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.

Accuracy of 2- and 8-hour urine collections for measuring creatinine clearance in the hospitalized elderly.

The accuracy of 2- and 8- hour urine collections for estimating creatinine clearance was compared with that of the standard 24-hour procedure in 45 hospitalized elderly patients (age > or = 65 yrs) with indwelling urethral catheters. Urine was collected at blocked intervals from 0-2, 2-8, and 8-24 hours and then added together to determine the 8- and 24-hour clearances. The mean 8-hour creatinine clearance was not significantly different from the 24-hour value, whereas the mean 2-hour creatinine clearance was significantly different. The 8-hour value was less biased (2.2 and 10.7 ml/min, respectively) and more precise (11.7 and 25.3 ml/min, respectively) than the 2-hour value. Regardless of age, renal function, serum creatinine level, or diuretic use, the 8-hour value was less biased, usually more precise, and clinically more accurate. Thus it can be used in stable, hospitalized, elderly patients with indwelling catheters to determine degrees of renal impairment and provide optimum drug dosing.

Attitudes toward discussing life-sustaining treatments in extended care facility patients.

OBJECTIVE: To determine nursing home residents' attitudes toward discussing life-sustaining treatment plans with their physicians and the factors associated with these attitudes. DESIGN: Random-sample, interviewer-administered survey. SETTING: Forty-one nursing homes in which some residents were cared for by house-staff physicians of the Hennepin County (Minnesota) Medical Center Extended Care Department. PATIENTS: Random sample of 150 nursing home residents receiving primary care from Extended Care Department physicians, 131 (87%) of whom completed the interview. RESULTS: Older individuals were less likely to have spoken with physicians and family members about treatment plans (p < 0.05), and to have felt that they had more say than necessary in their treatment (P < 0.05). Only 19 (14.5%) residents had formal treatment plan discussions about limiting life-sustaining treatment. Although perceived current health status did not differ between residents with and without treatment plans, those residents who had discussions about advance directives were more likely to report health improvement over the past 6 months (P < 0.05). Residents with formal advance directives were, on average, 8.4 years younger than those without them (P < 0.05). CONCLUSIONS: Younger patients are more likely to have had discussions about life-sustaining treatment and are also more frequently involved in plan development. Preferences for level of involvement should be considered during advance directive planning, and it should be recognized that these preferences may vary with age. Future research should evaluate whether this age relationship is a true age or a cohort effect.

Predictive performance of equations to estimate creatinine clearance in hospitalized elderly patients.

OBJECTIVE: To ascertain the clinical accuracy of equations that estimate creatinine clearance to predict the correct drug doses in hospitalized elderly patients DESIGN: Single 24-hour creatinine clearance measurement compared with estimated creatinine clearances derived from eight equations using total and modified ideal body weight SETTING: Nonintensive care medical and surgical units at a county hospital PATIENTS: 15 patients with urethral catheters were enrolled in each of three age groups: 65-75, 76-85, and greater than or equal to 86 years MAIN OUTCOME MEASUREMENTS: Drug-dose predictions, bias, precision, and absolute errors RESULTS: The bias for all equations was -4.0-42.0 mL/min (-0.07-0.70 mL/s) and the precision was 10.8-47.4 mL/min (0.18-0.88 mL/s). The Jelliffe 1973, Hull et al., and Mawer et al. equations were the least biased and the Jelliffe 1973 was the most precise, followed by the Mawer et al., Hull et al., and Cockcroft-Gault equations. The percent of patients with absolute percent errors greater than 20 percent were 38 percent for Jelliffe 1973, 36 percent for Mawer et al., 40 percent for Hull et al., and greater than 50 percent for the other equations. The percent of patients receiving correct drug doses was 67 percent for Jelliffe 1973, 58 percent for Gates, 51 percent for Mawer et al. and Hull et al., and less than 50 percent for the other equations. Within various age, renal function, serum creatinine, and albumin subgroups, the Jelliffe 1973 estimates were least biased and most precise, followed by the Cockcroft-Gault estimates. Generally, estimates using modified lean body weight performed better than did those using total body weight. CONCLUSIONS: The Jelliffe 1973 equation with modified lean body weight was the best equation, followed by the Cockcroft-Gault equation. Even with the best equation, 33 percent of the patients would have received an incorrect drug dose. Therefore, some elderly patients may still require a measured creatinine clearance.

Health care cost containment measures and mortality in Hennepin County's Medicaid elderly and all elderly.

In Minnesota, several health care cost containment measures occurred about the time Medicare's Prospective Payment System (PPS) was implemented. These included a moratorium on additional nursing home beds, preadmission screening of nursing home applicants, and rapid growth in HMO (health maintenance organization) enrollment by Medicare recipients. Hospital days per elderly Medicaid recipient decreased by 38 percent for those in nursing homes and by 35 percent for those not in nursing homes from 1982 to 1984. By 1986, hospital days per recipient had decreased 53 and 55 percent, respectively, from the 1982 level. Age-adjusted mortality rates for elderly Medicaid nursing home residents for the period 1977 through 1986 showed an increasing trend after 1982. Estimated age-adjusted mortality rates for the entire County population, which had decreased steadily from 1970 to 1982, rose significantly above the projected rate in 1984, 1985, 1986, and 1987. We conclude that, coincident with the institution of the PPS and other health care cost containment measures, use of hospital care has fallen for all elderly Medicaid recipients, age-adjusted mortality rates among those in nursing homes have increased, and the mortality rate trend for the total Hennepin County elderly population has stopped declining.