Sustained 3-Day Intravenous Cocaine Exposure Decreases Appetite and Hunger But Does Not Alter Food...
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CLINICAL PHARMACOLOGY & THERAPEUTICS vo~,uM~ 73, NUMBER2 American Society for Clinical Pharmacology and Therapeutics P35 PII-21 PHARMACOKINETICS AND SAFETY OF TELITHROMYCIN AFTER SINGLE AND MULTIPLE DOSES IN PATIENTS WITH RENAL IMPAIRMENT. J. Shi, MD, G. Montay, PhD, S. Chapel, PhD, P. Hardy, MS, J. Barrett, PhD, M. Sack, MD, T. Marbury, MD, S. Swan, MD, R. Vargas, MD, V. Leclerc, MD, B. Leroy, MD, V. Bhargava, PhD, Aventis, Radiantresearch, Orlando Clinical Research Center, DaVita Clinical Research and Hennepin County Medical Center, Clinical Research Center, Bridgewater, NJ. The pharmacokinetics (PK) and safety of telithromycin (TEL) were assessed in subjects with varying degrees of renal function in single dose (SD) and multiple dose (MD) studies. In SD study, 40 subjects received an oral dose of TEL 800mg. In MD study, oral doses of 400, 600 or 800mg TEL were administered qd for 5 days, in 36 patients with renal impairment receiving 2 of the 3 regimens in a balanced incomplete cross-over design. 9 healthy subjects (controls) received TEL 800mg. Drug concentrations in plasma and urine were determined at pre-set time points. Serial 12-lead ECGs were recorded on Day -1 (before drug) and Day 5. In healthy controls in both studies, renal clearance (CLa) accounted for ,<_20% of TEL elimina- tion. PK parameter estimates are summarized: SD, 800rag MD, 800rag qd CLcR n Cm,~ AUC(o_~ ) CLca n Cmax,ss AUC(o_24)~ mL/min mg/L mg/L.h mL/min mg/L mg/L.h >80 10 2.3 10.1 >80 9 2.1 12.4 41-80 10 3.0 14.3 50-80 8 2.6 16.0 11-40 10 3.3 16.0 30-49 8 2.2 14.8 <10 10 2.1 10.8 <30 8 3.0 23.6 In both studies, there was no correlation between Cm,~ and CLcR , whereas a linear relationship between CL R and CLcR was observed. In MD study, CL R was independent of dose. In subjects with CLcR <30mL/min, C ...... and AUC(o_24)s s increased 1.4- to 1.9-fold, respectively, compared with healthy subjects. There were no serious adverse events and no noteworthy QTc prolongation related to the drug in either study. The effect of renal impairment on TEL PK is statistically significant in patients with CLcR <30mL/min receiving multiple doses. PII-22 EFFECT OF KETOCONAZOLE ON THE PHARMACOK1NET- ICS AND SAFETY OF TELITHROMYCIN AND CLARITHRO- MYCIN 1N ELDERLY SUBJECTS WITH DIMINISHED RENAL FUNCTION. J. Shi, MD, S. Chapel, PhD, G. Montay, PhD, P. Hardy, MS, J. Barrett, PhD, D. Sica, MD, S. Swan, MD, R. Noveck, MD, B. Leroy, MD, V. Bhargava, PhD, Aventis, Medical College of Virginia, DaVita Clinical Research and Hennepin County Medical Center, Clinical Research Center, New Orleans, Bridgewater, NJ. The effect of impaired renal function and inhibited CYP3A4 metabolic pathway on the pharmacokinetics of telithromycin (TEL) and clarithromycin (CLA) was studied in elderly subjects. 33 subjects (age 59-84 years) with creatinine clearance (CLcR) 24-79mL/min were randomized to receive ketoconazole (KEL) 400rag qd, alone (n= 11) or concomitantly with either TEL 800mg qd (n= 12) or CLA 500rag bid (n= 10) for 5 days. Drug concentrations in plasma and urine were determined at pre-set time points. Serial 12-lead ECGs were recorded on Day -1 (before dosing) and on Day 5 and liver function parameters were monitored. At comparable renal function (CLcR=30-79mL/min), TEL mean±SD C ........ was 3.6±0.8mg/L and AUC(o_24~ was 33.4- + 10.2mg/L.h (n= 10), while CLA C ....... was 6.2±2.3mg/L and AUC(o_t2)~~ was 56.1±22.9mg/L.h (n=6). Compared to historical data in healthy subjects receiving TEL or CLA alone, C ........ was increased --1.7 and 2.2 fold for TEL and CLA, respectively, in elderly subjects with mild/moderate renal im- pairment receiving KEL. In 2 subjects with severe renal impairment (CLc R <30mL/min), TEL C ......... was significantly higher than those with CLcR >30mL/min but within the highest threshold in Phase III studies. There were no serious adverse events, no liver enzyme changes and no noteworthy QTc prolongation among patients who received TEL and KEL. Multiple impairment was associated with a moderate increase in TEL plasma levels, with the greatest increase in subjects with CLcR<30mL/min. PII-23 ABSENCE OF TH1 OR TH2 CYTOKINE DIFFERENTIATION AFTER MEASLES VACCINE VIRUS IMMUNIZATION FAIL- URE. R. Bonilla Guerrero, MD, PhD, N. Dhiman, PhD, D. L O'Kane, PhD, R. M. Jacobson, MD, G. A. Poland, MD, Mayo Clinic, Rochester, MN. Background: To understand cytokine gene regulation after mea- sles vaccine virus (MVV) immunization and to further understand the development of protective immune responses, we compared cytokine mRNA expression in two populations. Methods: We recruited 4 subjects categorized as normal antibody (Ab) responders (N, n=2), and low Ab responders (LR, n=2) based on serum measles-specific IgG antibody level. Each subject underwent phlebotomy. Peripheral blood mononuclear cells (PBMCs) were isolated and cultured in the presence or absence of 2000 TCIDso of MVV. Total RNA was extracted (Qiagen RNeasy extraction kit) after 6 hours, and after day 3 and day 4 of incubation. The mRNA expression levels for 12 cytokines (IL-la, IL-lb, IL-2, IL-4, IL-5, IL-8, IL-10, iL-t2p35, IL-12p40, IFN-~, and TNF-c0 were assayed by TaqMan RT-PCR assay. Results: Normal and low responders have similar cytokine mRNA levels (P <0.0001). Normal responders have a larger fold change increase (12 vs. 1.5 fold) in stimulated PBMCs than low responders (P 0.007). We found no significant difference in Thl and Th2 cytokine mRNA in all subjects (P 0.1516). Conclusions: Despite differences in the Ab production between, we found simultaneous Thl and Th2 cytokine mRNA response after MVV stimulation. This suggests that at a critical point in the cytokine production pathway the production is dysrngulated, which underlies all variations in immune response phenotypes after measles vaccination, including vaccine failure. PII-24 SUSTAINED 3-DAY INTRAVENOUS COCAINE EXPOSURE DECREASES APPETITE AND HUNGER BUT DOES NOT AL- TER FOOD INTAKE PATTERNS IN COCAINE-DEPENDENT VOLUNTEERS. A. P. Manari, BS, N. Uemara, MD, PhD, R. P. Nath, MD, D. S. Harris, MD, R. T. Jones, MD, J. E. Mendelson, MD, University of California, San Francisco, San Francisco, CA. Cocaine use has been reported to decrease food intake in animals and hmnans. However, no data are available on the anorexic effect of sustained cocaine exposure in humans. As part of a study of the safety of substitution therapy in cocaine addicts, we assessed the effects of sustained intravenous cocaine exposure on caloric intake and visual analog scales (VAS) for "Appetite" and "Hunger". Seven cocaine~ dependent volunteers were admitted to the UCSF GCRC for 17 days mid underwent two double-blind, 3-day, 12-hour cocaine (0.375 mg/kg/h) or placebo infusions. Food and water were available ad libitum. VAS and caloric intake were measured on day 1 and day 3 of the cocaine infusions. Cocaine infusions significantly suppressed "Appetite" and "Hunger" on day 1 compared to placebo. However, tolerance developed to this anorexic effect of cocaine on day 3. By day 3, cocaine no longer suppressed VAS rated appetite or hunger. Cocaine infusions had no effect on total calories consumed and no weight changes were seen (70.9 kg -+ 12.6 baseline and 69.6 kg + 13.8 at the end of study). We conclude that: l) cocaine can briefly suppress appetite and hunger; 2) tolerance rapidly develops to these mild anorexic effects, and 3) food intake is unaffected by the mild suppression of hunger in cocaine-dependent volunteers.
Transcript of Sustained 3-Day Intravenous Cocaine Exposure Decreases Appetite and Hunger But Does Not Alter Food...
CLINICAL PHARMACOLOGY & THERAPEUTICS vo~,uM~ 73, NUMBER2 American Society for Clinical Pharmacology and Therapeutics P35
PII-21 PHARMACOKINETICS AND SAFETY OF TELITHROMYCIN
AFTER SINGLE AND MULTIPLE DOSES IN PATIENTS WITH RENAL IMPAIRMENT. J. Shi, MD, G. Montay, PhD, S. Chapel, PhD, P. Hardy, MS, J. Barrett, PhD, M. Sack, MD, T. Marbury, MD, S. Swan, MD, R. Vargas, MD, V. Leclerc, MD, B. Leroy, MD, V. Bhargava, PhD, Aventis, Radiantresearch, Orlando Clinical Research Center, DaVita Clinical Research and Hennepin County Medical Center, Clinical Research Center, Bridgewater, NJ.
The pharmacokinetics (PK) and safety of telithromycin (TEL) were assessed in subjects with varying degrees of renal function in single dose (SD) and multiple dose (MD) studies. In SD study, 40 subjects received an oral dose of TEL 800mg. In MD study, oral doses of 400, 600 or 800mg TEL were administered qd for 5 days, in 36 patients with renal impairment receiving 2 of the 3 regimens in a balanced incomplete cross-over design. 9 healthy subjects (controls) received TEL 800mg. Drug concentrations in plasma and urine were determined at pre-set time points. Serial 12-lead ECGs were recorded on Day -1 (before drug) and Day 5. In healthy controls in both studies, renal clearance (CLa) accounted for ,<_20% of TEL elimina- tion. PK parameter estimates are summarized:
SD, 800rag MD, 800rag qd
CLcR n Cm,~ AUC(o_~ ) CLca n Cmax,ss AUC(o_24)~ mL/min mg/L mg/L.h mL/min mg/L mg/L.h
>80 10 2.3 10.1 >80 9 2.1 12.4 41-80 10 3.0 14.3 50-80 8 2.6 16.0 11-40 10 3.3 16.0 30-49 8 2.2 14.8 <10 10 2.1 10.8 <30 8 3.0 23.6
In both studies, there was no correlation between Cm, ~ and CLcR , whereas a linear relationship between CL R and CLcR was observed. In MD study, CL R was independent of dose. In subjects with CLcR <30mL/min, C . . . . . . and AUC(o_24)s s increased 1.4- to 1.9-fold, respectively, compared with healthy subjects. There were no serious adverse events and no noteworthy QTc prolongation related to the drug in either study. The effect of renal impairment on TEL PK is statistically significant in patients with CLcR <30mL/min receiving multiple doses.
PII-22 EFFECT OF KETOCONAZOLE ON THE PHARMACOK1NET-
ICS AND SAFETY OF TELITHROMYCIN AND CLARITHRO- MYCIN 1N ELDERLY SUBJECTS WITH DIMINISHED RENAL FUNCTION. J. Shi, MD, S. Chapel, PhD, G. Montay, PhD, P. Hardy, MS, J. Barrett, PhD, D. Sica, MD, S. Swan, MD, R. Noveck, MD, B. Leroy, MD, V. Bhargava, PhD, Aventis, Medical College of Virginia, DaVita Clinical Research and Hennepin County Medical Center, Clinical Research Center, New Orleans, Bridgewater, NJ.
The effect of impaired renal function and inhibited CYP3A4 metabolic pathway on the pharmacokinetics of telithromycin (TEL) and clarithromycin (CLA) was studied in elderly subjects. 33 subjects (age 59 -84 years) with creatinine clearance (CLcR) 24-79mL/min were randomized to receive ketoconazole (KEL) 400rag qd, alone (n= 11) or concomitantly with either TEL 800mg qd (n= 12) or CLA 500rag bid (n= 10) for 5 days. Drug concentrations in plasma and urine were determined at pre-set time points. Serial 12-lead ECGs were recorded on Day -1 (before dosing) and on Day 5 and liver function parameters were monitored. At comparable renal function (CLcR=30-79mL/min), TEL mean±SD C ........ was 3.6±0.8mg/L and AUC(o_24~ was 33 .4 - + 10.2mg/L.h (n= 10), while CLA C ....... was 6.2±2.3mg/L and AUC(o_t2)~ ~ was 56.1±22.9mg/L.h (n=6). Compared to historical data in healthy subjects receiving TEL or CLA alone, C ........ was increased --1.7 and 2.2 fold for TEL and CLA, respectively, in elderly subjects with mild/moderate renal im- pairment receiving KEL. In 2 subjects with severe renal impairment (CLc R <30mL/min), TEL C ......... was significantly higher than those with CLcR >30mL/min but within the highest threshold in Phase III studies. There were no serious adverse events, no liver enzyme changes and no noteworthy QTc prolongation among patients who received TEL and KEL. Multiple impairment was associated with a moderate increase in TEL plasma levels, with the greatest increase in subjects with CLcR<30mL/min.
PII-23 ABSENCE OF TH1 OR TH2 CYTOKINE DIFFERENTIATION
AFTER MEASLES VACCINE VIRUS IMMUNIZATION FAIL- URE. R. Bonilla Guerrero, MD, PhD, N. Dhiman, PhD, D. L O'Kane, PhD, R. M. Jacobson, MD, G. A. Poland, MD, Mayo Clinic, Rochester, MN.
Background: To understand cytokine gene regulation after mea- sles vaccine virus (MVV) immunization and to further understand the development of protective immune responses, we compared cytokine mRNA expression in two populations. Methods: We recruited 4 subjects categorized as normal antibody (Ab) responders (N, n=2), and low Ab responders (LR, n=2) based on serum measles-specific IgG antibody level. Each subject underwent phlebotomy. Peripheral blood mononuclear cells (PBMCs) were isolated and cultured in the presence or absence of 2000 TCIDso of MVV. Total RNA was extracted (Qiagen RNeasy extraction kit) after 6 hours, and after day 3 and day 4 of incubation. The mRNA expression levels for 12 cytokines (IL-la, IL-lb, IL-2, IL-4, IL-5, IL-8, IL-10, iL-t2p35, IL-12p40, IFN-~, and TNF-c 0 were assayed by TaqMan RT-PCR assay. Results: Normal and low responders have similar cytokine mRNA levels (P <0.0001). Normal responders have a larger fold change increase (12 vs. 1.5 fold) in stimulated PBMCs than low responders (P 0.007). We found no significant difference in Thl and Th2 cytokine mRNA in all subjects (P 0.1516). Conclusions: Despite differences in the Ab production between, we found simultaneous Thl and Th2 cytokine mRNA response after MVV stimulation. This suggests that at a critical point in the cytokine production pathway the production is dysrngulated, which underlies all variations in immune response phenotypes after measles vaccination, including vaccine failure.
PII-24 SUSTAINED 3-DAY INTRAVENOUS COCAINE EXPOSURE
DECREASES APPETITE AND HUNGER BUT DOES NOT AL- TER FOOD INTAKE PATTERNS IN COCAINE-DEPENDENT VOLUNTEERS. A. P. Manari, BS, N. Uemara, MD, PhD, R. P. Nath, MD, D. S. Harris, MD, R. T. Jones, MD, J. E. Mendelson, MD, University of California, San Francisco, San Francisco, CA.
Cocaine use has been reported to decrease food intake in animals and hmnans. However, no data are available on the anorexic effect of sustained cocaine exposure in humans. As part of a study of the safety of substitution therapy in cocaine addicts, we assessed the effects of sustained intravenous cocaine exposure on caloric intake and visual analog scales (VAS) for "Appetite" and "Hunger". Seven cocaine~ dependent volunteers were admitted to the UCSF GCRC for 17 days mid underwent two double-blind, 3-day, 12-hour cocaine (0.375 mg/kg/h) or placebo infusions. Food and water were available ad libitum. VAS and caloric intake were measured on day 1 and day 3 of the cocaine infusions. Cocaine infusions significantly suppressed "Appetite" and "Hunger" on day 1 compared to placebo. However, tolerance developed to this anorexic effect of cocaine on day 3. By day 3, cocaine no longer suppressed VAS rated appetite or hunger. Cocaine infusions had no effect on total calories consumed and no weight changes were seen (70.9 kg -+ 12.6 baseline and 69.6 kg + 13.8 at the end of study). We conclude that: l) cocaine can briefly suppress appetite and hunger; 2) tolerance rapidly develops to these mild anorexic effects, and 3) food intake is unaffected by the mild suppression of hunger in cocaine-dependent volunteers.
