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Publication Date: October 2005
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THE ROLE OF ROZEREM, THE
FIRST MELATONIN RECEPTOR
AGONIST, IN THE TREATMENT
OF INSOMNIA

Fiona Du Tran, Pharm.D. Candidate


Over 100 million Americans of all ages fail to get
a good night sleep. Approximately 70 million suffer
from insomnia but only 6% are diagnosed. Further-
more, only half of those diagnosed receive treatment
for their condition. Women are twice as likely as
men to have difficulties falling asleep or staying
asleep. The gender difference may be due to men-
strual cycles, pregnancy, menopause, or post-
menopausal factors.1'2 When left untreated insomnia
can lead to depression, impaired productivity, absen-
teeism from work, increased risk of accidents, and
decreased quality of life. Insomnia has been linked to
a variety of health problems including obesity, diabe-
tes, hypertension, heart disease, and depression. Ac-
cording to the National Sleep Foundation, $14 billion
is spent annually on healthcare related to insomnia
and $28 billion is lost in productivity, medical ex-
penses, sick leave, and property and environmental
damage. Additionally, the prevalence of insomnia
increases in the elderly a rapidly expanding sector.
In the elderly, untreated insomnia can complicate
other common medical conditions such as arthritis,
diabetes, heart disease, and depression.2
Insomnia is characterized by difficulty falling
asleep, staying asleep, or poor quality of sleep lead-
ing to impairment of next-day functioning. Insomnia
can be divided into acute and chronic. Acute insom-
nia is often caused by emotional or physical discom-


fort, including significant life stress, acute illness, jet
lag, and environmental disturbances such as noise,
light, and temperature. Chronic insomnia can be
caused by various factors acting singly or in combi-
nation, and usually occurs in conjunction with other
health problems. Factors such as chronic stress, hy-
perarousal, poor sleep hygiene and behavioral condi-
tions can all cause chronic insomnia. Psychiatric dis-
orders, medications, substance abuse, or specific
sleep disorders such as restless leg syndrome (RLS),
periodic limb movement disorder (PLMD), sleep ap-
nea, and circadian rhythm sleep disorders are often
seen in patients with chronic insomnia.3
There are various options available for the treat-
ment of insomnia. Hypnotic medications are primar-
ily for short-term management of insomnia, either as
the sole treatment modality or as adjunctive therapy
until the underlying problem is controlled. Barbitu-
rates were formerly the gold standard but have fallen
out of favor due to significant drug-drug interactions,
respiratory depression, tolerance, psychological and
physical dependence, and severe withdrawal compli-
cations. The most commonly prescribed hypnotic
agents are benzodiazepines. They can induce, main-
tain, and improve sleep.3 However, prolonged use or
use of long-acting agents can lead to daytime sleepi-
ness, cognitive impairment, coordination difficulties,


INSIDE THIS ISSUE:
THE ROLE OF ROZEREM THE FIRST MELATONIN
RECEPTOR AGONIST, IN THE TREATMENT OF
INSOMNIA

INDEX FOR VOLUME 20 (OCT. 2004-SEP. 2005)

I, I


PharmaNote


VOLUME 21, ISSUE 1 OCTOBER 2005
Lir







and worsening depression. Roth et al. showed a sig-
nificant decrease in memory recall after subjects
were given flurazepam, lorazepam, and triazolam for
two consecutive nights per week for 4 weeks.4 Addi-
tionally, this class of medications can exhibit residual
effects on attention.5 Furthermore, their hypnotic ef-
fects were found to diminish after repeated admini-
stration.6 They can alter sleep architecture by reduc-
ing the percentage of slow-wave sleep (SWS) and
rapid eye movement (REM) sleep, increasing time
spent in stage 2 and decreasing the number of stage
shifts.7 Newer non-benzodiazepines agents (i.e. zol-
pidem, zaleplon, and eszopiclone) exert their actions
via modulation of the GABA-receptor complex.
Even though they alter sleep architecture, residual
effects on psychomotor performance and cognition
are less pronounced compared to benzodiazepines.
Like benzodiazepines, they exhibit the potential for
drug dependence, amnesia, and dose-dependent re-
bound insomnia.8 All of these medications are sched-
ule IV controlled substances except barbiturates
whose schedule varies based on the specific agent.
Antidepressants are also commonly prescribed for
insomnia even though they are not FDA-approved
for this indication. They may be of greatest benefit in
patients with concurrent psychiatric disorders. Tri-
cyclic antidepressants have multiple side effects in-
cluding anticholinergic effects, cardiac toxicity, or-
thostatic hypotension, and sexual dysfunction.3'9 An-
tihistamines, such as diphenhydramine and doxyl-
amine, are frequently found in over-the-counter sleep
aids. These agents can cause daytime drowsiness,
cognitive impairments, and anticholinergic effects.
Tolerance and withdrawal effects have also been ob-
served.3,8
Melatonin is a hormone released by the pineal
gland that is thought to regulate sleep-wake cycles in
human and other mammals. The production of mela-
tonin varies according to the circadian rhythm, which
is controlled by neuronal output from the suprachias-
matic nucleus (SCN) of the hypothalamus. In hu-
mans, melatonin production correlates with nocturnal
sleep. An increase in melatonin levels in the evening
is associated with the onset of sleepiness and an in-
crease in sleep propensity. Exogenous melatonin has
direct sleep-promoting actions. Endogenous secretion
declines with age, which may explain the prevalence
of sleep disturbances in the elderly.10
Ramelteon (Rozerem), a novel melatonin
receptor agonist manufactured by Takeda Inc., was
approved by the FDA for the treatment of insomnia


in July 2005. Ramelteon does not alter sleep archi-
tecture or cause tolerance, psychological or physical
dependence, or rebound insomnia.10 The intent of
this article is to review the pharmacology, pharma-
cokinetics, adverse drug reactions, drug interactions
and cost of ramelteon.

Pharmacology
Melatonin exerts its action through G-protein
coupled receptors. The three subtypes of mammalian
melatonin receptors that have been identified are
MT1, MT2, and MT3. The MT1 and MT2 receptors in
the SCN are involved in the maintenance of cir-
cadian rhythm. Ramelteon is a melatonin receptor
agonist with high affinity for both MT1 and MT2, and
with low activity at MT3. The MT1 receptor regulates
sleepiness while MT2 helps the body shift easily be-
tween phases of day and night. Together they main-
tain the circadian rhythm, regulating the normal
sleep-wake cycle. Ramelteon has no appreciable af-
finity for the GABA receptor complex or for recep-
tors that bind neuropeptides, cytokines, serotonin,
dopamine, noradrenaline, acetylcholine, and opiates.
Its major metabolite, M-II, is active and has approxi-
mately one tenth to one fifth the binding affinity of
the parent molecule for the MT1 and MT2 receptors.
In in vitro functional assays, it is 17- to 25-fold less
potent than the parent molecule. However, M-II cir-
culates at higher concentration than the parent com-
pound producing 20 100-fold greater mean sys-
temic exposure. M-II has a weak affinity for 5-HT2B,
but no appreciable affinity for other receptors.1
In animal models, ramelteon has a sleep-
promoting action without causing learning, memory,
or motor function impairment. It also has no poten-
tial for abuse. Preclinical studies conducted in rats by
Miyamoto and colleagues demonstrated that per-
formance was unaffected in both the Morris water
maze and delayed matching position test by ra-
melteon doses ranging from 3 to 30 mg/kg.12 On the
contrary, performance in these learning tasks showed
a dose-related impairment following the administra-
tion of diazepam and triazolam. Additionally, the
effects of ramelteon and diazepam on motor coordi-
nation were assessed. Diazepam caused a dose-
dependent impairment of motor coordination while
ramelteon did not. Furthermore, unlike benzodiazepi-
nes and morphine, ramelteon did not exhibit reward-
ing properties in the conditioned place preference
test. Therefore, it is postulated that ramelteon does
not exhibit an abuse potential.11







Table 1. Summary of phase II clinical trials.
Study Design Inclusion Endpoints Treatment arms Results

LPS (mins)
R16- 14.115.1
Usual sleep duration of (p<.001*)
6.5 to 8.5 h Primary LPS Single oral dose R64 15.515.4
Roth et Usual sleep latency of < measured by PSG of 16 mg, 64 mg, (p<.001*)
al.17 DB, MC, 30 minutes Others TST, or placebo given PBO 24.6+21.9
(n=375) RD, PBC Bedtime between WASO, time in or plebo gien TST (mins)
(n=375) 30 minutes prior
8:30pm and midnight each stage, number R16 425.437.6
to bedtime
Within 20% of IBW of awakenings (p<.007)
Overall good health R64 422.434.8
(p<.033)
PBO 411.341.7


LPS (mins)
R4 24.0
R8 24.3
R16 24.0
Insomnia complaints >3 R16 24.0
months Single oral dose R32 22.9
months
rmn t n > mn of 4, 8, 16, or 32 PBO 37.7
Erman et Mean LPS >20 min- ,
al. s DB, RD, utest LPS, TST, subjec- mg or placebo (p<0.001
(n=107) PBC, CO Mean wake time tive sleep efficiency given 30 minutes TST (mins)
(n=107) Mean wake time
>60m or 2 prior to bedtime R4 411.0
>60min over 2 nights
Sfor 2 nights R8 412.9
R16 411.2
R32 418.2
PBO 400.2
(p=NA"


DB: double-blind. MC: multi-center. RD: randomized. PBC: placebo-control. PBO= placebo. CO= Cross-over. LPS: latency to persistent sleep. PSG: polysomnogra-
phy. TST: total sleep time. WASO: wake time after sleep onset. R: ramelteon. *Pairwise comparison with placebo by the Dunnett t test (from analysis of variance).
Measured by polysomnography. P value for every dose of ramelteon. P value was not reported.


Pharmacokinetics
Ramelteon is rapidly absorbed with median
peak concentrations occurring at approximately 0.75
hours following oral administration in a fasting state.
In a phase I study of six healthy male subjects, a sin-
gle oral dose of ramelteon 16 mg was rapidly ab-
sorbed with time to maximum concentration (Tmax)
of 0.3 hours with a half-life (t 12) of 1.2 hours. Of the
total dose, 84% was eliminated via the kidneys while
only 4% was eliminated in the feces. Another phase I
study in eighteen healthy male subjects compared a
single oral dose of ramelteon 16 mg to ramelteon 2
mg intravenous (IV) infusion. Although 84% is ab-
sorbed, only approximately 1.8% is bioavailable.
From the results of these studies, ramelteon appears
to undergo extensive-first pass metabolism.11,13,14
When administered with a high-fat meal, the
area under the curve (AUC) of ramelteon was in-
creased, peak plasma concentration (Cmax) was de-
creased, and Tmax was delayed. The effect of food


was studied in 24 healthy subjects randomized to re-
ceive a single dose of 16 mg ramelteon orally with or
without food. The results over a 24-hour period
showed that the presence of food increased AUC by
31%, Cmax was lowered by 22%, and Tmax was de-
layed by approximately 55 minutes (P<0.001). The
similar effects of foods on AUC values are observed
with M-II metabolite. Based on these findings, the
manufacturer recommends against taking ramelteon
with or immediately after a high-fat meal.11'15
In vitro studies showed that 82% of ra-
melteon is bound to plasma protein (70% to albu-
min). Furthermore, plasma protein binding is inde-
pendent of concentration. The mean volume of distri-
bution after intravenous administration is 73.6 L,
suggesting substantial tissue distribution. The drug is
metabolized primarily via oxidation to hydroxyl and
carbonyl derivatives, with glucuronidation as a sec-
ondary metabolic pathway. CYP1A2 is the major
isozyme involved in the hepatic metabolism of ra-







melteon; the CYP2C subfamily and CYP3A4
isozymes also metabolize ramelteon to a lesser de-
gree.
A phase I study by Greenblatt and colleagues
evaluated the effects of age and gender on ra-
melteon's pharmacokinetics. Subjects were divided
into four treatment groups: young (age 18-34), eld-
erly (age 63-79), male and female. Following oral
administration of 16 mg ramelteon, blood samples
were obtained during the 24 hours after administra-
tion to analyze plasma concentrations of ramelteon
and its major metabolite, M-II. Results indicated that
AUC values for both the parent compound and M-II
were significantly elevated in the elderly, regardless
of gender. Subsequent studies showed that not only
was AUC elevated in the elderly, Cmax and t 1/2 values
of both parent and M-II were significantly elevated. 16
The study suggests that gender does not have an im-
pact on the pharmacokinetic of ramelteon whereas
age has a prominent effect.

Clinical Trials
Table 1 summarizes two separate phase II clini-
cal trials which found that ramelteon had significant
effects on promoting sleep.
Roth et al conducted a randomized, double-blind,
placebo-controlled study to evaluate the efficacy of
ramelteon for the treatment of transient insomnia in
healthy adults. A total of 375 subjects were random-
ized to three arms, 16 mg (n=126), 64 mg (n=126),
and placebo (n=123). The primary efficacy measure
was the mean latency to persistent sleep (LPS) as
measured by polysomnography (PSG). Other effi-
cacy measures were total sleep time (TST), wake
time after sleep onset (WASO), percentage of sleep
time in each sleep stage, and number of awakenings.
There were no significant differences in the baseline
demographics and characteristics between the three
arms. Subjects were administered a single-dose of
placebo or ramelteon 30 minutes prior to scheduled
bedtime followed by PSG recordings performed con-
tinuously for 8 hours. Ramelteon dosages of 16 mg
and 64 mg decreased the mean LPS compared to pla-
cebo (14.1 min, 15.5 min, 24.6 min, respectively,
P<0.001). Similarly, 16 mg and 64 mg of ramelteon
demonstrated an increased in TST compared to pla-
cebo (425.4 min P=00.7, 422.4 min P=0.033, 411.3
min, respectively). However, the differences between
WASO, number of awakenings, and percentage of
sleep time in each stage were not statistically signifi-


cantly different. Subjects receiving 16 mg of ra-
melteon reported the shortest subjective sleep la-
tency. Adverse effects were reported by at least 2%
of subjects in each treatment group but no serious
adverse effects were reported or observed. The dose-
response curve appears to be flat. Despite a 4-fold
increase in dose, there are only small differences in
LPS and TST.17 Thus, lower doses may offer the
similar benefit with fewer side effects.
Erman and colleagues evaluated the efficacy and
dose-related safety of ramelteon for the treatment of
primary chronic insomnia as defined by the Diagnos-
tic and Statistical Manual of Mental Disorders
(DSM-IV). This was a double-blind, placebo-
controlled, crossover study comprised of 107 sub-
jects who were randomized to 4, 8, 16, or 32 mg of
ramelteon or placebo. Medication was administered
30 minutes prior to bedtime for two consecutive
nights. PSG was performed continuously for 8 hours
each night. The results were similar to those ob-
served by Roth et al. All doses of ramelteon re-
vealed a significant reduction in LPS with mean val-
ues of 24.0, 24.3, 24.0, 22.9, and 37.7 minutes
(P<0.001) for 4, 8, 16, 32 mg, and placebo, respec-
tively. There were no statistically significant differ-
ences between the five arms in WASO, subjective
TST, orsleep quality.18

Dosage and Administration
Ramelteon is available in 8 mg tablets. The
recommended dose of ramelteon is 8 mg taken 30
minutes prior to bedtime. From one phase II study,
ramelteon appears to have a flat dose-response curve,
thus the need for a higher dose should be investi-
gated further. The package insert recommends that
ramelteon not be taken with or immediately after a
high fat meal. Pharmacokinetic characteristics of ra-
melteon studied in subjects with mild and moderate
hepatic impairment yielded an increase of 4- fold and
10-fold in exposure of the drug, respectively. Expo-
sure to M-II increased slightly. Ramelteon should be
used with caution in patients with mild to moderate
hepatic impairment. Pharmacokinetics have not been
evaluated in patients with severe hepatic impairment,
therefore this population should not receive ra-
melteon. Pharmacokinetic characteristics in popula-
tions with mild, moderate, severe renal impairment
and those on chronic hemodialysis suggest renal ad-
justment is not needed.11







Table 2. Adverse events in phase II clinical trials.17'18
Adverse Effects Placebo Ramelteon 4-32 mg Ramelteon 16-64 mg
Headache (%) 1.6 19.6 6.3-7.1
Somnolence (%) 2.4 7.5 2.4-4.8
Nausea (%) 0.0 -- 1.6-2.4
Dizziness (%) 0.8 -- 0.8-2.4
Fatigue (%) 0.0 -- 2.4-4.0
Pharyngolaryngeal (%) -- 7.5 --


Adverse Effects
Results from two phase II studies have shown
that ramelteon ranging from 4 mg to 32 mg does not
cause serious adverse effects. However, subjects who
have received 64 mg reported a statistically signifi-
cant decrease in alertness and ability to concentrate.
The most common adverse event was headache.
Other side effects include fatigue, somnolence, nau-
sea, and dizziness. Table 2 summarizes the side ef-
fects from two phase II studies. 17,1
Three long-term studies comprised of a total
of 2082 subjects, of whom 829 were elderly, showed
no evidence of rebound insomnia. In a 35-night, dou-
ble-blind, placebo-controlled, parallel-group study in
adults with chronic insomnia, patients were divided
into two groups receiving either 8 mg or placebo.
There was no difference in next-morning residual
effects between ramelteon-treated patients versus
placebo-treated patients.11

Drug Interactions
Ramelteon is metabolized primarily in the
liver, mainly via the CYP1A2 isozyme; the CYP2C
subfamily and CYP3A4 have minor involvement.
Therefore inhibitors, inducers, or substrates of
CYP1A2 will alter the pharmacokinetics of ra-
melteon. Co-administration of fluvoxamine, a strong
CYP1A2 inhibitor, resulted in a 190-fold and 70-fold
increase of AUC and Cmax of ramelteon, respectively.
Therefore, ramelteon should not be taken with flu-
voxamine. Even though the impact of other weaker
CYP1A2 inhibitors in combination with ramelteon
have not been adequately studied, ramelteon should
be prescribed with caution to patients who are on
these drugs. Ketoconazole and fluconazole increase
exposure to ramelteon as well as M-II. Rifampin, a
strong CYP enzyme inducer, decreased the total ex-
posure of both ramelteon and M-II approximately
80% after a single dose of 32 mg of ramelteon.11
Cost


The average retail cost for a one-month supply of
ramelteon is $96.09. (Survey of retail pharmacies in
Gainesville, FL area.)

Summary
Ramelteon is a novel melatonin receptor ago-
nist that works by stimulating MT1 and MT2 recep-
tors, thereby reducing sleep latency and improving
overall quality of sleep. The novel mechanism of ac-
tion provides a new approach to managing insomnia.
Results from clinical studies in animals and humans
showed no potential for dependence or tolerance.
Ramelteon is an alternative to benzodiazepines and
non-benzodiazepine agents, especially in patients
with a history of substance abuse. Ramelteon is not a
controlled substance and the abuse potential is lower
compared with sedative hypnotics. Furthermore, ra-
melteon has a favorable side effect profile. Ra-
melteon does not cause rebound insomnia, next-
morning residual effects, nor alter the architecture of
sleep. Ramelteon should effectively complement the
current pharmacological arsenal for treating insom-
nia.

References
1. SleepMed Online. Facts and Statistics. Available from:
URL: lhp \ \\ \ .sleepmedonline.com/res/stats.htm. Aug
8, 2005.
2. National Sleep Foundation. Available from: htt://
www.sleepfoundation.org/hottopics/index.php?
secid=9&id=34. Aug 15, 2005.
3. National Center on Sleep Disorders Research and Office of
Prevention, Education, and Control. Insomnia: Assessment
and Management in Primary Care. Available from: URL:
http://www.nhlbi.nih.gov/health/prof/sleep/insom pc.pdf.
Aug 8, 2005.
4. Roth T, Hartse KM, Saab PG, Piccione PM, Kramer M.
The effects of flurazepam, lorazepam, and triazolam on
sleep and memory. Psychopharmacology (Berl)
1980;70:231-7.
5. Jurado JL, Fernandez-Mas R, Ferandez-Guardiola A. Ef-
fects of 1 week administration of two benzodiazepines on
the sleep and early daytime performance of normal objects.







Psychopharmacology (Berl) 1989;99:91-3.
6. Roehrs T, Kribbs N, Zorick F, Roth T. Hypnotic residual
effects of benzodiazepines with repeated administration.
Sleep 1986;9:309-16.
7. Borbely AA, Mattmann P, Loepfe M, Strauch I, Lehmann
D. Effect of benzodiazepine hypnotics on all-night sleep
EEG spectra [abstract]. Hum Neurobiol 1985;4:189-94.
8. Trombetta DP. Pharmacologic options for managing in-
somnia and sleep disorders. Presented at: the American
Society of Health-System Pharmacists Midyear Meeting;
2004;Orlando.
9. Clinical Pharmacology. http://cpip.gsm.com/. Aug 8, 2005.
10. Kato K, Hirai K, Nishiyama K, Uchikawa O, Fukatsu K,
Ohkawa S et al. Neurochemical properties of ramelteon
(TAK-375), a selective MT1/MT2 receptor agonist. Neuro-
pharmacology 2005;48:301-310.
11. Ramelteon (Rozerem) [Package Insert]. Takeda Inc. Aug 8,
2005.
12. Miyamoto M, Hirai K, Kita M, Ohta H, Nishikawa H, Fuji-
wara Y. Ramelteon (TAK-375) accelerates reentrainment
of circadian rhythm after a phase advance of the light-dark
cycle in rats. Journal of Biological Rhythms 2005
Feb;20:27-37.
13. Stevenson S, Cornelissen K, Clarke E, Hibberd M. Study
of the absorption, metabolism, and excretion of (14C)-
ramelteon (TAK-375). Clin Pharmacol Ther 2004
Jun;75:P22.
14. Amakye DD, Hibberd M, Stevenson SJ. A phase I study to
investigate the absolute bioavailability of a single dose of
ramelteon (TAK-375) in healthy male subjects [abstract].
Sleep 2004;27:A54.
15. Karim A, Tolbert D, Cao C, et al. Effect of food on the
systemic exposure of ramelteon (TAK-375) following a
single dose [abstract]. J Clin Pharmacol 2004;44:1210.
16. Greenblatt DJ, Harmatz JS. Age and gender effects on the
pharmacokinetics of TAK-375 [abstract]. Sleep
2003;26:A81.
17. Roth T, Stubss C, Walsh JK. Ramelteon (TAK-375), a
selective MT1/MT2-receptor agonist, reduces latency to
persistent sleep in a model of transient insomnia related to
a novel sleep environment. Sleep 2005;28:303-307.
18. Erman M, Seiden D, Zammit G. Phase II study of the se-
lective ML-1 receptor agonist TAK-375 in subjects with
primary chronic insomnia. Sleep 2003;26 Suppl:A298
[abstract].

Index for Volume 20 (Oct. 2004 Sep. 2005)


Topic


Acamprosate
Apidra
Arcoxia


B-C-D
Benzodiazepines for
delirium tremens
BiDil
Boniva


Issue (Page)

June 2005 (01)
Feb 2005 (01)
Dec 2004 (01)


Oct 2004 (01)

Sep 2005 (01)
Aug 2005 (01)


Camparal
Cymbalta
Duloxetine


E-F-G-H-I-J
Etoricoxib
Ezetimibe/Simvastatin
Hydralazine/Isosorbide
Insulin glulisine
Ibandronate

K-L-M-N
Lyrical
Natrecor
Nesiritide
Levalbuterol

O-P-Q-R
Rifaximin
Pregabalin

S-T-U-V
Sanctura
Simvastatin/Exzetemibe
Tigecycline
TygacilTM
Trospium
Vaspressors in the ICU
VytorinTM

W-X-Y-Z
XifaxanTM
Xopenex


June 2005 (01)
Jan 2005 (01)
Jan 2005 (01)


Dec 2004 (01)
Mar 2005 (01)
Sep 2005 (01)
Feb 2005 (01)
Aug 2005 (01)


Apr 2005 (01)
Nov 2004 (01)
Nov 2004 (01)
May 2005 (01)


Jan 2005 (04)
Apr 2005 (01)


Feb 2005 (05)
Mar 2005 (01)
Sep 2005 (05)
Sep 2004 05)
Feb 2005 (05)
June 2005 (05)
Mar 2005 (01)


Jan 2005 (04)
May 2005 (01)


The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida



John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

Benjamin J. Epstein Assistant Editor
Pharm.D.



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