting on the initial plasma sample cannot be used for background correction. Then the average of counting numbers from empty sample and sample with H20 is used.
5 Ved måling af omsætningshastigheden af mærket hCG er det muligt at fastlægge den rene eliminationshastighed af mærket5 When measuring the rate of turnover of the mark hCG it is possible to determine the pure elimination rate of the mark
-1 O C-1 ° C
hCG, fortrinsvis L^3I-hCG, idet der jo ikke produceres mærket hCG i den humane organisme. Endvidere foretages en immunologisk bestemmelse af den samlede mængde hCG i prøver, for-10 trinsvis udtaget samtidig som prøverne til bestemmelse af aktivitet. Da den injicerede mængde mærket hCG er lille i forhold til den samlede mængde hCG, vil denne måling afspejle såvel produktions- som eliminationsforhold for hCG.hCG, preferably L ^ 3I-hCG, since no labeled hCG is produced in the human organism. Furthermore, an immunological determination of the total amount of hCG is made in samples, preferably taken at the same time as the samples for activity determination. Since the injected amount of labeled hCG is small relative to the total amount of hCG, this measurement will reflect both production and elimination ratios of hCG.
Ved at sammenligne plasmaforsvindingskurven fundet ved immu-15 nologisk bestemmelse af den samlede mængde hCG i plasma med plasmaforsvindingskurven for 125I-hCG er det muligt at fastlægge, hvorvidt der sker en fortsat hCG-produktion. Såfremt de to kurver har et parallelt forløb, viser dette nemlig, at der, uanset en forlænget halveringstid, ikke længere sker 20 nogen hCG-produktion, og at den forlængede halveringstid derfor skyldes eliminationsforhold og ikke hCG-produktion. Foreligger der ikke længere nogen hCG-produktion, kan behandlingen med f.eks. kemoterapi derfor indstilles.By comparing the plasma disappearance curve found by immunological determination of the total amount of hCG in plasma with the plasma disappearance curve of 125 I-hCG, it is possible to determine whether continued hCG production occurs. If the two curves have a parallel course, this shows that, regardless of an extended half-life, no longer 20 hCG production occurs, and that the extended half-life is therefore due to elimination conditions and not hCG production. If there is no longer any hCG production, the treatment with e.g. chemotherapy is therefore discontinued.
Opfindelsen angår endvidere anvendelse af et middel ifølge op-25 findelsen til fastlæggelse af patofysiologisk dannet hCG's elimination hos mennesker. Anvendelsen af mærket hCG som eliminationsmarkør har således givet væsentligt forbedrede muligheder for at vælge terapi til patienter med sygdomme, der ledsages af en unormal hCG-produktion.The invention further relates to the use of an agent according to the invention for the determination of pathophysiologically generated hCG elimination in humans. Thus, the use of labeled hCG as an elimination marker has provided significantly improved opportunities to select therapy for patients with diseases accompanied by abnormal hCG production.
30 Det nye beslutningsgrundlag hviler således på patientens egen omsætning af mærket hCG som udtryk for hCG-eliminination, med baggrund i patientens egen fysiologi og patofysiologi, frem for normalværdier for hCG-elimination approximeret og ekstra- DK 171745 Bl 6 poleret fra videnskabelige undersøgelser på andre patienter eller dyremodeller.30 The new decision basis thus rests on the patient's own circulation of the labeled hCG as an expression of hCG elimination, based on the patient's own physiology and pathophysiology, rather than normal values for hCG elimination approximated and extra- polished from scientific studies on other patients or animal models.
På baggrund af ovenstående teknik kan der også, når eliminationsorganer for hCG er endeligt fastlagt, fastlægges fald-5 hastigheder af 125I-hCG, som korrelerer med den aktuelle organfunktion. Herved tilvejebringes væsentligt forbedret mulighed for at fastlægge de pågældende organers funktion.Based on the foregoing technique, when elimination means for hCG are finally determined, drop-rates of 125 I-hCG which correlate with the current organ function can also be determined. This provides a significantly improved opportunity to determine the functioning of the organs concerned.
Opfindelsen angår derfor også anvendelsen af et middel ifølge opfindelsen til fastlæggelse af organfunktion.The invention therefore also relates to the use of an agent according to the invention for determining organ function.
10 Opfindelsen belyses nærmere under henvisning til figurerne, hvor fig. 1 viser hCG-målinger under og efter kemoterapi hos en patient med cancer testis, samt hvorledes halveringstid for hCG vurderes på et givet tidspunkt, 15 fig. 2 målinger af såvel Ι-hCG som samlet mængde hCG under og efter kemoterapi hos samme patient, fig. 3 målinger af såvel 125I-hCG som samlet mængde hCG under og efter kemoterapi hos en patient med mola, fig. 4 målinger af såvel 125I-hCG som samlet mængde hCG hos 20 en patient uden nyrefunktion, fig. 5 målinger af såvel 125I-hCG som samlet mængde hCG hos en rask forsøgsperson, og fig. 6 sammenligning af målinger af 125I-hCG hos en patient uden nyrefunktion og hos en rask forsøgsperson, opnået ud fra 25 fig. 4 og 5.The invention is further elucidated with reference to the figures, in which fig. 1 shows hCG measurements during and after chemotherapy in a patient with cancer testis, as well as how the half-life of hCG is assessed at a given time; 2 measurements of both Ι-hCG and total amount of hCG during and after chemotherapy in the same patient; 3 measurements of both 125I-hCG as well as total amount of hCG during and after chemotherapy in a patient with mola; 4 measurements of both 125 I-hCG as well as the total amount of hCG in a patient without renal function; 5 measurements of 125 I-hCG as well as the total amount of hCG in a healthy subject, and fig. 6 comparing measurements of 125 I-hCG in a patient without renal function and in a healthy subject, obtained from FIG. 4 and 5.
Fig. 1 viser et forløb for hCG-fald hos en patient med forhøjet hCG. Pilene angiver startdag for en 5 dages kemoterapi.FIG. Figure 1 shows a course of hCG decrease in a patient with elevated hCG. The arrows indicate the start day of a 5 day chemotherapy.
DK 171745 B1 7DK 171745 B1 7
Den stiplede linie angiver påvisningsgrænsen for hCG målt ved immunologisk teknik. hCG målt ved immunologisk teknik er angivet ved cirkler.The dotted line indicates the detection limit of hCG measured by immunological technique. hCG measured by immunological technique is indicated by circles.
Initialt ses et langsomt fald (dag 0 til 5). Herefter falder 5 halveringstiden (T^) til ca. 1,8 døgn (dag 8 til 20), for ved anden behandling (dag 20) at stige til ca. 16 døgn. Under den sidste fase af forløbet (dag 60 til 132) ses halveringstiden at være forlænget til ca. 40 døgn.Initially, a slow decline (day 0 to 5) is seen. Thereafter, the half-life (T 1.8 days (days 8 to 20), to increase to approx. 16 days. During the last phase of the course (days 60 to 132) the half-life is seen to be extended to approx. 40 days.
De forlængede halveringstider (længere end 3 dage) efter dag 10 20 ville man ifølge den kendte teknik have taget som udtryk for fortsat hCG-produktion og dermed nødvendiggøreIse af fortsat behandling.The prolonged half-lives (longer than 3 days) after day 10 would, according to the prior art, have been expressed as continued hCG production and thus necessitated continued treatment.
Fig. 2 viser samme patient, men med fald i plasmaaktivitet efter 1 2 3^5I-hCG-injektion afsat i samme koordinatsystem 15 (angivet ved stjerner). Sammenlignes de to kurver ses, at Ι-hCG (injiceret i patienten) forsvinder på samme måde som den samlede mængde hCG (produceret i patienten). Ud fra dette ses, at der ikke er grund til at antage fortsat hCG-produkti-on. Den forlængede halveringstid skyldes derfor et eliminati-20 onsproblem, og der skal på denne baggrund ikke gives yderligere behandling.FIG. 2 shows the same patient but with decrease in plasma activity after 1 2 3 ^ 5I-hCG injection deposited in the same coordinate system 15 (indicated by stars). When comparing the two curves, it is seen that Ι-hCG (injected in the patient) disappears in the same way as the total amount of hCG (produced in the patient). From this it can be seen that there is no reason to assume continued hCG production. Therefore, the extended half-life is due to an elimination problem and no further treatment should be given on this basis.
Metoden er således et værdifuldt supplement til den øvrige overvågning af behandlingsforløbet.The method is thus a valuable supplement to the other monitoring of the course of treatment.
det følgende beskrives konkrete eksempler til illustration 25 af opfindelsen.The following are described concrete examples of illustration 25 of the invention.
Eksempel 1 2Example 1 2
Patient med cancer testis og forhøjet hCG-niveau har to gange modtaget 5 dages kemoterapi med 21 dages mellemrum. Der er mistanke om resistens over for kemoterapien, da halverings - 3 0 tiden for hCG er længere end 3 døgn (fig. 1 ved dag ca. 34 DK 171745 B1 8 til 43 vurderet grafisk som angivet).Patient with cancer testis and elevated hCG level twice received 5 days of chemotherapy at 21 day intervals. Resistance to chemotherapy is suspected since the half-life of hCG is longer than 3 days (Fig. 1 at day approximately 34 DK 171745 B1 8 to 43 assessed graphically as indicated).
Patientens skjoldbruskkirtel iodblokeres med 400 mg kalium-iodid per os minimum 1 time inden undersøgelsens start for at i n c undgå optagelse af frit I. Herved nedsættes stråledosis 5 til skjoldbruskkirtlen betydeligt.The patient's thyroid iodine is blocked with 400 mg of potassium iodide per ounce at least 1 hour before the start of the study to avoid the absorption of free I. This reduces the dose of radiation 5 to the thyroid significantly.
Der anlægges en velfungerende intravenøs adgang (f.eks. venflon) i patientens armvene. Der udtages 10 ml blod til baggrundsplasmaprøve samt 5 ml blod til bestemmelse af den samlede hCG-mængde i plasma til tiden 0.Well-functioning intravenous access (eg venflon) is established in the patient's arm veins. 10 ml of blood is taken for background plasma sample and 5 ml of blood to determine the total amount of hCG in plasma at time 0.
10 Herefter injiceres 3,3215 MBq 125I-hCG leveret fra Isopharma, Kjeller, Norge.10 Then 3,3215 MBq 125I-hCG delivered from Isopharma, Kjeller, Norway is injected.
Der udtages 2 blodprøver å henholdsvis 10 ml og 5 ml til bestemmelse af aktiviteten af henholdsvis 125I-hCG og den samlede mængde hCG i plasma til tiden 2 timer. Herefter 15 udtages tilsvarende prøver til tiden dag 1, 2, 4, 5, 6, 7, 8, 10, 11, 12, 21, 28, 34, 35, 36, 37, 42, 49, 57, 62, 75, 83, 89, 96 og 104, indtil patienten er hCG-negativ, dvs. at den samlede hCG-mængde er under påvisningsgrænsen.Two blood samples of 10 ml and 5 ml are taken, respectively, to determine the activity of 125 I-hCG and the total amount of hCG in plasma over time, 2 hours. Then 15 samples are taken on time 1, 2, 4, 5, 6, 7, 8, 10, 11, 12, 21, 28, 34, 35, 36, 37, 42, 49, 57, 62, 75, 83, 89, 96 and 104 until the patient is hCG negative, i.e. that the total hCG amount is below the detection limit.
Samtlige blodprøver centrifugeres ved 3000 omdrejninger per 20 min. i 10 min., og plasma afpipetteres. Der benyttes 3 ml plasma til bestemmelse af aktiviteten af 125I-hCG og 1 ml plasma til bestemmelse af den samlede hCG-mængde. Aktiviteten i de enkelte plasmaprøver tælles i brøndtæller i spektret 15 til 75 KeV. Alle prøver tælles samtidig for at undgå korrek- i n r 25 tion for fysisk henfald af 1Z3I, idet tælleperioden er << fysisk for 125I.All blood samples are centrifuged at 3000 rpm for 20 minutes. for 10 min, and plasma is pipetted. 3 ml of plasma are used to determine the activity of 125 I-hCG and 1 ml of plasma to determine the total amount of hCG. The activity of the individual plasma samples is counted in well counts in the range 15 to 75 KeV. All samples are counted at the same time to avoid correction for physical decay of 1Z3I, with the count period being << physical for 125I.
Aktiviteten af 125I-hCG i de enkelte plasmaprøver afsættes i et semilogaritmisk koordinatsystem med tidspunktet for prøve-tagning som abscisse (fig. 2). I samme koordinatsystem afsæt-30 tes den samlede mængde hCG målt ved immunologisk teknik som funktion af tidspunktet for prøvetagning.The activity of 125 I-hCG in the individual plasma samples is plotted in a semilogarithmic coordinate system with the time of sampling as abscissa (Fig. 2). In the same coordinate system, the total amount of hCG measured by immunological technique as a function of time of sampling is plotted.
DK 171745 B1 9DK 171745 B1 9
Kurverne sammenholdes: Der ses et parallelt forløb af de to kurver (fig. 2) til trods for forlænget halveringstid for hCG (T-jy2 > 3 døgn) . Dette tolkes som ophørt produktion af hCG og dermed ingen levende hCG-producerende cancerceller.The curves are compared: a parallel course of the two curves (Fig. 2) is observed, despite the extended half-life of hCG (T-jy2> 3 days). This is interpreted as discontinued production of hCG and thus no live hCG-producing cancer cells.
5 På denne baggrund standses yderligere kemoterapi, efter at patienten har modtaget standardbehandlingen på 4 gange 5 dages kemoterapi. Patienten er således blevet helbredt med mindre kemoterapi, end man ville have anvendt forud for den foreliggende opfindelse.5 Against this background, further chemotherapy is halted after the patient has received the standard treatment of 4 times 5 days of chemotherapy. Thus, the patient has been cured with less chemotherapy than would have been used prior to the present invention.
10 Eksempel 2Example 2
Dette eksempel angår en kvinde med mola, der til trods for kemoterapi fortsat har forhøjet hCG-niveau.This example concerns a woman with mola who, despite chemotherapy, continues to have elevated hCG levels.
Der er mistanke om resistens over for kemoterapi, da patienten har stigende hCG-niveau (fig. 3).Resistance to chemotherapy is suspected as the patient has increasing hCG levels (Fig. 3).
15 Patientens skjoldbruskkirtel iodblokeres med 400 mg kalium-iodid per os minimum 1 time inden undersøgelsens start for at undgå optagelse af frit 125I. Herved nedsættes stråledosis til skjoldbruskkirtlen betydeligt.15 The patient's thyroid iodine is blocked with 400 mg of potassium iodide per ounce at least 1 hour before the start of the study to avoid uptake of free 125I. This reduces the dose of radiation to the thyroid significantly.
Der anlægges en velfungerende intravenøs adgang (f.eks.Well-functioning intravenous access (e.g.
20 venflon) i patientens armvene. Der udtages 10 ml blod til baggrundsplasmaprøve samt 5 ml blod til bestemmelse af den samlede hCG-mængde i plasma til tiden 0. Herefter injiceres 3,1415 MBq 125I-hCG leveret fra Isopharma, Kjeller, Norge.20 venflon) in the patient's arm veins. 10 ml of blood is taken for background plasma sample as well as 5 ml of blood to determine the total amount of hCG in plasma at time 0. Next, 3,1415 MBq 125I-hCG delivered from Isopharma, Kjeller, Norway is injected.
Der udtages 2 blodprøver å henholdsvis 10 ml og 5 ml til 25 bestemmelse af aktiviteten af henholdsvis 125I-hCG og den samlede hCG-mængde i plasma til tiden 2 timer. Herefter udtages tilsvarende prøver til tiden dag 4, 7, 14, 17, 21, 24, 52, 55, 58, 62, 77, 84, 94, 98, 107 og 121 (fig. 3).Two blood samples of 10 ml and 5 ml are taken, respectively, to determine the activity of 125 I-hCG and the total amount of hCG in plasma over time, 2 hours. Subsequently, corresponding samples are taken on time 4, 7, 14, 17, 21, 24, 52, 55, 58, 62, 77, 84, 94, 98, 107 and 121 (Fig. 3).
DK 171745 B1 10DK 171745 B1 10
Blodprøverne undersøges på tilsvarende måde som i eksempel 1, og resultaterne afsættes i et semilogaritmisk koordinatsystem.The blood samples are examined in a similar manner as in Example 1 and the results are plotted in a semilogarithmic coordinate system.
Kurverne sammenholdes: patienten er hCG-negativ på dag 20 5 (fig. 3), og der ses et ensartet forløb af kurverne. Dette tolkes som ophør af produktion af hCG, idet faldet i hCG-niveau er foregået med samme hastighed som faldet i aktivitet fra 125I-hCG. Der er således ingen levende hCG-producerende celler, og mistanken om tilstedeværelse af kemoterapiresi-10 stente hCG-producerende celler har vist sig ubegrundet.The curves are compared: the patient is hCG negative on day 20 5 (Fig. 3) and a uniform course of the curves is seen. This is interpreted as the cessation of hCG production, with the decrease in hCG level occurring at the same rate as the decrease in activity from 125 I-hCG. Thus, there are no live hCG producing cells and the suspicion of the presence of chemotherapy resistant hCG producing cells has proved unfounded.
Patienten er således helbredt og kan fortsætte almindelig kontrol.Thus, the patient is cured and can continue regular monitoring.
Eksempel 3Example 3
Dette eksempel viser anvendelsen af midlet ifølge opfindelsen 15 til vurdering af funktionen af omsætningsorganer for små proteiner, hvor hCG anvendes som modelstof.This example illustrates the use of the agent of the invention 15 for assessing the function of small protein reaction organs where hCG is used as a model substance.
Hos en patient, hvor der ønskes en vurdering af omsætningen af små proteiner, dvs. proteiner med en molekylvægt på under ca. 50.000 Daltons, såsom proteinerne b2-microglobulin og 20 retindbindende protein, blokeres skjoldbruskkirtlens iodoptagelse ved indgift af 400 mg kaliumiodid minimum 1 time inden undersøgelsens start for at undgå optagelse af frit 125I. Herved nedsættes stråledosis til skjoldbruskkirtlen betydeligt. Der anlægges en velfungerende intravenøs adgang 25 (f.eks. venflon ) i patientens armvene. Der udtages 10 ml blod til baggrundsplasmaprøve samt 5 ml blod til bestemmelse af den samlede mængde hCG i plasma til tiden 0.In a patient where an assessment of the turnover of small proteins is desired, ie. proteins with a molecular weight of less than ca. 50,000 Daltons, such as the b2 microglobulin proteins and 20 retinal binding protein, block thyroid iodine uptake by administering 400 mg of potassium iodide at least 1 hour before the start of the study to avoid uptake of free 125 I. This reduces the dose of radiation to the thyroid significantly. Well-functioning intravenous access 25 (eg venflon) is provided in the patient's arm veins. 10 ml of blood is taken for background plasma sample and 5 ml of blood to determine the total amount of hCG in plasma at time 0.
1 oc1 oc
Herefter injiceres 2,9415 MBq Ι-hCG leveret fra Isopharma, Kjeller, Norge.Subsequently, 2.9415 MBq Ι-hCG delivered from Isopharma, Kjeller, Norway is injected.
DK 171745 B1 11DK 171745 B1 11
Der udtages 2 blodprøver å henholdsvis 10 og 5 ml til bestemmelse af aktiviteten af henholdsvis 125I-hCG og den samlede mængde hCG i plasma til tiden 2 timer. Herefter udtages tilsvarende prøver til tiden dag 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 5 og 14 (fig. 4).Two blood samples of 10 and 5 ml are taken, respectively, to determine the activity of 125 I-hCG and the total amount of hCG in plasma over time, respectively. Subsequently, corresponding samples are taken on time 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 5 and 14 (Fig. 4).
Blodprøverne undersøges på tilsvarende måde som i eksempel 1, og resultaterne heraf afsættes i et semilogaritmisk koordinatsystem.The blood samples are examined in a similar manner as in Example 1, and the results are plotted in a semilogarithmic coordinate system.
Dette kurveforløb sammenholdes med kurveforløbet fundet ved 10 undersøgelse af en normal person, idet denne undersøgelse foretages analogt med den ovenfor anførte undersøgelse (fig.This curve is compared with the curve found on 10 examinations of a normal person, this study being done analogously to the study mentioned above (fig.
5) .5).
Kurveforløbene sammenholdes (fig. 6) . Det ses, at patienten har en langsommere omsætning af den indgivne 125I-hCG, og der 15 er derfor ingen tvivl om, at patientens omsætningsorganer for små proteiner fungerer dårligere end hos en rask forsøgsperson .The curve paths are compared (Fig. 6). It is seen that the patient has a slower turnover of the administered 125 I-hCG, and therefore there is no doubt that the patient's small protein turnover works poorly than in a healthy subject.
DK 171745 B1 12DK 171745 B1 12
Litteraturliste 1. Birken S, Canfield RE. Structural and immunochemical properties of human choriogonadotropin, pp. 47-80. [Review]. In: McKerns KW, ed 1978; Structure and function.Literature List 1. Birken S, Canfield RE. Structural and immunochemical properties of human choriogonadotropin, pp. 47-80. [Review]. In: McKerns KW, ed 1978; Structure and function.
5 2. Nisula BC, Blithe DL, Akar A, Lefort G, Wehmann RE. Meta bolic fate of human choriogonadotropin. [Review]. J Steroid Biochem 1989; 33: 733-737.5 2. Nisula BC, Blithe DL, Akar A, Lefort G, Wehmann RE. Meta bolic fate or human choriogonadotropin. [Review]. J Steroid Biochem 1989; 33: 733-737.
3. van der Lugt B, Drogendijk AC. The disappearance of human chorionic gonadotropin from plasma and urine following indu- 10 ced abortion. Disappearance of hCG after induced abortion. Acta Obstet Gynecol Scand 1985; 64: 547-552.3. van der Lugt B, Drogendijk AC. The disappearance of human chorionic gonadotropin from plasma and urine following induced abortion. Disappearance of hCG after induced abortion. Acta Obstet Gynecol Scand 1985; 64: 547-552.
4. Steier JA, Bergsjo P, Myking OL. Human chorionic gonadotropin in maternal plasma after induced abortion, spontaneous abortion, and removed ectopic pregnancy. Obstet Gynecol 1984; 15 64: 391-394.4. Steier JA, Bergsjo P, Myking OL. Human chorionic gonadotropin in maternal plasma after induced abortion, spontaneous abortion, and removed ectopic pregnancy. Obstet Gynecol 1984; 15 64: 391-394.
5. Thyssen HH, Christensen H, Schebye O, Berget A, Arends J, Larsen SO. Elimination of human chorionic gonadotropin in serum and urine after uncomplicated induced abortion during the first trimester. [Danish]. Ugeskr Laeger 1992; 154: 2071- 20 2072.5. Thyssen HH, Christensen H, Schebye O, Berget A, Arends J, Larsen SO. Elimination of human chorionic gonadotropin in serum and urine after uncomplicated induced abortion during the first trimester. [Danish]. Ugeskr Laeger 1992; 154: 2071-202072.
6. Vejerslev LO, Arends J, Larsen SO. Spontaneous regression of serum hCG in 18 patients following evacuation of uncomplicated androgenic moles. [Danish]. Ugeskr Laeger 1988; 150: 2081-2083.6. Vejerslev LO, Arends J, Larsen SO. Spontaneous regression of serum hCG in 18 patients following evacuation of uncomplicated androgenic moles. [Danish]. Ugeskr Laeger 1988; 150: 2081-2083.
25 7. Mann K, Sailer B, Hoermann R. Clinical use of hCG and hCG7. Mann K, Sailer B, Hoermann R. Clinical use of hCG and hCG
beta determinations. [Review] . Scand J Clin Lab Invest Suppl 1993; 216: 97-104.beta determinations. [Review]. Scand J Clin Lab Invest Suppl 1993; 216: 97-104.
8. Paus E, Fossa SD, Risberg T, Nustad K. The diagnostic value of human chorionic gonadotrophin in patients with testi- DK 171745 B1 13 cular seminoma. Br J Urol 1987; 59: 572-577.8. Pause E, Fossa SD, Risberg T, Nustad K. The diagnostic value of human chorionic gonadotrophin in patients with testi- cular seminoma. Br J Urol 1987; 59: 572-577.
9. Toner GC, Geller NL, Tan C, Nisselbaum J, Bosi GJ. Serum tumor marker half-life during chemotherapy allows early prediction of complete response and survival in nonseminomatous 5 germ cell tumors. Cancer Res 1990; 50: 5904-5910.9. Toner GC, Geller NL, Tan C, Nisselbaum J, Bosi GJ. Serum tumor marker half-life during chemotherapy allows early prediction of complete response and survival in nonseminomatous 5 germ cell tumors. Cancer Res 1990; 50: 5904-5910.
10. Motzer RJ, Gulati SC, Crown JP, et al. High-dose chemotherapy and autologous bone marrow rescue for patients with refractory germ cell tumors. Early intervention is better tolerated. Cancer 1992; 69: 550-556.10. Motzer RJ, Gulati SC, Crown JP, et al. High-dose chemotherapy and autologous bone marrow rescue for patients with refractory germ cell tumors. Early intervention is better tolerated. Cancer 1992; 69: 550-556.
10 11. Gerl A, Clemm C, Lamerz R, Mann K, Wilmanns W. Prognostic implications of tumour marker analysis in non-seminomatous germ cell tumours with poor prognosis metastatic disease. Eur J Cancer 1993; 29A: 961-965.10 11. Gerl A, Clemm C, Lamerz R, Mann K, Wilmanns W. Prognostic implications of tumor marker analysis in non-seminomatous germ cell tumors with poor prognosis metastatic disease. Eur J Cancer 1993; 29A: 961-965.
12. Droz JP, Kramar A, Ghosn M, et al. Prognostic factors in 15 advanced nonseminomatous testicular cancer. A multivariate logistic regression analysis. Cancer 1988; 62: 564-568.12. Droz JP, Kramar A, Ghosn M, et al. Prognostic factors in 15 advanced nonseminomatous testicular cancers. A multivariate logistic regression analysis. Cancer 1988; 62: 564-568.
13. Cassels JW, Jr., Mann K, Blithe DL, Nisula BC, Wehmann RE. Reduced metabolic clearance of acidic variants of human choriogonadotropin from patients with testicular cancer.13. Cassels JW, Jr., Mann K, Blithe DL, Nisula BC, Wehmann RE. Reduced metabolic clearance of acidic variants of human choriogonadotropin from patients with testicular cancer.
20 Cancer 1989; 64: 2313-2318.Cancer 1989; 64: 2313-2318.
14. Kuhbock J, Aiginger P, Kuzmits R, Spona J. Prognostic value of tumor marker determinations in testicular cancer patients. Cancer Detect Prev 1987; 10: 389-392.14. Kuhbock J, Aiginger P, Kuzmits R, Spona J. Prognostic value of tumor marker determinations in testicular cancer patients. Cancer Detect Prev 1987; 10: 389-392.
15. Klein EA. Tumor markers in testis cancer. Urol Clin North 25 Am 1993; 20: 67-73.15. Small EA. Tumor markers in testis cancer. Urol Clin North 25 Am 1993; 20: 67-73.
16. Wehmann RE, Nisula BC. Metabolic and renal clearance rates of purified human chorionic gonadotropin. J Clin Invest 1981; 68: 184-194.16. Wehmann RE, Nisula BC. Metabolic and renal clearance rates of purified human chorionic gonadotropin. J Clin Invest 1981; 68: 184-194.
DK 171745 B1 14 17. Saal W, Glowania HJ, Hengst W, Happ J. Pharmacodynamics and pharmacokinetics after subcutaneous and intramuscular injection of human chorionic gonadotropin. Fertil Steril 1991; 56: 225-229.DK 171745 B1 14 17. Saal W, Glowania HJ, Hengst W, Happ J. Pharmacodynamics and pharmacokinetics after subcutaneous and intramuscular injection of human chorionic gonadotropin. Fertil Steril 1991; 56: 225-229.
5 18. Horwich A, Peckham MJ. Serum tumour marker regression rate following chemotherapy for malignant teratoma. Eur J Cancer Clin Oncol 1984; 20: 1463-1470.5 18. Horwich A, Peckham MJ. Serum tumor marker regression rate following chemotherapy for malignant teratoma. Eur J Cancer Clin Oncol 1984; 20: 1463-1470.
19. Pedersen BN. Tumour markers in testicular germ cell tumours. Acta Oncol 1984; 24: 287-294.19. Pedersen BN. Tumor markers in testicular germ cell tumors. Acta Oncol 1984; 24: 287-294.
10 20. van der Gaast A, Hoekstra JW, Croles JJ, Splinter TA.10 20. van der Gaast A, Hoekstra JW, Croles JJ, Splinter TA.
Elevated serum tumor markers in patients with testicular cancer after induction chemotherapy due to a reservoir of markers in cystic differentiated mature teratoma. J 1991; 145: 829-831.Elevated serum tumor markers in patients with testicular cancer after induction chemotherapy due to a reservoir of markers in cystic differentiated mature teratoma. J 1991; 145: 829-831.
Claims (6)
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK16995A DK171745B1 (en) | 1995-02-15 | 1995-02-15 | Method for determining the elimination of labeled hCG in humans, agent for use in the method, and its use for determining pathophysiologically formed hCG elimination or for determining organ function |
| EP96902902A EP0809518A1 (en) | 1995-02-15 | 1996-02-14 | A METHOD FOR THE IN VITRO MEASUREMENT OF THE ELIMINATION OF LABELLED hCG IN HUMANS, AN AGENT TO BE USED IN THE METHOD AS WELL AS THE USE THEREOF FOR THE ESTABLISHMENT OF THE ELIMINATION OF PATHO-PHYSIOLOGICALLY PRODUCED hCG OR FOR THE ESTABLISHMENT OF ORGAN FUNCTION |
| AU47127/96A AU4712796A (en) | 1995-02-15 | 1996-02-14 | A method for the in vitro measurement of the elimination of labelled hcg in humans, an agent to be used in the method as well as the use thereof for the establishment of the elimination of patho-physiologically produced hcg or for the establishment of organ function |
| PCT/DK1996/000070 WO1996025180A1 (en) | 1995-02-15 | 1996-02-14 | A METHOD FOR THE IN VITRO MEASUREMENT OF THE ELIMINATION OF LABELLED hCG IN HUMANS, AN AGENT TO BE USED IN THE METHOD AS WELL AS THE USE THEREOF FOR THE ESTABLISHMENT OF THE ELIMINATION OF PATHO-PHYSIOLOGICALLY PRODUCED hCG OR FOR THE ESTABLISHMENT OF ORGAN FUNCTION |
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| DK16995 | 1995-02-15 | ||
| DK16995A DK171745B1 (en) | 1995-02-15 | 1995-02-15 | Method for determining the elimination of labeled hCG in humans, agent for use in the method, and its use for determining pathophysiologically formed hCG elimination or for determining organ function |
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| EP (1) | EP0809518A1 (en) |
| AU (1) | AU4712796A (en) |
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- 1996-02-14 AU AU47127/96A patent/AU4712796A/en not_active Abandoned
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| WO1996025180A1 (en) | 1996-08-22 |
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