Topical gentamicin and ethacrynic acid: effects on cochlear function

OBJECTIVE: To determine whether concurrent intravenous administration of the loop diuretic ethacrynic acid potentiates the toxicity of the aminoglycoside antibiotic gentamicin applied topically on the round window. STUDY DESIGN: The authors studied the effects on cochlear sensitivity of co-administered intracardiac ethacrynic acid (40 mg/kg) and high-dose topical gentamicin solution (100%) applied to the round window. Comparisons were made with animals receiving ethacrynic acid plus systemic gentamicin (100 mg/kg); topical gentamicin alone; systemic gentamicin alone; and intravenous ethacrynic acid alone. METHODS: Experiments were carried out on pigmented guinea pigs weighing 400 to 500 g. Changes in cochlear function were characterized by monitoring shifts in compound action potential (CAP) thresholds by use of chronic indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. RESULTS: After 20 days animals receiving ethacrynic acid in combination with topical gentamicin to the round window failed to demonstrate a significant deterioration in cochlear sensitivity, whereas all animals receiving systemic gentamicin plus ethacrynic acid experienced profound increases in CAP thresholds. CONCLUSIONS: This study supports the contention that ethacrynic acid potentiates aminoglycoside ototoxicity by facilitating the entry of the antibiotics from the systemic circulation into the endolymph. In addition, this study answers important clinical concerns regarding the safety of the use of topical aminoglycoside agents in combination with loop diuretics.     

Predicting length of stay in an acute psychiatric hospital

OBJECTIVE: Multivariate statistical methods were used to identify patient-related variables that predicted length of stay in a single psychiatric facility. The study investigated whether these variables remained stable over time and could be used to provide individual physicians with data on length of stay adjusted for differences in clinical caseloads and to detect trends in the physicians' practice patterns. METHODS: Data on all patients discharged over two six-month periods were collected at an acute psychiatric inpatient facility. Stepwise multiple regression analyses were conducted on the two datasets. RESULTS: The results from both analyses revealed that five variables significantly predicted length of stay and were stable over time. They were a primary diagnosis of schizophrenia, the number of previous admissions, a primary diagnosis of a mood disorder, age, and a secondary diagnosis of an alcohol- or other drug-related disorder. For some physicians, the mean length of stay of their patients differed significantly from the length predicted by the regression model--generally, it was shorter. CONCLUSIONS: The results demonstrate that patient-related predictors of length of stay in a single psychiatric hospital can be identified using relatively simple statistical procedures and can be consistent across a large dataset and over time.     

Improving indoor air quality through the use of continual multipoint monitoring of carbon dioxide and dew point

This article summarizes an approach for improving the indoor air quality (IAQ) in a building by providing feedback on the performance of the ventilation system. The delivery of adequate quantities of ventilation to all building occupants is necessary for the achievement of good IAQ. Feedback on the performance includes information on the adequacy of ventilation provided, the effectiveness of the distribution of this air, the adequacy of the duration of operation of the ventilation system, and the identification of leakage into the return plenum, either of outdoor or supply air. Keeping track of ventilation system performance is important not only in terms of maintaining good IAQ, but also making sure that this system continues to perform as intended after changes in building use. Information on the performance of the ventilation system is achieved by means of an automated sampling system that draws air from multiple locations and delivers it to both a carbon dioxide monitor and dew point sensor. The use of single shared sensors facilitates calibration checks as well as helps to guarantee data integrity. This approach to monitoring a building's ventilation system offers the possibility of achieving sustainable performance of this important aspect of good IAQ.     

Comparison of the resistance of C57BL/6 and C3H/He mice to infection with Mycobacterium paratuberculosis

Susceptibility of C57BL/6 (Bcgs) and C3H/HeN (Bcgr) mice to an intraperitoneal infection with Mycobacterium paratuberculosis strain 19698 was compared (by histopathology and the number of mycobacteria isolated from the spleen). Mycobacterial counts from the spleen of Bcgr mice progressively decreased over the course of infection but remained unchanged in Bcgs mice. Granulomatous lesions and acid-fast bacteria were consistently present in the liver and lymph nodes of Bcgs mice, whereas lesions were transient or absent in Bcgr mice. These results indicate that Bcgr mice are inherently resistant to M. paratuberculosis, whereas Bcgs mice are inherently susceptible. These differences may prove useful in elucidating the mechanisms of resistance and susceptibility to paratuberculosis and other mycobacterial infections.     

Identification of a novel inhibitor (NSC 665564) of dihydroorotate dehydrogenase with a potency equivalent to brequinar

A novel inhibitor of dihydroorotate dehydrogenase (DHO-DH) has been discovered using data from the National Cancer Institute's in vitro drug screen. Upon analysis of cytotoxicity results from the sixty tumor cell lines used in this screen, the COMPARE program predicted that NSC 665564 was likely to have the same mechanism of inhibition as brequinar, a known potent inhibitor of DHO-DH. We validated this prediction experimentally using MOLT-4 lymphoblast and found the IC50 of brequinar (0.5 microM) and NSC 665564 (0.3 microM) were comparable and that this induced cytotoxicity was reversed by either uridine or cytidine. The enzyme target of NSC 665564 was shown to be identical to that of brequinar when incubation with each drug followed by a 1 h pulse with [14C] sodium bicarbonate resulted in cellular accumulation of [14C]N-carbamyl-L-aspartic acid and [14C]L-dihydroorotic acid, with concurrent marked depletion of CTP and UTP. The Ki's for NSC 665564 and brequinar were 0.14 and 0.24 microM, respectively, when partially purified MOLT-4 mitochondria (the site of DHO-DH) were used. These results show that mechanistic predictions obtained using correlations from the COMPARE algorithm are independent of structure since the structure of NSC 665564 is dissimilar to that of other established DHO-DH inhibitors.     

Phase I trial of weekly scheduling and pharmacokinetics of titanocene dichloride in patients with advanced cancer

PURPOSE: To determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of a weekly schedule of titanocene dichloride (TD) and to define the pharmacokinetics of titanium in plasma and urine. PATIENTS AND METHODS: Twenty patients with a median age of 58 years received 83 courses of TD. TD was given as 1-hour infusion at escalating doses from 70 to 185 mg/m2/wk. Pharmacokinetic analysis was performed in eight patients for total plasma titanium (TPTi) and in three patients for ultrafiltrable titanium (UFTi). RESULTS: At the fifth dose level (185 mg/m2/wk), a variety of DLTs were seen in five patients: fatigue in three, bilirubinemia in one, and hypokalemia in two. A further six patients were treated at 140 mg/m2; only one had dose-limiting creatinine elevation and this dose was therefore defined as the MTD. No myelosuppression or alopecia were observed. One patient with adenocarcinoma of unknown primary had a minor response. Pharmacokinetic analysis showed that TPTi maximum concentration (Cmax) values were linear with dose and elimination of TPTi was triphasic with a long terminal half-life (t1/2; median, 165 hours; range, 89 to 592). Between 7% and 24.3% of the total of administered titanium was eliminated in urine over the first 24 hours. In contrast, UFTi elimination was described by a one-compartment model with a t1/2 of 0.41 hours; peak levels of UFTi were 5.2% +/- 2.5% those of TPTi. CONCLUSION: The MTD of TD given on a weekly schedule is 140 mg/m2, with cumulative, but reversible creatinine and bilirubin elevation being the DLTs.     

Potent piperazine hydroxyethylamine HIV protease inhibitors containing novel P3 ligands

The 2-isopropyl thiazolyl group is a highly optimized P3 ligand for C2 symmetry-based HIV protease inhibitors, as exemplified in the drug ritonavir. Here we report that incorporation of this P3 ligand into a piperazine hydroxyethylamine series also yielded novel, highly potent inhibitors. In tissue culture assays, the presence of human serum was less deleterious to the activity of these inhibitors than to that of ritonavir. Furthermore, potent activity against ritonavir resistant HIV was observed.