St. Thomas' Hospital cardioplegia: enhanced protection with exogenous creatine phosphate.

BACKGROUND: Experimentally, creatine phosphate (CP) improves postischemic recovery of function and reduces postischemic arrhythmias. METHODS: We studied 50 patients undergoing valve replacement. They were randomized into either a control group, who received St. Thomas' Hospital cardioplegic solution No. 1, or a CP-treated group, receiving the same cardioplegic solution plus CP (10 mmol/L). There were no preoperative clinical differences between groups. Assessment was by electrocardiographic analysis, inotropic drug requirement, quantitative birefringence, myocardial high-energy phosphate content, function, and semiquantitative ultrastructural assessment. RESULTS: Direct-current shocks were reduced in the CP-treated group (0.88 +/- 0.15) compared with the control group (1.40 +/- 0.14; p < 0.02), as was the total number of joules (22.0 +/- 3.5 versus 34.4 +/- 3.7, respectively; p <0.02). The incidence of spontaneous sinus rhythm was higher in the CP-treated group (40% versus 8%; p < 0.05) and the incidence of postoperative arrhythmias, lower (8% versus 32%; p < 0.05). Prolonged inotropic administration (12 hours or longer) occurred in fewer patients in the CP-treated group (4% versus 28%; p < 0.05). Response to inotropic support (in the subset of patients requiring this treatment) was significantly greater in the CP-treated group than in the control group. There were no differences in recovery of function, birefringence changes, myocardial high-energy phosphate content, or ultrastructure between groups. CONCLUSIONS: St. Thomas' Hospital cardioplegic solution No. 1 plus CP enhanced myocardial protection and conferred a direct benefit to the patient by reducing postoperative arrhythmias and need of prolonged inotropic support.

[The efficacy of creatine phosphate in the treatment of patients with heart failure. Its echographic evaluation after acute and protracted treatment]. / Efficacia della creatina fosfato nel trattamento dei pazienti con insufficienza cardiaca. Valutazione ecocardiografica dopo trattamento acuto e protratto.

The hemodynamic effects of acute and long-term administration of creatine phosphate were studied in 23 patients with heart failure (NYHA classes II and III) under stabilized treatment. Acute creatine phosphate (5 g i.v.) induced a significant increase of the ejection fraction (FE) and of other parameters of cardiac contractility. Once these improvements of cardiac contractility were obtained by acute treatment, further significant increases in cardiac function were observed if treatment was continued for six days, i.e. telesystolic diameter and volume, as well as parietal stress were significantly reduced, and ejection fraction and shortening fraction were significantly increased. Creatine phosphate treatment has a favourable influence on the hemodynamics of patients with an obvious contractility deficit and chronic ischemia of the myocardium.

[Molecular and cellular aspects of the cardioprotective mechanism of phosphocreatine]. / Molekuliarnye i kletochnye aspekty mekhanizma kardioprotektivnogo deistviia fosfokreatina.

The present state of investigations on molecular and cellular mechanisms of cardioprotective effects of phosphocreatine (PCr) is reviewed. The protective effect of PCr is manifested as significant improvement of heart contractile function recovery, lowering of diastolic pressure elevation and myocardial enzymes release during postischemic reperfusion as well as better preservation of high energy phosphates in comparison with control. Data from multidisciplinary studies using physico-chemical, physiological, pharmacological etc. approaches suggest that one of the key mechanisms of PCr action is its interaction with the sarcolemmal membrane. The authors own data obtained with the use of spin-labeled ESR-probe incorporated into the isolated sarcolemmal vesicles provide direct evidence in favor of the ordering effect of PCr sarcolemmal phospholipid packing with essential involvement of Ca2+ ions. PCr transform membrane phospholipids into more structured gel-like state. The results of biomedical studies suggest that the mechanism of this protective action is complex and includes at least four components: 1) inhibition of lysophosphoglyceride accumulation in the ischemic myocardium and preservation of cardiac cell sarcolemma structure via zwitterionic interaction with PCr molecules; ii) extracellular action consisting in inhibition of platelet aggregation via ADP removal in the extracellular creatine kinase reaction and increasing plasticity of red blood cells; iii) PCr penetration into cells maintenance of high local ATP levels is possible; iiii) inhibition of adenine nucleotide degradation at the step of 5'-nucleotidase reaction in cardiac cell sarcolemma.

Effects of doxefazepam on normal sleep. An EEG and neuropsychological study.

The effects on sleep of a putative hypnotic, benzodiazepine (doxefazepam), were studied in 7 healthy volunteers. Subjects were administered placebo or the active compound at 10-, 20-, and 40-mg oral dose prior to 13 consecutive nights during which they slept in the EEG laboratory. Full-night EEG recordings were obtained, and the hypnogram was determined. The subjective characteristics of sleep (quality, dreams, etc.) were defined by self-administered rating scales; neuropsychological and quantitative waking EEG measurements were performed before drug/placebo administration and in the morning following the final awakening, in order to identify possible signs of 'hangover'. Volunteers thereafter slept at home for 15 nights, self-administering 10 mg doxefazepam each night, and returned to the laboratory for 2 additional full-night sleep recordings. The drug plasma concentration was monitored during the study. Doxefazepam (10 mg) reduced the number of intermediate awakenings and the shifts between distinct sleep phases; single 20- or 40-mg doses or a 2-week administration of 10 mg doxefazepam increased significantly the total sleep duration and the percent duration of the phase 2 and the synchronized sleep and decreased the percent duration of phase 1 and of the intermediate awakenings. Volunteers reported an improvement in the subjective 'quality' of sleep, while evident signs of 'hangover' were not observed. The compound appeared to be of potential use as a sleep regulator.

Prolactin secretion during reserpine and syrosingopine treatment.

In 20 mild hypertensive women, reserpine induced a significant increase in mean plasma PRL, both under basal conditions (from 6.6 +/- 0.9 to 17.9 +/- 2.9 ng/ml), and on repeated determinations during the day. In contrast to reserpine, the administration of syrosingopine, a synthetic compound derived from reserpine, to the same subjects was not followed by a significant change in prolactin level. Beyond their pharmacological interest, these results are of clinical importance when considering that rauwolfia alkaloids are used for long term treatment, and that an increase in PRL levels is important in pathology, both in relation to the function of the hypophyseogonadal axis and in view of its possible facilitation of the growth and development of mammary cancer.

Sedative-hypnotic properties of a new benzodiazepine in comparison with flurazepam. Pharmacological and clinical findings.

The sedative-hypnotic effects of a new benzodiazepine, 1-(2-hydroxyethyl)-3-hydroxy-7-chloro-1,3-dihydro-5-(o-fluorophenyl)-2H-1,4-benzodiazepin-2-one (SAS 643), were compared with those of flurazepam in mice and rats as well as in a double-blind clinical trial. It was found that SAS 643 has a potency 2--4 times greater than that of flurazepam while it is about one half less toxic than the latter drug. The results of the clinical trial confirm the greater activity of SAS 643 and indicate that the new benzodiazepine causes a significantly less amount of hangover than flurazepam.