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Aims Therapeutic windows for residual platelet reactivity in patients with coronary artery disease on P2Y12 inhibitors were proposed in a consensus document. We aimed to explore the level of agreement between windows for different platelet function tests (PFTs) used to classify patients in low, optimal, and high on-treatment platelet reactivity categories, and to identify variables contributing to the level of agreement.Methods and results In this explorative clinical study, the VerifyNow P2Y12, Multiplate adenosine diphosphate (ADP), and light transmission aggregometry (LTA) 20 mu mol/L ADP were performed simultaneously in 145 consecutive vulnerable patients. Measurements were performed within 6 months of percutaneous intervention. Patients were considered vulnerable if they had >= 2 risk factors for bleeding or ischaemic events. Window-agreement between PFT pairs was slight to moderate. Multiplate-VerifyNow agreed in 72 patients (50%), kappa = 0.41; VerifyNow-LTA agreed in 76 patients (52%), kappa = 0.36; and LTA-Multiplate agreed in 64 patients (44%), kappa = 0.20. Several variables including the type of P2Y12 inhibitor, aspirin, haemoglobin level, platelet count, age, and previous stroke significantly influenced agreement between PFTs.Conclusions Our results suggest that the PFTs, with accompanying therapeutic windows, are not interchangeable when determining the response to antiplatelet therapy in vulnerable coronary artery disease patients on P2Y12 inhibitors. Hence, the type of PFT can directly affect the treatment strategy, which may be especially relevant for patients with multiple factors influencing individual PFTs and thereby test agreement.

SummaryPatients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease. Previous studies have suggested that patients with CKD have less therapeutic benefit of antiplatelet therapy. However, the relation between renal function and platelet reactivity is still under debate. On-treatment platelet reactivity was determined in parallel by ADP- and AA-induced light transmittance aggregometry (LTA) and the VerifyNow® System (P2Y12 and Aspirin) in 988 patients on dual antiplatelet therapy, undergoing elective coronary stenting. Patients were divided into two groups according to the presence or absence of moderate/severe CKD (GFRClinical Trial Registration: www.clinicaltrials.gov: NCT00352014.

To investigate the impact of genotypes on the basis of the loss-of-function variant CYP2C19*2 and the gain-of-function variant CYP2C19*17 on on-treatment platelet reactivity and on the occurrence of Thrombolysis in Myocardial Infarction (TIMI) major bleedings in 820 clopidogrel-treated patients who underwent elective coronary stenting.On-treatment platelet reactivity was quantified using ADP-induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay. Postdischarge TIMI major bleedings within 1 year after enrollment were recorded.In total, 25 major bleedings (3.0% of the study population) were observed. Patients with the CYP2C19*1/*17 and *17/*17 diplotypes exhibited a lower magnitude of platelet reactivity as compared with patients with the CYP2C19*1/*1 diplotype (for the light transmittance aggregometry-adjusted mean difference: -5.8%, 95% confidence interval: -9.6 to -2.1, P=0.002). Patients with the *1/*17 and *17/*17 genotype had a 2.7-fold increased risk in the occurrence of major bleedings [adjusted hazard ratio: 2.7, 95% confidence interval: 1.1-7.0, P=0.039]. The diplotypes *2/*17, *1/*2, and *2/*2 exhibited higher on-treatment platelet reactivity as compared with the wild type (P0.0001). However, this was not translated into an altered risk on major bleedings as compared with the wild type [hazard ratio: 1.3 (0.45-4.0), P=0.60]. Results have not been adjusted for multiple testing.Patients with the CYP2C19*1/*17 and *17/*17 diplotype have a lower magnitude of on-treatment platelet reactivity and are at a 2.7-fold increased risk of postdischarge TIMI major bleeding events after coronary stenting than patients with the *1/*1 genotype. The diplotypes *2/*17, *1/*2, and *2/*2 are associated with increased on-treatment platelet reactivity; however, this is not translated into a lower risk of bleeding events.

Summary. Background: The pathophysiology of stent thrombosis (ST) has evolved from the identification of single causative factors to a complex multifactorial model. Objectives: The aim of the present study was to investigate whether patients with a history of ST exhibit heightened platelet reactivity to clopidogrel and aspirin. Patients/methods: Pretreatment and on-treatment platelet reactivity to clopidogrel and aspirin, as well as dual antiplatelet therapy resistance, was determined in 84 patients with a history of definite ST (cases: 41 early ST; 43 late ST) and in 103 control patients with a previously implanted coronary stent but no ST after the index procedure. Platelet function was evaluated with optical aggregometry, the VerifyNow P2Y12 and aspirin assays, the PFA-100 Innovance P2Y* cartridge, the flow cytometric vasodilator-stimulated phosphoprotein assay and urine 11-dehydrothromboxane B2 measurement before and after the administration of a 600-mg loading dose of clopidogrel and 100 mg of aspirin. The study was registered at ClinicalTrials.gov, number NCT01012544. Results: Patients with a history of early ST clearly demonstrated higher on-clopidogrel platelet reactivity than controls. Patients with both early and late ST exhibited heightened on-aspirin platelet reactivity status, and dual antiplatelet therapy resistance was more frequent. Conclusions: Patients with a history of early ST exhibit a poor response to clopidogrel. Furthermore, both early and late ST are strongly and independently associated with heightened on-aspirin platelet reactivity, and dual antiplatelet therapy resistance is more frequent.

Aim High on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) are associated with atherothrombotic events following coronary stenting. There are, however, few data concerning high on-treatment platelet reactivity to both aspirin and clopidogrel simultaneously. The aim of the present study was to determine the incidence of dual high on-treatment platelet reactivity (DAPR) and its impact on clinical outcome. Methods On-treatment platelet reactivity was measured in parallel by ADP- and arachidonic acid-induced light transmittance aggregometry (LTA) (n¼921) and the point-of-care VerifyNow system (P2Y12 and aspirin) (n¼422) in patients on dual antiplatelet therapy undergoing elective stent implantation. HCPR and HAPR were established by receiver-operator characteristic curve analysis. The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and ischaemic stroke at 1-year follow-up. Results The incidence of DAPR varied between 14.7% and 26.9% depending on the platelet function test used. DAPR, assessed by LTA and the VerifyNow system, was highly associated with an adverse clinical outcome. At 1-year follow-up the primary endpoint occurred more frequently in patients with isolated HCPR (11.7%), isolated HAPR (9.6%) or DAPR (10.7%) compared with patients without high on-treatment platelet reactivity (4.2%, all p

Summary. Background: High on-aspirin platelet reactivity (HAPR) is associated with atherothrombotic events following percutaneous coronary intervention (PCI). The aim of the present study was to identify the platelet function test sensitive for platelet cyclooxygenase-1 inhibition that best predicts atherothrombotic events. Methods and results: Nine hundred and fifty-one consecutive patients on dual antiplatelet therapy undergoing elective PCI were enrolled. On-aspirin platelet reactivity was measured in parallel by arachidonic acid (AA)-induced light transmittance aggregometry (AA-induced LTA), the VerifyNow® Aspirin Assay (VerifyNow® Aspirin Assay), the arachidonic acid prestimulated IMPACT-R (IMPACT-R AA) and the PFA-100 collagen/epinephrine cartridge (PFA COL/EPI). Cut-offs for HAPR were established by receiver-operator characteristic curve analysis. At 1-year follow-up, the composite of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and ischemic stroke occurred more frequently in patients with HAPR when assessed by LTA [10.1% vs. 6.0%, P = 0.020 (n = 925)] and VerifyNow® [13.3% vs. 5.9%, P = 0.015 (n = 422)]. The VerifyNow® ASA assay (AUC = 0.78) and, to a lesser extent, AA-induced LTA (AUC = 0.73) added significantly to a model consisting of clinical and procedural risk factors in predicting atherothrombotic events. In contrast, the IMPACT-R (n = 791) and the PFA Collagen/Epinephrine (n = 719) were unable to discriminate between patients with and without primary endpoint at 1-year follow-up. None of the platelet function tests was able to identify patients at risk for bleeding. Conclusions: AA-induced LTA and the VerifyNow® ASA test were able to identify aspirin-treated patients undergoing PCI with stenting at risk for atherothrombotic events. The VerifyNow® Aspirin Assay had the highest predictive accuracy. None of the tests was able to identify patients at higher risk of bleeding.

The prodrug, clopidogrel, plays an important role in the prevention of thrombotic events in patients undergoing coronary stenting. However, a substantial number of atherothrombotic events still occur, which can partially be explained by heightened residual platelet reactivity. Several studies report that the genetic variation in CYP2C19 (*2) is associated with an impaired response to clopidogrel.To evaluate the effect of genetic variants affecting clopidogrel's absorption (ABCB1 C1236T, G2677T/A, C3435T), metabolism (CYP2C9*2, *3, CYP2C19*3, CYP3A4*1B, and CYP3A5*3), and pharmacodynamics (P2Y1 A1622G) on top of the influence of CYP2C19*2 on platelet reactivity in patients undergoing elective coronary stenting on dual antiplatelet therapy.Platelet function was assessed by light transmittance aggregometry and VerifyNow P2Y12 assay in 428 consecutive patients. Patients were either on chronic clopidogrel maintenance therapy (75 mg/day foror =5 days before the intervention) or received a 300 mg clopidogrel loading dose (1-5 days before the intervention, followed by 75 mg/day). Linear and logistic regressions were used to assess the associations between genetic variants and platelet reactivity and poor responder status.In both the treatment groups, CYP2C19*2-carriage was associated with higher platelet reactivity (P0.002) and poor responder status; 75 mg group: adjusted odds ratio (ORadj): 3.8, 95% confidence interval (CI): 2.0-7.2, 300 mg group: ORadj: 4.1, 95% CI: 1.6-10.4. In the 300 mg group, CYP2C9*3-carriage was associated with higher platelet reactivity (P0.05) and poor responder status (ORadj: 11.1, 95% CI: 1.6-78.8, P=0.016).Besides CYP2C19*2, the variant allele CYP2C9*3 plays an important role in the response to clopidogrel in patients on dual antiplatelet therapy undergoing coronary stenting.

Background An inadequate response to clopidogrel is mainly attributable to the variable formation of its active metabolite. The CYP2C19*2 loss-of-function polymorphism leads to reduced generation of the active metabolite and is, similarly to high on-treatment platelet reactivity (HPR), associated with recurrent atherothrombotic events following coronary stent implantation. Aim To determine the relative contribution of CYP2C19*2 genotype to HPR. Methods and results CYP2C19*2 genotyping and platelet function testing using 5 and 20 μmol/l ADP-induced light transmittance aggregometry (LTA), the PlateletWorks assay and the VerifyNow P2Y12 assay, were performed in 1069 clopidogrel pretreated patients undergoing elective coronary stenting (POPular study, http://clinicalTrials.gov/NCT00352014). The relative contributions of CYP2C19*2 genotype and clinical variables to the interindividual variability of on-treatment platelet reactivity and the occurrence of HPR were established using multivariate regression models. CYP2C19*2 carrier status was associated with a more frequent occurrence of HPR. CYP2C19*2 genotype alone could explain 5.0%, 6.2%, 4.4% and 3.7% of the variability in 5 and 20 μmol/l ADP-induced LTA, the PlateletWorks assay and the VerifyNow P2Y12 assay, respectively, which increased to 13.0%, 15.2%, 5.6% and 20.6% when clinical variables were considered as well. Besides the CYP2C19*2 genotype, multiple clinical variables could be identified as independent predictors of HPR, including age, gender, body mass index, diabetes mellitus, clopidogrel loading dose regimen, use of amlodipine and platelet count. Conclusion The CYP2C19*2 loss-of-function polymorphism is associated with a more frequent occurrence of HPR. However, the part of the interindividual variability in on-treatment platelet reactivity explained by CYP2C19*2 genotype is modest.

The relevance of P2Y12-receptor gene variation for the outcome of clopidogrel-treated patients undergoing elective coronary stent implantation: A clinical follow-up

Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite1,2. The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors, but the specific genes and mechanisms underlying clopidogrel bioactivation remain unclear. Using in vitro metabolomic profiling techniques, we identified paraoxonase-1 (PON1) as the crucial enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite formation. We tested the clinical relevance of the PON1 Q192R genotype in a population of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy. PON1 QQ192 homozygous individuals showed a considerably higher risk than RR192 homozygous individuals of stent thrombosis, lower PON1 plasma activity, lower plasma concentrations of active metabolite and lower platelet inhibition. Thus, we identified PON1 as a key factor for the bioactivation and clinical activity of clopidogrel. These findings have therapeutic implications and may be exploited to prospectively assess the clinical efficacy of clopidogrel.

Aims Despite treatment with clopidogrel on top of aspirin, stent thrombosis (ST) still occurs being the most serious complication after percutaneous coronary interventions (PCIs). In this study, we aimed to determine the effect of variations in genes involved in the absorption (ABCB1 C1236T, G2677T/A, C3435T), metabolism (CYP2C19*2 and *3, CYP2C9*2 and *3, CYP3A4*1B and CYP3A5*3), and pharmacodynamics (P2Y1 A1622G) of clopidogrel on the occurrence of ST. Methods and results The selected genetic variants were assessed in 176 subjects who developed ST while on dual antiplatelet therapy with aspirin and clopidogrel and in 420 control subjects who did not develop adverse cardiovascular events, including ST, within 1 year after stenting. The timing of the definite ST was acute in 66, subacute in 87, and late in 23 cases. The presence of the CYP2C19*2 and CYP2C9*3 variant alleles was significantly associated with ST (ORadj: 1.7, 95% CI: 1.0–2.6, P = 0.018 and ORadj: 2.4, 95% CI: 1.0–5.5, P = 0.043, respectively). The influence of CYP2C19*2 (ORadj: 2.5, 95% CI: 1.1–5.5, P = 0.026) and CYP2C9*3 (ORadj: 3.3, 95% CI: 1.1–9.9, P = 0.031) was most strongly associated with subacute ST. No significant associations of the other genetic variations and the occurrence of ST were found. Conclusion Carriage of the loss-of-function alleles CYP2C19*2 and CYP2C9*3 increases the risk on ST after PCI.

SummaryBoth heightened platelet reactivity and an occluded infarct related artery (IRA) on initial angiography and at the time of primary percutaneous coronary intervention (PCI) are associated with a worsened clinical outcome in patients with ST-elevation myocardial infarction (STEMI). However, the relationship between platelet reactivity and IRA patency has not yet been established. Consecutive STEMI-patients were enrolled in this study. Patients who had TIMI-flow (thrombolysis in myocardial infarction) 0 or 1 on initial angiography constituted the occluded IRA group and patients having TIMI-flow 2 or 3 comprised the IRA patent group. Platelet function measurements were performed using the PFA-100 COL/ADP cartridge and light transmittance aggregometry without agonist (spontaneous) and after stimulation with adenosine diphosphate (ADP) and arachidonic acid (AA). Ninety-nine patients were enrolled, of whom 49 presented with an occluded IRA. Multivariate analysis identified the following independent factors to be associated with an occluded IRA; short COL/ADP closure time (ORper quartile increase= 0.60; 95% CI, 0.39-.93; p=0.02), the 20 μM ADP-induced light transmittance aggregometry (ORper quartile increase =1.77; 95% CI, 1.15–l2.73; p=0.01) and leukocyte counts (odds ratio [OR]=1.21; 95% CI, 1.05–1.39; p = 0.008). In conclusion, heightened platelet reactivity and elevated leukocyte counts are associated with an occluded IRA upon presentation in STEMI-patients. These results emphasise the importance of potent antithrombotic therapy early after the onset of symptoms, to obtain early recanalisation of the IRA.

BackgroundInadequate platelet inhibition despite aspirin and clopidogrel therapy during and after a percutaneous coronary intervention is associated with an impaired clinical outcome. Cangrelor, a direct and reversible P2Y12 inhibitor that is currently in development, has the potential to achieve higher levels of inhibition of ADP-induced platelet aggregation than clopidogrel. The aim of the present study was to compare the magnitude of platelet inhibition in clopidogrel-pretreated patients before and after the in vitro addition of a subtherapeutic dose of cangrelor. MethodsBlood samples were drawn from patients pretreated with clopidogrel and aspirin who were undergoing elective percutaneous coronary intervention (n=39). Platelet function analysis with ‘classical’ light transmittance aggregometry (both peak and late aggregation [at 6 min]) was performed before and after the in vitro addition of cangrelor (0.25 μmol/l) to platelet-rich plasma (PRP). After an incubation period of five minutes, platelet aggregation was induced by 5 and 20 μmol/l ADP. ResultsThe in vitro addition of 0.25μmol/l cangrelor to the PRP from clopidogrel-treated subjects resulted in an additional reduction in ADP-induced platelet aggregation. For ADP concentrations of 5 and 20 μmol/l, peak aggregation showed a decrease of 75 and 85%, respectively (p

Multiple studies have demonstrated the effectiveness of dual or triple antiplatelet therapy with aspirin, clopidogrel and glycoprotein (GP) IIb/IIIa therapy in patients with acute coronary syndromes as well as in patients undergoing coronary stent implantation. In the last few years, it is becoming clear that not all patients receive the full benefits with the current standard dosages of antiplatelet therapy. Specifically, numerous studies have revealed a wide interindividual variability in the response to these antiplatelet agents and, more importantly, both nonresponsiveness as well as a heightened residual platelet reactivity have been linked to the occurrence of adverse cardiovascular events. Therefore, assays that identify those patients with an impaired responsiveness or a heightened platelet reactivity despite dual antiplatelet therapy may contribute to better risk stratification and will probably improve clinical outcome when appropriate action is initiated. Likewise, a considerable number of patients do not achieve the minimal inhibition of aggregation threshold with the current recommended weight-adjusted dosages of GP IIb/IIIa therapy. Identifying and optimizing the absolute degree of platelet inhibition in this subgroup of patients will probably improve clinical outcome. The VerifyNow platform is one of the most user friendly point-of-care platelet function test systems because it produces rapid results at the patient bedside. The purpose of the present paper is to give insight into the principal mechanisms of the VerifyNow system, to discuss its clinical utility for the monitoring of antiplatelet therapy and to discuss the proposed cut-off levels to segregate responders from non-responders for the different types of antiplatelet therapy.

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Context High on-treatment platelet reactivity is associated with atherothrombotic events following coronary stent implantation. Objective To evaluate the capability of multiple platelet function tests to predict clinical outcome. Design, Setting, and Patients Prospective, observational, single-center cohort study of 1069 consecutive patients taking clopidogrel undergoing elective coronary stent implantation between December 2005 and December 2007. On-treatment platelet reactivity was measured in parallel by light transmittance aggregometry, Verify Now P2Y12 and Platelet works assays, and the IMPACT-R and the platelet function analysis system (PFA-100) (with the Dade PFA collagen/adenosine diphosphate (ADP) cartridge and Innovance PFA P2Y). Cutoff values for high on-treatment platelet reactivity were established by receiver operating characteristic curve (ROC) analysis. Main Outcome Measurement The primary end point was defined as a composite of all-cause death, nonfatal acute myocardial infarction, stent thrombosis, and ischemic stroke. The primary safety end point included TIMI (Thrombolysis In Myocardial Infarction) criteria major and minor bleeding. Results Kaplan-Meier analysis demonstrated that at 1-year follow-up, the primary end point occurred more frequently in patients with high on-treatment platelet reactivity when assessed by light transmittance aggregometry (52 [11.7%; 95% confidence interval {CI}, 8.9%-15.0%] vs 36 [6.0%;95%CI, 4.2%-8.2%] P.001; n=1049),Verify Now (54 [13.3%; 95% CI, 10.2%-17.0%] vs 37 [5.7%; 95% CI, 4.1%-7.8%]P.001; n=1052), Platelet works (33 [12.6%; 95% CI, 8.8%-17.2%] vs 21 [6.1%;95% CI, 3.8%-9.2%] P=.005; n=606), and Innovance PFA P2Y (18 [12.2%; 95%CI; 7.4%-18.6%] vs 28 [6.3%; 95% CI, 4.3%-8.9%] P=.02; n=588). ROC-curve analysis demonstrated that light transmittance aggregometry (area under the curve[AUC], 0.63; 95% CI, 0.58-0.68), Verify Now (AUC, 0.62; 95% CI, 0.57-0.67), and Platelet works (AUC, 0.61; 95% CI, 0.53-0.69) had modest ability to discriminate between patients with and without primary end point at 1-year follow-up. The IMPACT-R(n=905) and the Siemens PFA Collagen/ADP (n=812) were unable to discriminate between patients with and without the primary end point at 1-year follow-up (all AUCs included 0.50 in the CI). None of the tests identified patients at risk for bleeding. Conclusions Of the platelet function tests assessed, light transmittance aggregometry,Verify Now, Platelet works, and Innovance PFA P2Y were significantly associated with the primary end point. However, the predictive accuracy of these 4 tests was only modest. None of the tests provided accurate prognostic information to identify patients at higher risk of bleeding following stent implantation. Trial Registration clinical trials.gov Identifier: NCT00352014 [corrected].

1. (1) A procedure for isolating pure ubiquinone-50 form horse heart is described. 2. (2) A method of determining the ubiquinone content of heart and heart-muscle preparation is give. 3. (3) Treatment of ubiquinone with ascorbic in HCl in the presence of pyrogallol gives a reduction product,in about 30% yield, whihc is not the smae as ubiquinol. Its properties suggest that is is ubichromanoll or derivative thereof. 4. (4) This product is not distinguishable from α-tocopherol by the procedure previously used for measuring the α-tocopherol content of heart-muscle preparationa nd is responsible for the “extra α-tocopherol” previoulsly reported therein. 5. (5) Vitamin K 1 treated under similar conditions also gives a stable reduction product which is also probably a chromanol. 6. (6) Our previous reporat that the Keilin and Hartree heart-muscle preparation contained α-tocopherol has been confiremd. The tocopherol was identified by chromatography on ZnCO 3 -impregnated paper and on alumina ( 14 C-labelled α-tocopherol acting as a marker), by its u.v.-absorption spectrum and by the absorption spectrum characteristic of α-tocopherylquinone obtained by oxidation with AuCl 3 . 7. (7) The Keilin and Hartree heart-muscle preparatino from horse containes on the average 0.4 μmole α-tocopherol/g protein (9 preparations) and 9.1 μmoles ubiquinone/g protein (9 preparations). For ox, the values are 0.8 (3 preparations) adn 2.9 (one determination) respectively. Little if any α-tocopherylquinone (less than μmole/g protein) was found in the ox preparation. 8. (8) Virtually all the α-tocopherol and ubiquinone found in the heart is located in the sarcosomes (mitochondria). 9. (9) α-Tocopherol is not a precursor in the biosyngthesis of ubiquinone in rabbit heart or liver. 10. (10) α-Tocopherol, α-tocopherylquinol adn ubiquinol inhibit the ATP-P 1 exchange reaction fo rat-liver mitochondria and stimulate the ATPase.

A method for the determination of insulin potency using circular chromatography is described. The eluted spots are measured with respect to a standard which is run simultaneously with the unknown. The results of this determination do not differ significantly from those obtained by biological assay, at least for preparations with a potency higher than 19 I.U./mg on a moisture-free basis. For the determination of less pure samples the use of a standard insulin of corresponding purity is recommended. The precision of the method compares with that of a biological assay with 250 rabbits. Protamine and excess of zinc do not interfere with the determination.

The effect of combination chemotherapy (bleomycin, actinomycin D, vindesine and DTIC) on taste sensation in patients with malignant melanoma was evaluated. Five concentrations of 4 basic tastes (sweet, bitter, sour and salt) were tested. Lowest concentrations of all tastes were subjectively rated more intense after chemotherapy than before. This change was significant for sweet, sour and salt. The highest concentration of sweet was rated significantly less intense following chemotherapy. The discrimination between highest and lowest concentration was diminished for sweet, sour and bitter and marginally for salt. The changes in taste sensation following chemotherapy could attribute to anorexia in cancer patients treated with cytostatic agents.

THE possible role of vitamin E in respiratory enzyme systems has often been suggested; but supporting evidence of the actual presence of vitamin E in active enzyme preparations has not been published. We have now found appreciable amounts in heart sarcosomal (mitochondrial) fragments (Keilin and Hartree heart-muscle preparation).

Before, during, and after 19 courses of chemotherapy given to patients with disseminated malignant melanoma plasma spermidine levels were determined with a radioimmunoassay. Baseline values were normal in 17 courses, a doubling of plasma levels following chemotherapy occurred in 13 courses. There was no relation between the occurrence of a tumor response and an increase in spermidine levels nor between hematological toxicity or digestive tract toxicity and spermidine levels.