Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia

Background

In preclinical studies the heat shock protein 90 (Hsp90) inhibitor tanespimycin induced down-regulation of checkpoint kinase 1 (Chk1) and other client proteins as well as increased sensitivity of acute leukemia cells to cytarabine. We report here the results of a phase I and pharmacological study of the cytarabine + tanespimycin combination in adults with recurrent or refractory acute leukemia.

Design and Methods

Patients received cytarabine 400 mg/m²/day continuously for 5 days and tanespimycin infusions at escalating doses on days 3 and 6. Marrow mononuclear cells harvested before therapy, immediately prior to tanespimycin, and 24 hours later were examined by immunoblotting for Hsp70 and multiple Hsp90 clients.

Results

Twenty-six patients were treated at five dose levels. The maximum tolerated dose was cytarabine 400 mg/m²/day for 5 days along with tanespimycin 300 mg/m² on days 3 and 6. Treatment-related adverse events included disseminated intravascular coagulation (grades 3 and 5), acute respiratory distress syndrome (grade 4), and myocardial infarction associated with prolonged exposure to tanespimycin and its active metabolite 17-aminogeldanamycin. Among 21 evaluable patients, there were two complete and four partial remissions. Elevations of Hsp70, a marker used to assess Hsp90 inhibition in other studies, were observed in more than 80% of samples harvested 24 hours after tanespimycin, but down-regulation of Chk1 and other Hsp90 client proteins was modest.

Conclusions

Because exposure to potentially effective concentrations occurs only for a brief time in vivo, at clinically tolerable doses tanespimycin has little effect on resistance-mediating client proteins in relapsed leukemia and exhibits limited activity in combination with cytarabine.     

Safety,risk, and aggression: Health professionals’ experiences of caring for people affected by methamphetamine when presenting for emergency care

The crystalline form of methamphetamine, commonly known as crystal meth (crystal methamphetamine) or ICE, is a highly‐addictive and powerful stimulant. Users of crystal meth often require emergency care, and are associated with a substantial burden of care by emergency care providers. The aim of the present qualitative study was to explore health professionals’ experiences of providing care for patients affected by ICE who presented to the emergency department (ED). Nine semistructured interviews were conducted. The major theme, ‘staying safe’, was revealed, in which participants described their experiences of being exposed to potentially unsafe situations, and their responses to challenging behaviours, including aggression. The findings highlight the need for ED staff to understand the nature of ICE use and its adverse impact on the mental and physical health of users. Furthermore, it is clear that establishing and maintaining safety in the emergency care setting is of utmost importance, and should be a priority for health‐care managers.     

Nurses' attitudes and concerns pertaining to HIV and AIDS

A pilot study was conducted to identify nurses' attitudes and concerns pertaining to the care of people with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) Data were collected using an anonymous, voluntary questionnaire, which was made available to all nurses at a Wellington Area Health Board (New Zealand) hospital Of 562 nursing staff, 286 (51%) responded, of which 74 (25 9%) had previously attended an HIV/AIDS workshop for Area Health Board staff Of those staff handling blood, 132 (49 4%) always wore gloves, and only half of the respondents (n = 148, 51%) treated all body fluids as potentially HIV positive The possible attrition rate from nursing positions in the canvassed hospital was 2 8%, with a further 43 (15 0%) undecided about resigning from their post Only 56 nurses (12 5%) believed the employer did not provide adequate safety measures The provision of education regarding HIV/AIDS, by the employer, was considered inadequate by 61 (213%) respondents This study demonstrates that further safety and education needs should be attended to or reinforced     

Withdrawal of life-support treatment: the experience of critical care nurses

Technological advances in health care have made it possible to restore and prolong life for patients who would have died in the past. Unfortunately, one consequence of this is that some patients linger in intensive care units (ICUs), dependent on the technologies but with no hope of recovery. Therefore, decisions regarding withdrawal of life-support treatment are increasingly being faced by the health-care team.

This study aimed to explore the lived experience of critical care nurses who had cared for patients during withdrawal of life-support. The methodology employed was interpretive phenomenology. Interviews were conducted with seven critical care nurses, with the meanings of the experience of withdrawal of life-support treatment for these nurses extrapolated from the narratives and clustered into themes.

The study highlighted the importance of honest communication during the processes of decision-making and withdrawal of treatment. It was important for these nurses to be sure that family members were well-informed regarding the process of withdrawal of life-support treatment and that they could provide support and ensure that the patient's comfort and dignity were maintained during the process. The need to debrief after the event became evident but formal debriefing processes were rarely undertaken.     

Family presence during resuscitation and invasive procedures

The practice of allowing family to be present during patient resuscitation or invasive procedures (Family Presence) is gaining acceptance in North America and the United Kingdom in controlled circumstances. Research into Family Presence has demonstrated multiple benefits for the patient, family and health care team. These advantages include helping the family to understand the severity of the illness/trauma and to see that appropriate attempts were undertaken to save their loved one. Family Presence can also facilitate improved communication between the health care team and family. In spite of evidence supporting Family Presence as a useful practice for patient, family and health care team, the use of Family Presence is uncommon within Australian emergency departments and hospitals. Clear expectations at organisational, governmental and professional levels are essential to effectively implement this approach. To be supported in the clinical area, the success of a Family Presence program requires an inclusive approach to program development. A critical component of a successful Family Presence program is a family facilitator who is adequately prepared for the role and committed to supporting the family during resuscitation or invasive procedures. Research exploring Family Presence in Australia is lacking and highlights the need for context specific research in this area.     

Busulfan clearance in renal failure and hemodialysis

The impact of hemodialysis on the clearance of busulfan was determined in a patient with chronic renal failure undergoing autologous peripheral stem cell transplantation for non-Hodgkin's lymphoma. The extraction ratio for busulfan across the dialyzer was 0.530 +/- 0.026 at a blood flow of 400 ml/min, which corresponds to a hemodialysis clearance of 2.23 +/- 0.11 ml/min/kg body weight. Apparent oral clearance of busulfan without hemodialysis was 3.38 +/- 0.56 ml/min/kg. Thus, a 4 h hemodialysis session enhanced the apparent oral clearance of busulfan by 65%. We conclude that hemodialysis effectively removes busulfan from circulating blood, but a standard hemodialysis period (ie, 4 h) does not significantly alter busulfan exposure. Bone Marrow Transplantation(2000) 25, 201-203.     

The role of selection bias in comparing cesarean birth rates between physician and midwifery management.

OBJECTIVE: The midwifery service at our hospital has been observed to have a 2% cesarean birth rate consistently over a 10-year period. There are substantial differences in labor management style between the midwives and physicians. We sought to test the hypothesis that the low cesarean birth rate on the midwifery service was the result of patient selection bias. METHODS: A randomized blinded clinical trial was conducted in which 492 low-risk patients were assigned to either physician or midwifery management. The provider responsible for labor management was unable to determine group assignment. Patients in the midwifery group were managed by previously established protocols, and outcome was attributed to the midwives even if the patients subsequently required transfer to physician management. Route of delivery was the primary outcome measurement. Continuous variables were analyzed using Student t test and discrete variables using chi 2. RESULTS: There were no demographic differences between the groups, and the admission pelvic examinations were the same. The patients assigned to the midwifery group had a 2.1% cesarean birth rate, whereas those assigned to physician management had a 0.4% rate. The higher rate of operative vaginal deliveries in the physician group was statistically significant. There were no differences in neonatal outcomes. The physician-managed group had significantly more episiotomies and third- and fourth-degree extensions. CONCLUSIONS: The 2% cesarean birth rate observed on the midwifery service appeared to be the result of patient selection bias. A low cesarean birth rate can be achieved by either physician or midwifery management in a selected low-risk population.     

Preclinical pharmacology of ecteinascidin 729, a marine natural product with potent antitumor activity

 Ecteinascidins are marine natural products with potent antiproliferative activity under evaluation as chemotherapeutic agents by the National Cancer Institute. Ecteinascidins bind the minor groove of DNA and may form covalent adducts with DNA by binding the N-2 of guanine in a fashion similar to saframycin antibiotics. The most potent ecteinascidin is ET-729 with antitumor activity observed following administration of 3.8 and 10 μg/kg to mice bearing P388 leukemia and B16 melanoma, respectively. A reverse-phase high-performance liquid chromatography (HPLC) assay and an L1210 cell bioassay were developed for ET-729 and utilized for stability and murine pharmacokinetic studies. HPLC analysis showed that ET-729 was stable in organic solvents, mobile phase and acidic buffer (t_1/2 > 100 h). Stability was diminished under neutral and basic conditions (t_1/2 < 14 h). Following a 48-h incubation with L1210 cells in growth medium in the absence and presence of 2.5% murine plasma, the 50% growth inhibitory concentrations (IC₅₀) of ET-729 were 37 and 72 pM, respectively. Following intravenous administration of ET-729 to male CD2F₁ mice, the disappearance of antiproliferative activity determined by the bioassay was described by a two-compartment open model. The mean values of the elimination half-life and plasma clearance were 28 min and 39.7 ml/min per kg, respectively. Following intraperitoneal administration, peak plasma concentrations of antiproliferative activity were observed 6–15 min after injection and antiproliferative concentrations remained above 1 nM for longer than 1 h. Intraperitoneal bioavailability varied over a wide range (20–91%). Antiproliferative activity was detected in every urine sample following intravenous and intraperitoneal administration, but the total 48-h urinary recovery was less than 0.1%. Received: 23 September 1994/Accepted: 6 December 1995     

A memory clinic at a geriatric hospital: a report on 577 patients assessed with the CAMDEX over 9 years

OBJECTIVE: To report 9 years' experience of an Australian memory clinic using the -Cambridge Mental Disorders in the Elderly Examination (CAMDEX) assessment schedule, summarizing patient demographics, diagnoses at presentation and the utility of four instruments used in distinguishing patients with and without dementia. METHODS: All patients seen at the clinic between December 1989 and September 1998 were assessed using the CAMDEX. Diagnoses were determined according to criteria of the International Classification of Diseases, tenth edition (ICD-10). RESULTS: The mean age of 577 patients seen was 72.9 years and 60.8% were female. Over 40% fulfilled ICD-10 diagnostic criteria for dementia in Alzheimer's disease. A further 24% had another dementing illness. Only 28 patients were "normal". There was no significant difference in the ability of the 107-item Cambridge cognitive examination, the 30-item mini-mental state examination, the 10-item abbreviated mental test score and the 26-item informant questionnaire on cognitive decline in the elderly to differentiate dementia patients from those who were normal or had functional psychiatric disorders. The four cognitive screening tools had high correlations with one another (r = - 0.57 to 0.93). CONCLUSION: Patient demographics and diagnoses were similar to those found in other clinics. Most people who attended the memory clinic had significant cognitive or psychiatric disorders.     

Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer's disease

OBJECTIVE: This subanalysis of a large, double-blind, placebo-controlled trial examined the prevalence of behavioral symptoms in moderate to severe Alzheimer's disease (AD), and the effect of treatment with donepezil. METHODS: Two hundred ninety patients with moderate to severe AD (standardized Mini-Mental State Examination scores 5-17) were randomized to receive 24 weeks of once-daily doses of donepezil 5 mg/day for 28 days, and 10 mg/day thereafter per the clinician's judgment (n = 144), or placebo (n = 146). The outcome measure of interest was the 12-item Neuropsychiatric Inventory (NPI). RESULTS: Baseline demographics were similar between the treatment groups. Least squares mean (+/- SE) baseline NPI 12-item total scores were 19.55 +/- 1.48 and 19.30 +/- 1.45, respectively. At baseline, the most common symptoms were apathy/indifference (67%), aberrant motor behavior (53%), depression/dysphoria (52%), anxiety (49%), and agitation/aggression (45%). NPI individual item change from baseline scores at Week 24 using a last observation carried forward (LOCF) analysis showed benefits with donepezil treatment compared with placebo for all items, with significant treatment differences for depression/dysphoria, anxiety, and apathy/indifference (p < .05). Symptoms present at baseline that improved significantly for donepezil- compared with placebo-treated patients at Week 24 LOCF included anxiety, apathy/indifference, and irritability/lability (p < .05). When patients who were not receiving psychoactive medications at baseline were analyzed separately, significant improvements in NPI (continued) 12-item total score were observed with donepezil compared with placebo at most visits and at Week 24 LOCF (p < .05). CONCLUSIONS: Behavioral symptoms of the magnitude observed in this moderate to severe AD population improved with donepezil.