[Early cardiotoxicity of Hydroxychloroquine]. / Cardiotoxicité précoce de l'hydroxychloroquine.

INTRODUCTION: Hydroxychloroquine (HCQ) is most frequently used in the treatment of systemic inflammatory diseases. Cardiac complications of anti-malarial drugs are uncommon, and most of the time are the result of a long-term exposition. In this case, cardiotoxicity is the consequence of the lysosomal dysfunction and the result of intracytoplasmic granular material inclusions. CASE REPORT: We report a 77-year-old woman who presented a very early and reversible cardiotoxicity, probably related to the quinidine like effect of the HCQ, 10 days after initiation of therapy for Whipple endocarditis. CONCLUSION: We discuss the different mechanisms of cardiotoxicity of anti-malarial drugs and their clinical manifestations.

Predictors of newly diagnosed atrial fibrillation in cryptogenic stroke: a cohort study.

BACKGROUND AND PURPOSE: A significant proportion of cryptogenic ischaemic strokes are due to paroxysmal atrial fibrillation (AF). As paroxysmal AF appears to inexorably progress to persistent or permanent AF, this study with long-term follow-up was designed to establish the profile of patients who developed AF after hospital discharge. METHODS: All patients with cryptogenic ischaemic stroke over a 1-year period were included (n = 164). Patients were prospectively followed up at the outpatient clinic. Information on long-term outcome included the presence of newly diagnosed AF (NDAF). A specific NDAF assessment was performed at least 2 years after the index stroke using a structured telephone interview. Baseline clinical, laboratory, and echocardiographic data of these patients were retrospectively recorded. Independent predictive factors were then used to produce a predictive grading score for NDAF, derived by logistic regression analysis. RESULTS: With a median follow-up of 854 days, 22 cases of NDAF (13%) were observed. On multivariate analysis, factors associated with NDAF were age ≥72 years (two points), history of coronary artery disease (one point) or stroke (one point), and left atrial area ≥16 cm(2) (two points) (total score ranging from 0 to 6). Patients with a score ≤1 point did not have NDAF during follow-up. CONCLUSIONS: In cryptogenic ischaemic stroke, the NDAF score can be used to target patients at high risk of developing AF after hospital discharge, as a score of 0-1 was highly predictive of the absence of NDAF during follow-up. These results need to be confirmed in prospective studies.

Quantification of docetaxel and its main metabolites in human plasma by liquid chromatography/tandem mass spectrometry.

Docetaxel is an antineoplastic agent widely used in therapeutics. The objective of this study was to develop and validate a routine assay, using liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS), for the simultaneous quantification of docetaxel and its main hydroxylated metabolites in human plasma. A structural analogue, paclitaxel, was used as the internal standard. Determination of docetaxel and four metabolites (M1, M2, M3 and M4) was achieved using only 100 microL of plasma. Liquid-liquid extraction was used for sample preparation, with extraction efficiency of at least 90% for all analytes. Detection used positive-mode electrospray ionization in selected reaction monitoring mode. The lower limit of quantification (LLOQ) was 0.5 ng/mL for all analytes. The assay was linear in the calibration curve range 0.5-1000 ng/mL and acceptable precision and accuracy (<15%) were obtained with concentrations above the LLOQ. This method was sufficiently selective and sensitive for quantification of metabolites in plasma from cancer patients receiving docetaxel chemotherapy, and is suitable for routine analyses during pharmacokinetic studies.

Population pharmacokinetics of cisplatin in patients with advanced ovarian cancer during intraperitoneal hyperthermia chemotherapy.

The objective of this study was to determine the pharmacokinetic profile of total platinum administered by hyperthermic peritoneal perfusion (HPP) in 16 patients with ovarian cancer. The patients had a performance status of lIIalpha/b/c on the FIGO scale. They received 60, 80 or 100 mg of cisplatin. The percent of cisplatin remaining in the body after the peritoneum was emptied averaged 65% (41.7-85.4%). The average ratio between peritoneal drug concentrations and plasma concentrations was 73. A Bayesian estimation of individual phamacokinetic parameters was carried out using the non-linear mixed-effect modeling approach as implemented in the NONMEM computer program. A two-compartment model with an additional peritoneal cavity compartment was used to fit the data. Large interindividual variability of the pharmacokinetic parameters occurred The maximum platinum concentration in plasma was reached between 1 and 1.5 hours after the beginning of administration; it ranged from 0.37 to 1.7 microg/ml (1.9 to 8.72 microM). The elimination half-life was 80 hours (48-152 hours and the area under the plasma concentration time curve normalized to a 100 mg cisplatin dose was 79 mg/liter x hours. The simultaneous fit of perfusate and plasma concentrations allowed us to estimate the percent of cisplatin that reached the systemic circulation at about 20%. At time infinity, the urinary cisplatin recovery accounted for only 20% of the administered dose. The results in this study showed that a high proportion of the cisplatin dose was absorbed by target tumor cells. In spite of the advanced disease of patients at the time of HPP, 37.5% of them were still alive three years after HPP (ie., 3-6 years after cancer diagnosis) and 12.5%, 7 years after HPP (i.e., 8 years after cancer diagnosis).

Laboratory data in healthy volunteers: reference values, reference changes, screening and laboratory adverse event limits in Phase I clinical trials.

OBJECTIVE: Laboratory data are key evaluation procedures for Phase I clinical pharmacology for two reasons. Firstly, laboratory data are used within the screening process to exclude subjects with asymptomatic diseases, which could result in increased danger to themselves or confuse interpretation of the study results. Secondly, during study implementation, safety evaluation and in particular maximum tolerated dose determination have to be done by a case-by-case analysis, sometimes using laboratory adverse events (LAEs). Thus, relevant limits are needed to discriminate between a usual common variation and a significant abnormality, which is considered to be a LAE. This report presents laboratory data distribution, reference values and reference changes and, based on previously published new methods, suggests inclusion limits at screening and laboratory adverse event limits for analysis during study implementation. SUBJECTS AND METHODS: Nine hundred and twenty-seven young healthy male volunteers were recruited in one centre (Association de Recherche Thérapeutique). A standard screening process was carried out. Protocols were approved by the local ethics committee. Blood sampling was performed in the same conditions. Reference values (at screening and at baseline) were determined by a non-parametric procedure selecting 2.5% and 97.5% of the distribution of data. Reference changes were also defined as the 2.5-97.5% interval of distribution of the variations between the end of treatment and baseline. Inclusion limit and LAE limit methods of determination used had been specified in previous articles. RESULTS: Detailed results of laboratory data distribution, reference values at screening and at baseline, reference changes, inclusion limits and LAE limits are presented in tables with number of subjects, mean, median, standard deviation, minimal and maximal values and the 2.5-97.5% interval for each laboratory parameter. CONCLUSION: The key aims of this paper are to provide clinical pharmacologists with data, reference values or changes obtained in the real conditions of Phase I study implementation, and to propose relevant limits, either for screening as inclusion limits, or during studies as LAE limits. Thus, these data, reference values and specific limits improve the capacity to screen healthy volunteers and to analyse LAEs during Phase I studies.

Is vitamin K1 supplementation necessary in long-term parenteral nutrition?

BACKGROUND: I.v. lipid emulsions contain vitamin K in substantial quantities and in 1989, we therfore stopped supplying vitamin K1 to patients receiving home parenteral nutrition (HPN). METHODS: Nine patients (group I) receiving HPN before 1989 (10 mg i.v. vitamin K1 supplementation weekly until 1989, which was discontinued thereafter) and six patients with an initial low plasma vitamin K1 concentration (related to their malabsorption) (group II) receiving HPN after 1989 were studied. Prothrombin time (PT), plasma vitamin K1 concentration, and vitamin K1, content in lipid emulsions were measured throughout the period of HPN. RESULTS: All lipid emulsions, except for Eurolip 20% and Clinoleic 20% (Baxter SA, Maurepas, France) contained vitamin K1, with concentration ranges from 179 +/- 39 to 353 +/- 78 ng/L. Group I patients had an initial high plasma vitamin K1 concentration due to the vitamin K1 supplementation. After this supplementation was discontinued, plasma vitamin K1 decreased and remained in normal ranges with a normal PT. Throughout the HPN period after 1989, patients received 255 +/- 104 micrograms of vitamin K1 weekly through lipid emulsions. The PT and plasma vitamin K1 concentrations in group II patients were restored by lipid emulsions, which contained 418 +/- 143 micrograms/wk of vitamin K1. CONCLUSIONS: In patients receiving i.v. lipids (except for Eurolip and Clinoleic), a normal vitamin K1 status can be maintained during long-term HPN without vitamin K1 supplementation. However, vitamin K supplementation cannot be abandoned until the vitamin K content of emulsions is standardized by manufacturers. A weekly supply of 250 to 400 micrograms of vitamin K1 is enough to maintain and even restore a normal vitamin K1 status in HPN.

Study of the pharmacokinetics of mitomycin C in humans during intraperitoneal chemohyperthermia with special mention of the concentration in local tissues.

The aim of this work is to estimate the 24-hour distribution and elimination of mitomycin C (MMC) during and after intraperitoneal chemohyperthermia (IPCH) in 18 patients (13 gastric adenocarcinoma, 3 pancreatic adenocarcinoma, 2 malignant mesothelioma) who received 60 mg MMC during 90-120 min in 6 liters of heating solution HS; (42 degrees C) or HS flowing at 0.4 liters/min in a closed circuit. MMC assay in the serum, urine, HS and in local biopsies were performed by high performance liquid chromatography. The amount of MMC in HS decreased by 54.1 +/- 13.6% during IPCH. The maximum MMC levels in serum reached 0.4 +/- 0.18 mg/l 45 min after the start of IPCH, then rapidly decreased. Only 1.77 +/- 0.93 mg were recovered in urine in 24 h. These data are consistent with a large and rapid absorption, mostly in local tissue, demonstrated by the level in 7 post-IPCH biopsies (8.3 +/- 7.6 mg/kg).

Stability of fat-soluble vitamins A (retinol palmitate), E (tocopherol acetate), and K1 (phylloquinone) in total parenteral nutrition at home.

Our purpose was to extend previous studies of the stability of vitamins A (retinol palmitate), E (tocopherol acetate), and K1 (phylloquinone) to total parenteral nutrition at-home (TPNH) admixtures. First, stability over 20 days was tested. Experimental conditions included presence or absence of lipids, presence or absence of trace elements, and storage in a glass bottle or in a single or multi-layer plastic bag (ethylene vinyl acetate, polyvinyl chloride, Stedim 5, and Stedim 6). The 20-day storage studies were conducted at 4 degrees C or at ambient air temperature. The second part of the study consisted of exposing to natural light TPNH admixtures with or without lipids, but with trace elements, in the same containers (except polyvinyl chloride). Finally, a clinical situation of TPNH was simulated with a TPNH admixture prepared 11 days before the test in a Stedim 6 plastic bag and stored at 4 degrees C in total darkness. For vitamins A, E, and K1, we observed good stability for 20 days; the final concentrations ranged from 75% to 100% of initial concentrations whatever the conditions studied. It appears that there is no significant difference of action between all containers and that the presence or absence of lipids and trace elements in admixtures stored at 4 degrees C or ambient temperature makes no difference. With exposure to sunlight, vitamin losses were 100% at 3 hours for vitamin A and 50% for vitamin K1; vitamin E concentrations were unchanged after 12 hours of experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in hepatic vitamin K1 levels after prophylactic administration to the newborn.

We undertook a study of hepatic concentrations of vitamin K (vitamin K1 or phylloquinone, vitamin K1-epoxide, and menaquinones) in 18 infants, ages 1-8 days, with or without vitamin K1 supplementation. The infants who had no supplementation had a total hepatic storage ranging between 0.1 and 0.9 micrograms. Also, hepatic storage of phylloquinone was poor (< 1 microgram) when compared with daily requirements. Moreover, we did not detect any menaquinone in the livers of these infants in our study. The prophylaxis applied to the other infants was very efficient. Hepatic vitamin K1 concentrations, obtained < 24 h after administration, were very high (62.8-93.5 micrograms/g). Vitamin K1-epoxide concentrations were high, which proved the efficiency of the vitamin K cycle. In contrast, the decrease in vitamin K1 concentrations was also very rapid, since the median value after 48 h was 8.4 micrograms/g and only 2.9 micrograms/g 5 days after administration. However, hepatic total storage after 5 days in one infant with vitamin K1 supplementation was much higher (112 micrograms) than in infants who had not received supplementation. In conclusion, hepatic phylloquinone storage at birth was poor (< 1 microgram). The newborn infant might be in a situation of potential deficiency. After prophylactic oral administration of phylloquinone, uptake by the liver was quite satisfactory, but concentrations dropped quickly. However, phylloquinone hepatic storage remained elevated (112 micrograms) after 5 days.

Three electrophoretic techniques comparison for des-gamma-carboxyprothrombin detection.

Des-gamma-carboxyprothrombin (DCP) is a marker that appears in the blood when modifications of vitamin K-dependent proteins carboxylation cycle occur. About 280 human plasma samples of diverse origins were tested by three different electrophoretic techniques for the evaluation of DCP: rocket immunoelectrophoresis (RIE) before and after barium carbonate adsorption, crossed affinoimmunoelectrophoresis (CAIE) and polyacrylamide gel electrophoresis in presence of calcium lactate followed by immunoblotting (PAGE-blot). A good correlation was found between CAIE and PAGE-blot in the CAIE detection limit, but not between RIE and the two other techniques. PAGE-blot was more sensitive than RIE and CAIE and allowed reliable quantification of abnormal prothrombin in plasma.

Hepatic concentration of vitamin K active compounds after application of phylloquinone to chickens on a vitamin K deficient or adequate diet.

Liver and serum concentrations of vitamin K active compounds were measured in two groups of (deficient and normal) broilers after administration of phylloquinone 1 mg/kg. Assays were performed by HPLC after extraction and purification of these compounds. The only menaquinone found in the chicken was menaquinone-4. In the deficient group, the chickens exhibited hepatic concentrations of vitamin K1, vitamin K1 epoxide and menaquinone-4 markedly lower than those of the control group. After administration of phylloquinone, vitamin K and vitamin K epoxide levels fell sharply. There is no hepatic storage of vitamin K comparable to that of vitamin A. However, while menaquinone levels were found to be stable in the control group, they rose significantly in the deficient group after vitamin K injection. The question is: is there a transformation of vitamin K into menaquinone and/or is there a preferential utilization of one of the vitamin K active compounds?

Impairment of gamma carboxylation of circulating osteocalcin (bone gla protein) in elderly women.

Osteocalcin, also called bone gla protein, is a unique noncollagenous protein of the extracellular matrix of bone that circulates in blood. Oseteocalcin contains three residues of the vitamin K-dependent gamma-carboxyglutamic acid (gla) responsible for the affinity of osteocalcin for bone mineral. In animals treated with the vitamin K antagonist warfarin, the osteocalcin content of bone is markedly reduced and the fraction of osteocalcin released into the circulation is increased. Most studies have shown that osteocalcin increases with aging in women, reflecting an increase in bone turnover, especially after the menopause. To determine if this increase in osteocalcin could be associated with impaired carboxylation, we measured total and noncarboxylated osteocalcin in the serum of 72 women of various ages: 22 premenopausal (31 +/- 7 years old), 20 early postmenopausal (54 +/- 3 years), and 30 elderly women (85 +/- 8 years). As previously reported, total serum osteocalcin was significantly increased in early postmenopausal and elderly women. Noncarboxylated serum osteocalcin was slightly increased in early postmenopausal women (0.95 +/- 0.4 versus 0.65 +/- 0.5 ng/ml in premenopausal women), markedly elevated in elderly women (1.59 +/- 1.1 ng/ml, p less than 0.001), and correlated with age (r = 0.47, p less than 0.001). Elderly women had values of the same magnitude as in 10 patients on chronic warfarin therapy (1.94 +/- 1.1 ng/ml). As a consequence, the increase in carboxylated serum osteocalcin was significant in early postmenopausal women but not in elderly women. Serum levels of vitamin K1 and of menaquinones 6, 7, and 8 were measured in some of the young and elderly women.(ABSTRACT TRUNCATED AT 250 WORDS)

Des-gamma-carboxyprothrombin detection by immunoblotting after polyacrylamide gel affinoelectrophoresis in human plasmas.

In the absence of vitamin K or in the presence of the vitamin K antagonists, abnormal nonfunctional forms of prothrombin circulate in the blood. A reliable and reproducible technique, derived from traditional crossed affinoimmunoelectrophoresis in presence of calcium lactate, was developed and optimized. The technique is based on nondenaturing polyacrylamide gel affinoelectrophoresis, with calcium lactate, of plasma samples, followed by immunoblotting with rabbit anti-human prothrombin serum and detection with an anti-rabbit immunoglobulin peroxidase conjugate. Depending on the plasmas, one or two bands were visualized and quantified by densitometry of the immunoblots. The technique was able to detect abnormal des-gamma-carboxylated prothrombins at concentration of 0.1 microgram/mL.

[Echodoppler evaluation of the normally functioning Saint-Jude's aortic valve prosthesis]. / Evaluation par écho-doppler du fonctionnement normal de la prothèse de Saint-Jude en position aortique.

The aims of this study were: to define Doppler echocardiographic criteria of normality of aortic St Jude Medical (SJM) valve prostheses with respect to their size and to verify the validity of the continuity equation in the determination of prosthetic valve functional surface area. Forty patients with apparently normally functioning SJM prostheses without other cardiac disease were investigated at least one month after surgery. The group consisted in 1 n. 19, 6 n. 21, 9 n. 23, 12 n. 25 and 12 n. 27 SJM prostheses. The following parameters were measured: the maximum transprosthetic velocity, maximum and mean transprosthetic pressure gradients, permeability index and the Doppler surface area calculated by the continuity equation using the method proposed by Skjaerpe. The global results were as follows: maximum velocity = 2.5 +/- 0.4 m/s (1.8-3.7 m/s); maximum gradient = 26.9 +/- 9.8 mmHg (14-53 mmHg); mean gradient = 13.7 +/- 5.6 mmHg (7-30 mmHg); permeability index = 0.41 +/- 0.09 (0.23-0.57); Doppler surface area = 1.89 +/- 0.66 cm2 (0.73-3.23 cm2). When the prostheses were considered according to their sizes a weak negative correlation was observed between the mean pressure gradients and the size of the prostheses: r = -0.43, p less than 0.05 and a positive correlation between Doppler surface area and the theoretical prosthetic surface area: r = 0.71, p less than 0.005; SD = 0.45 cm2. No significant differences were observed between the pressure gradients and velocities of each size of prosthesis except when sizes 21 + 23 were compared with the large sizes (n. 25 + 27).(ABSTRACT TRUNCATED AT 250 WORDS)

[Treatment of cardiac insufficiency by beta-blockaders. A review of the literature and discussion]. / Traitement de l'insuffisance cardiaque par les bêtabloquants. Revue de la littérature et discussion.

The use of beta-blockers in the treatment of heart failure at first seems paradoxical because of their negative inotropic effect. Nonetheless, clinical studies performed over the last ten or so years in patients with dilated cardiomyopathy or ischemic heart failure indicate functional improvement and a tendency to reduced mortality. These preliminary studies were carried out with a limited number of patients and were sometimes by nature methodologically imperfect. They have since been succeeded by large, randomized, prospective studies also based on solid experimental arguments concerning the supposed mechanisms of action of beta-blockers. The themes of these studies include: protection against the cardiotoxicity of catecholamines, up-regulation, reduction in myocardial energy requirements and in heart rate, improved diastolic function and compliance, inhibition of vasoconstriction induced by catecholamines, and antiarrhythmic action.