An evaluation of numerical integration algorithms for the estimation of the area under the curve (AUC) in pharmacokinetic studies

Six numerical integration algorithms based on linear and log trapezoidal methods as well as four cubic-spline methods were proposed for estimation of area under the curve (AUC). These six different algorithms were implemented using IMSL/IDL^TM command language and evaluated using data simulated under five different dosing conditions and two different sampling conditions. Comparisons between AUC estimations using these six different algorithms and the theoretical results were made in terms of both overall AUC values and the superimposability of the concentration-time profiles. In well designed studies with ample data points, the algorithm based on IMSL/IDL^TM function CSSHAPE with concavity preservation gave the best performance. In contrast, when the frequency of blood collection was limited, the algorithm based on the log trapezoidal rule proved to be stable with reasonable accuracy, and is recommended as the practical method for numerical interpolation and integration in pharmacokinetic studies. Algorithms based on the combination of the log trapezoidal rule and cubic-spline methods using IMSL/IDL^TM function CSSHAPE can be developed to enhance overall performance.     

In Vivo Proton Spectroscopy of Intracranial Infections and Neoplasms

The chemical characteristics of 10 neoplastic and 11 infectious brain masses were studied by in vivo ¹H magnetic resonance spectroscopy. In tumors, peak height ratios of n-acetyl-L-aspartate to choline were decreased compared to those in normal brain tissue and infectious masses (p < 0.02), but the ratios in normal brains and those with infections did not differ. N-acetyl-L-aspartate—to-creatine/phosphocreatine ratios were significantly lower in infectious masses and tumors compared to normal brain tissue (p = 0.003). However, in progressive multifocal leukoencephalopathy, N-acetyl-L-aspartate appeared relatively unchanged. Lactate was greater than choline in 9 of 11 brains with infection, 0 of 14 control brains, and 1 of 10 tumors. Lactate-to-choline ratios were significantly elevated in infectious masses compared with tumors (p < 0.01). ¹H magnetic resonance spectroscopy is promising for the noninvasive diagnosis of focal brain masses.     

Evaluation of a clinical case definition of AIDS in African children

In July 1986, a provisional clinical case definition of AIDS in children, developed by the World Health Organization (WHO) for surveillance purposes in Africa, was tested on 159 patients hospitalized in the Department of Pediatrics at Mama Yemo Hospital, Kinshasa, Zaire. Twenty-one (13%) of these children were seropositive for HIV. In this population, the clinical case definition of pediatric AIDS was found to be fairly specific (87%) but lacked sensitivity (35%). The positive predictive value for HIV seropositivity was 25%. This study suggests that it is more difficult to define AIDS clinically in children than in adults and that the utility of the proposed WHO clinical case definition for pediatric AIDS for surveillance of children's AIDS in Africa is limited.     

OXYGEN FREE RADICAL IN HUMAN OSTEOARTHRITIS

The xanthine oxidase catalysed release of superoxide free radicals (O2-) from endogenous hypoxanthine was determined in homogenates of synovium obtained from three groups of patients, those undergoing primary or revision total hip replacement (THR) for osteoarthritis and those undergoing arthroscopy of the knee for semilunar disc injuries. The concentrations of hypoxanthine in homogenates obtained during THR were found to be significantly higher than those in the group with semilunar disc injuries. The results suggest that there is a greater predisposition to free radical release and tissue damage in osteoarthritis.     

Ambulatory Surgery Patients May Be Discharged before Voiding after Short-acting Spinal and Epidural Anesthesia

Background: Voiding before discharge is usually required after outpatient epidural or spinal anesthesia because of concern about bladder overdistention and dysfunction. Shorter duration spinal and epidural anesthesia may allow return of bladder function before overdistention occurs in low-risk patients (those younger than age 70, not having hernia, rectal, or urologic surgery, and without a history of voiding difficulty), and predischarge voiding may not be necessary.

Methods: After institutional review board approval and informed consent, 201 low-risk ambulatory patients were prospectively studied in either a standard or accelerated pathway after undergoing spinal or epidural anesthesia with procaine, lidocaine, 2-chloroprocaine, or less than 7 mg bupivacaine; epinephrine was not used in any anesthetic. Standard pathway patients (n = 70) were required to void before discharge. Accelerated pathway (n = 131) patients were not required to void. (After randomization of an initial 163 patients to one of the two tracks, 38 additional patients were assigned to the accelerated pathway.) If accelerated pathway patients voided, they were discharged when all other discharge criteria were met. If they did not spontaneously void after block resolution, a bladder ultrasound (BUS) was performed. If the BUS indicated a urine volume of less than 400 ml, the patients were discharged and instructed to return to the emergency department if they were unable to void within 8 h of discharge. If the BUS indicated a urine volume of greater than 400 ml, the patients were reassessed in 1 h and were discharged if they could void spontaneously. If they could not void spontaneously, they were catheterized to facilitate discharge. All patients were contacted the next day to assess the return of normal bladder function.

Results: All standard pathway patients voided without difficulty, and were discharged in 153 +/- 49 (SD) min. 62 patients in the accelerated pathway voided spontaneously after resolution of their block and were discharged in 127 +/- 41 min. 46 patients were discharged with a BUS less than 400 ml in 120 +/- 42 min. 23 patients had a BUS greater than 400 ml: of these, 20 patients voided within an hour and were discharged in 162 +/- 45 min. Three were catheterized after 1 h, and were discharged in 186 +/- 61 min. Mean discharge time for all patients in the accelerated pathway was 22 min shorter than the standard pathway (P = 0.002). No patients had difficulty voiding or returned to the hospital for urinary problems. None reported new urologic symptoms.     

Safety and efficacy of atorvastatin in heart transplant recipients.

BACKGROUND: Pravastatin and simvastatin prolong survival and reduce transplant-related coronary vasculopathy, although low-density lipoprotein (LDL) lowering with these agents is only modest. The objective of this study was to assess the safety of moderate dose atorvastatin and its efficacy when prior treatment with another statin had failed to lower LDL to < 100 mg/dl. METHODS: Data from 185 patients were retrospectively evaluated for adverse events, duration of exposure (person-days), and the mean atorvastatin dose exposure. Changes in lipid parameters, and prednisone and cyclosporine doses were determined. RESULTS: Safety: 48 patients received atorvastatin for 24,240 person-days at a mean dose exposure of 21 +/- 10 mg. Rhabdomyolysis, myositis, myalgias, and hepatotoxicity occurred in 0, 2, 2, and 0 patients, respectively. All events occurred at the 10-mg dose, within the first 3 months, and were rapidly reversible with atorvastatin discontinuation. Efficacy: Thirty-four patients evaluable for efficacy analyses had a pre-atorvastatin LDL of 145 +/- 38 mg/dl on the following statins: pravastatin (n = 30, 40 +/- 0mg), fluvastatin (n = 3, 33 +/- 12 mg), simvastatin (n = 1, 40 mg). After atorvastatin (21 +/- 9 mg/day) for 133 +/- 67 days, LDL was reduced to 97 +/- 24 mg/dl (relative reduction 31 +/- 20%, p < 0.0001). At the end of the observation period (418 +/- 229 days, atorvastatin final dose 24 +/- 14 mg/day), LDL was further decreased to 88 +/- 23 mg (relative reduction 37 +/- 17%, p < 0.0001). CONCLUSION: Atorvastatin, when used at moderate doses and with close biochemical and clinical monitoring, appears to be safe and is effective in aggressively lowering LDL in heart transplant recipients when treatment with other statins has failed to achieve LDL goals.