Phase I study of the novel Cdc2/CDK1 and AKT inhibitor terameprocol in patients with advanced leukemias.

PURPOSE: Inhibiting survivin and Cdc2 (CDK1) has preclinical anti-leukemic activity. Terameprocol is a small molecule survivin and Cdc2/CDK1 inhibitor that was studied in a Phase I dose-escalation trial. PATIENTS AND METHODS: Sixteen patients with advanced acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) were enrolled and 15 treated with Terameprocol in three dose cohorts intravenously three times per week for 2 weeks every 21 days. RESULTS: Patients had AML (n = 11), chronic myelogeneous leukemia in blast phase (CML-BP, n = 2) and one each T-cell acute lymphoblastic leukemia (T-ALL) and MDS. Four, five and six patients were treated at the 1000, 1500 and 2200 mg Terameprocol dose cohorts respectively. Common related treatment emergent adverse events (TEAE) were grade 1 or 2 headache, transaminitis and pruritus, with one grade 4 serious AE (SAE) of pneumonia. No dose limiting toxicity (DLT) was observed, however, due to other observed grade 3 TEAE the recommended phase 2 dose (RP2D) was determined at 1500 mg 3×/week for 2 weeks of a 21-day cycle. Partial remission and transfusion independence in a CML-BP patient (1500 mg cohort) and hematological improvement in erythroid (HI-E) and platelet lineage (HI-P) in an AML patient were observed. Five AML patients had stable disease greater/equal to 2 months. Pharmacodynamic studies showed a reduction of CDK1 and phospho-AKT protein expression. CONCLUSION: Terameprocol can be safely administered to advanced leukemia patients, sufficient drug exposure was obtained and clinical activity and biomarker modulation were observed.

Disentangling Cation and Anion Dynamics in Li3PS4 Solid Electrolytes.

A prerequisite for the realization of solid-state batteries is the development of highly conductive solid electrolytes. Li3PS4 is the archetypal member of the highly promising thiophosphate family of Li-ion conductors. Despite a multitude of investigations into this material, the underlying atomic-scale features governing the roles of and the relationships between cation and anion dynamics, in its various temperature-dependent polymorphs, are yet to be fully resolved. On this basis, we provide a comprehensive molecular dynamics study to probe the fundamental mechanisms underpinning fast Li-ion diffusion in this important solid electrolyte material. We first determine the Li-ion diffusion coefficients and corresponding activation energies in the temperature-dependent γ, ß, and α polymorphs of Li3PS4 and relate them to the structural and chemical characteristics of each polymorph. The roles that both cation correlation and anion libration play in enhancing the Li-ion dynamics in Li3PS4 are then isolated and revealed. For γ- and ß-Li3PS4, our simulations confirm that the interatomic Li-Li interaction is pivotal in determining (and restricting) their Li-ion diffusion. For α-Li3PS4, we quantify the significant role of Li-Li correlation and anion dynamics in dominating Li-ion transport in this polymorph for the first time. The fundamental understanding and analysis presented herein is expected to be highly applicable to other solid electrolytes where the interplay between cation and anion dynamics is crucial to enhancing ion transport.

Fabrication and mechanical properties of large-scale freestanding nanoparticle membranes.

Thin-film membranes consisting of nanoparticles are of interest in applications ranging from nanosieves to electric, magnetic, or photonic devices and sensors. However, the fabrication of large-scale membranes in a simple but controlled way has remained a challenge, due to the limited understanding of their mechanical properties. Systematic experiments on ultrathin, freestanding nanoparticle membranes of different core materials, core sizes, and capping ligands are reported. The results demonstrate that a drying-mediated self-assembly process can be used to create close-packed monolayer membranes that span holes tens of micrometers in diameter. Containing up to approximately 10(7) particles, these freely suspended layers exhibit remarkable mechanical properties with Young's moduli of the order of several GPa, independent of membrane size. Comparison of three different core-ligand combinations suggests that the membrane's elastic response is set by how tightly the ligands are bound to the particle cores and by the ligand-ligand interactions.

The cardiac anxiety questionnaire: development and preliminary validity.

Heart-focused anxiety (HFA) is the fear of cardiac-related stimuli and sensations because of their perceived negative consequences. Although HFA is common to a wide variety of persons who experience chest pain and distress, it often is unrecognized and misdiagnosed, particularly in cardiology and emergency room patients without and with heart disease. To address these concerns, this article reports on the development and preliminary psychometric evaluation of the Cardiac Anxiety Questionnaire (CAQ) designed to measure HFA. In Study 1, 188 cardiology patients completed the CAQ. Item and factor analyses indicated a three-factor solution pertaining to heart-related fear, avoidance, and attention. Reliability analysis of the 18-item CAQ revealed good internal consistency of the total and subscale scores. In Study 2, 42 patients completed the CAQ and several other anxiety-related questionnaires to assess its convergent and divergent properties. Although preliminary validity results are promising, further psychometric study is necessary to cross-validate the CAQ, examine its test-retest reliability, and confirm the stability of the factor structure. Taken together, the CAQ appears to assess HFA, and may therefore be a useful instrument for identifying patients with elevated HFA without and with heart disease.

Anxiety and its determinants in patients undergoing magnetic resonance imaging.

This study assessed anxiety reactions in 40 adults outpatients undergoing MRI. Ninety-five percent of the patients completed the procedure although 37% reported moderate to severe anxiety. It is concluded that (a) anxiety in patients undergoing MRI is a multifaceted phenomenon involving fear of enclosed places (claustrophobia), pain, the unknown, as well as apprehension about what the test might reveal, and (b) the best way to avoid traumatizing the patient is to assess these variables in advance of the procedure. Methods to reduce anxiety can then be tailored to the needs of the patient.

Sexual fears are increasing.

This study compared scores from three samples of college students (N = 810) on the Sexual Aversion Scale, a measure of sexual anxiety based on DSM-III-R criteria for diagnosing sexual aversion disorder. Measurements were taken in 1988, 1991, and 1992. There was a significant increase in sexual anxiety during this period, most of it attributable to fear of acquiring AIDS. Although the women reported more sexual anxiety than the men over-all, there was no difference on fear of AIDS. These findings could foreshadow an increase in sexual dysfunctions and desire disorders.

[Removing a femoral catheter]. / Le retrait de la gaine d'un cathéter fémoral.

Nurses at the University of Ottawa Heart Institute are removing femoral sheaths on post-angioplasty patients. The authors describe this new technique and explain how nurses can benefit by doing it. They discuss practical considerations before delegating this sanctioned medical act to nurses. Prevention and management of complications are also discussed as are research projects to evaluate the technique.

The Chief Scientist reports.... Voluntary agency support for people with mental health problems.

The development of a cohesive support system is vital to the success of community based services and day care is an essential component of any system of support. McCreadie et al in a Scottish study of psychiatric hospital provision showed that while there was wide variation around Scotland in the provision of hospital based care, there was a general dearth of health service and local authority community-based services. Philip and Stuckey in a survey of NHS long term non-resident patients of the Royal Edinburgh Hospital found that hospital staff felt that such patients would have benefited from additional daytime activity different from that provided in the health service. These authors found that some patients did make significant use of voluntary agencies, but were unable to elicit any systematic reasons for using or not using these agencies. Surveys in the statutory and voluntary sectors completed to date have tended to concentrate on the opinions of staff groups about the requirements and needs of clients. There has been no systematic survey of the facilities and opportunities most desired by users of voluntary sector support agencies. This survey, which received support from the Chief Scientist Organisation Mini-Project Scheme, aims to remedy this lack and to provide a factual basis from which the NHS, local authorities and voluntary agencies can draw, in their mutual aim of helping people with mental health problems. The results of the survey, while carried out in Edinburgh, may have relevance to planners and providers further afield in Scotland.

Survey of four day care facilities at the Royal Edinburgh Hospital.

A survey is described which compared patients' rehabilitation status, activities, needs and reasons for attending at four different psychiatric day care units attached to one hospital. The views of staff and patients were also examined.

Comparative pharmacokinetics of bismuth from ranitidine bismuth citrate (GR122311X), a novel anti-ulcerant and tripotassium dicitrato bismuthate (TDB).

GR122311X (ranitidine bismuth citrate, Glaxo Group Research Ltd.) is a salt of ranitidine with a complex of bismuth and citric acid which is being developed for the treatment of peptic ulceration. In this study, 4 groups of 12 healthy male subjects were dosed for 10 days with either GR122311X 500 mg bid (301 mg bismuth per day), GR122311X 1.0 g bid (602 mg bismuth per day), tripotassium dicitrato bismuthate (TDB, DeNoltab, Gist Brocades Ltd., Weybridge, England) 240 mg bid (431 mg bismuth per day) or placebo. After the last dose the geometric mean for Cmax for 500 mg bid of GR122311X was 5 ng.g-1, for 1.0 g bid GR122311X it was 12 ng.g-1 and it was 21 ng.g-1 for 240 mg TDB bid. The corresponding trough plasma levels were 2 ng.g-1, 4 ng.g-1 and 4 ng.g-1, respectively. The AUC over a dosing interval after the last dose (AUC tau) were 34 ng.h.g-1, 71 ng.h.g-1 and 79 ng.h.g-1, respectively. The bismuth urinary recoveries over the last dosing interval (Ae tau) were 97 micrograms, 227 micrograms and 309 micrograms, respectively, which is less than 1% of the administered doses. The renal clearance of bismuth was less than the glomerular filtration rate. After adjustment for bismuth dose, the Cmax for GR122311X 500 mg was 35% that of TDB, while for GR122311X 1.0 g the Cmax was 42% that of TDB. Similar differences were observed for Ae tau. In conclusion bismuth pharmacokinetics after oral administration of GR1223311X exhibited lower Ae tau and Cmax, with a much narrower Cmax range than those observed for TDB.

Cardiovascular and behavioral response to social confrontation: measuring real-life stress in the laboratory.

Laboratory investigations of cardiovascular reactivity to mental stress often ignore concomitant differences in cognitive, affective, and behavioral responses that are commonly observed among study participants. To provide a more systematic laboratory methodology to examine relations among cardiovascular, behavioral, and self-report measures of cognitive and affective responses to stress, we developed and tested a social confrontation procedure involving standardized interactions during two scenes. Results of three investigations are presented to illustrate the utility of the social confrontation procedure. In the first two studies, this multidimensional assessment strategy produced results which may foster research projects that bridge separate areas of psychological inquiry. In one application, persons with hypertensive parents, in contrast to persons with normotensive parents, exhibited characteristic negative behavioral responses during both interactions as well as the more commonly-observed exaggerated blood pressure reactions. In the other study, students from less functional families (regarding cohesion and adaptability) were shown to exhibit exaggerated blood pressure reactions in addition to their commonly-reported negative cognitive and behavioral coping styles. Finally, a third study examined how a simple instructional set regarding the expression or suppression of anger influenced participants' responses. Significant differences were observed across response domains, with anger expression resulting in a more intense response than anger suppression. In sum, the social confrontation procedure represents an important methodological development for exploring the relation between response domains, the relation between cardiovascular response to stress and psychosocial risk for cardiovascular disease, and the physiological and behavioral distinction between anger expression and anger suppression.

Clinical pharmacology of ondansetron in postoperative nausea and vomiting.

Ondansetron is a 5-HT3 receptor antagonist which is effective and well tolerated as an antiemetic for emesis induced by cancer chemotherapy and radiation therapy, and in the prevention and treatment of postoperative nausea and vomiting. Ondansetron is rapidly absorbed after oral administration (tmax 1.9 h) with an absolute bioavailability of around 60%. Its terminal elimination half-life is 3.5 h and it is extensively hepatically metabolized. Plasma clearance is 0.38 litre h-1 kg-1 and volume of distribution is 1.8 litre kg-1. Plasma clearance is reduced by age (31% reduction) and hepatic failure (80% reduction in severe failure). In patients undergoing general anaesthesia there is a slight prolongation of terminal half-life, which is not of clinical significance. Ondansetron is very well tolerated in volunteer studies. Headache, mild abdominal pain, and constipation occur infrequently. There is no evidence for effects of ondansetron on cardiac function (electrocardiogram, cardiac output, blood pressure and heart rate), and haemostatic function in volunteers and patients. Respiratory depression induced during general anaesthesia is not potentiated by ondansetron. No drug interactions have been noted with temazepam, atracurium, alfentanil and alcohol in man. There are also no interactions seen in animal studies using pentobarbitone, morphine, neostigmine, prednisolone and diazepam.

Metabolism of remifentanil during liver transplantation.

We have investigated the pharmacokinetics of remifentanil and its less potent metabolite, GR90291, in six adult patients undergoing orthotopic liver transplantation (OLT). A single bolus infusion of remifentanil 10 micrograms kg-1 min-1 was given at the beginning of the dissection and anhepatic phases of OLT. Remifentanil and GR90291 concentrations were measured in subsequent serial arterial and mixed venous blood samples. Mean arterial clearance of remifentanil was significantly greater (P = 0.02) in the dissection phase (79.54 ml min-1 kg-1) than in the anhepatic phase (39.57 ml min-1 kg-1). Steady state volumes of distribution were not significantly different. Clearance of remifentanil during the anhepatic phase was similar to that of healthy adult patients. Mean maximum concentration (Cpmax) of GR90291 was lower in the dissection phase than in the anhepatic phase (P = 0.026). There was no significant pulmonary metabolism of remifentanil.

Remifentanil reduces auditory and somatosensory evoked responses during isoflurane anaesthesia in a dose-dependent manner.

We studied 60 patients during stable isoflurane anaesthesia (0.4 MAC) after premedication with temazepam. Patients were allocated randomly to one of three dose regimens of remifentanil: 1 microgram kg-1 i.v. over 1 min and an infusion of 0.2 microgram kg-1 min-1 (low dose); 2.5 micrograms kg-1 and 0.5 microgram kg-1 min-1 (medium dose); and 5 micrograms kg-1 and 1 microgram kg-1 min-1 (high dose). The auditory (AER) and median nerve somatosensory (SER) responses were elicited throughout, and recorded before and after tracheal intubation, and surgical incision, together with systolic and diastolic arterial pressure and heart rate. Venous blood concentrations of remifentanil were measured at the above times. After administration of remifentanil, Pa and Nb amplitudes of the AER increased at the low dose, remained constant at the medium dose and decreased at the high dose. This dose-related effect was linear and significant (P = 0.012, P = 0.05). Pa amplitude correlated inversely with remifentanil blood concentrations before and after intubation and incision (P = 0.002, P < 0.001, P < 0.001 and P < 0.001). In the SER, P15-N20 amplitudes decreased after administration of remifentanil (P < 0.001), whereas P25-N35 and N35-P45 amplitudes increased at all dose concentrations (P < 0.001 and P < 0.001). After intubation, P15-N20 and N35-P45 amplitudes increased at the low dose, did not change at the medium dose and decreased at the high dose (P = 0.001, P = 0.027). After remifentanil, systolic and diastolic arterial pressure and heart rate decreased in a linearly dose-related manner (P = 0.033, P < 0.001, P < 0.001). At all doses the three variables increased after intubation (P = 0.001, P < 0.001, P < 0.01), and systolic and diastolic arterial pressure increased after incision (P = 0.027, P = 0.039).