Albumini u bolesnika sa solidnim tumorima

The manufacture of albumin derived from human plasma started by Professor E. J. Cohn during World War II has expanded into international business over the past sixty years (1). In vital situations, albumin was used as a plasma expander. This is a biological preparation and always potentially dangerous. The manufacture of albumin is getting more and more expensive as the preparation has to meet standards ever higher. With the market abundant in artificial macro-molecular plasma expanders, improved parenteral nutrition, and studies questioning the effectiveness of albumin use, the administration of albumin has been reduced. Because of the nature of their disease and chemoradiotherapy treatment, patients with tumors are prone to having low protein levels. However, indications for albumin therapy are restricted, the same as that in other patient groups. With the quality parenteral and enteral nutrition available, the use of albumin to correct hypoalbuminemia is not justified.Proizvodnju albumina iz ljudske plazme započeo je profesor Cohn E. J. tijekom Drugog svjetskog rata; koja je u posljednjih šezdesetak godina prerasla je u internacionalni biznis (1). U vitalnim situacijama; albumin je upotrebljavan kao plazmaekspander. To je biološki preparat i uvijek je potencijalno opasan. Proizvodnja albumina sve je skuplja; jer preparat mora zadovoljavati sve više i više standarde. Uz bogato tržište umjetnih makromolekularnih plazmaekspandera; unaprijeđene intravenske prehrane i studije koje govore o upitnom djelovanju albumina; njegova primjena je u padu. Tumorski bolesnici; zbog prirode bolesti i liječenja kemoradioterapijom; skloni su nižim razinama proteina. Međutim; indikacije albuminske terapije su restriktivne; iste kao i kod ostalih skupina bolesnika. Uporaba albumina za korekciju hipoalbuminemije nije opravdana pored kvalitetne parenteralne i enteralne prehrane

Hemovigilancija i poslijetransfuzijske reakcije na krvne sastojke u bolesnika sa solidnim tumorima

Hemovigilance is a system of surveillance and alarm in transfusion activities from blood donor selection to the followup of the blood component recipients, gathering and analyzing all untoward effects of blood transfusion in order to correct their cause and prevent recurrence. A 5-year surveillance (2005-2009) showed the overall consumption of 6790 unit doses (1358/year): erythroconcentrate (EC) 973.4 ± 71, platelet concentrate (PC) 216 ± 66.93, fresh frozen plasma (FFP)122.4 ± 59.05 and cryoprecipitate (CP) 46.2 ± 26.63. During the five years, there were 38 adverse events (22 non-hemolytic febrile transfusion reactions (NHFTR), 16 allergic reactions (AR), or an average annual rate of 7.6 reactions ( 4.4 NHFTR, 3.2 AR). Neither serious adverse events nor death was reported. EC caused 0.043% of NHFTR (risk 1:2,326) and 0.015% of AR (risk 1:3,125), while FFP lead to 0.18% of NHFTR (risk 1:556) and 1.18% of AR (risk 1:85). No reaction to PC and CP was reported. The annual rate for 10,119 blood components (EC,PC, FFP,CP) was 0.043% of NHFTR (risk 1:2,326), and 0.032% of AR (risk 1:3,125). Our results are within the range of worldwide standards.Hemovigilancija je sustav nadzora i alarma u transfuzijskoj medicini. Prati tijek krvi i krvnih pripravaka davatelja do krajnjeg potrošača. Prikuplja i analizira neželjene doga|aje kako bi ih bilo manje u budućnosti. Potrošnja doza praćena je 5 godina (2005-2009) i bila je 6790 (1358/god): eritrokoncentrata (EK) 973;4 ± 71; trombokoncentrata (TK) 216 ± 66;93; svježe smrznute plazme (SSP)122;4 ± 59;05 i krioprecipitata (KP) 46;2 ± 26;63. Tijekom 5 godina bilo je 38 neželjenih reakcija (22 nehemolitičnih febrilnih transfuzhijskih reakcija NHFTR; 16 alergijskih reakcija AR). Prosječno godišnje 7;6 reakcija (4;4 NHFTR; 3;2 AR). Nije bilo težih reakcija i smrti. EK su izazvali 0;043% NHFTR (rizik 1:2326) i 0;015% AR (rizik 1:3125); a SSP 0;18% NHFTR (rizik 1:556) i 1;18% AR (rizik 1:85).Reakcija na TK i KP nije bilo. Na 10119 pripravaka (EK;TK;SSP;KP) godišnje bilo je 0;043% NHFTR (rizik 1:2326); te 0;032% AR (rizik 1:3125). Naši rezultati su u rangu svjetskih standarda

Hemovigilancija i poslijetransfuzijske reakcije na krvne sastojke u bolesnika sa solidnim tumorima

Hemovigilance is a system of surveillance and alarm in transfusion activities from blood donor selection to the followup of the blood component recipients, gathering and analyzing all untoward effects of blood transfusion in order to correct their cause and prevent recurrence. A 5-year surveillance (2005-2009) showed the overall consumption of 6790 unit doses (1358/year): erythroconcentrate (EC) 973.4 ± 71, platelet concentrate (PC) 216 ± 66.93, fresh frozen plasma (FFP)122.4 ± 59.05 and cryoprecipitate (CP) 46.2 ± 26.63. During the five years, there were 38 adverse events (22 non-hemolytic febrile transfusion reactions (NHFTR), 16 allergic reactions (AR), or an average annual rate of 7.6 reactions ( 4.4 NHFTR, 3.2 AR). Neither serious adverse events nor death was reported. EC caused 0.043% of NHFTR (risk 1:2,326) and 0.015% of AR (risk 1:3,125), while FFP lead to 0.18% of NHFTR (risk 1:556) and 1.18% of AR (risk 1:85). No reaction to PC and CP was reported. The annual rate for 10,119 blood components (EC,PC, FFP,CP) was 0.043% of NHFTR (risk 1:2,326), and 0.032% of AR (risk 1:3,125). Our results are within the range of worldwide standards.Hemovigilancija je sustav nadzora i alarma u transfuzijskoj medicini. Prati tijek krvi i krvnih pripravaka davatelja do krajnjeg potrošača. Prikuplja i analizira neželjene doga|aje kako bi ih bilo manje u budućnosti. Potrošnja doza praćena je 5 godina (2005-2009) i bila je 6790 (1358/god): eritrokoncentrata (EK) 973;4 ± 71; trombokoncentrata (TK) 216 ± 66;93; svježe smrznute plazme (SSP)122;4 ± 59;05 i krioprecipitata (KP) 46;2 ± 26;63. Tijekom 5 godina bilo je 38 neželjenih reakcija (22 nehemolitičnih febrilnih transfuzhijskih reakcija NHFTR; 16 alergijskih reakcija AR). Prosječno godišnje 7;6 reakcija (4;4 NHFTR; 3;2 AR). Nije bilo težih reakcija i smrti. EK su izazvali 0;043% NHFTR (rizik 1:2326) i 0;015% AR (rizik 1:3125); a SSP 0;18% NHFTR (rizik 1:556) i 1;18% AR (rizik 1:85).Reakcija na TK i KP nije bilo. Na 10119 pripravaka (EK;TK;SSP;KP) godišnje bilo je 0;043% NHFTR (rizik 1:2326); te 0;032% AR (rizik 1:3125). Naši rezultati su u rangu svjetskih standarda

Albumini u bolesnika sa solidnim tumorima

The manufacture of albumin derived from human plasma started by Professor E. J. Cohn during World War II has expanded into international business over the past sixty years (1). In vital situations, albumin was used as a plasma expander. This is a biological preparation and always potentially dangerous. The manufacture of albumin is getting more and more expensive as the preparation has to meet standards ever higher. With the market abundant in artificial macro-molecular plasma expanders, improved parenteral nutrition, and studies questioning the effectiveness of albumin use, the administration of albumin has been reduced. Because of the nature of their disease and chemoradiotherapy treatment, patients with tumors are prone to having low protein levels. However, indications for albumin therapy are restricted, the same as that in other patient groups. With the quality parenteral and enteral nutrition available, the use of albumin to correct hypoalbuminemia is not justified.Proizvodnju albumina iz ljudske plazme započeo je profesor Cohn E. J. tijekom Drugog svjetskog rata; koja je u posljednjih šezdesetak godina prerasla je u internacionalni biznis (1). U vitalnim situacijama; albumin je upotrebljavan kao plazmaekspander. To je biološki preparat i uvijek je potencijalno opasan. Proizvodnja albumina sve je skuplja; jer preparat mora zadovoljavati sve više i više standarde. Uz bogato tržište umjetnih makromolekularnih plazmaekspandera; unaprijeđene intravenske prehrane i studije koje govore o upitnom djelovanju albumina; njegova primjena je u padu. Tumorski bolesnici; zbog prirode bolesti i liječenja kemoradioterapijom; skloni su nižim razinama proteina. Međutim; indikacije albuminske terapije su restriktivne; iste kao i kod ostalih skupina bolesnika. Uporaba albumina za korekciju hipoalbuminemije nije opravdana pored kvalitetne parenteralne i enteralne prehrane

Vitamin K umjesto svježe smrznute plazme

The educational effect on the use of vitamin K and fresh frozen plasma (FFP) for the treatment of coagulation disorders in patients with solid tumors was monitored. The use of FFP was reduced and that of vitamin K increased by 39% and 137.5%, respectively, without any evidence of consequent increase in patient bleeding. The ratio of FFP and vitamin K unwanted side effects and price was 30:0 and 50:1, respectively. The rational administration of both FFP and vitamin K is more efficacious and cost-effective than the use of FFP alone.Praćen je edukacijski učinak na potrošnje vitamina K i svježe smrznute plazme (SSP) u liječenju koagulacijskih poremećaja bolesnika sa solidnim tumorima. Smanjena je potrošnja SSP za 39% i povećana potrošnja vitamina K za 137,5 %. U bolesnika zbog toga nije bilo povećanog krvarenja. Odnos neželjenih nuspojava SSP i vitamina K bio je 30:0. Cijena SSP i vitamina K bila je u omjeru 50:1. Racionalna primjena SSP i vitamina K je efikasnija i isplativija, nego sama uporaba SSP

Acetilsalicilna kiselina (ASA) i nesteroidni protuupalni lijekovi (NSAID) u prevenciji tromboze i raka

A trend towards a reduced risk of thrombosis and cancer has been observed among people taking acetylsalicylic acid (ASA) or any of nonsteroidal anti-inflammatory drugs (NSAID). ASA is the active substance in both German Aspirin and Croatian Andol. The key action of these drugs is that they block cyclooxygenase (COX) enzymes catalyzing the conversion of arachidonic acid (ADA) to prostaglandins (PG) and thromboxanes (TXA). ADA metabolites are associated with inflammatory process, thrombosis, carcinogenesis and tumor growth. Increased expression of COX-2 has been observed in both inflammations and tumors including: head and neck tumors, tumors of the upper aerodigestive tract, oropharyngeal leukoplakia, premalignant oral lesions, pancreatic, esophageal, gastric and skin cancer, melanoma, prostate, urinary bladder, lung, ovarian and cervical cancer, lymphoma, leukemia, breast cancer, colon cancer, etc. ASA and NSAID act preventively at the COX level and reduce the occurrence and growth of tumors, enhancing the radio- and chemotherapy effect on tumor. Besides at the COX level, ASA/NSAID also show antitumor activity at other levels acting as inhibitors of: aromatase gene, transforming growth factor- (TGF-), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), activator protein-1 (AP-1), serine kinase IKK-, nuclear factor kappa B (NF-B), urokinase-type plasminogen activator (PA), mitogen-activated protein p38 (p38 MAP) activation, etc. In addition, ASA/NSAIDs are efficient in other diseases including: infections, rheumatism, diabetes mellitus, blood vessel diseases, hypertension, eclampsia, Alzheimer’s disease, etc. To reduce the occurrence of cancer, the World Health Organisation promotes decreased body mass, increased physical activity and plant-based diet, which contains fewer calories, abounds in cellulose fibers, vitamins and ASA. Exceeding the recommended dose of ASA may cause serious side effects. On the other hand, 5-aminosalicylic acid (5-ASA), shown to successfully treat gastrointestinal inflammations (GIT) and reduce risk of tumor occurrence causes less adverse side effects. Nitric oxide-donating aspirin (NO-ASA) and nitric oxide donating NSAID (NO-NSAID) do not cause damage to the gastrointestinal mucosa, and they are very successful in the treatment of inflammation and prevention of intestinal and other cancers. Under medical supervision, low doses of ASA / NSAID are recommended to be taken daily for cancer prevention, then after cancer surgery and during chemotherapy and radiotherapy to reduce the risk of cancer recurrence and thrombosis.Uočen je smanjen rizik pojave tromboze i raka u ljudi koji su rabili acetilsalicilnu kiselinu (ASA) ili neke druge lijekove iz skupine nesteroidnih protuupalnih lijekova (NSAID). ASA je aktivni sastojak njemačkog Aspirina i hrvatskog Andola. Ključ djelovanja tih lijekova je blokada enzima ciklooksigenaze (COX) koji sudjeluju u razgradnji arahidonske kiseline (ADA) na prostaglandine (PG) i tromboksane (TXA). Metaboliti ADA povezani su s upalom; trombozom; karcinogenezom i rastom tumora. Pojačana ekspresija COX-2 uočena je u upalama i tumorima kao što su: tumori glave i vrata; gornjeg aerodigestivnog trakta; orofaringelane leukoplakije; premaligne oralne lezije; karcinom pankreasa; ezofagusa; želuca; raka kože; melanoma; prostate; mjehura; pluća; jajnika; vrata maternice; limfoma; leukemije; dojke; crijeva; itd. ASA i NSAID djeluju preventivno na razini COX-a i smanjuju pojavu i rast tumora; te pojačavaju učinak zračenja i kemoterapije na tumor. Osim na razini COX-a; ASA/NSAID djeluju antitumorski i na drugim razinama; kao što su inhibicije: aromatase gena; transformirajućeg faktora rasta _ (TGF-_); faktora rasta iz trombocita (PDGF); insulinu sličnog faktora rasta (IGF); aktivatora proteina-1 (AP-1); serine kinaza IKK-_; nuklearni faktor kappa B (NF-_B); urokinazni aktivator plasminogena (_PA); aktivacija mitogenom aktiviranog proteina p38 (p38 MAP); itd. Koristan je učinak ASA/NSAID i u drugim bolestima kao što su: infekcije; reuma; diabetes mellitus; krvožilne bolesti; hipertenzija; eklampsija; Alzheimerova bolest; itd. Radi smanjenja pojavnosti karcinoma Svjetska zdravstvena organizacija propagira manju tjelesnu masu; veću fizičku aktivnost i biljnu prehranu koja je manje kalorična; bogata celuloznim vlaknima; vitaminima i ASA. Zbog neželjenih nuspojava; prekoračenje dozvoljenih doza ASA može biti opasno. Manje neželjenih posljedica ima 5-aminosalicilna kiselina (5-ASA) koja uspješno liječi upale probavnog trakta (GIT) i smanjuje rizik pojave tumora. NO-ASA i NSAID (NO-NSAID); ne oštećuju sluznicu probavnog trakta. Vrlo su uspješni u liječenju upale i prevenciji raka crijeva i ostalih rakova. Uz liječničku kontrolu ASA / NSAID se preporučaju svakodnevno u malim dozama za prevenciju raka; te poslije operacije raka; u tijeku liječenja raka kemoterapijom i radioterapijom za smanjenje rizika recidiva i tromboze

Hipoksija u bolesnika sa solidnim tumorima

Anemia is the main cause of hypoxia in tumor patients. Hemoglobin (Hb) at concentration of 150 g/L, 100% saturated, carries about 200 mL O2/L blood, while Hb 75 g/L carries about 100 mL O2/L. Under normal conditions, O2 extraction ratio (O2ER) is 0.25, meaning that Hb 150 g/L releases 50 mL O2/L in tissues, and Hb 75 g/L releases 25 mL O2/L (hypoxia). In healthy persons, compensatory mechanisms may increase O2ER to the borderline value of 0.50. In tumor patients, Hb concentration should be carefully monitored as their compensatory mechanisms for O2 delivery to cells are disordered. Under anaerobic conditions (without O2), from 1 mol glucose only 5% of necessary energy is released, requiring anemia correction in tumor patients. Hypoxia promotes malignant tumor progression and reduces the sensitivity of tumor cells to radio- and chemotherapy. Despite the fact that some patients survived surgery with Hb 50 g/L, and that, for economic benefits, the aim is to lower a transfusion trigger or erythropoietin Hb < 80 g/L, the verified borderlines of Hb 100 g/L and hematocrit 0.300 are still considered to be safe. It has been known that patients with higher Hb concentration respond better to surgery, chemotherapy and radiotherapy, having a better quality of life and longer survival time.Anemija je glavni uzrok hipoksije u tumorskih bolesnika.Hemoglobin (Hb) u koncentraciji od 150 g/L, zasićen 100%, prenosi oko 200 mL O2/L krvi, dok Hb 75 g/L prenosi oko 100 mL O2/L. U normalnim uvjetima O2 ekstrakcija u tkiva (O2ER) je 0.25, što znači da Hb 150 g/L ostavlja tkivu 50 mL O2/L, a Hb 75 g/L ostavlja 25 mL O2/L - hipoksija. U zdravih osoba kompenzatornim mehanizmima O2ER se može povisiti do graničnih 0.50. U tumorskih bolesnika vrlo je važno paziti na Hb koncentraciju, jer su kompenzatorni mehanizmi dovoda O2 u stanicu poremećeni. U anaerobnim uvjetima (bez O2) iz 1 mola glukoze osloba|a se samo 5% potrebne energije, stoga je jako važna korekcija anemije u tumorskih bolesnika. Hipoksija potiče malignu progresiju tumora i smanjuje osjetljivost tumora na radiokemoterapiju. Iako su neki ljudi preživljeli operacije s Hb 50 g/L, iako se iz ekonomskih razloga „trigger“ transfuzije ili eritropoietina nastoji spustiti na Hb < 80 g/L, još uvijek se provjerenom granicom smatra Hb 100 g/L i hematokrit 0.300. Zna se da ljudi s višom koncentracjom Hb povoljnije reagiraju na operaciju, kemoterapiju i radioterapiju, da imaju bolju kvalitetu života i duže preživljenje

Hipoksija u bolesnika sa solidnim tumorima

Anemia is the main cause of hypoxia in tumor patients. Hemoglobin (Hb) at concentration of 150 g/L, 100% saturated, carries about 200 mL O2/L blood, while Hb 75 g/L carries about 100 mL O2/L. Under normal conditions, O2 extraction ratio (O2ER) is 0.25, meaning that Hb 150 g/L releases 50 mL O2/L in tissues, and Hb 75 g/L releases 25 mL O2/L (hypoxia). In healthy persons, compensatory mechanisms may increase O2ER to the borderline value of 0.50. In tumor patients, Hb concentration should be carefully monitored as their compensatory mechanisms for O2 delivery to cells are disordered. Under anaerobic conditions (without O2), from 1 mol glucose only 5% of necessary energy is released, requiring anemia correction in tumor patients. Hypoxia promotes malignant tumor progression and reduces the sensitivity of tumor cells to radio- and chemotherapy. Despite the fact that some patients survived surgery with Hb 50 g/L, and that, for economic benefits, the aim is to lower a transfusion trigger or erythropoietin Hb < 80 g/L, the verified borderlines of Hb 100 g/L and hematocrit 0.300 are still considered to be safe. It has been known that patients with higher Hb concentration respond better to surgery, chemotherapy and radiotherapy, having a better quality of life and longer survival time.Anemija je glavni uzrok hipoksije u tumorskih bolesnika.Hemoglobin (Hb) u koncentraciji od 150 g/L, zasićen 100%, prenosi oko 200 mL O2/L krvi, dok Hb 75 g/L prenosi oko 100 mL O2/L. U normalnim uvjetima O2 ekstrakcija u tkiva (O2ER) je 0.25, što znači da Hb 150 g/L ostavlja tkivu 50 mL O2/L, a Hb 75 g/L ostavlja 25 mL O2/L - hipoksija. U zdravih osoba kompenzatornim mehanizmima O2ER se može povisiti do graničnih 0.50. U tumorskih bolesnika vrlo je važno paziti na Hb koncentraciju, jer su kompenzatorni mehanizmi dovoda O2 u stanicu poremećeni. U anaerobnim uvjetima (bez O2) iz 1 mola glukoze osloba|a se samo 5% potrebne energije, stoga je jako važna korekcija anemije u tumorskih bolesnika. Hipoksija potiče malignu progresiju tumora i smanjuje osjetljivost tumora na radiokemoterapiju. Iako su neki ljudi preživljeli operacije s Hb 50 g/L, iako se iz ekonomskih razloga „trigger“ transfuzije ili eritropoietina nastoji spustiti na Hb < 80 g/L, još uvijek se provjerenom granicom smatra Hb 100 g/L i hematokrit 0.300. Zna se da ljudi s višom koncentracjom Hb povoljnije reagiraju na operaciju, kemoterapiju i radioterapiju, da imaju bolju kvalitetu života i duže preživljenje

Rezistentnost trombocita blesnika sa solidnim tumorima na anatiagregacijski učnak acetilsalicilne kiseline

The anti-aggregating effect of acetylsalicylic acid (ASA 100 mg/day and 200 mg/day) was monitored in platelets of 351 solid tumor patients. As ASA increases the aggregation time, its anti-aggregating effect plays an important role in the prevention of thrombosis. Measurements were performed using the Siemens PFA 100 aggregometer with a collagen/EPI test cartridge. The mean age of patients was 64.33 ± 11.67 years. Among them, there were 74 (21.08%) male and 277 (78.91%) female patients suffering from head and neck tumors - 34 pts (9.69% ), breast cancer - 222 pts (63.2%), lung cancer - 4 pts (1.14%), abdominal cancer - 54 pts (15.4% ), urinary - 4 pts (1.14%), and genital tract cancer - 33 pts (9.4% ). Aggregation levels >160 seconds show the ASA effect on circulating platelets. The anti-aggregating effect of ASA 100 mg/day reported in 142 (40%) pts was absent in 209 (60%) pts. The mean anti-aggregating effect of ASA 100 mg/day for male and female patients was 169.29 ± 79.54 and 168.51 ± 69.71 seconds, respectively. No statistically significant difference was found between the male and female platelet aggregation results (p = 0.759). Interindividual variability in aggregation profiles was observed with the coefficient of variation CV = 41-47%. From the group not responding to ASA 100 mg/day, 40 patients were singled out to receive ASA 200 mg/day; of them 17 (42%) were responsive, and 23 (58%) patients were not responsive. No statistically significant difference was found between the two measurements carried out on samples from the same 38 patients with a 1-month interval (p = 0.063) to show the intraindividual stability of platelet aggregation. Whereas the antiaggregating effect of both ASA 100 mg/day and 200 mg/day has been shown in only 40% patients, dose tailoring based on the individual aggregation result is recommended.Praćen je antiagregacijski učinak acetilsalicilne kiseline (ASK 100 mg/dan i 200 mg/dan) na trombocite 351 bolesnika sa solidnim tumorima. ASK produžuje vrijeme agregacije; pa je njen antiagregacijski učinak važan u prevenciji tromboze. Korišten je agregometar Siemens PFA-100 s kolagenskim/epinefrinskim uloškom. Prosječna dob bolesnika bila je 64;33 ± 11;67 godina. Muškaraca je bilo 74 (21;08%); a žena 277 (78;91%). Bolesnici su bolovali od tumora glave i vrata 34 (9;69% ); dojke 222 (63;2% ); pluća 4 (1;14%); trbuha 54 (15;4% ); mokraćnog 4 (1;14%) i spolnog sustava 33 (9;4%). Vrijednosti agregacije >160 sekundi pokazuju djelovanje ASK na trombocite. Antiagregacijski učinak ASK 100 mg/dan bio je u 142 (40%) bolesnika; a nije ga bilo u 209 (60%). Prosječni antiagregacijski učinak ASK 100mg/dan za muškarce bio je 169;29 ± 79;54 sekundi; a za žene 168;51 ± 69;71 sekundi. Statistički značajne agregacijske razlike izme|u rezultata muškaraca i žena nije bilo (p = 0;759). Interindividualna varijabilnost agregacije pokazuje koeficijent varijabilnosti CV = 41-47%. Iz skupine koja nije reagirala na ASK 100 mg/dan izdvojeno je 40 bolesnika i liječeno primjenom ASK 200 mg/dan. Reagiralo je 17 (42%); a nije 23 (58%). Nije bilo statistički značajne razlike dvaju mjerenja uzoraka 38 istih osoba; u razmaku od mjesec dana (p =0;063); što pokazuje intraindividualnu stabilnost agregacije. S obzirom na to da se samo u 40% osoba uočava antiagregacijski učinak ASK 100 mg/dan i 200 mg/dan; preporučuje se individualno doziranje oslonjeno na agregacijski nalaz