and 40 mg smoked (SM) d-methamphetamine in 8 subjects. F was determined by administering 10 mg deuterium-labeled methamphetamine-d 3 (MA-d3) ...
CLINICALPHARMACOLOGY& THERAPEUTICS
VOLUM~73,NUMBER2
American Societyfi)r Clinical Pharmacology and Therapeutics
OII-B-3 THE BIOAVAILABILITY OF INTRANASAL AND SMOKED METHAMPHETAMINE. J. E. Mendelson, MD, H. Boxenbaum, PhD, D. S. Harris, MD, N. Uemura, MD, PhD, R. P. Nab, MD, E. T. Everhart, PhD, R. T. Jones, MD, University of California, San Francisco, San Francisco, CA. Methamphetamine (MA) abuse is increasing in all areas of the world and abusers use several novel mechanisms to administer doses. This study evaluated the bioavailability (F) of 50 mg intranasal (IN) and 40 mg smoked (SM) d-methamphetamine in 8 subjects. F was determined by administering 10 mg deuterium-labeled methamphetamine-d3 (MA-d3) simultaneously with the IN and SM doses. IN dosing was performed with a 20% MA solution applied as a mist to the nasal mucosa. Smoking was accomplished with a temperature regulated pipe. Levels of MA, MA-d > and the pharmacologically active metabolite amphetamine (Amph) were measured by GC-MS. Pharmacoldnetic (PK) parameters for MA-d 3 (t~a 10.4 hour, Vss 3.9 L/kg, clearance 280 ml/kg/hr, hepatic extraction ratio 19%) were not affected by IN or SM dosing. The F of IN methamphetamine was 79 + 13%. Smoking can be inefficient, with substantial amounts of drug left in the smoking apparatus or destroyed by pyrolysis. Therefore, we estimated F for both the total 40 mg dose and after subtracting residual methamphetamine remaining in the pipe. F for the uncorrected 40 mg dose was 37_+ 14%, but increased to 67-+8% with correction for residual pipe MA. The fractional excretion of MA into urine varied from 10-90%, possibly due to variations in urine pH. Amph had a high renal clearance ( - 9 0 0 ml/h/kg), indicating active tubular secretion. SM produces a shorter T .... (1.2 vs. 3 hours), but all other PK estimates were similar between conditions.
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OII-C-1 RELATIONSHIP BETWEEN CORTICOSTEROID THERAPY AND ATHEROSCLEROSIS IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS. Y. Asanuma, MD, PhD, A. Oeser, A. Shintani, PhD, P. Raggi, MD, C. M. Stein, MD, Vanderbilt University School of Medicine, Tulane University School of Medicine, Nashville, TN. Purpose: In patients with inflammatory diseases it is unclem" whether corticosteroids accelerate atherosclerosis through proatherogenic effects on lipids or retard it through anti-inflammatory effects. Patients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis but the mechanism and relationship to corticosteroid therapy is not known. Methods: The relationship between corticosteroid therapy (cumulative and maximum dose, duration and current use) and coronary calcium by electron beam computed tomography (EBCT), plasma homocysteine, lipids, lipoprotein (a) [Lp(a)] and clinical characteristics was determined in 42 patients with SLE (age 40 + 11 (SD) years). Results: Lp(a) concentrations correlated with duration (P=0.007) and current use (P=0.035) of corticosteroid therapy. Current therapy was associated with triglyceride (P=0.01) but not LDL cholesterol concentrations (P=0.44). Coronary calcium was present in 13 SLE patients and was associated with current (P 0.05) but not with cumulative corticosteroid use (P=0.9). There was no correlation between cumulative corticosteroid dose or duration of therapy and total cholesterol, LDL or homocysteine. Conclusion: In patients with SLE, duration of corticosteroid therapy is correlated with Lp(a) concentrations, but cumulative exposure is not associated with coronary calcimn or worsening of atherosclerotic risk factors. Accelerated atherosclerosis in SLE appears to be independent of corticosteroid treatment.
OII-B-4 THREE DAY 12-HOUR COCAINE INFUSION PRODUCES TOLERANCE IN CARDIOVASCULAR AND SUBJECTIVE EF FECTS, BUT DOES NOT ALTER COCAINE SELFADMINISTRATION BEHAVIOR IN HUMANS. N. Uemura, MD, PhD, A. Manari, BS, R. P. Nath, MD, D. S. Harris, MD, R. T. Jones, MD, J. E. Mendelson, MD, University of California, San Francisco, San Francisco, CA. Previously we have shown that a 12 or 24-hour cocaine infusion (0.25-0.5 mg/kg/h, total dose 6 mg/kg) suppresses cocaine craving and self-administration in humans. To evaluate the safety and efficacy of a longer cocaine exposure, 8 cocaine-dependent volunteers underwent a double-blind, randomized, crossover study to receive 3 day t2-hour cocaine infusions (0.375 mg/kg/h, or placebo). To determine the efficacy in suppressing self-administration and craving or altering the pharmacologic response to cocaine, subjects were allowed to self-administer intravenous cocaine doses in a computerassisted paradigm (self-administered dose, 0.15 mg/kg; minimal interdose interval, 15 rain; duration, 4 hours for a total maximal cocaine dose of 2.4 mg/kg) on days before and after infusion. One subject required discontinuation due to abnormal vital signs (HR>t00, SBP>160, or DBP>100 for more than 30 min) on the first day of cocaine infusion. Infusions were well tolerated in other subjects and produced only small, clinically insignificant changes in heart rate and blood pressure. Tolerance developed to cardiovascular and subjective measures during the 3 day 12-hour cocaine infusion. The degree of tolerance was greater in subjective measures and less in cardiovascular measures. The 3 day 12-hour infusion of cocaine (0.375 mg/ kg/hr) did not decrease the number of self-administered doses, at least in the DDRC self-administration paradigm.
OII-C-2 N-ACETYLCYSTE1NE TO PREVENT CONTRAST-INDUCED NEPHROTOXICITY: EFFECTS ON RENAL FUNCTION, NITRIC OXIDE METABOLISM AND OXIDATIVE STRESS. S. Efrati, MD, V. Dishy, MD, M. Averbuch, MD, A. Blatt, MD, R. I(rakover, MD, J. Weissgarten, MD, J. Morrow, MD, C. M. Stein, MD, A. Golik, MD, Asaf Harofe Medical Center, Vanderbilt University Medical Center, Zerifin, Israel. Contrast media induced nephrotoxicity is a serious complication of coronary angiography in patients with chronic renal failure (CRF). N-acetylcysteine (NAC), a drug with antioxidant and other properties, is renoprotective but the mechanism is not known. Forty-nine patients with CRF (serum creatinine 1.5-+0.07 mg/dl), undergoing coronary angiography, were randomized to receive oral NAC (lg bid, 24 hours before and after coronary angiography, n=24) or placebo (n-25). All patients received standard saline hydration and a low osmolar non-ionated contrast agent. Creatinine clearance (CrC1), was measured before, 24 and 96 hours after angiography. Urinary F2isoprostanes (F2-iso), a measure of oxidant stress, and nitric oxide metabolites (NOx) were measured in the first consecutive 25 patients. Following angiography, CrC1 decreased significantly from baseline in the placebo group, (-14-+2.9 ml/min after 24 hours and .-12+3.1 ml/min after 96 hours, p
