A controlled trial of leuprolide with and without flutamide in prostatic carcinoma

To test the hypothesis that maximal androgen blockade improves the effectiveness of the treatment of prostatic cancer, we conducted a randomized, double-blind trial in patients with disseminated, previously untreated prostate cancer (stage D2). All 603 men received leuprolide, an analogue of gonadotropin-releasing hormone that inhibits the release of gonadotropins, in combination with either placebo or flutamide, a nonsteroidal antiandrogen that inhibits the binding of androgens to the cell nucleus. As compared with the 300 patients receiving leuprolide and placebo, the 303 patients randomly assigned to receive leuprolide and flutamide had a longer progression-free survival (16.5 vs. 13.9 months; P = 0.039) and an increase in the median length of survival (35.6 vs. 28.3 months; P = 0.035). The differences between the treatments were particularly evident for men with minimal disease and good performance status; however, further studies should be conducted in this subgroup. Symptomatic improvement was greatest during the first 12 weeks of the combined androgen blockade, when leuprolide alone often produces a painful flare in the disease. We conclude that in patients with advanced prostate cancer, treatment with leuprolide and flutamide is superior to treatment with leuprolide alone.     

The Effect of Functional Pelvic Tilt on the Three-Dimensional Acetabular Cup Orientation in Total Hip Arthroplasty Dislocations

BackgroundAnterior and posterior pelvic tilt appears to play a role in total hip arthroplasty (THA) stability. When changing from the standing to the sitting position, the pelvis typically rotates posteriorly while the hips flex and this affects the femoro-acetabular positions. This case-control study compares changes in 3-D acetabular cup orientation during functional pelvic tilt between posterior THA dislocations vs stable THAs.MethodsStanding and sitting 3-D cup orientation was compared between fifteen posterior dislocations vs 233 prospectively followed stable THAs. 3-D cup orientation was calculated using previously validated trigonometric algorithms on biplanar radiographs. Those algorithms combine the angles in the three anatomical planes (coronal inclination, transverse version, and sagittal ante-inclination) in the standing position with the change in sagittal pelvic tilt from standing to sitting to calculate the 3-D orientation in the sitting position.ResultsThe standing cup orientation of the dislocated THAs was only characterized by a lower coronal inclination (P = .039). Compared with the controls, from standing to sitting, they showed less posterior pelvic tilt (P < .001). This led to a significant lower coronal inclination (P < .001) and sagittal ante-inclination (P < .001) in the sitting position but similar transverse version (P = .366).ConclusionsComparing posterior THA dislocations to stable THAs, there is a lower increase of all three orientation angles from standing to sitting. This leads to a decreased sitting coronal inclination and sagittal ante-inclination which may lead to an increased risk of impingement ensued by THA instability. By contrast, the transverse version was not significantly different in both positions. This confirms the importance of biplanar data on functional cup orientation.Level of EvidenceDiagnostic, Level III.     

Anatomic Porous Replacement hip arthroplasty: first 100 consecutive cases

One hundred consecutive Anatomic Porous Replacement (Intermedics Orthopaedics, Austin, TX) hip replacements were followed for 4 years. Eighty percent of patients had bone ingrowth fixation, 14% stable fibrous, and 6% unstable fibrous (loose) with 4% revised. Only two hips changed fixation grade after 2 years. Bone remodeling showed cancellous hypertrophy of the cortex, usually along the lateral cortex, and 7% had stress shielding (atrophy) of the proximal cortices. Adaptive bone remodeling almost always occurred in type B and C bone. Bone remodeling was statistically related to bone type, prosthetic fill, stem-bone ratio, and collar loading. We concluded that proximal bone ingrowth fixation with proximal load transfer provides good clinical results and excellent bone remodeling. Also, collar loading improves bone response. To expand this fixation in a predictable fashion to all type B and some type C bone requires geometry changes, which have been accomplished in the Anatomic Porous Replacement II.     

Preclinical pharmacokinetics and antitumor activity of imexon

Summary Imexon is an aziridine compound originally studied for immune-enhancing effects on lymphocytes. The drug was well-tolerated in humans and was shown to be active in a variety of animal tumor models. Recently, imexon has demonstrated antitumor activity in human multiple myeloma cell linesin vitro. The pharmacokinetics of the compound using a normal phase HPLC assay were studied in normal mice and in dogs with mast cell tumors. Doses of 100 mg/kg given intraperitoneally produced peak plasma levels over 100 (ml in mice and the drug was rapidly eliminated with half lives of 8 minutes ( phase) and 29 minutes ( phase). Only 20% of an oral imexon dose was absorbed in the mouse. In dogs, the and phase half lives ranged from 18–26 minutes and 91–110 minutes, respectively. Peak levels over 100 g/ml were obtained following intravenous doses of 12.5 mg/kg and 25 mg/kg. Imexon was active in mice bearing either P-388 or L-1210 leukemia, but not in mice with B-16 melanoma. These results suggest that cytotoxic drug concentrations can be obtainedin vivo and that imexon is active in lymphoproliferative tumors.     

The pharmacokinetics and safety profile of oral ganciclovir combined with zalcitabine or stavudine in asymptomatic HIV- and CMV-seropositive patients

Two open-label, randomized, multiple-dose, three-way crossover studies were performed to assess the pharmacokinetics and safety of oral ganciclovir 1000 mg q8h in asymptomatic patients seropositive for human immunodeficiency virus and cytomegalovirus. Ganciclovir was administered alone and in combination with zalcitabine 0.75 mg q8h (study 1) or stavudine 40 mg q12h (study 2). In the presence of zalcitabine, the only statistically significant change in the pharmacokinetic parameters of ganciclovir was a 22.2% mean increase in AUC0-8. However, there was no significant change in the renal clearance of ganciclovir when coadministered with zalcitabine, suggesting that the increase in serum ganciclovir concentration cannot be attributed to competition for active renal tubular secretion. No change in zalcitabine pharmacokinetics was observed in combination with ganciclovir. There were no significant changes in the pharmacokinetics of ganciclovir or stavudine when coadministered. Ganciclovir was well tolerated when given alone and in combination with either zalcitabine or stavudine.     

Inhibition of intracellular Ca2+ signalling, cytotoxicity and antitumor activity of the herbicide oryzalin and its analogues

Purpose: Studies were conducted on oryzalin (3,5-dinitro-N,N-di(n-propyl)sulfanilamide), a widely used dinitroaniline sulfonamide herbicide, which was identified from plant extracts as an inhibitor of mitogen- and growth factor-mediated intracellular free Ca²⁺ ([Ca²⁺]_i) signalling in mammalian cells. Methods and Results: Oryzalin inhibited vasopressin, bradykinin and platelet-derived growth factor [Ca²⁺]_i signalling in Swiss 3T3 fibroblasts with IC₅₀ values of 14, 16 and 18 μM, respectively. ⁴⁵Ca²⁺ uptake into nonmitochondrial stores of saponin-permeabilized Swiss 3T3 cells was inhibited by oryzalin with an IC₅₀ of 34 μM. Oryzalin inhibited colony formation of HT-29 colon carcinoma cells with an IC₅₀ of 8 μM and inhibited the growth of a number of other cancer cell lines and primary human tumors in vitro with IC₅₀ values in the range 3 to 22 μM. A number of oryzalin analogues were studied and an association was found between the ability to inhibit [Ca²⁺]_i signalling and inhibition of the growth of HT-29 human colon cancer cells (P=0.001) and of CCRF-CEM human leukemia cells (P=0.016). Oryzalin at doses up to 600 mg/kg administered orally or subcutaneously daily to mice for 3 to 10 days beginning a day after tumor inoculation inhibited the growth of murine B16 melanoma by 63% but showed no appreciable activity when administered subcutaneously or intraperitoneally to mice beginning a number of days after tumor inoculation against a variety of human tumor xenografts. The peak plasma concentration of oryzalin following repeated subcutaneous administration of oryzalin at 600 mg/kg per day to mice was 37 μM and of its major metabolite N-depropyl oryzalin was 53 μM. Conclusion: It is unlikely that the absence of significant antitumor activity of oryzalin is a result of the inability to achieve adequate plasma concentrations. Received: 24 December 1996 / Accepted: 20 March 1997     

Impact of Generalist Care Managers on Patients with Diabetes

Objective. To determine how the addition of generalist care managers and collaborative information technology to an ambulatory team affects the care of patients with diabetes.
Study Setting. Multiple ambulatory clinics within Intermountain Health Care (IHC), a large integrated delivery network.
Study Design. A retrospective cohort study comparing diabetic patients treated by generalist care managers with matched controls was completed. Exposure patients had one or more contacts with a care manager; controls were matched on utilization, demographics, testing, and baseline glucose control. Using role-specific information technology to support their efforts, care managers assessed patients' readiness for change, followed guidelines, and educated and motivated patients.
Data Collection. Patient data collected as part of an electronic patient record were combined with care manager-created databases to assess timely testing of glycosylated hemoglobin (HbA1c) and low-density lipoprotein (LDL) levels and changes in LDL and HbA1c levels.
Principal Findings. In a multivariable model, the odds of being overdue for testing for HbA1c decreased by 21 percent in the exposure group ( n =1,185) versus the control group ( n =4,740). The odds of being tested when overdue for HbA1c or LDL increased by 49 and 26 percent, respectively, and the odds of HbA1c <7.0 percent also increased by 19 percent in the exposure group. The average HbA1c levels decreased more in the exposure group than in the controls. The effect on LDL was not significant.
Conclusions. Generalist care managers using computer-supported diabetes management helped increase adherence to guidelines for testing and control of HbA1c levels, leading to improved health status of patients with diabetes.