INTRAMURAL RESEARCH PROJECT Z01 CL-0070-01 PHAR

October 1, 1996 to September 30, 1997

Title of Project: Development of a Once Daily Aminoglycoside Dosing
Nomogram Specific for Critically Ill Patients

Principal Investigator: G.M. Susla, Pharm.D.
PHAR, CC, NIH, Bethesda, MD 20892

Others Personnel: S.C. Piscitelli, R.Ph., PHAR, CC

Collaborating Unit: George Washington University Medical Center
(A. Rosenberg, M.D.; R.B. Becker, M.D.)

Staff-Years: 0.5

Human Subjects: x (a) Human subjects (b) Human tissues (c) Neither

(a1) Minors

(a2) Interviews

Summary of Work: It has been suggested that peak aminoglycoside concentrations 4 to
8 times the minimum inhibitory concentration (MIC) are necessary to treat infections commonly found in critically ill patients, such as gram-negative sepsis and pneumonia. Consol-
idating conventional multiple daily doses into a single large daily dose has been proposed
in order to take advantage of aminoglycoside concentration-dependent killing and to ensure peak aminoglycoside concentrations above the MIC of organisms. Using once-daily amino-
glycoside dosing may be a way of attaining high peak concentrations and immeasurable trough concentrations without increased risk of nephrotoxicity and ototoxicity. Recently, Nicolau et al. studied once-daily aminoglycosides in 2,184 adult patients, and developed
a once-daily dosing nomogram using a fixed volume of distribution (Vd) of 0.3 L/kg.
However, the study excluded patients with highly variable or altered aminoglycoside
pharmacokinetic parameters, including critically ill patients. Therefore, this nomogram
may not predict aminoglycoside doses in critically ill patients. The rationale for developing
a dosing nomogram individualized to the ICU patient is to tailor aminoglycoside therapy using pharmacokinetic parameters specific for critically ill patients to optimize peak serum concentrations while avoiding measurable trough concentrations.

This study will develop a once-daily aminoglycoside dosing nomogram specific for critically ill patients.

An initial nomogram has been developed using mean aminoglycoside pharmacokinetic parameters of 134 dosing segments of 94 adult critically ill patients who received single
or multiple courses of aminoglycoside therapy during their admission to the Medical Intensive Care Unit. The nomogram recommendations will be prospectively evaluated with aid
of serial measurements of aminoglycaside plasma levels in patients above age 18 with
gram-negative infections needing treatment with aminoglycoside. The study will exclude pediatric patients and patients with changing renal function. The study will be conducted
at the National Institutes of Health, W.G. Magnuson Clinical Center, Medical Intensive Care Unit, and the Clinical Pharmacokinetics Research Laboratory. Due to the low patient census seen in the Clinical Center Medical Intensive Care Unit, the investigators also request the approval of George Washington University Hospital's Medical Intensive Care Unit as an additional site for study. (Return to the project list.)

INTRAMURAL RESEARCH PROJECT Z01 CL-0102-02 PHAR

October 1, 1995 to September 30, 1997

Title of Project: A Multiple Drug Interaction Study of Stavudine With Agents
for Opportunistic Infections in HIV-Infected Patients

Principal Investigator: S. Piscitelli, Pharm.D.
PHAR, CC, NIH, Bethesda, MD 20892

Others Personnel: H. Masur, M.D., CCMD, CC

Collaborating Unit: LIR, NIAID (M. Polis, M.D.; R.T. Davey, M.D.; J. Falloon, M.D.)

Staff-Years: 0.55

Human Subjects: x (a) Human subjects (b) Human tissues (c) Neither

(a1) Minors

(a2) Interviews

Summary of Work: This drug interaction study in HIV-infected patients sought to characterize the pharmacokinetics of stavudine (D4T) when given alone and in combination with three drugs commonly used to manage opportunistic infections.

Ten patients (1 female, 9 males) were enrolled in the study: 8 Caucasians, 1 Hispanic, and
1 African-American. The mean CD4 count at enrollment was 62 cells/mm³ (range 9-143).

There were 2 Grade III toxicities: 2 patients had neutropenia, presumably due to their (trimethoprim/sulfamethoxazole) prophylaxis. These episodes were resolved by switching the patients to aerosolized pentamidine. Adverse effects by study medication included (1) for D4T, 1 patient reported peripheral neuropathy; (2) for clarithromycin, 4 patients reported "bad taste," 3 reported gastrointestinal symptoms, and 1 reported rash; (3) for rifabutin,
1 patient reported rash; and (4) for fluconazole and ganciclovir, 3 patients each reported gastrointestinal symptoms.

As of January 1997, only the D4T levels have been analyzed. Combinations of fluconazole, rifabutine, clarithromycin, and ganciclovir did not significantly alter the peak D4T level,
D4T area under the curve, or time to maximum D4T level. These findings suggest that
these drugs can be safely used in combination with D4T.

Pharmacokinetic studies of the concomitant drug levels are ongoing; final results are expected in the next 3-4 months.

This study is terminated. (Return to the project list.)

INTRAMURAL RESEARCH PROJECT Z01 CL-0113-01 PHAR

October 1, 1996 to September 30, 1997

Title of Project: Comparison of Asymptomatic Carotid Atherosclerosis Between
Frequent and Infrequent Blood Donors

Principal Investigator: F.L. Lockwood, Pharm.D.
PHAR, CC, NIH, Bethesda, MD 20892

Other Personnel: S. Leitman, M.D., DTM, CC
G. Csako, M.D., CP, CC
P. Choyke, M.D., DR, CC
M. Leser, R.D., NUTR, CC
B. Sink, R.N., DTM, CC
X. Fu, RN, DTM, CC
F. Pucino, Pharm.D., PHAR, CC

Collaborating Unit: IR, NHLBI (R. Cannon, M.D.; K. Koh, M.D.; A. Blum, M.D.)

Staff-Years: 0.5

Human Subjects: x (a) Human subjects (b) Human tissues (c) Neither

(a1) Minors

(a2) Interviews

Summary of Work: Iron has been proposed to contribute to atherogenesis in humans
by facilitating the oxidation of lipoproteins. This observational study will evaluate the
association between frequency of blood donation expected to be associated with
relatively reduced body iron stores in frequent donors and carotid atherosclerosis.
The primary outcome variable will be whether the presence and extent of asymptomatic carotid atherosclerosis (as measured by ultrasound) is greater in infrequent ( 1 donation/
year 5 years) vs. frequent ( 4 donations/year 5 years) blood donors. Body iron stores, lipid and hemostatic parameters, nitric oxide formation, inflammatory parameters, and markers of vascular oxidative stress will be analyzed as secondary outcome measures.
Laboratory analysis and ultrasound testing will be performed blinded to the patient's
phlebotomy and iron status. Sixty frequent (n = 40 males > 40 y/o, n = 20 females >
50 y/o) and 60 infrequent (n = 40 males > 40 y/o, n = 20 females > 50 y/o) blood
donors will be recruited for this study from the Department of Transfusion Medicine,
W.G. Magnuson Clinical Center. All donors will be assessed for study eligibility and
cardiovascular risks during the screening visit. The presence of atherosclerotic lesions
by carotid ultrasound and secondary outcome parameters will be assessed during a
second visit. (Return to the project list.)

INTRAMURAL RESEARCH PROJECT Z01 CL-0122-01 PHAR

October 1, 1996 to September 30, 1997

Title of Project: The Early Reversibility of Rocuronium By Different Doses
of Neostigmine

Principal Investigator: G.M. Susla, Pharm.D.
PHAR, CC, NIH, Bethesda, Md 20892

Others Personnel: K.S. Williams, M.D., ANES, CC
S.W. Menis, M.D., ANES, CC

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: The purpose of this study is to determine the dose of neostigmine necessary for the early reversal of rocuronium-induced paralysis. 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, non-depolarizing, neuromuscular blocking agent produces paralysis within 60 seconds
as does succinylcholine, but has an approximate 20 to 30 minute duration of paralysis.
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. (Return to the project list.)

INTRAMURAL RESEARCH PROJECT Z01 CL-05081-02 PHAR

October 1, 1995 to September 30, 1997

Title of Project: Comparison of a Restrictive and Non-Restrictive
Levothyroxine Formulary System

Principal Investigators: F. Pucino, Pharm.D.
T. Dorworth, M.S.
PHAR, CC, NIH, Bethesda, MD 20892

Other Personnel: K. Ain, M.D., Lexington, KY
J. Drass, R.N., NURS, CC
G. Csako, M.D., CP, CC
R. Wsley, Ph.D., IS, CC
C. Clark, R.Ph., PHAR, CC
K. Crawford, Ph.D., IBP, NIDDK
P. Gobel, PHAR, CC
P. Ketteridge, R.Ph., Seattle, WA

Collaborating Units: PHAR, CC; LBP, NIDDK; NURS, CC; IS, CC; Seattle, WA;
Lexington, KY

Staff-Years:

Human Subjects: x (a) Human subjects (b) Human tissues (c) Neither

x (a1) Minors

x (a2) Interviews

Summary of Work: Levothyroxine is a thyroid hormone product that is commercially avail-
able in 11 different dose strengths, of which only 5 strengths are permissible in the hospital formulary. The purpose of this prospective, randomized, controlled trial is to determine whether limiting dosage strengths of levothyroxine affect physicians' ability to effectively manage patients. This trial will assign participating endocrinologists from the NICHD and NIDDK outpatient clinics to restrictive (25, 50, 100, 125, and 150 µg dosage formulations permitted) or non-restrictive (25, 50, 75, 88, 100, 112, 125, 150, 175, 200, and 300 µg dosage formulations permitted) levothyroxine prescribing groups. Success in achieving therapeutic objectives as measured by thyroid function studies and clinic visits, medication distribution accuracy, and inventory cost will be compared statistically between groups.

Preliminary results from 241 patients of 33 endocrinologists suggest that the differences in therapeutic success between restricted and non-restricted thyroid patients were not clinically significant. The compliance, frequency of thyroid function tests, clinical visits, and medication errors were also similar. The restricted formulary however, was significantly
more often associated with complex levothyroxine dosing regimens. Further, the inventory and prescription costs were slightly lower with use of the non-restrictive formularly system. Presently, 890 patients are being followed in this protocol. (Return to the project list.)

INTRAMURAL RESEARCH PROJECT Z01 CL-05084-04 PHAR

October 1, 1996 to September 30, 1997

Title of Project: Effects of Niacin-Induced Changes in Lp(a) on Fibrinolytic
Parameters in Hyperlipidemic Lupus and Membranous
Nephropathy Patients

Principal Investigators: F. Pucino, Pharm.D.
PHAR, CC, NIH, Bethesda, MD 20892
L.R. Macklin, Pharm.D
University of Montana

Other Personnel: K. Goad, M.D., CP, CC
H. Gnalnick, M.D., CP, CC
C. Yarboro, R.N., NURS, CC

Collaborating Units: MD, NHLBI (J. Hoef, M.D.); SARB, NIAMS (J. Pando, M.D.);
ARB, NIAMS (J.H. Klippel, M.D.); FDA, NIAMS (D. Scott, M.D.); FDA, NHLBI (T. Eggerman, M.D.)

Staff-Years: 0.1

Human Subjects: x (a) Human subjects (b) Human tissues (c) Neither

(a1) Minors

(a2) Interviews

Summary of Work: Systemic lupus erythematosus (SLE) is a relatively common rheumatologic condition affecting 1 in 700 females. Besides SLE, another autoimmune disorder is idiopathic membranous nephropathy which is the most common primary
cause of nephrotic syndrome in adults in Western societies. Both SLE and membranous nephropathy are associated with an increased risk of coronary artery disease (CAD) and thrombotic events. Hypercholesterolemia, common to these autoimmune diseases, is a risk factor for CAD. Additionally, elevated levels of lipoprotein a [Lp(a)], an independent risk factor for CAD in the general population, are also frequently seen in these patient populations. Lp(a) is a low-density plasma lipoprotein composed of lipids and two major protein components, apolipoprotein (apo) B-100 and apo (a). Apo(a) has structural similarities to plasminogen, but is not a protease zymogen. Several studies have shown that Lp(a) competes with plasminogen for the cell surface binding sites that are necessary for tissue-type plasminogen activator (t-PA) to cleave plasminogen to plasmin. Additionally, elevated levels of Lp(a) may be a risk factor for thrombotic events, as increased levels have been associated with cerebrovascular disease.

This study will evaluate the effects of niacin-induced changes in cholesterol and Lp(a)
on fibrinolytic parameters (FP). This open-label, paralled-design pilot trial involves a total
of 30 patients who have SLE and/or membranous nephropathy with hyperlipidemia and normolipidemia (15 with and 15 without elevated Lp(a) 25mg/dL). Patients will receive niacin 3 g/day for a 6-week period following an initial 4-week titration period. FP will
be assessed at baseline, at Weeks 2 and 4 of the titration period, and at Weeks 7 and 10
of full-dose niacin therapy. Niacin therapy will then be discontinued, and FP will be
reassessed in 6 weeks. (Return to the project list.)

INTRAMURAL RESEARCH PROJECT Z01 CL-05085-04 PHAR

October 1, 1996 to September 30, 1997

Title of Project: Effects of Thyroid Hormone-Induced Changes in Lp(a) on
Hemostasis in Thyroid Cancer Patients

Principal Investigator: F. Pucino, Pharm.D.; K. Sing, Pharm.D.
PHAR, CC, NIH, Bethesda, MD 20892

Other Personnel: K. Goad, M.D., CP, CC
G. Csako, M.D., CP, CC
D. Blum, R.N., NURS, CC
R. Wesley, Ph.D., IS, CC
H. Granlnick, M.D., CP, CC
P. Merryman, CP, CC

Collaborating Units: NIDDK (M. Skarulis, M.D.); FDA (A. Patterson, M.D.;
T. Eggerman, M.D.)

Staff-Years: 0.1

Human subjects: x (a) Human subjects (b) Human tissues (c) Neither

(a1) Minors

(a2) Interviews

Summary of Work: Lipoprotein a [Lp(a)] is a low-density lipoprotein that is structurally similar to plasminogen. Although it competes for plasminogen binding sites, it is not cleaved
to plasmin by t-PA. In vitro studies suggest an association between elevated Lp(a) serum concentration and altered fibrinolysis. In vivo data is lacking. Thyroid hormones stimulate synthesis, mobilization, and degradation of plasma lipids, including Lp(a). The natural course of current thyroid cancer management predisposes patients to definite and often extreme fluctuations in thyroid hormone levels, making this population potentially useful for observing maximal thyroid hormone-induced changes in Lp(a). This open-label pilot trial involves
a total of 26 thyroid cancer patients receiving levothyroxine suppression therapy who are scheduled for radioiodine scanning. The study will evaluate the effects of thyroid hormone-induced changes in plasma Lp(a) concentration on hemostasis. Patients will discontinue levothyroxine and triiodothyronine therapy 6 and 2 weeks prior to the thyroid scan, respectively. Hemostatic parameters will be assessed at baseline (while receiving suppression therapy), at the time of scan (clinically hypothyroid), and after Weeks 1 and 6 of restart-
ing full-dose thyroid hormone treatment. (Return to the project list.)