Destiny of candidates for heart transplantation in the Eurotransplant heart allocation system

OBJECTIVE: We analyzed the prognosis of candidates for heart transplantation (HTx) after being listed with 'urgent status' for donor heart allocation or after ventricular assist device (VAD) implantation without application for urgent status. METHODS: Urgent status as used in this study refers to both the high urgency (HU) status awarded by Eurotransplant until August 31, 2005 and the urgent (U) status that replaced it from then on. Patients who underwent primary VAD implantation between January 2001 and December 2006 and who were listed as transplantable (T) (group VAD-prim, n=159), and patients listed primarily in urgent status before VAD implantation and/or HTx during the same period (group U-prim, n=168) were enrolled in the study. Group U-prim consists of subgroups: group U-HTx (n=123), who underwent primarily HTx in urgent status; group U-VAD (n=25), who underwent primarily VAD implantation in urgent status; patients who died in urgent status before HTx or VAD implantation (n=6); and patients in urgent status without HTx or VAD implantation (n=14). The survival rate in each group was studied. RESULTS: Survival rates after VAD implantation in group VAD-prim were comparable to those after urgent status listing in group U-prim (67.0% vs 68.5% for 1-year survival, 56.6% vs 65.8% for 2-year survival, respectively). Actuarial survival after listing for urgent status in group U-HTx was significantly better than that in group U-VAD (73.7% vs 46.0% for 1-year survival, p<0.05, log-rank test). Actuarial survival during mechanical circulatory support after the VAD implantation (censored at HTx or weaning from the device) in group VAD-prim was significantly better than that in group U-VAD (80.7% vs 56.2% for 3-month survival, p<0.001, log-rank test). CONCLUSIONS: In order to receive urgent HTx, HTx candidates may choose urgency listing without primary VAD implantation at the risk of failed donor heart allocation in urgent status. However, the prognosis of the patients in the latter situation is poor.     

Folinic acid modulation of fluorouracil: tissue kinetics of bolus administration

Summary Thymidylate synthase (TS) is the enzyme target of 5-fluorouracil (FUra) that recent laboratory and clinical studies with folinic acid (calcium leucovorin) suggest may mediate important antitumor cytotoxicity. Measurement in carcinoma tissue of parameters related to TS inhibition by 5-fluorodeoxyuridylate (FdUMP), by analogy to hormone receptor analysis, should be useful to determine which patients should receive fluoropyrimidine drug therapy and to evaluate folinic acid requirements. Folinic acid is metabolized to 5,10-methylenetetrahydropteroylglutamine (CH₂FH₄), which must be present in large excess to effect desired levels of maximal inhibition of TS, by promoting formation and stabilization of TS-FdUMP-CH₂FH₄ ternary complexes. In patients with metastatic disease, serial biopsies of tumor and normal tissues for studies of pharmacodynamic responses to test-dose FUra or folinic acid are shown to be easily added to routine intraoperative management. A suitable methodologic approach is described and examples given of assays of free TS, FdUMP, dUMP, and CH₂FH₄ levels after FUra or folinic acid, that may be useful in future studies aimed at improving the cost-effectiveness of FUra-folinic acid combinations.Abbreviations TS Thymidylate Synthase (EC 2.1.1.45) - FUra 5-fluorouracil - FdUMP 5-fluorodeoxyuridylate - dUMP deoxyuridylate - CH₂FH₄ 5,10-methylenetetrahydropteroylglutamate - 5-CH₃FH₄ 5-methyltetrahydropteroylglutamate     

Identification of Phenolic Antioxidants in Elastomers for Pharmaceutical and Medical Use

Phenolic antioxidants were identified by thin-layer chromatography (TLC) in 102 samples of pharmaceutical and medical rubber articles. Despite the large number of antioxidants proposed for elastomers, only eight compounds were found in the articles analyzed. The choice of antioxidants apparently does not depend on the sterilizing processes or on the use or brand of articles.     

U-80816: A novel partial muscarinic agonist

U-80816 (1-(4-(5-methyl-1H-imidazol-1-yl)-2-butynyl)-2-pyrrolidinone is an acetylenic amine which has been investigated as a partial agonist of muscarinic receptors. In vitro U-80816 inhibited binding of (³H)-N-methylscopolamine [(³H)-NMS] and (methyl-³H) oxotremorine-M acetate [³H)-Oxo-M] to the cortical membrance preparation with Ki's of 75 and 3.24 nM, respectively. In the M1 cell line, U-80816 increased phosphatidylinositol (Pl) hydrolysis. However, the maximum increase in the Pl hydrolysis was significantly (P < 0.01) less than oxotremorine and RS 86. Intraperitoneal administration of U-80816 dose-dependently increased striatal acetylcholine (ACh) concentration, and the effect was significant (P < 0.01) at 30 mg/kg. In the presence of hemicholinium-3 (HC-3), U-80816 inhibited the release of (³H)-ACh from hippocampal slices. On the other hand, in the presence of eserine, U-80816 increased the release of (³H)-ACh. In in vivo pharmacological tests, U-80816 produced hypothermia and tremors in mice. This compound failed to produce lacrimation or salivation in mice when administered up to 100 mg/kg. U-80816 antagonized oxotremorine-induced salivation. It is bioavailable to the brain in a significant amount after oral administration and has a sufficiently long duration of action. The in vitro and in vivo pharmacological investigations indicate that U-80816 is a partial agonist of muscarinic receptors.     

Perceived stress in medical school: Resistors, persistors, adaptors and maladaptors

A longitudinal study of perceived medical student stress (PMSS) was conducted on 305 first year medical students. Data were collected at orientation in September and again in May, 2 weeks before exams. Four types of students were identified using a standardized and reliable measure of PMSS. These included students whose PMSS scores began and ended low (resistors), whose PMSS scores began and remained high (persistors), whose PMSS scores decreased from high to low (adaptors) and whose PMSS scores increased from low to high (maladaptors). The four groups differed predictably on indices of distress and were also distinguishable by a variety of psychosocial variables including type A personality, anger expression and coping. In contrast, life events played a minor role in distinguishing the groups. The results are discussed in relation to previous research on medical student stress.     

Chemotherapy by fotemustine in cerebral metastases of disseminated malignant melanoma

Summary A total of 42 patients with cerebral metastases of malignant melanoma were included in this study of the nitrosourea fotemustine. The treatment plan consisted of a 1-h i. v. infusion of 100 mg/m² fotemustine every week for 3–4 weeks, followed by a 4- to 5-week rest period. Responding or stabilised patients then received 100 mg/m² fotemustine every 3 weeks. Among the 39 evaluable patients, 2 complete responses and 9 partial responses were documented, leading to an overall response rate of 28.2%. Most of the responses were obtained in previously untreated patients and/or those presenting with a single cerebral metastasis. Toxicity was mild and mainly hematological, especially in patients previously treated by polychemotherapeutic regimen. Our study confirms the activity of fotemustine in cerebral metastases of disseminated malignant melanoma.Others institutions involved in this trial: A. Bernadou, Hôtel Dieu, Paris; J. Clavier, CHR de Brest; M. Delaunay, Hôpital Pellegrin Tripode, Bordeaux; J. P. Escande, Hôpital Tarnier, Paris; P. Fargeot, Centre George François Leclerc, Dijon; P. Lauret, Hôpital Charles Nicolle, Rouen; R. Leblay, Hôpital Sud, Rennes; P. Litoux, CHR de Nantes; G. Lorette, Hôpital Trousseau, Tours; R. Metz, Centre Alexis Vautrin, Nancy; A. Monnier, CHR Boulloche, Montbelliard; M. Mousseau, CHR de la Tronche, Grenoble; J. P. Olivier, Hôpital Dupuytren, Limoges; R. Touraine, Hôpital Henri Mondor, Créteil; F. Truchetet, Hôpital de Thionville, France     

A comparison of the efficacy and duration of action of candesartan cilexetil and losartan as assessed by clinic and ambulatory blood pressure after a missed dose, in truly hypertensive patients : A placebo-controlled, forced titration study

The purpose of this double-blind, forced titration study was to compare the antihypertensive effect duration of candesartan cilexetil, which has a long-lasting binding to the human AT₁-receptor, to that of losartan on ambulatory BP (ABP) not only during the 24-h dosing interval but also during the day of a missed dose intake. After a 4-week placebo lead-in period, 268 patients with sitting diastolic BP 95 to 110 mm Hg and mean awake ambulatory DBP ≥85 mm Hg were randomized to receive either 8 mg of candesartan, 50 mg of losartan, or placebo for a 4-week period. Thereafter, the doses were doubled in all patients for an additional 4-week period. Ambulatory BP monitoring was performed for 36 h after dosing and clinic BP measured 48 h after dosing.

Candesartan cilexetil (16 mg) reduced ABP to a significantly greater extent than 100 mg of losartan, particularly for systolic ABP during daytime (P < .05), nighttime (P < .05), and 24-h (P < .01) periods, systolic (P < .01) and diastolic (P < .05) ABP between 0 and 36 h, and both systolic (P < .001) and diastolic (P < 0.001) ABP during the day of a missed dose. Clinic BP at 48 h after dosing was significantly reduced exclusively with 16 mg of candesartan. The differences in BP reduction between 8 mg of candesartan and 50 mg of losartan were statistically significant for systolic ABP during daytime (P < .01), nighttime (P < .05), 24-h (P < .01), 0 to 36 h (P < .05) and during the day of missed dose (P < .05). Moreover, although losartan did not significantly reduce ambulatory BP in a dose-related manner, ambulatory systolic and diastolic BP reductions with 16 mg of candesartan were significantly greater (P < .01 and < .001) than those seen with 8 mg of candesartan during every period at the ABP supporting a dose–response relationship.

In conclusion, this forced titration study in ambulatory hypertensive patients demonstrates that candesartan cilexetil provides significant dose-dependent reduction in both clinic and ambulatory BP in doses ranging from 8 to 16 mg once daily. Furthermore, candesartan cilexetil is superior to losartan in reducing systolic ABP and in controlling both systolic and diastolic ABP on the day of a missed dose. The differences observed between both agents are most likely attributable to a tighter binding to, and a slower dissociation from, the receptor binding site with candesartan cilexetil.