ISSN
1916-694X

2010;
Volume 1 (Number 1): Pages 15-23

ORIGINAL RESEARCH

Trends in prescription claims
following the withdrawal of rofecoxib from the Canadian market

Olivier DESJARDINS, Jennifer MANLEY, Natasha
NANWA, Y. Ingrid GOH, Ryan SMITH, Thomas R. EINARSON

Leslie Dan Faculty of Pharmacy, University of Toronto,
Toronto, Ontario, Canada

*Corresponding author:
[email-masked]

ABSTRACT

Objective:
Rofecoxib (Vioxx, MK996) was voluntarily removed
from the Canadian market by Merck in September 2004. No studies have examined
the impact of its removal on utilization of other NSAIDs. We examined
the utilization (i.e., numbers of claims) of NSAIDs, proton pump inhibitors
(PPIs) and salicylic acid derivatives (SADs) in Ontario and Québec one year
prior to and after rofecoxib’s withdrawal from the Canadian market. Methods: Monthly claims of coxibs
occurring between October 2003 and November 2005 were obtained from Brogan Inc.
NSAIDs were analyzed as a group and by chemical class. Interrupted time series
(segmented regression) was used to examine changes in utilization of other
coxibs, COX-1 NSAIDs, PPIs and SADs after rofecoxib’s removal. Results: Segmented regression analysis
revealed that the monthly number of claims for all NSAIDs (including coxibs)
decreased by 19%, from 622,347 to 500,397 between October 2003 and November
2005. We also identified a marked reduction for all NSAIDs  between
September    2004    and
January    2005  (-141,524 claims/month; 95%CI -188,889 to ‑94,159;
P <0.001). Monthly coxibs claims decreased after rofecoxib’s withdrawal
(-156,883 claims/month; 95%CI= ‑184,393 to -129,373; P <0.001). Non-selective COX-1
inhibitors exhibited the opposite trend; monthly claims increased 32% to
414,813 at study end. No shift in utilization of PPIs or SADs was observed. Conclusions: The removal of rofecoxib
from the Ontario and Québec markets resulted in an immediate decrease followed
by a slow increase in all NSAID claims.

Key words

Claims analysis; Drug utilization; Linear
models; Non-steroidal anti-inflammatory agents; Regression analysis

RÉSUMÉ

Objectif: Le rofecoxib (Vioxx, MK 996) a été volontairement
retiré par Merck du marché canadien en septembre 2004. Comme il n’y avait pas
d’étude sur l’impact de l’utilisation des autres AINS, nous avons examiné
l’utilisation (nombres de demandes) des AINS, des inhibiteurs de la pompe à
proton (IPP) et des dérivés de l’acide acétylsalicylique (AAS) dans l’Ontario
et le Québec l’année précédant et celle suivant le retrait du rofecoxib du
marché canadien. Méthodes: La demande mensuelle des coxibs entre octobre 2003
et novembre 2005 a été obtenue de Brogan Inc. Les AINS ont été analysés en tant
que groupe et d’après leur classe chimique. Les changements de l’utilisation
des autres coxibs, des inhibiteurs de la COX-1, des IPPs et des dérivés de
l’AAS ont été analysés au moyen de séries interrompues dans le temps (analyse
de régression segmentée). Résultats:
L’analyse de régression segmentée a montré que le nombre mensuel de demandes
des AINS (incluant les coxibs) a diminué de 19 %, de 622,347 à 500,397,
entre octobre 2003 et novembre 2005. La demande de tous les AINS a également
diminué significativement entre septembre 2004 et janvier 2005 (-141,524
demandes/mois; 95% CI -188,889 – -94,159; P <0,001). La demande mensuelle
des coxibs a diminué après retrait du marché du rofecoxib (-156,883
demandes/mois; 95% CI -184,393 – -129,373; P <0,001). Les inhibiteurs
non-sélectifs de la COX-1 ont montré une tendance en sens opposé: les demandes
mensuelles ont augmenté de 32 %, atteignant 414,813 à la fin de l’étude.
Nous n’avons pas identifié de changement dans l’utilisation des IPPs ou des
AAS. Conclusions: Le retrait du
rofecoxib des marchés ontarien et québécois a entraîné une diminution immédiate
suivie par une lente augmentation des demandes des AINS.

Mots clés

Analyses de
demandes; Utilisation des médicaments; Modèles linaires; Anti-inflammatoires
non-stéroïdiens; Analyses de régression

RESUMEN

Objetivo: Rofecoxib (Vioxx, MK 996) fue retirado
voluntariamente del mercado canadiense por Merck en septiembre del 2004. Sin
embargo, no existen estudios que examinen el impacto de su retiro en la
utilización de otros AINES. En este estudio examinamos la utilización (i.e.
número de solicitudes) de los AINES, de los inhibidores de la bomba de protones
(IBP) y de los derivados del ácido salicílico (ASA) en Ontario y Quebec el año
antes y después del retiro de rofecoxib del mercado canadiense. Métodos: Las solicitudes de estos
medicamentos generadas entre octubre del 2003 y noviembre del 2005, fueron
obtenidas de Brogan Inc. Los AINES fueron analizados como grupo y como clase de
acuerdo a su estructura química. Los
cambios  en  la
utilización  de  otros
coxibs,  COX-1,  AINES,
IBP,  y derivados del ASA después
del retiro del rofecoxib se analizaron mediante series temporales interrumpidas
(regresión segmentaria). Resultados:
El análisis de regresión segmentaria reveló que el número mensual de
solicitudes de todos los AINES (incluyendo coxibs) disminuyó 19%, de 622,347 a
500,397, entre octubre del 2003 y noviembre del 2005. Entre septiembre del 2004
y enero del 2005, se observó una marcada reducción en la solicitud de todos los
AINES (-141,524 solicitudes/mes; 95%CI -188,889 a ‑94,159; P <0.001).
Los inhibidores COX-1 no selectivos mostraron la tendencia opuesta; las
solicitudes mensuales incrementaron 32% a 414,813 al final del  estudio. No se observaron cambios en la
utilización de los IBP o de los derivados del ASA. Conclusiones: El retiro del rofecoxib de los mercados de Ontario y
Quebec resultó en una inmediata disminución, seguida de un lento incremento, en
las solicitudes de AINES.

Palabras clave

Análisis
de solicitudes; Utilización de medicamentos; Modelos lineales; Agentes anti-inflamatorios
no esteroideos; Análisis de regresión;

INTRODUCTION

Non-steroidal
anti-inflammatory drugs (NSAIDs) are comprised of
non-selective cyclo-oxygenase (COX) inhibitors, selective COX-2 inhibitors and
acetylsalicylic acid (ASA). They are commonly indicated for the treatment of
inflammation, arthritis, and musculoskeletal problems [1]. In addition, they are among the most frequently
prescribed medications worldwide [2].

Non-selective NSAIDs have been associated
with adverse gastrointestinal (GI) event complications including dyspepsia, ulcers,
bleedings, and perforations [3]. These complications are secondary to COX-1
inhibition resulting in a reduction of protective GI mucosal prostaglandins.
Approximately 2-4% of NSAID users will have a serious adverse GI event each
year [4]. Selective COX-2 inhibitors exert the beneficial
effects of non-selective NSAIDs but are associated with lower rates of GI
complications [5].

COX-2 inhibitors were first listed on the
Ontario Drug Benefit formulary in April 2000. Mamdani et al. [6] reported a 68% increase in the total number of claims
for NSAIDs (both COX-2 and non-selective) seen between March and November 2000.

Rofecoxib (Vioxx) is a selective COX-2
inhibitor indicated for the treatment of osteoarthritis, rheumatoid arthritis,
acute pain, and menstrual symptoms [7]. Rofecoxib was initially introduced in the market as
a novel drug because it was associated with fewer gastrointestinal symptoms
than traditional NSAIDs [8] [9] [10]. In September 2004, rofecoxib was voluntarily removed
from the Canadian market by its manufacturer, Merck & Co., Inc. following
preliminary analysis of data from the Adenomatous Polyp Prevention On Vioxx
(APPROVe) study [11]. The preliminary results suggested an association
between cardiovascular events and rofecoxib use.

The sudden withdrawal of rofecoxib from the
market resulted in two consequences: first, rofecoxib users were left to find alternative
treatments, and second, other drugs in the COX-2 family including
valdecoxib  and celecoxib were closely
scrutinized for similar cardiovascular events [12].

To our knowledge, there have not been any
published studies examining the impact of rofecoxib removal on the utilization
of other medications. Therefore, the objective of this study was to examine the
Ontario and
Québec utilization (i.e., numbers of claims) of NSAIDs, salicylic acid
derivatives (SADs) and proton pump inhibitors (PPIs) in the year prior to and
after the withdrawal of rofecoxib from the Canadian market. Specifically, we
explored the association of the removal of rofecoxib from the market with the
utilization of other coxibs, as well as on COX-1 inhibitor NSAIDs [acetic acid
derivatives (AADs), propionic acid derivatives (PADs), and oxicams], SADs, and
PPIs.

METHODS

Data sources

Monthly claims were collected electronically
from the PharmaStat database, provided by Brogan Inc [13]. The PharmaStat database included information on the
number of claims, units and cost of prescribed medications for all of the
publicly funded federal and provincial drug benefit programs with the
exceptions of Prince Edward Island and Alberta, as well as over 65% of private
drug plans.

The study time horizon was chosen to include
at least one year prior to and at least one year after market withdrawal of
rofecoxib. Monthly data were available starting from January 2003; however, the
period from January 2003 to September 2003 was excluded from analysis since
only Ontario
data were available.

Drugs were classified according to the
Anatomical Therapeutic Chemical (ATC) system [14]. Monthly numbers of claims for NSAIDs, SADs, and PPIs
for Ontario
and Québec were retrieved for the period between October 2003 (13 months before
market withdrawal of rofecoxib) and November 2005 (14
months after).

Analysis

Data grouping

NSAIDs were first analyzed as a group and
after stratifying them by individual chemical classes in order to identify
changes in resource utilization for the different NSAIDs. The SADs dataset
included only acetylsalicylic acid products, while the PPI dataset obtained was
a subclass of the ATC group ‘drugs for peptic ulcer and gastro-esophageal
reflux disease’.

Interrupted
time-series model and data transformation

An interrupted time-series design by
segmented regression was used to study the effects of rofecoxib withdrawal from
the market on the utilization of other coxibs, as well as on COX-1 inhibitor
NSAIDs, SADs, and PPIs [15] [16]. Series were plotted (utilization versus time) and
were visually inspected to identify apparent trends or cycles. Descriptive
statistics were computed. Different models (e.g., ARIMA, log linear trends with
or without seasonal effects) were fitted to each independent series in order to
account for autocorrelation. Autocorrelation was tested using the AUTOREG
procedure from SAS and first order autocorrelations were tested with a
Durbin-Watson test [17]. In addition, residuals were plotted and tested for
normality, using a Shapiro-Wilks test.

Segmented
regression of interrupted time series

The trend of the outcome variables, (i.e.,
number of claims) was observed over time. Where appropriate (i.e., allowing for
a transition period and market stabilization), an intervention (break point)
was introduced into the time-series as an explanatory variable. This regression
was then tested to determine if there had been a change in intercept and/or
slope, using a segmented regression test [15].

We first tested for a shift in the time-series
occurring in October 2004 (i.e., the month following rofecoxib withdrawal from
the market).  Series were analyzed using
a regression model. We used dichotomous dummy variables in the model to
differentiate between the period before rofecoxib withdrawal (including
September 2004) and the period after rofecoxib withdrawal. If necessary, a
transition period was also taken into consideration, when time-series showed a
delayed response after the removal of rofecoxib from the market. The full
regression model is presented in the following equation:

where yt is the total number of
claims at time t, b0 is the baseline level of the outcome variable yt,
b1 is the slope of the trend before the intervention, b2
is the magnitude of the intervention, and b3 is the difference in
slope of the trend post intervention. The variable dummy represents the
dichotomous dummy variable inserted in the regression model to discriminate
between the two periods. Differences between intercepts and slopes for each
trend were assessed using regressions as part of the AUTOREG procedure in SAS.
All descriptive and statistical analyses were performed using SAS version 9.1 [17].

RESULTS

Model fit

All time-series could be fitted with either
an ARIMA or a log linear trend. In most cases, a seasonal component was
present, although the series did not show strong cycles. The R2
values were relatively high, ranging from 0.79 to 0.98, indicating a good fit
in each case. No first-order autocorrelation was observed, as identified by
the Durbin-Watson test. Detailed results are presented in Table 1.

Monthly number of claims

Between October 2003 and November 2005, the
monthly number of claims for all NSAIDs (including coxibs) decreased by 19%,
from 622,347 to 500,397 (Figure 1). The reduction
rate for the period prior to rofecoxib withdrawal was not significantly
different than zero (m= -691.0; 95%CI= -2,492 to 1,110; P =0.407). In addition,
the monthly number of claims for the period between January and November 2005
(between 4 and 14 months after rofecoxib market withdrawal) did not show a
significant change (∆m= 1,815; 95%CI= -1,017 to 4,647; P =0.169). Thus,
this reduction can be attributed for the most part to the decrease in the
monthly number of claims observed during the three months following the removal
of rofecoxib from the market (a decrease of 18% in January 2005, compared to
September 2004). Regression parameter estimates are presented in Table 2.

A marked reduction in the monthly claims of
coxibs was observed after September 2004 (Figure 1).
This reduction coincides with the withdrawal of rofecoxib from the market [11]. For the post-rofecoxib period, the reduction compared
to baseline was significant (∆i= -156,883; 95%CI= -184,393 to -129,373;
P <0.001). Furthermore, a significantly decreasing month-to-month trend
was found after January 2005 (∆m = -2,319; 95%CI= -3,933 to ‑704.9;
P <0.001).

While the month-to-month number of claims
for all NSAIDs decreased during the study period, monthly claims for
non-selective COX-1 inhibitors increased by 32% to 414,813 per month in
November 2005 (Figure 1). The monthly trend during
the baseline period (before rofecoxib withdrawal) and the post-rofecoxib
period was found to remain constant (Table 2).

A closer examination of the different
subclasses of COX-1 inhibitors revealed different trends for the post-rofecoxib
period. Only PADs and AADs experienced a significant increase in monthly claims
after the withdrawal of rofecoxib (Table 2).
Furthermore, while the number of claims for PADs increased immediately after
the removal of rofecoxib, this increase was more gradual for AADs, following a
transition period similar to the one observed with coxibs, but in the opposite
direction (Figure 2).

The month-to-month trend of COX-1 claims for
the baseline period was constant except for oxicams, where there was an
increase over time (m= 136.5; 95%CI= 2.795 to 270.1; P =0.039). This trend did
not change during the post-rofecoxib period. This was not the case for PADs and
AADs, as both classes showed a significant increase in the monthly number of
claims in comparison to the trend observed during the baseline period (Table 2). For all other COX-1 inhibitors, there was no
significant change identified by the segmented regression analysis.

With the decreased use of coxibs and
increased use of COX-1 inhibitors, it was postulated that PPIs use would
increase accordingly to counteract the GI events associated to non-selective
NSAIDs [18]. We therefore investigated the post-rofecoxib impact
on PPI use, in comparison with the baseline period. No increase was observed
after rofecoxib withdrawal from the market, as depicted in Figure 1 and Table 2.  Similar results were found in the resource
utilization of SADs where no change was observed during the post-rofecoxib
period (Figure 1).

Table 1

Fitted model and resulting first order
autocorrelation for each medication class series

Autocorrelation

Medication
Class Name

(ATC
class number)

Model

R2

Durbin-Watson

Test

P
< DW

(Positive AC)

P
> DW

(Negative AC)

Coxibs
(M01AH)

ARIMA

(0,1,0)
(1,0,1)s

0.98

2.106

0.314

0.686

ASA
derivatives (M01AB)

ARIMA

(2,0,0)
(0,0,1)s

0.95

1.794

0.105

0.895

Oxicams

(M01AC)

ARIMA

(2,0,0) (1,0,0)s

0.85

1.843

0.131

0.869

Propionic
Acid Derivatives (M01AE)

ARIMA

(3,0,0) (1,0,0)s

0.95

2.030

0.269

0.731

Other
NSAIDs*

Log-linear
with seasonal dummies

0.87

2.017

0.292

0.708

All
NSAIDs

ARIMA

(2,0,0)
(1,0,0)s

0.93

2.454

0.653

0.347

NSAIDs

(without
coxibs)

ARIMA

(2,1,0)
(1,0,0)s

0.88

1.764

0.095

0.905

PPIs
(A02BC)

Log-linear
with seasonal dummies

0.98

2.047

0.263

0.737

SADs
(N02BA)**

ARIMA

(2,1,0)
(1,0,1)s

0.79

2.002

0.244

0.756

AC = autocorrelation,
DW = Durbin-Watson; see the text for other abbreviations.*Other NSAIDs include
the following classes: M01AA (Butylpyrazolidines), M01AG (Fenamates) and
M01AX (Other antiinflammatory and antirheumatic agents, non-steroids).
**Salicylic acid derivatives include only acetylsalicylic acid (N02BA01)

Figure 1

Graphical
representation of the monthly number of claims in Ontario and Québec for
non-steroid anti-inflammatory drugs (all, without coxibs and coxibs only),
proton-pump inhibitors and salicylic acid derivatives.

Abbreviations:
NSAIDs= non-steroid anti-inflammatory drugs, PPIs = proton-pump inhibitors.

Figure 2

Graphical
representation of the monthly number of claims in Ontario and Québec for different
medication classes of non-steroid anti-inflammatory drugs. Note: Other NSAIDs
are plotted against the secondary y-axis.

Abbreviations: NSAIDs= non-steroid
anti-inflammatory drugs.

Table 2

Parameter estimates, standard
errors and p-values from the regression models predicting monthly number
of   claims for each class of
medication for the periods prior and post rofecoxib withdrawal

Baseline

Post-Intervention

Medication
Class Name

(Regression
pooled R2)

Period

(2003-2004)

b0

(SE)

P

value*

b1

(SE)

P
value

Period

b2

(SE)

P
value

b3

(SE)

P
value

Coxibs

(0.997)

Nov
– Sep

310,534

(3,995)

<0.001

1,069

(537.1)

0.066

Jan–Nov
2005

-156,883

(12,161)

<0.001

-3,272

(781.1)

0.001

ASA
derivatives

(0.999)

Oct
–Sep

91,245

(398.1)

<0.001

62.21

(56.86)

0.292

Jan–Nov
2005

33,077

(1,521)

<0.001

447.3

(92.64)

<0.001

Oxicams

(0.991)

Oct
– Sep

75,632

(421.9)

<0.001

136.5

(59.99)

0.039

Oct
2004 – Nov 2005

16,521

(1,584)

<0.001

34.69

(95.82)

0.723

Propionic
Acid Derivatives

(0.995)

Oct
– Sep

126,861

(513.9)

<0.001

-76.90

(71.12)

0.295

Oct
2004 – Nov 2005

763.0

(1,062)

0.482

1,665

(78.10)

<0.001

Other
NSAIDS**

(0.564)

Oct
– Sep

5,897

(179.8)

<0.001

-30.45

(24.67)

0.234

Oct
2004 – Nov 2005

211.6

(416.1)

0.618

25.45

(31.02)

0.423

All
NSAIDs

(0.972)

Oct
– Sep

623,038

(5,718)

<0.001

-691.0

(808.3)

0.407

Jan
2005 – Nov 2005

-141,524

(20,938)

<0.001

1,815

(1,252)

0.169

NSAIDs
(without coxibs)

(0.995)

Oct
– Sep

300,740

(2,756)

<0.001

172.1

(388.5)

0.665

Jan–Nov
2005

62,313

(10,078)

<0.001

1,190

(603.3)

0.069

PPI

(0.949)

Oct
– Sep

600,577

(6,037)

<0.001

7,941

(863.7)

<0.001

Jan–Nov
2005

-43,942

(22,942)

0.076

2,082

(1,386)

0.155

SADs

(0.943)

Oct
– Sep

552,257

(8,253)

<0.001

5,251

(1,102)

<0.001

Oct
2004 –Nov 2005

-7,257

(14,975)

0.635

1,387

(1,185)

0.259

*For
b0 and b1, the regression tested if the slope (b0)
or the intercept (b1) was significantly different than 0.  For all other parameters, the regression
tested for bi= bi-2. **Other NSAIDs include the
following classes: M01AA (Butylpyrazolidines), M01AG (Fenamates) and M01AX
(Other antiinflammatory and antirheumatic agents, non-steroids)

DISCUSSION

A decrease in all NSAID claims was observed
following rofecoxib withdrawal. Further extrapolation of the data illustrates
that this reduction may be accounted for by a significant decrease in claims of
coxibs. This decrease in coxib claims could be a result of safety concerns
provoked by the removal of rofecoxib [11]. Physicians may have been cautious about prescribing
other COX-2 inhibitors.

Incidentally, valdecoxib was eventually
removed from the market in April 2005 [6] [19]. In addition, Health Canada released new restrictions
on celecoxib use [19]. Although there was a slight increase of celecoxib
claims immediately after the removal of rofecoxib, this increase lasted only
one month. This finding reaffirms the possible concerns of the coxib family as
a whole.

The significant decrease in coxib claims was
stabilized three months after the removal of rofecoxib. This time delayed
stabilization could be explained by several factors. First, frequent visits by
pharmaceutical representatives providing samples of rofecoxib may have enabled
physicians to continue distributing samples to patients who previously
benefited from the drug [20]. Second, patients in Ontario are able to fill
prescriptions for up to a 100 day supply [21], and may have been finishing their supply during the
three month-transition period.

When NSAID claims were observed after
excluding COX-2 inhibitors, different trends were noted within the other
classes. These trends could be due to patients’ switching to alternative NSAIDs
such as AADs (i.e., diclofenac), PADs (i.e., naproxen and ibuprofen), and SADs
(e.g., Aspirin). Diclofenac, naproxen, and ibuprofen were commonly utilized as
controls in initial clinical trials of rofecoxib [22] [23] [24] [25] [26] [27] [28] [29] [30]. As such, physicians may have switched their patients
to these standard therapies, therefore suggesting an explanation for the significant
increase in claims of AADs and PADs after the removal of rofecoxib. No
significant changes were observed with SADs perhaps due to the fact that SADs
have several indications other than those shared with rofecoxib. For example,
ASA is an analgesic, anti-inflammatory, antipyretic, anti-rheumatic, and
anti-thrombotic drug [31]. Therefore, the multiple indications of SADs may have
masked the overall effect of rofecoxib’s removal.

With the potential increased use of
non-selective COX-1 inhibitor NSAIDs due to the decreased use of COX-2
inhibitors, we postulated that there would be a higher demand for PPIs as they
are commonly prescribed to patients using non-specific NSAIDs to decrease the
chances of adverse GI events [18].

However, no significant changes in PPI
claims were observed. Since PPIs have many indications, it is not possible to
make a definitive association with the removal of rofecoxib from the market.
For example, the PPI omeprazole is used not only for NSAID-associated gastric
and duodenal ulcers, but also for eradication of H. pylori, reflux esophagitis,
gastroesophageal reflux disease (GERD), and Zollinger-Ellison syndrome [31].

LIMITATIONS OF THE STUDY

The nature of the design of the study
precludes the establishment of causality, thus, it is only possible to infer
that the steady increase of NSAID claims were due to the removal of rofecoxib.
Another limitation is that only NSAIDs were examined as the alternative therapy
for COX-2 inhibitors. Therefore, changes in over-the-counter, other
prescriptions (disease modifying anti-rheumatic drugs, biological response modifiers),
and natural health products, may have experienced significant changes in sales.
Moreover, the data we collected was solely based on claims, and therefore it
was not possible to account for alternative therapies that were not covered by
this method.  Similarly, use of
combination therapy (COX-1 NSAIDs and PPIs) could not be identified. Therefore,
we were not able to identify the magnitude of the change, if any, in the
proportion of patient using combination therapy after rofecoxib was withdrawn.
Furthermore, we were unable to ascertain the indications for the claims.  This is pertinent information for medications
with multiple indications, as seen with rofecoxib, SADs and PPIs.

In conclusion, the removal of rofecoxib from
the Ontario and Québec market was associated with an immediate decrease
followed by a slow increase in NSAID claims.
The marked increase of COX-1 after September 2004 suggests that a
portion of traditional coxibs users switched to these non-selective NSAIDs. No
apparent association could be observed between rofecoxib withdrawal and the
monthly number of SADs and PPIs claims.
It would be beneficial to investigate the claims from a Canada-wide
perspective to observe if the associations observed in this study are
representative of Canada.

AUTHORS’ PARTICIPATION

OD performed the analyses and contributed to
the text of the results and discussion. JM, NN, and YIG performed the review of
the literature and contributed to the text of the introduction and discussion.
RS contributed to the results and discussion sections. TRE significantly
contributed to all parts of this manuscript.

ACKNOWLEDGEMENTS

The data were kindly provided by Brogan
Inc., Ottawa, Canada.

CONFLICT OF INTERESTS/DISCLAIMERS

This research was done as part of the
requirements for the course PHM1118H in the Graduate Faculty of Pharmaceutical
Sciences, University
of Toronto. No external
funding was received for this project. TRE is member of the Editorial Board of
the journal.

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