Impact of the COVID-19 pandemic on hospitalizations for acute coronary syndromes: a multinational study.

BACKGROUND: COVID-19 has challenged the health system organization requiring a fast reorganization of diagnostic/therapeutic pathways for patients affected by time-dependent diseases such as acute coronary syndromes (ACS). AIM: To describe ACS hospitalizations, management, and complication rate before and after the COVID-19 pandemic was declared. DESIGN: Ecological retrospective study. Methods: We analyzed aggregated epidemiological data of all patients > 18 years old admitted for ACS in twenty-nine hub cardiac centers from 17 Countries across 4 continents, from December 1st, 2019 to April 15th, 2020. Data from December 2018 to April 2019 were used as historical period. RESULTS: A significant overall trend for reduction in the weekly number of ACS hospitalizations was observed (20.2%; 95% confidence interval CI [1.6, 35.4] P = 0.04). The incidence rate reached a 54% reduction during the second week of April (incidence rate ratio: 0.46, 95% CI [0.36, 0.58]) and was also significant when compared to the same months in 2019 (March and April, respectively IRR: 0.56, 95%CI [0.48, 0.67]; IRR: 0.43, 95%CI [0.32, 0.58] p < 0.001). A significant increase in door-to-balloon, door-to-needle, and total ischemic time (p <0.04 for all) in STEMI patents were reported during pandemic period. Finally, the proportion of patients with mechanical complications was higher (1.98% vs. 0.98%; P = 0.006) whereas GRACE risk score was not different. CONCLUSIONS: Our results confirm that COVID-19 pandemic was associated with a significant decrease in ACS hospitalizations rate, an increase in total ischemic time and a higher rate of mechanical complications on a international scale.

Effects of amifostine in a patient with an advanced-stage myelodysplastic syndrome.

We report on a 63-year-old man with myelodysplastic syndrome at the stage of a refractory anemia with an excess of blasts in transformation (MDS-RAEB-T), first diagnosed in December 1996. After a period of stability, with no need for transfusions, the MDS progressed into acute myeloid leukemia (AML) in August 1998 with the emergence of a cytogenetic abnormality (11q-). Two courses of chemotherapy were given, resulting in prolonged pancytopenia; however, no clearance of bone marrow (BM) blasts was achieved. At that time, severe infections and daily epistaxis occurred. Frequent transfusions of packed red blood cells (RBC) and platelets (2-3/week) were necessary. After 2 months of persisting severe pancytopenia, we started a therapy with amifostine: 4 x 250 mg intravenously (i.v.) weekly for 1 month, followed by a maintenance therapy with 500 mg once weekly. After 2 weeks of amifostine therapy, hematopoiesis began to improve. In the subsequent 2 months, the patient became completely independent of the platelet transfusions; the transfusion frequency of RBC was permanently reduced (2 RBC transfusions/month) and a significant decrease of BM blasts was achieved. After 30 weeks of amifostine therapy, the morphology of the MDS switched to a chronic myelomonocytic leukemia (CMML)-like appearance, with continuously increasing leukocytes, so that we discontinued amifostine therapy for 1 month to exclude a possible side effect of amifostine. At that time, leukocytes further increased to 74,000/microl; thus, we decided to perform a cytoreductive chemotherapy (hydroxycarbamide) and continued weekly amifostine infusions. During 1 year of amifostine therapy, the patient had a good quality of life, with no need for hospitalization and a complete cytogenetic remission. We conclude that, in this case, amifostine had two effects: a significant improvement of impaired hematopoiesis and a slowing down of disease progression. Thus, amifostine might be a therapeutic option in older patients with advanced MDS.

Carboplatin pharmacokinetics in patients receiving carboplatin and paclitaxel/docetaxel for advanced lung cancers: impact of age and renal function on area under the curve.

PURPOSE: To further define the most appropriate way of choosing the dose of carboplatin. PATIENTS AND METHODS: The pharmacokinetics of carboplatin were analyzed in 30 patients with advanced lung cancer receiving a total of 48 cycles of carboplatin plus paclitaxel/ docetaxel combination chemotherapy. Platin concentrations of ultrafiltrated plasma and urine samples were determined by flameless atomic absorption spectrometry. A multiple regression analysis was performed for interactions between pharmacokinetic parameters and pretreatment characteristics. RESULTS: Using a twocompartment-model, the following parameters were obtained (mean, coefficient of variation): initial half-life, 0.903 h (48%); terminal half-life, 13.6 h (116%); maximum plasma concentration (Cmax), 38.5 microM (86%); AUC, 111.9 microM/h (86%); volume of distribution, 411 l (130%); total clearance (Ct), 579 ml/min (75%); renal clearance (Cr), 453 ml/min (80%); renal elimination, 76% of dose (17%). In the univariate analysis, age was significantly related to Cmax (P = 0.0303), AUC (P = 0.0050), Ct (P = 0.0020), Cr (P = 0.0092). Plasma creatinine (Crp) was related to Cmax (P = 0.0228), and 1/[Crp] was related to Cmax (P = 0.0015) and AUC (P = 0.0054), while body weight was related to Cmax (P = 0.0365). No interaction with the schedule of application of the two drugs was observed. In the multivariate analysis, factors significantly related to AUC were 1/[Crp] (P < 0.01) and age (P < 0.01). Crp (P < 0.05) and 1/[Crp] (P < 0.01) were significantly associated with Cmax. CONCLUSIONS: These data stress the importance of dosing carboplatin according to renal function and age and warrant further analyses to validate this concept prospectively.

Microalbuminuria during cisplatin therapy: relation with pharmacokinetics and implications for nephroprotection.

BACKGROUND: To assess the relation of cisplatin-induced nephrotoxicity to its pharmacology. PATIENTS AND METHODS: In 22 chemonaive patients (median age, 32 years) receiving 100-150 mg/m2 cisplatin for a total of 54 courses of therapy pharmacokinetics of ultra-filtrable platin were analyzed. Nephrotoxicity was sensitively assessed by nephelometric analyses of urinary marker-proteins. RESULTS: The parameters calculated for ultrafiltrable platin were (two-compartment-model): terminal half-life, 36 hours (coefficient of variation [CV], 22%); AUC, 12852 ng h/ml (33%); volume of distribution, 3531 (44%); total clearance, 285 ml/min (30%); renal clearance, 149 ml/min (23%); maximum concentration, 1720 ng/ml (66%); renal elimination, 57% of applied dose (26%). A pathological urinary excretion of albumin > 20 mg/l and alpha-1-microglobulin > 10 mg/l was detected in 39 out of 54 and 42 out of 54 cycles, respectively. The degree of albuminuria was related with urinary monoaquoplatin concentrations (p = 0.003). CONCLUSION: Nephrotoxicity of cisplatin appears to depend on the urinary monoaquoplatin concentrations which may be modulated by application of saline.

Oxaliplatin pharmacokinetics during a four-hour infusion.

A new platin compound, oxaliplatin, has significant activity in advanced colorectal carcinomas. However, its pharmacokinetics have not been characterized adequately yet. This study extensively analyzes the pharmacokinetics of both ultrafiltrable (free) and protein-bound platin in 13 patients receiving 130 mg/m2 oxaliplatin as a 4-h infusion in combination with 375 mg/m2 5-fluorouracil as a 24-h infusion for advanced colorectal carcinomas. The interpatient variability was very low for all parameters analyzed. The levels of free platin decreased triphasically, with a mean terminal half-life of 27.3+/-10.6 h. The area under the time-concentration curve was 20.17+/-6.97 microg.h/ml and the total and renal clearances amounted to 222+/-65 and 121+/-56 ml/min, respectively. The values for the volume of distribution and for the maximum concentration at the end of infusion were 349+/-132 liters and 1612+/-553 ng/ml, respectively. On the basis of the simulation of the plasma levels and the urinary excretion of platin following the long-term administration of oxaliplatin as a constant-rate and a chronomodulated infusion, additional analyses are warranted to fully characterize the pharmacokinetics of the drug in these settings.

[Brief interdisciplinary oncology: a model for ambulatory, multimodal treatment of tumor patients]. / Interdisziplinäre Kurzzeit-Onkologie (IKO): Ein Modell zur ambulanten, multimodalen Behandlung von Tumorpatienten.

Since 10/1994 the Interdisziplinäre Kurzzeit-Onkologie (IKO) is an outpatient department for the treatment of patients with cancer used by the departments of hematology/oncology and surgery. Between 09/1995 and 02/1997, 818 patients received 2024 cytotoxic therapies with neoadjuvant (15%), adjuvant (65%) or palliative (20%) intention-mostly within multicenter clinical studies. Ambulatory operations like removal of lymph nodes for diagnosis or the implantation of venous catheter systems prepared the way for specialized modalities of cancer therapy. The high compliance and consent of patients, combined with better understanding of cancer therapy, resulted in an enhanced quality of life and optimized therapy. Standardization in diagnostics and fast realisation of interdisciplinary treatment schedules lead to reduction of costs and to enhancement of quality and security in cancer therapy.

Oral idarubicin pharmacokinetics--correlation of trough level with idarubicin area under curve.

Idarubicin is the first anthracycline that can be successfully administered via the oral route and thus may facilitate antineoplastic chemotherapy in an improved quality of life. These perspectives are somewhat hampered by the large variation in bioavailability between individual patients and the obvious requirement to monitor plasma concentration and area-under-the-curve values (AUC) for an appropriate adjustment of idarubicin dose. In this study we describe the pharmacokinetics of idarubicin and its main metabolite idarubicinol in 12 patients after oral application of 20 mg/m2 idarubicin on 3 consecutive days and demonstrate that the 24 h trough levels show a high correlation with AUC and may thus allow a rapid and easy determination of individual drug concentrations and an appropriate dose adjustment. The average terminal half-life was 30.5 h for idarubicin and 66.9 h for idarubicinol. The AUC for idarubicin and its main metabolite idarubicinol revealed a substantial interpatient variation with AUC values ranging from 25.7 to 114 ng x h/ml (average 58.1 ng x h/ml) for idarubicin and from 109.4-445.2 ng x h/ml (average 287.3 ng x h/ml) for idarubicinol. However, the ratio of idarubicin/idarubicinol differed only two folds from 1:3.7 to 1:7.7 with an average of 1:5.1. Both idarubicin and idarubicinol concentrations were highly reproducible, however, upon measurements after repeated applications within individual patients. Moreover, idarubicinol and idarubicin AUCs showed a good correlation with r = 0.78, indicating that the interindividual variation of idarubicin AUC reflects differences in absorption rather than in metabolism. In order to describe the interindividual bioavailability of idarubicin - represented by the respective AUC - measurement of a single data point with a high correlation with the AUC would be ideal. Our study demonstrates that the 24 h trough level shows such an excellent correlation (r = 0.96) with AUC, making it the perfect candidate for fast estimates of the individual bioavailability in a given patient. On this basis, the longitudinal measurement of the 24 h trough level may allow assessment of the impact of interindividual variations in AUC on clinical outcome and toxicity.

Response to cytarabine ocfosfate (YNK01) in a patient with chronic lymphocytic leukemia refractory to treatment with chlorambucil/prednisone, fludarabine, and prednimustine/mitoxantrone.

Cytarabine ocfosfate (YNK01) is a novel orally applicable prodrug of cytosine arabinoside. Recent pharmacokinetic studies have revealed a prolonged release of the cytotoxic agent cytosine arabinoside (araC) from hepatocytes into the systemic circulation, resulting in a half-life of approximately 24 h for araC. The specific pharmacokinetic characteristics of cytarabine ocfosfate lead to a prolonged exposure of leukemic cells to this antineoplasstic agent during the 14-day cycle. the oral applicability during outpatient treatment and the sustained antineoplastic activity of araC against slowly proliferating leukemic B-cells suggest that cytarabine ocfosfate might be a useful drug in the treatment of chronic lymphocytic leukemia. Four years after diagnosis of B-CLL, a 50-year-old patient was started on cytarabine ocfosfate. Sequentially, the patient's disease had proved refractory to treatment with chlorambucil/prednisone (31 months), fludarabine (5 months), and prednimustine/mitoxantrone (3 months). These established regimens were discontinued because of increasing lymphocytosis, significant thrombocytopenia, and progressive B-symptoms. Following three cycles of cytarabine ocfosfate B-symptoms resolved, lymphadenopathy disappeared, and thrombocytopenia was significantly reduced. The patient has been free of these symptoms on a dosage of 1500 mg cytarabine ocfosfate/day (cycle of 14 days with intervals of 14-21 days) for 24 months and remains in an ongoing partial remission.

Oral idarubicin pharmacokinetics--correlation of trough level with idarubicin area under curve.

Idarubicin is the first anthracycline that can be successfully administered via the oral route and thus may facilitate antineoplastic chemotherapy at an improved quality of life. These perspectives are somewhat hampered by the large variation in bioavailability between individual patients and the obvious requirement to monitor plasma concentration and area-under the curve values (AUC) for an appropriate adjustment of idarubicin dose. In this study we describe the pharmacokinetics of idarubicin and its main metabolite idarubicin in 12 patients after oral application of 20 mg/m2 idarubicin on 3 consecutive days and demonstrate that the 24-h trough levels shows high correlation with AUC and may thus allow a rapid and easy determination of individual drug concentrations and an appropriate dose adjustment. The average terminal half-life was 30.5h for idarubicin and 66.9 h for idarubicinol. The AUC for idarubicin and its main metabolite idarubicinol revealed a substantial interpatient variation with AUC values ranging from 25.7 to 114 ng x h/ml (average 58.1 ng x h/ml) for idarubicin and from 109.4 - 445.2 ng x h/ml (average 287.3 ng x h/ml) for idarubicinol. However, the ratio of idarubicin/idarubicinol differed only two-fold from 1:3.7 to 1:7.7 with an average of 1:5.1. Both idarubicin and idarubicinol concentrations were highly reproducible, however, upon measurements after repeated applications within individual patients. Moreover, idarubicinol and idarubicin AUCs showed a good correlation with r=0.78, indicating that the interindividual variations of idarubicin AUC reflects differences in absorptions rather than metabolism. In order to describe the interindividual bioavailability of idarubicin - represented by AUC - measurement of a single data point with a high correlation with the AUC would be ideal. Our study demonstrates that the 24-h trough level shows such an excellent correlation (r=0.96) with AUC, making it the perfect candidate for fast estimates of the individual bioavailability in a given patient. On this basis, the longitudinal measurement of the 24-h trough level may allow the assessment of the impact of interindividual variations in AUC of clinical outcome and toxicity.

Detection and determination of the major metabolites of [3H]cytosine arabinoside by high-performance liquid chromatography.

An ion-pair high-performance liquid chromatographic assay involving solid-phase scintillation detection was established for the rapid identification and determination of all major metabolites of tritium-labelled cytosine arabinoside (Ara-C) in an in vitro system. In a single run of 50 min, Ara-C, Ara-CMP, Ara-CDP-choline, Ara-CDP, Ara-U, Ara-UMP, Ara-CTP, Ara-UDP and Ara-UTP can be measured. The method is fast, sensitive, with limits of detection ranging from 40 to 200 pg (absolute), and highly reproducible.

Highly sensitive high-performance liquid chromatographic assay for 1-beta-D-arabinofuranosylcytosine-5'-stearyl phosphate (cytarabine-ocfosfate).

An ion-pair HPLC method for the determination of 1-beta-D-arabinofuranosylcytosine-5'-stearyl phosphate (cytarabine-ocfosfate I) was developed, using a phenyl-bonded column under reversed-phase conditions with a mobile phase of acetonitrile-buffered water (pH 6.8) (50:50) for isocratic elution. A reproducible sample clean-up was achieved by solid-phase extraction. In order to reach the low limit of detection of 2 ng/ml, an enrichment switching system was used. The present validation leads to a limit of quantification of 5 ng/ml with a coefficient of variation (C.V.) of 10%. The total time of measurement was shortened by a back-flush procedure to restore the conditions after each run. UV detection at 275 nm was applied. The recoveries for plasma samples ranged from 56.4 to 64.1%, regardless of drug concentrations. The intra-assay C.V. was about 4% (40 measurements at four different concentrations). The inter-assay recovery (ten measurements over ten days) at a plasma concentration of 50 ng/ml was 57% with a C.V. of 8.25%. Based on this HPLC method, the pharmacokinetics of I were measured during a clinical phase I/II study.

Albuminuria in HIV-infected patients.

Albumin excretion, Analysis of urinary proteins by polyacrylamide gel electrophoresis (PAGE), and clinical evaluation were performed in 90 HIV-infected patients to assess subclinical renal involvement in HIV infection. Thirteen percent of all patients showed an albumin excretion > 20 mg/liter. Seven of four homosexual patients had albuminuria. Albuminuria occurred exclusively with T4 cell counts below 200/mm3. Polyacrylamide gel electrophoresis indicated glomerular lesions and showed no tubular proteinuria in patients with increased albumin excretion. It is concluded that subclinical renal involvement is not uncommon in HIV infection with T4 cell counts > 200/mm3. HIV-associated nephropathy and heroin-associated nephropathy may not be the main causes of renal involvement. In some cases, opportunistic viral infections may be the cause of microalbuminuria.

New aspects on the pharmacokinetics of mitoxantrone and its two major metabolites.

In spite of its broad clinical application in the treatment of malignant disorders, the pharmacokinetics of mitoxantrone are still not fully understood and warrant further investigation. Information is also limited about interindividual differences in the plasma AUC infinity (area-under-the-curve concentration to time infinity) and renal elimination of mitoxantrone and its main metabolites, mono- and dicarboxylic acid. In the present study, the plasma concentration of mitoxantrone was measured by HPLC during 120 h after the end of a 30-min infusion of 10 mg/m2 in 18 patients undergoing combination therapy with mitoxantrone and high-dose cytosine arabinoside for acute myeloid leukemia. Plasma kinetics and renal elimination of mono- and dicarboxylic acid were analyzed in addition in eight of these patients, and in five cases with chronic lymphocytic leukemia receiving a 30-min infusion of 5 mg/m2 mitoxantrone weekly for 3 consecutive weeks. Fitting the results to a three compartment model, a substantial interindividual variation was observed for plasma and urine pharmacokinetics. Plasma AUC infinity for mitoxantrone differed approximately 13-fold between individual patients and varied between 80-1030 ngh/ml. The corresponding values for mono- and dicarboxylic acid ranged from 23-147 ngh/ml and 51-471 ngh/ml, respectively. The median terminal half-life for mitoxantrone was similar to that of the mono- and dicarboxylic acid and was 75 h. Cumulative renal elimination ranged from 670-1950 micrograms for mitoxantrone, from 366-852 micrograms for monocarboxylic acid, and from 792-3420 micrograms for dicarboxylic acid. Renal clearance of mitoxantrone reached a median level of 69 ml/min and for the total plasma clearance a median of 1136 ml/min was found. The corresponding values for the mono- and dicarboxymetabolites were 57 and 67 ml/min. In contrast to the great interindividual differences in pharmacokinetic results, a low intraindividual variability was observed upon repeated determinations of renal elimination of mitoxantrone and its metabolites at weekly intervals in five patients. These data provide new insights into the pharmacokinetic of mitoxantrone and its main metabolites revealing substantial differences in drug metabolism and elimination between individual patients. Further studies are needed to explore the potential impact on response and/or toxicity and the requirement of a pharmacokinetic directed adjustment of drug dosage in clinical trials.

Column-switching solid-phase trace-enrichment high-performance liquid chromatographic method for measurement of buprenorphine and norbuprenorphine in human plasma and urine by electrochemical detection.

We describe a new high-performance liquid chromatographic method using electrochemical detection for the determination of buprenorphine and norbuprenorphine in plasma and urine. The minimum concentration for detection of buprenorphine and norbuprenorphine is 40 pg/ml. The intra-assay coefficient of variation (C.V.) in plasma and urine samples ranges from 6 to 17% depending on the drug concentration. At a plasma concentration of 500 pg/ml the inter-assay C.V. is 8% for buprenorphine and 9% for norbuprenorphine. The analysis duration is 16 min. After solid-phase extraction and evaporation a valve-switching system with two Rheodyne valves enables sample enrichment, optimal sample cleaning and rapid elution of long-retained substances.

[Comparison of automated micro-disc electrophoresis for the analysis of urine proteins with a conventional system]. / Vergleich der automatisierten Mikro-Disc-Elektrophorese zur Harnproteinanalyse mit einem herkömmlichen System.

Recently a new system for analyzing urinary proteins due to their molecular weight distribution has been introduced. The whole system is automatically driven and uses a silver staining. Due to the small amount of protein necessary for analysis native urine samples can be used. The data presented here show that the automatic micro-disc-electrophoresis (Phast-system) is very useful for any routine testing due to the quick (2 hours) and easily obtainable results with a very high reproducibility. The clinical relevance of urinary protein analysis seems to be much higher using this system.