The Early Reversibility of Rocuronium-induced Paralysis with Different Doses of Neostigmine
Pharmacokinetics of BID Versus QID Dosing of Sulfadiazine in HIV-infected Patients
The Effect of Garlic on the Pharmacokinetics of Saquinavir in Healthy Volunteers
Evaluation of the Effect of Melatonin on the Activities of Cytochrome p450 1A2, 2D6, 3A4, NAT2, and Xanthine Oxidase
Evaluation of the Potential Effect of St. John's Wort on Carbamazepine Steady State Pharmacokinetics in Normal, Healthy Volunteers
INTRAMURAL
RESEARCH PROJECT
Z01 CC-00122-04 PHAR
October 1, 1999 to September 30, 2000
Title of Project:
The Early Reversibility of Rocuronium-induced Paralysis with Different Doses
of Neostigmine
Principal Investigator:
G.M. Susla, Pharm.D.
PHAR, CC, NIH
Bethesda, MD 20892
Other Personnel:
K.S. Williams, M.D., ANES
H. Preas, M.D., ANES
Collaborating Unit:
None
Staff-Years:
0.5
Human Subjects:
x (a) Human subjects (b) Human tissues (c) Neither
(a1) Minors (a2) Interviews
Summary of Work: Neuromuscular blocking agents are commonly used to facilitate endotracheal intubation. Succinylcholine, an ultra-short-acting depolarizing neuromuscular blocking agent, is the most commonly used agent for paralysis in this setting because of its rapid onset and short duration of paralysis. In patients with contraindications to succinylcholine or in whom a difficult airway is anticipated, a neuromuscular blocking agent with a pharmacodynamic profile similar to succinylcholine would be an attractive alternative. Rocuronium, a new intermediate-acting nondepolarizing neuromuscular blocking agent, produces paralysis within 60 seconds, which is similar to succinylcholine, but has a duration of paralysis of approximately 20 to 30 minutes.
If rocuronium-induced paralysis could be chemically reversed within 10 to 15 minutes after the administration of an intubating dose, it may be an appropriate alternative in patients with contraindications to succinylcholine or in patients for whom a difficult airway is anticipated. Neostigmine is an anticholinesterase agent that inhibits the hydrolysis of acetylcholine by competing with acetylcholine for attachment to acetylcholinesterase. Inhibition of the breakdown of acetylcholine allows the neurotransmitter to be present in the neuromuscular junction for a longer period of time, so that each molecule can bind repeatedly with the acetylcholine receptor. The purpose of this study is to determine the dose of neostigmine necessary for the early reversal of rocuronium-induced paralysis.
INTRAMURAL
RESEARCH PROJECT
Z01 CC-05089-03 PHAR
October 1, 1999 to September 30, 2000
Title of Project:
Pharmacokinetics of BID Versus QID Dosing of Sulfadiazine in HIV-infected Patients
Principal Investigator:
S.C. Piscitelli, Pharm.D.
PHAR, CC, NIH
Bethesda, MD 20892
Other Personnel:
W. Knebel, Pharm.D., PHAR
Collaborating Units:
NIAID; OP8 clinic, 11 West Day Hospital
NIAID (R. Davey, M.D.; R. Walker, M.D.; J. Fallon, M.D.; M. Polis, M.D.)
CCMD (H. Masur, M.D.; J. Kovacs, M.D.)
Staff-Years:
0.5
Human Subjects:
x (a) Human subjects (b) Human tissues (c) Neither
(a1) Minors (a2) Interviews
Summary of Work: This study is an open-label, randomized crossover study to compare the pharmacokinetics of sulfadiazine given on a twice-daily basis with a four-times-daily schedule. Ten HIV-infected patients with CD4 counts below 500 will be enrolled. Patients must not have concurrent opportunistic infections and must be willing to comply with the study regimen. The study is designed to compare pharmacokinetic parameters and serum concentrations of sulfadiazine at two doses: 1000mg QID and 2000mg BID. Additionally, this study will assess the safety and tolerability of these dosage regimens. Currently, the study has received Institute Review Board approval and will begin enrolling within the next 1 to 2 months.
INTRAMURAL
RESEARCH PROJECT
Z01 CC-05090-01 PHAR
October 1, 1999 to September 30, 2000
Title of Project:
The Effect of Garlic on the Pharmacokinetics of Saquinavir in Healthy Volunteers
Principal Investigator:
S.C. Piscitelli, Pharm.D.
PHAR, CC, NIH
Bethesda, MD 20892
Other Personnel:
A. Burstein, Pharm.
D. S. Vogel, B.S.N.
N. Welden, B.S.N.
C. Daniels, Ph.D.
Collaborating Unit:
None
Staff-Years:
0.2
Human Subjects:
x (a) Human subjects (b) Human tissues (c) Neither
(a1) minors (a2) interview
Summary of Work: Complementary and alternative medicines are widely used in the HIV-infected population. Recent data have shown serious drug interactions between certain complementary medicines and protease inhibitors. Garlic is a commonly used dietary supplement, and data are available suggesting that it has single-dose inhibitory effects and multiple-dose inducing effects on cytochrome P4503A4. To evaluate the effect of garlic on the protease inhibitor saquinavir (SQV), ten healthy subjects will receive SQV (Fortovase) alone and in combination with an over-the-counter garlic preparation. SQV initially will be administered alone at a dose of 1200 mg TID for three days, and serial samples will be collected for determination of SQV pharmacokinetics after the morning dose on day 4. Beginning on day 5, garlic will be administered as one capsule TID for 21 days. On day 22 (day 18 of garlic), saquinavir will be started again at 1200 mg TID and continued for three days. On the morning of study day 25, subjects will receive their last dose of garlic and will be administered a dose of saquinavir with collection of serial samples. There will then be a 10-day washout period with no drugs, after which SQV will be given again for three days. Samples will be collected on the morning of the fourth day to evaluate the offset of the effects of garlic. SQV concentrations in plasma will be determined using a validated HPLC method. Steady-state noncompartmental parameters of SQV in the presence and absence of garlic will be determined. Pharmacokinetic parameters will be compared using an ANOVA that will include factors for a period effect and a treatment effect. Statistical analyses will include calculation of the mean ratio of the AUC in the treatment phases compared with saquinavir alone and determination of 95 percent confidence intervals. This study will help define the drug interaction potential of complementary and alternative therapies in HIV-infected patients.
INTRAMURAL
RESEARCH PROJECT
Z01 CC-05091-01 PHAR
October 1, 1999 to September 30, 2000
Title of Project:
Evaluation of the Effect of Melatonin on the Activities of Cytochrome p450 1A2,
2D6, 3A4, NAT2, and Xanthine Oxidase
Principal Investigator:
A. Burstein, Pharm.D.
PHAR, CC, NIH
Bethesda, MD 20892
Other Personnel:
S. Sato, M.D.
Collaborating Unit:
NINDS (K. Liow, M.D.)
Staff-Years:
0.5
Human Subjects:
x (a) Human subjects (b) Human tissues (c) Neither
(a1) Minors (a2) Interview
Summary of Work: Melatonin is an endogenous hormone administered in supraphysiologic doses for promoted uses of antioxidant, antiaging, contraception, adjunct therapy with cancer chemotherapy, and treatment of sleep disorders. Despite its widespread use, there are no data regarding the potential for drug interactions. The purpose of this study is to determine the effect of administration of melatonin for 1 week on the activity of cytochrome p450 1A2, 2D6, 3A4, NAT2, and Xanthine Oxidase (XO). Fifteen healthy volunteers will undergo enzyme activity phenotyping by ingesting 2 mg/kg of caffeine and 30 mg of dextromethorphan followed by an overnight urine collection on five occasions. Subjects will take, in a randomized, crossover design, 3 mg of melatonin at bedtime for 1 week and ketoconazole 200 mg once daily for 5 days each separated by a one-week washout period. Beginning the evening before and following each course of therapy, subjects will undergo enzyme activity phenotyping again as described above. Enzyme activity following 7 days of melatonin will be compared with pre-treatment values to characterize the magnitude of inhibition of cytochrome p450 1A2, 2D6, 3A4, NAT2, and XO activity.
INTRAMURAL
RESEARCH PROJECT
Z01 CC-05092-01 PHAR
October 1, 1999 to September 30, 2000
Title of Project:
Evaluation of the Potential Effect of St. John's Wort on Carbamazepine
Steady State Pharmacokinetics in Normal, Healthy Volunteers
Principal Investigator:
A. Burstein, Pharm.D.
PHAR, CC, NIH
Bethesda, MD 20892
Other Personnel:
W. Theodore, M.D.
Collaborating Units:
NINDS (T. Dunn, M.D.)
NURS, CC (R. Horton, R.N.)
Staff-Years:
0.5
Human Subjects:
x (a) Human subjects (b) Human tissues (c) Neither
(a1) Minors (a2) Interview
Summary of Work: Alternative or complementary therapies are widely used by patients with epilepsy. St. John's Wort is one of the most popular herbal dietary supplements, with a variety of claims including mood elevation and stabilization, stress relief, antiviral effects, and enhancement of the immune system. Recent preliminary data suggest that St. John's Wort is a potent inducer of cytochrome P-4503A4-mediated drug metabolism. Carbamazepine shares this metabolic pathway, suggesting that plasma concentrations of carbamazepine may be decreased during concomitant use. Such an effect could result in treatment failure (increased seizure frequency, loss of pain relief). To evaluate this potential drug interaction, as well as the effect of St. John's Wort on epoxide hydrolase activity, eight normal, healthy subjects will be enrolled in this pharmacokinetic study. Subjects will take carbamazepine for 3 weeks to establish steady state conditions. Serial blood samples for carbamazepine and carbamazepine epoxide plasma concentrations will be collected over 24 hours following 3 weeks of dosing. Subjects will then begin taking a standardized formulation of St. John's Wort three times daily for 2 weeks. During this period, subjects will continue to take carbamazepine. Following 2 weeks of St. John's Wort, subjects will again have serial blood samples collected for carbamazepine and carbamazepine epoxide plasma concentrations. The total carbamazepine and carbamazepine epoxide exposure as measured by area under the plasma concentration time curve (AUC) and maximal concentrations (Cmax) will be compared between treatment phases to characterize the potential drug interaction.
Index:
Annual Report of Clinical Research Activities FY 2000
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