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Journal of the Malta College

of Pharmacy Practice

Issue 19 Summer 2013


ISSN 1811-9514

Lung health and outdoor air pollution - a review


Joseph Cacciottolo 4

Treatment of lower urinary tract infections in an era


of increased antimicrobial resistance
Ian Mifsud 8

Metformin revisited an old drug with a new beginning


Sandro Vella

12

Medicinal product quality defects reporting


Karl De Marco

16

Asian mosquito tiger: a nuisance, threat or both?


Tanya Melillo 17

The pill in the future


- pharmacological contraception in science fiction
Victor Grech, Clare Thake-Vassallo, Ivan Callus

21

Hypopituitarism:

a review on the diagnosis and management

of central hypoadrenalism and hypothyroidism

Mark Gruppetta 25


www.mcppnet.org

Keeping updated
Maria Cordina

The extemporaneous compounding of


paediatric medicines at Mater Dei Hospital
Antonella Aquilina 28

A unique action at the core


of chronic venous disease

No.

phlebotropic drug
worldwide
Presentation
and composition:
Micronized, purified
flavonoid fraction 500 mg:
diosmin 450 mg; hesperidin
50 mg. Therapeutic properties: Vascular protector and venotonic. Daflon 500 mg acts on the return
vascular system: it reduces venous distensibility and venous stasis; in the microcirculation, it normalizes capillary permeability and reinforces capillary resistance. Pharmacokinetics: Micronization of Daflon 500 mg increases its gastrointestinal absorption compared with nonmicronized diosmin (urinary excretion 57.9%
vs 32.7%). Therapeutic indications: Treatment of organic and idiopathic chronic venous insufficiency of the lower limbs with the following
symptoms: heavy legs; pain; nocturnal cramps. Treatment of hemorrhoids and
acute hemorrhoidal attacks. Side effects: Some cases of minor gastrointestinal and
autonomic disorders have been reported, but these never required cessation of treatment.
Drug interactions: None. Precautions: Pregnancy: experimental studies in animals have not
demonstrated any teratogenic effects, and no harmful effects have been reported in man to date. Lactation: in the absence of data concerning the diffusion into breast milk, breast-feeding is not recommended during treatment. Contraindications: None. Dosage and administration: In venous disease: 2 tablets daily. In acute hemorrhoidal attacks: the dosage can be increased to up to 6 tablets
daily. As prescribing information may vary from country to country, please refer to the complete data
sheet supplied in your country.
Les Laboratoires Servier - France. - Correspondent: Servier International 35, rue de Verdun - 92284 Suresnes Cedex - France. Website: www.servier.com
Daflon 500 mg (MPFF) is also registered under various trade names, including: Detralex,
Arvenum 500, Elatec, Alvenor, Ardium, Capiven, Variton
1 - Ramelet AA, Clin Hemorheol Microcir. 2005;33:309-319. 2 - Nicolaides A, Int Ang. 2008;27:1-60.

Chronic venous disease

2 tablets daily

Journal of the Malta College


of Pharmacy Practice
Issue 19 Summer 2013
ISSN 1811-9514
The Official Publication of
the Malta College of Pharmacy Practice
c/o Department of Clinical Pharmacology
and Therapeutics,
University of Malta, Msida
Email: info@mcppnet.org
www.mcppnet.org
Chairperson of Publications
Lorna Marie West BPharm(Hons), MSc Clin Pharm (Aberdeen)
Editor in Chief
Maria Cordina BPharm(Hons), PhD(QUB)
Editorial Board

Keeping updated

Marketing Editor
Francesca Buttigieg BPharm(Hons), MSc(Sunderland)
Members
Claude Farrugia BPharm(Hons), PhD(UIC), MRSC
Sandra Mifsud Bonnici BPharm(Hons), BA, LP
Patricia Vella Bonanno BPharm(Hons), MSc(Belfast) PhD

Maria Cordina BPharm (Hons) (Melit) PhD (QUB)


Editor
Email: president@mcppnet.org

In todays exceptionally fast-paced world,


one of the main laments that health
care professionals have is that they have
difficulty finding time to keep up with
the barrage of new knowledge available.
It is indeed because there is so much new
information out there that keeping updated
is essential since we are bound to make
the best decisions for the optimal health
outcomes of our patients.
The Malta College of Pharmacy Practice,
which is an autonomous institution and
whose council is made up of members who
voluntarily dedicate their time to supporting
professional development, offers a service
to health care professionals by addressing
issues of particular relevance to the local
situation.
This issue of the Journal is evidence
of this. Our opening paper by Cacciottolo
addresses an issue of national concern which
is very topical, mainly lung health and
outdoor air pollution. It is an issue in which
we need to be well versed in order to advise
our patients. Antibiotic resistance has been
addressed on numerous occasions. However
this is a subject which requires repeated
attention. Mifsud presents a very interesting
paper with a very practical approach based
on years of experience. Metformin is a drug
that has been around for quite some time
Issue 19 Summer 2013

yet is being prescribed and dispensed for


indications other than that for which is was
originally licensed. The present paper gives
us a comprehensive overview of this.
We are all familiar with the Asian Tiger
Mosiquito. Melillo traces its entry into
Malta, highlights the threat that it poses
and provided information on avoidance
and management which we should do well
to heed. Victor Grech and colleagues once
again transport us into the realm of science
fiction this time addressing pharmacological
contraception in science fiction - a very
enjoyable read!
Grupetta presents a highly evidence
based review of hypopituitarism. This paper
provides solid practice information on
diagnosis and management.
Our last contribution by Aquilina
provides a showcase of the essential services
of extemporaneous compounding that is
provided at Mater Dei Hospital. This service
provides the medication in the required
formulation to both children and adults
whose access to medication would otherwise
be hampered.
I would like to take this opportunity to
thank not only our authors for their excellent
contributions but also our long list of
anonymous reviewers whose service ensures
the quality of our journal.

The opinions expressed in this publication


are those of the respective authors and do not
necessarily reflect the opinions of the
editor or publisher.
Advertising Policy
applicable to all official publications
of the Malta College of Pharmacy Practice
Advertisers are liable for the contents
of any of their advertisements published
according to the instructions. The advertisers shall
indemnify and hold harmless the Malta College of
Pharmacy Practice against and from any and all
claims, damages, liabilities, costs and expenses
whatsoever, including counsel fees, arising from
the content of any of their advertisements.
Instructions to Authors
Before submitting an article to The Journal of the
Malta College of Pharmacy Practice, please read
and carefully follow the instructions to authors
which are found at www.mcppnet.org

The Council
President
Maria Cordina BPharm(Hons), PhD(QUB)
Secretary
Ruth Theuma BPharm(Hons), MSc Clin Pharm (Aberdeen)
Registrar
Charlotte Carabott Castagna BPharm(Hons)
Chairperson of Publications
Lorna Marie West BPharm(Hons), MSc Clin Pharm (Aberdeen)
Treasurer
Josette Farrugia BPharm

Journal of the Malta College of Pharmacy Practice

Lung health and outdoor


air pollution - a review
Joseph Cacciottolo MD, DSc, FRCP
Environmental Management and Planning Division
Institute of Earth Systems, University of Malta
Email: joseph.cacciottolo@um.edu.mt
Educational aims



To review the relationship between air pollution and lung health


To increase awareness of the hazards of air pollution, particularly on lung health
To discuss the impact of air pollution on three common lung diseases
To provide a list of references as a base for further reading

Key words
Lung health, pollution, particulate matter, ozone
Abstract

The lung is one of the interfaces between the body and the exterior
environment. The maintenance of lung health depends on several
factors, among them ones genetic makeup, the environment,
socioeconomic circumstances and natural ageing. Persons respond
differently and uniquely to environmental circumstances, and this
often makes the exposure-disease relationship difficult to assess.
Air pollution most commonly causes irritation of the respiratory
tract, resulting in discomfort, cough and breathlessness. It is also a
major factor in exacerbating existing respiratory diseases and may also
be the potential cause of lung disorders. The relationships between
air pollution, increased incidence of respiratory conditions and
severity of airway diseases are well recognized and robustly supported
by epidemiological, toxicological and clinical studies.
Outdoor air pollution is caused by aerosols and gases in amounts
that may affect health, and the major contaminants in urban
environments are a wide variety of particulate matter and ozone.
Common specific lung disorders are known to be linked with urban
air pollution: asthma and chronic obstructive pulmonary disease
are frequently exacerbated following exposure to contaminated
air, while with regard to lung cancer, the relationship is a causal
one. Air pollution also poses a significant public health problem
and concomitant approaches are necessary in order to improve air
quality and to lessen the negative impact of airborne pollution on
lung health. Control and mitigation of this problem requires effective
health education, and sound preventive strategies through a combined
community, administrative and political approach.
4

Journal of the Malta College of Pharmacy Practice

Introduction
The human body interfaces with the outside
milieu through skin, respiratory tract
and the alimentary canal. The lungs are
the most sensitive and delicate interface
with the exterior environment; as such
they react rapidly to irritation and are
susceptible to harm, causing long term
impairment and possible disability. The
effects of interaction of the lungs with
the environment depend on a wide variety
of extrinsic and intrinsic factors, among
them such personal factors as ones genetic
makeup, socioeconomic circumstances and
ageing itself.
A spectrum of personal and general
adverse environmental factors, as well as
certain occupations and working conditions
influence lung health and may possibly lead
to the development of pulmonary disorders.
Persons respond differently and uniquely
to identical environmental circumstances
and an accurate assessment of risk may
be confounded by genetic predisposition
and interaction. The exposure-disease
relationship may not be easy to identify and
assess, not only because of the usually longterm and possibly variable exposure, but
also because of the difficulty to separate the
impact of comorbid conditions in the same
individual.
A moderately active adult inhales about
20m3 of air daily, of varying quality, and
weighing more than 24kg. The respiratory
tract itself is protected by various
mechanisms. The nose, acting as a coarse
pre-filter, traps relatively large particles
(>5m) and the epithelial lining acts as
a filtration mechanism to trap smaller
(>3-5m) inhaled particles which are then
moved out of the airways by the mucociliary
process. The layer of mucus within the
respiratory bronchioles traps very small
particles and the alveolar fluid also affords
a medium where particles are engulfed and
destroyed by macrophages. The coughing
and sneezing reflexes both act as protective
mechanisms, as well as efficient systems for
rapidly cleansing the respiratory tract from
relatively large particulate matter, however
they are ineffective with regard to gaseous
air pollutants.
In clinical terms, exposure to polluted air
impacts negatively on lung health by causing
respiratory symptoms, principally coughing,
breathlessness and chest tightness. It is
also a major factor in exacerbating existing
respiratory diseases and may also be the
potential cause of lung disorders. Repeated
Issue 19 Summer 2013

Key points
Healthy lungs have extremely efficient protective mechanisms.
Lung function and structure may be compromised by repeated exposure to
contaminated air.
Ambient air in urban areas with heavy traffic flow may be polluted by particulate
matter and ozone.
Exposures to both particulate matter and ozone have a negative impact on lung
health, varying from discomfort to serious disability.
Air pollution frequently causes exacerbation and deterioration of both asthma and
chronic obstructive pulmonary disease, and may be a potential cause for lung cancer.
Control of airborne pollution requires effective health education and preventive
strategies, through combined community, administrative and political approaches.
exposure may lead to decline in lung
function, increased susceptibility to chest
infections, and permanent damage leading
to premature death. Children, the elderly
and persons with pre-existing cardiovascular
disease, respiratory problems and diabetes
mellitus appear to be at a greater risk
to develop complications related to air
pollution.1,2
The urban environment and outdoor air
pollution
Outdoor air pollution is caused by solids,
liquids, or gases in amounts that may
adversely affect health, and the environment
itself. In its milder form, air pollution often
interferes with the comfortable enjoyment of
life and property and most commonly causes
irritation of the respiratory tract and the eye.
For many centuries, airborne dust, smoke
and obnoxious fumes have been known to
be sources of discomfort and illness. In the
United Kingdom, the Industrial Revolution,
beginning around 1730, was fueled primarily
by the use of coal, and furnaces were often
in close proximity to densely populated
areas. Industrial use of coal, together with
its use as a source of domestic heating,
caused very high levels of air pollution,
which were made worse when the weather
was foggy.
The first well-documented widespread
occurrence of airborne pollution happened in
December 1930 in the Meuse valley, Belgium.
Then, a lethal combination of industrial air
pollution and thermal inversion, trapping
fog over the heavily populated area of the
narrow valley caused several thousand cases
of acute pulmonary attacks and 60 deaths.
The Commission investigating this disaster
was of the opinion that sulphur dioxide or
its oxidation products were the cause for this
disaster, however later studies suggest that
the probable cause was acute intoxication by
Issue 19 Summer 2013

gaseous fluorine compounds.3


In December 1952, the London smog
episode was the result of pollution from
domestic coal use and industrial furnaces,
together with adverse atmospheric
conditions. Over a short period, tons of
particulate matter filled the air, eventually
turning the sky almost black, stinging eyes
and causing acute respiratory symptoms.
Visibility was so much reduced, that traffic
flow was practically brought to a standstill.
This episode was the immediate cause
of around 4000 deaths, together with an
indeterminate number due to delayed
effects. Most of those who succumbed were
elderly or already infirm.4
The damage that urban air pollution
causes to health is multifactorial and usually
follows exposure to multiple contaminants
present concurrently. With regard to lung
disorders, the relationship between air
pollution, increased incidence of respiratory
conditions and severity of airway diseases
is well supported by epidemiological,
toxicological and clinical studies.5
In European Union states, quite
significant segments of urban dwellers are
exposed to unacceptably high levels of
airborne pollutants (Figure 1).6 In a general
European context, aerosol particles and to a
lesser extent ozone, are the pollutants that
mostly compromise lung and cardiovascular
health. 7 There are no established safe
levels for exposure to either particulate
matter or ozone and they pose a risk to
health even at concentrations below current
guidelines for air quality.8
Particulate matter
Atmospheric particulate matter (PM) refers
to a wide range and mix of particles of
varying sizes and chemical composition:
they may derive either from natural sources,
or as a result of human activities and

industry. Suspended dusts, pollen and seaspray are the commoner natural PM, while
combustion of fossil fuels in vehicles and
power-generating plants are the source of
most of man-made or anthropogenic PM.
The finer particles are classified as having
an aerodynamic diameter of 2.5m or less
(PM2.5).
The effects of chronic exposure of
airborne PM on lung function and overall
health are complex and to a very large
extent beyond control of individuals. The
negative effect of particulate air pollution
on respiratory well-being is independent and
consistent among different communities.
Such a causal relationship holds for acute
respiratory infections in children, obstructive
pulmonary disorders, lung cancer, and for
mortality from cardiopulmonary problems.9
Children are especially vulnerable, as there is
clear association between decreased growth
in lung function and exposure to airborne
PM. This association is consistent across
communities that are ethnically different and
geographically separate.10,11
In the European Union, the average
life expectancy is 8.6 months lower due
to exposure to anthropogenic PM2.5, while
mortality rates due to air contamination
are higher by 1520% in cities with levels
of pollution that exceed those observed in
cities with relatively cleaner air.12
Ozone
Ozone (O3) is formed as a result of chemical
reactions involving daylight UV rays,
following emission of precursor gases
resulting principally from fuel combustion.
Ozone is a powerful oxidizing agent that
not only irritates the respiratory tract, but
also reduces lung function. High ambient
ozone concentrations are also clearly and
independently associated with a significant
risk of death from respiratory causes: the
evidence is particularly compelling when
considering results deriving from a largescale study over an 18-year period and
involving over 448000 subjects.13
Both acute and long-term exposures
to ozone are associated with increased
morbidity and mortality and the absolute
effect of the gas on mortality is higher
among older adults and during warmer
weather.14 Children, persons who work or
exercise outdoors, persons with pre-existing
respiratory disorders and persons suffering
from cardiovascular conditions are especially
vulnerable to damage caused by breathing
ozone. 15,16,17

Journal of the Malta College of Pharmacy Practice

Figure 1: Percentage of EU urban population potentially exposed to air pollution exceeding acceptable
EU air quality standards. Source: EEA, 2011c (CSI004).5
100

% of urban population

80

60

40

20

0
1997

1998

1999

2000

Specific lung diseases and air pollution


Asthma
Air pollution is a recognized cause for
destabilizing well-controlled asthma, and for
exacerbating this inflammatory condition.
This is especially so among children, who are
more susceptible to air pollution than adults,
even when levels of pollution are relatively
low and within acceptable ranges.18,19
Hospital admissions because of acute
asthma may be due to a variety of provoking
factors, among them exposure to air polluted
with a wide range of PM. The causal
relationship between hospitalization rates
for asthma and ambient air contamination
is both consistent and widespread across
all age-groups and among different
communities. Exposure to traffic-related air
pollution over a long period also increases
the risk of hospitalization because of
unstable asthma among older persons,
however children are probably at an even
higher risk.20
There is a clear relationship between
ambient ozone concentrations and increased
symptoms of asthma. Persons with asthma
might be more sensitive to ozone, and may
therefore develop respiratory symptoms
either at lower concentrations of the gas, or
with greater magnitude than persons who
do not have this condition. Admissions to
hospital for control of asthma have been
found to be more frequent on days following
6

2001

2002

NO

PM

2003
2.5

2004
3

2005

SO

2007

2008

2009

exposure to raised ambient ozone levels,


while minor adverse respiratory symptoms
and decreased lung function also persist for
several days. Predictably, the effects tend
to be more pronounced during the warm
season.21
While the role of air pollution as a
trigger factor for exacerbating pre-existing
asthma is well documented, there is no
evidence that it may actually cause asthma,
and any role that it may possibly play in
initiating it, is yet undetermined.
Cancer of the lung
Several large epidemiological studies have
documented a link between air pollution and
lung cancer in non-smokers. Persons who
live in areas with high ambient air pollution
are more likely to develop lung cancer than
those who live in areas with cleaner air.
Recent evidence shows a clear relationship
between concentrations of ambient PM2.5over
a 26-year period and mortality from lung
cancer among persons who never smoked.22
The relationship between ambient diesel
exhaust specifically and lung cancer is less
clear, and most of the evidence derived
from population studies is not considered
adequate to prove the diesel-lung cancer
hypothesis.23 However, with regard to
occupational exposure to diesel fumes, a
large multicentre study showed a consistent
association between cumulative diesel motor

Journal of the Malta College of Pharmacy Practice

2006

exhaust and increased risk of lung cancer:


this association was well-adjusted for bias
and confounding factors.24
Chronic obstructive pulmonary disease
The role of air pollution as a direct cause
of chronic obstructive pulmonary disease
(COPD) has been explored by several studies,
however any possible causal relationship is
still unclear.25 A large Danish cohort study
suggests that exposure to high levels of
air pollution in the long-term may itself
contribute to the development of COPD.
Persons who were exposed for more than 25
years ran a 7% higher risk, while the impact
of air pollution on persons who also had
asthma and diabetes was greater.26
The role of air pollution as a
complicating factor in COPD as a preexisting lung condition is however not in
any doubt, and the relationship has been
well-defined. 27 There is evidence to suggest
that some patients are more susceptible than
others to this environmental trigger and
react with increasing symptoms and acute
exacerbations: this has a cumulative effect
on emergency department visits, hospital
admissions and even mortality. 28,29
Conclusion
Air pollution poses clear and multiple health
hazards to individuals; however it is also a
Issue 19 Summer 2013

significant public health problem. Several


concurrent approaches are necessary in
order to improve air quality and lessen the
negative impact of airborne pollution on
lung health. Control of this problem requires
effective health education, and sound
preventive strategies through a combined
community, administrative and political
approach.
References
1. Perez L, Rapp R, Knzli N. The Year of the Lung:
outdoor air pollution and lung health. Swiss Med
Wkly. 2010;140:w13129.
2. Brook RD, Franklin B, Cascio W et al. American
Heart Association scientific statement: Air
Pollution and Cardiovascular Disease. Circulation.
2004; 109: 2655-2671.
3. Roholm K. The fog disaster in the Meuse Valley,
1930: A fluorine intoxication. J. Ind. Hyg. Toxicol
1937; 19 (3): 126137.
4. Stone R. Air pollution: counting the cost of
Londons killer smog. Science 2002; 298: 21062107.
5. Kelly FJ, Fussell JC. Air pollution and airway
disease. Clin Exp Allergy. 2011;41(8):1059-1071.
6. European Environment Agency. Exceedance of air
quality limit values in urban areas (Indicator CSI
004), EEA 2011c.
7. European Environment Agency. Air Quality
in Europe -2011 report. EEA technical report
12/2011. EEA Copenhagen 2011.
8. Air quality guidelines-global update 2005, World
Health Organization Regional Office for Europe,
Copenhagen 2006.

Issue 19 Summer 2013

9. Cohen AJ, Ross Anderson H, Ostroc B, et al. The


Global Burden of Disease Due to Outdoor Air
Pollution. J Toxicol Envir Health, A. 2005; 68,
:1301-1307.
10. Roy A, Hu W, Wei F, et al. Ambient particulate
matter and lung function growth in Chinese
children. Epidemiology 2012 May; 23(3):464-472.
11. Horak F, Studnicka M, Gartner c et al. Particulate
matter and lung function growth in children: a
3-yr follow-up study in Austrian schoolchildren.
Eur Respir J 2002; 19: 838845.
12. Air quality and health. WHO Fact sheet N313,
World Health Organization. Geneva, 2011.
13. Jerrett M, Burnett RT, Arden Pope C, et al. LongTerm Ozone Exposure and Mortality. N Engl J Med
2009; 60:1085-1095.
14. Bell ML, Dominici F, Samet JM. A meta-analysis of
time-series studies of ozone and mortality with
comparison to the national morbidity, mortality,
and air pollution study. Epidemiology 2005; 16:
436-445.
15. Thaller EI, Petronell SA, Hochman D, et al.
Moderate Increases in Ambient PM 2.5 and Ozone
Are Associated With Lung Function Decreases in
Beach Lifeguards. J Occp Environ Med. 2008; 50:
202-211.
16. Medina-Ramn M, Schwartz J. Who is more
vulnerable to die from ozone air pollution?
Epidemiology. 2008; 19: 672-679.
17. Peel JL, Metzger KB, Klein M, et al. Ambient
air pollution and cardiovascular emergency
department visits in potentially sensitive groups.
Am J Epidemiol. 2007; 165: 625-633;
18. Chew FT, Goh DY, Ooi BC et al. Association of
ambient air-pollution levels with acute asthma
exacerbation among children in Singapore. Allergy
1999; 54(4):320-329.
19. Pnk A, Virtanen M. Asthma and ambient air
pollution in Helsinki. J Epidemiol Community
Health. 1996;50 Suppl 1:s59-62.

20. Andersen ZJ, Bnnelykke K, Hvidberg M, et al.


Long-term exposure to air pollution and asthma
hospitalisations in older adults: a cohort study.
Thorax 2012;67:6-11.
21. Mortimer K M, Neas L M, Dockery D W, et al. The
effect of air pollution on inner-city children with
asthma. Eur. Respir. J. 2002;19: 699-705.
22. Turner MC, Krewski D, Arden Pope C et al. Longterm Ambient Fine Particulate Matter Air Pollution
and Lung Cancer in a Large Cohort of NeverSmokers. Am J Respir Crit Care Med. 2011;184,
12:1374-1381.
23. Gamble JF, Nicolich MJ, Boffetta P. Lung cancer
and diesel exhaust: an updated critical review of
the occupational epidemiology literature. Crit Rev
Toxicol 2012;42(7):549-598.
24. Olsson AC, Gustavsson P, Kromhout H, et al.
Exposure to diesel motor exhaust and lung cancer
risk in a pooled analysis from casecontrol studies
in Europe and Canada. Am J Respir Crit Care Med
2011;183:941948.
25. Schikowski T, Mills IC, Anderson HR, et al.
Ambient air pollution- a cause for COPD? Eur Respir
J. 2013 Mar 7. [Epub ahead of print]
26. Andersen, ZJ, M Hvidberg, SS Jensen, et al. 2010.
Chronic obstructive pulmonary disease and longterm exposure to traffic-related air pollution:
a cohort study. Am J Respir Crit Care Med
2011;183:455-461.
27. Sint T, Donohue JF, Ghio AJ. Ambient air pollution
particles and the acute exacerbation of chronic
obstructive pulmonary disease. Inhal Toxicol.
2008;20(1):25-29.
28. Harre ESM, Price PD, Ayrey RB, Respiratory
effects of air pollution in chronic obstructive
pulmonary disease: a three month prospective
study. Thorax 1997;52:10401044.
29. Ko FWS, Hui DS. Air pollution and chronic
obstructive pulmonary disease. Respirology 2012;
17,3:395401.

Journal of the Malta College of Pharmacy Practice

Treatment of lower
urinary tract infections
in an era of increased
antimicrobial resistance
Ian Mifsud

B.Pharm (Hons), MSc. Env. Mgt . PG Cert Clinical Pharmacy

Senior Pharmacist Rehabilitation Hospital Karen Grech


Email: ian.a.mifsud@gov.mt
Educational aims
To provide an overview of the OTC preparations available for the prophylaxis and
treatment of acute uncomplicated cystitis
To highlight the reasons as to why nitrofurantoin and co-amoxiclav are the
antimicrobials of choice in the empirical treatment of lower urinary tract infections
To illustrate the limitations of nitrofurantoin treatment
To demonstrate why fluoroquinolones are not the ideal choice in the treatment of
lower urinary tract infections
Key words
lower urinary tract infection, bacteruria, nitrofurantoin, co-amoxiclav, ESBL positive pathogens
Abstract

The antibiotic arsenal for treatment of lower urinary tract infection


is becoming increasingly limited. Co-trimoxazole has been lost in
the empirical treatment of urinary tract infection. Other agents
particularly fluoroquinolones are becoming ineffective. Locally, the
empirical treatment of such infection focuses on two antibiotics
nitrofurantoin and co-amoxiclav. Carbapenems are increasingly
being prescribed due to the emergence of ESBL (extended spectrum
beta lactamase) positive pathogens.
8

Journal of the Malta College of Pharmacy Practice

Introduction
Acute cystitis is a condition for which the
community pharmacist is likely to come
across on a regular basis. This condition
is normally characterised by dysuria,
urgency and/or frequency. However such
classical symptoms may not be apparent in
the elderly who may instead present with
confusion or incontinence. The presence of
symptoms such as fever, chills or back pain
are indicative of bacteraemia as well as
kidney involvement. Referral is also always
indicated in the latter cases, as is also for
all cases of lower urinary tract infections
in men, children and pregnant women. The
community pharmacist should also be aware
that there are other causes for dysuria, such
as sexually transmitted diseases.1 Suspicion
of such infections should always be referred
for appropriate treatment.
Bacteriuria does not always present
with symptoms. Asymptomatic bacteriuria
is a common occurrence in the elderly as
well as catheterised patients and does not
merit treatment. Treatment of asymptomatic
conditions in the elderly does not decrease
the frequency of symptomatic infection but
increases the risks of adverse drug reaction
and promotes urinary tract infection with
resistant organisms.2 In cases of long-term
indwelling catheters there is conflicting
evidence on whether use of antibiotics in
asymptomatic patients reduces the frequency
of symptomatic episodes but repeated use of
antibiotics increases the risk of colonisation
by resistant bacteria.2
OTC preparations for the treatment and
prophylaxis of cystitis
Women presenting with symptoms of cystitis
and who do not need to be referred should
be advised to maintain adequate hydration.
They can also be offered alkalinising
agents for a couple of days, although the
evidence base for this recommendation
is limited. The use of alkalinising agents
is not recommended in individuals with
hypertension or heart failure as these
preparations contain a high sodium or
potassium content. Caution should be
exercised when recommending potassium
alkalinising preparations to patients on
medication that predispose to hyperkalaemia
eg ACE inhibitors and potassium sparing
diuretics. Alkalinising agents should not be
used in patients prescribed nitrofurantoin,
as this drug requires an acidic urine pH to be
effective.2
Issue 19 Summer 2013

Other OTC preparations that are


commonly associated with cystitis are
cranberry products. Evidence to support
the use of these products for treatment of
cystitis is lacking. The recommendation
of such products should be restricted
to the prevention of such infections in
premenopausal women with a history of
recurrent infections.2 Evidence is also lacking
for the effectiveness of cranberry products
for their prophylactic effect in the elderly
and catheterised patients. The optimal
dose has not been established but giving a
minimum of 36 mg/day proanthocyanindin
A (the active compound), is favoured.3
It might be appropriate to recommend
cranberry capsules as an alternative to
the juice as a solid dosage form may be
more convenient to the patient. The use
of cranberry products is not generally
recommended in patients on warfarin as
interactions resulting in an increase the INR
can occur.4
Cystitis originates primarily from
pathogens in the bowel flora. By far the
most commonly implicated organism is
Escherichia coli. Traditionally co-trimoxazole
was prescribed for cystitis, however, over the
past decades local resistance has developed
to the degree that this antibiotic is no
longer indicated in the empirical treatment
of urinary tract infection. From local clinical
practice this antibiotic retains its high
efficacy against MRSA.
Empirical treatment in the community
Current local community guidelines indicate
nitrofurantoin and co-amoxiclav as the
drugs of choice.5 The exclusive indication
of nitrofurantoin is cystitis. This drug
lacks tissue penetration, only reaching
therapeutic concentrations within urine.
For this indication nitrofurantoin remains
the most efficacious oral agents with little
acquired resistance over the 60 year period
in clinical use. The bactericidal potency
of nitrofurantoin is affected by pH, its
potency reducing rapidly as urine becomes
more alkaline. For this reason nitrofurantoin
should not be prescribed for infections
characterised with a urine pH greater than
7. A high urinary pH may also be indicative
of a pathogen that produces urease enzymes,
such a Proteus or Serratia which are
intrinsically resistant to nitrofurantoin.6
Nitrofurantoin has various mechanism of
action, being bactericidal at concentration
normally reached with therapeutic doses.
Its spectrum of activity covers both
Issue 19 Summer 2013

gram positive as well as gram negative


organisms including multidrug resistant
strains such as MRSA, vancomycinresistant enterococci and the extended
beta lactamase enterobacteriaceae (esbl
positive organisms). One drawback of this
drug is that it is not licensed for use in
patients with renal impairment defined by an
estimated glomerular filtration rate (eGFR) of
less than 60 ml/min. This makes the drug of
limited use in the elderly. However literature
has shown that nitrofurantoin still remains
effective in renal impairment and can be
used with caution in patients with mild renal
impairment.7,8,9 In such cases the drug is
being prescribed off label.
Nitrofurantoin is prescribed on a 6
hourly basis and should be taken with
food primarily to improve absorption
but also to limit GI side effects such as
nausea (a side-effect which is less frequent
with the macrocrystalline formulation).
In premenopausal woman acute cystitis
usually responds to 3 days treatment. In
postmenopausal women or women having
well-controlled diabetes without urological
sequelae may be managed in the same way
as for acute uncomplicated cystitis. But a
7-day course is generally recommended since
cure rates with short-course therapy are not
as high.10
Co-amoxiclav is now the alternative to
nitrofurantoin for the empirical treatment
of cystitis. The higher dose formulations of
co-amoxiclav have often been prescribed on
a bd basis however the tds regimen is now
generally recommended except for specific
hepatic and renal considerations.11 For
cystitis the recommended dose being 625mg
every 8 hours. Previous to co-amoxiclav,
cefuroxime was widely recommended, having
a narrower spectrum than co-amoxiclav but
still retaining activity against uropathogens.
However the extensive overuse of
cephalosporins has led certain gram negative
pathogens to develop resistance by enzyme
activity - ESBL, enzymes that destroy the
beta-lactam ring. For this reason the use
of cefuroxime within hospitals has been
restricted.12
Restricting the use of fluoroquinolones
The prescription of fluoroquinolones for
cystitis should be guided by laboratory
results. Resistance to these antibiotics is
at a significant level.13 Limiting the use
of fluoroquinolones for when no suitable
alternative is available is a strategy that
will help mitigate increasing resistance

to this class of antibiotics, not only to


uropathogens but also to other pathogens
including MRSA.14 When fluoroquinolones
are indicated ciprofloxacin is the favoured
antibiotic for urinary tract infections, it has
good pharmacokinetic properties, the oral
formulation being well absorbed as well as
being well concentrated within urine. A low
dose (250mg bd) will suffice. Furthermore
ciprofloxacin is the gold standard in
the treatment of infections caused by P
aeruginosa. In such cases however a higher
doses (500mg bd) should be considered
as the minimum inhibitory concentration
for P aeruginosa is higher than for
other organisms. A good fluid intake is
recommended with the higher doses of
ciprofloxacin as cases of crystaluria have
been reported especially in alkaline urine.
Since ciprofloxacin absorption is inhibited
by multivalent metal ions, pharmacists
should advice patients not to take this
antibiotic with milk or milk products.
Patients on calcium supplementation or
multivitamin preparation should also be
adviced to take their regular medication
4 hours away from their antibiotic.
Pharmacists should also be aware that
fluoroquinolones may lower the seizure
threshold and may trigger seizures thus
should be used with extreme caution in
patients predisposed to seizures.15
Recurrent infections
Individuals with recurrent urinary tract
infections (defined as three episodes over
the past year or two in the past six months)
may be considered for a trial of antimicrobial
prophylaxis for up to 6 months if symptoms
are debilitating.2,16 Prophylactic antibiotics
should be given at night when urine flow
is low. Longer term use is however not
recommended as this promotes emergence
of resistance. Antibiotic prophylaxis is
generally not recommended in catheterised
patients. However they may be considered
if the frequency and intensity of symptoms
impinge on the well-being of the individual.2
Empirical treatment in hospitals
Antibiotic choice for the empiric treatment
of lower urinary tract infections in hospital
is similar to community guidelines but in
an era of increasing antibiotic resistance,
routine urine sampling is recommended in
symptomatic patients in order to determine
the sensitivity of the pathogen.17 Urinary
tract infection is the most common
nosocomial infection and hospitalisation

Journal of the Malta College of Pharmacy Practice

Key points
Nitrofurantoin is the antibiotic of choice for the empirical treatment of cystitis. Coamoxiclav is now the recommended alternative to nitrofurantoin.
Alkalinising agents should not be co-prescribed with nitrofurantoin. This may result
in therapeutic failure.
Cranberry products interact with warfarin. The Committee on Safety of Medicine in
the UK does not recommend their concomitant use.
Alkalinising agents should be used with caution in the elderly as such agents can
worsen hypertension and heart failure. Patients on medication which predispose to
hyperkalaemia should not use potassium containing preparations.
Cefuroxime is no longer recommended for the treatment of cystitis - Cephalosporins
have been implicated as the driving force for resistance in Gram-negative pathogens.
Second generation quinolones should be avoided in the empirical treatment
of cystitis as resistance is at a significant level. The use quinolones promotes
resistance not only among uropathogens but also other organisms.
Asymptomatic bacteriuria is common in certain categories such as the elderly and
individuals with long-term indwelling catheters. Such a condition does not merit
antimicrobial treatment.
should be considered a risk for infection with
ESBL-producing pathogens. An increasing
proportion of patients would have acquired
such organisms before hospital admission,
reflecting the regrettable over-prescribing
of antibiotics in the community. Treatment
with co-amoxiclav in such cases is likely
to fail and these pathogens could also
have acquired resistant to quinolones and
aminoglycosides. Carbapenems are increasing
becoming the only practical alternative
treatment available locally. Ertapenem has
an advantage over other carbapenems in
that it is given on a once daily basis; it
also has a narrower spectrum than other
carbapenems, it does not cover Pseudomonas
and Acinetobacter species. In Europe it is
used off-licence for urinary tract infection,
however it is registered for this indication
in the US.18,19 Carbapenems are not available
as oral formulations. Patients requiring such
antimicrobials have to undergo IV therapy,
an invasive procedure which in its own
right predisposes to a hospital acquired
infection.20 Some strains of Gram-negative
organisms have also developed resistance to
carbapenems thus limiting further the choice
of antibiotics.
A risk for urinary tract infections
catheterisation
Urinary catheterisation is a common
procedure in hospital and long-term care
facilities. This procedure predisposes the
individual to infection.20 Risk reduction
should be considered - the need and duration
for catheterisation should be carefully
assessed. Alternatives such as suprapubic or
condom catheters should be considered as
10

these carry a lower incidence of urinary tract


infections. The technique of intermittent
catheterisation is also encouraged especially
among spinal cord injury patients. Treatment
of catheter associated urinary tract
infections without kidney involvement is
the same as for patients without catheter.17
Treatment is only indicated in symptomatic
patients, who would also merit a catheter
change since biofilms tend to develop rapidly
along both the inner and outer surface of the
catheter lumen creating a barrier to effective
penetration by antibiotics and predisposing
to resistance. Biofilms are usually initially
caused by single species but rapidly become
polymicrobic.21 As a general guideline
seven days of antimicrobial treatment for
patients with catheter associated-UTI who
have prompt resolution of symptoms is
recommended, the duration is prolonged
to 1014 days for those with a delayed
response.22
Pivmecillinam and Fosfomycin
Two other antibiotics indicated for urinary
tract infection are available but have not
been discussed above since, as yet, they
are not registered locally. Both of these
antibiotics have been listed as first-line
agents in both European and American
guidelines.3,23 Pivmecillinam is registered in
some Nordic European countries. It is orally
bioavailable and has an extended spectrum
against gram-negative Enterobacteriaceae.
Its sole indication is urinary tract infection.
Fosfomycin is registered in the USA as well
as various European countries. Its favourable
characteristics include the convenience of a
single-dose regimen for acute uncomplicated

Journal of the Malta College of Pharmacy Practice

cystitis, very good activity against a range


of multi-drug resistant organisms including
resistant Enterobacteriaceae and minimal
propensity to induce resistance.23
Conclusion
Although antimicrobial resistance is
an inevitable natural phenomenon,
our professional behaviour is crucial in
determining the rate and extent to which
pathogens develop resistance. The emergence
of ESBL-positive pathogens is challenging our
practices and constraining the health care
professional to rely increasingly on secondline agents such as carbapenems.
Clinical judgement in the choice of
antibiotics, when indicated, is pivotal in
ensuring therapeutic success while minimising
the negative consequences of therapy.
References
1. Health Protection Agency, British Infection
Association. Diagnosis of UTI- quick reference Guide
for Primary Care.London: HPA; 2010. Available
at http://www.hpa.org.uk/webc/HPAwebFile/
HPAweb_C/1194947330877. Accessed 6th June 2013.
2. Scottish Intercollegiate Guidelines Network. 2012
Management of suspected bacterial urinary tract
infection in adults: a national clinical guideline.
Available at http://www.sign.ac.uk/pdf/sign88.pdf.
Accessed 6th June 2013.
3. Grade M et al. Guidelines on urological infections.
In European Association of Urology (EAU) Guidelines
edition presented at the 25th EAU Annual congress,
Barcelona 2010.
4. Medicines and Healthcare products Regulatory Agency.
Current Problems in Pharmacovigilance. 2004; 30: 10.
5. National Antibiotic Committee: Antibiotic treatment
guidelines for community care (Draft document for
consultation).
6. SPC Macrodantin 50mg capsule. Available at
http://old.medicinesauthority.gov.mt/products/
SPC_MA077%2000402_Macrodantin_Capsule_
Nitrofurantoin%2050mg_Goldshield%20
Pharmaceuticals%20Ltd._United%20Kingdom_PoM_
G04AC01_29.03.06.pdf. Accessed 6th June 2013.
7. Ashley C, Currie A, eds. The Renal Drug Handbook, 3rd
edition . Oxford: Radcliffe Medical Press, 2009.
8. Bains A, Buna D, Hoag NA. A retrospective review
assessing the efficacy and safety of nitrofurantoin in
renal impairment. Canadian Pharmaceutical Journal
2009: 142(5): 248-252.
9. Cunha BA, Schoch PE, Hage JR. Nitrofurantoin:
Preferred Empiric Therapy for Community-Acquired
Lower Urinary Tract Infections. Mayo Clin Proc. 2011:
86(12): 12431244.
10. Nicolle LE et al: SHEA Position Paper - Urinary tract
Infections in long-term-care facilities. Infection
Control and Hospital Epidemiology 2001: 22(3):
167-175.
11. European Medicines Agency. A review of Augmentin.
London: June 2009. Available at http://www.
emea.europa.eu/docs/en_GB/document_library/
Referrals_document/Augmentin_30/WC500014179.
pdf. Accessed 6th June 2013.

Issue 19 Summer 2013

12. Mater Dei Hospital. Circular No: MDH/96/2013.


13. European Centre for Disease Prevention and Control
Antimicrobial resistance surveillance in Europe
report 2011. Available at http://www.ecdc.europa.
eu/en/publications/Publications/antimicrobialresistance-surveillance-europe-2011.pdf.
14. Paterson DL: Collateral Damage from cephalosporin
or quinolone antibiotic therapy. Clinical Infectious
Diseases 2004:38(4) S341-S345.
15. Summary of Product Characteristics. Ciproxin.
Available at http://old.medicinesauthority.gov.
mt/products/SPC_MA513%2000703_Ciproxin%20
Tablets%20250mg_Tablet_Ciprofloxacin%20
250mg_Bayer%20PLC_United%20Kingdom_PoM_
J01MA02_27.11.06.pdf. Accessed on 6th June 2013.
16. Scottish Medicines Consortium: Good Practice
Recommendations for antimicrobial use in frail

Issue 19 Summer 2013

elderly patients in NHS Scotland. Feb. 2013.


17. Antibiotic Team Mater Dei Hospital: Guideline
algorithms for the antibiotic treatment of common
infectious diseases in the hospital setting (draft for
peer review). December 2011. Available at http://
mdhweb:81/AntibioticGuidelines.aspx.
18. Summary of Product Characteristics. Invanz 1g
powder for concentration for infusion. Available at:
http://invanz.co.il/secure/downloads/EU_SPC.pdf.
Accessed on 6th June 2013.
19. Invanz Information to health care professionals.
Available at Invanz http://www.invanz.com/
ertapenem_sodium/invanz/hcp/index.xhtml.
Accessed 6th June 2013.
20. Moulder E Healthcare-associated infection
intervention-related infection Hospital Pharmacist
2008:15: 13-15.

21. Nickel JC et al: Bacterial biofilms: influence on


the pathogenesis, diagnosis and treatment of
urinary tract infections Journal of Antimicrobial
Chemotherapy 1994:33, Suppl. A, 31-41.
22. Hooton TM et al: Diagnosis Prevention, and
Treatment of Catheter- Associated Urinary Tract
Infection in Adults: 2009 International Clinical
Practice Guidelines from the Infectious Disease
Society of America. Clinical Infectious Diseases
2010:50(5): 625-663.
23. Gupta K et al International clinical practice
guidelines for the treatment of acute uncomplicated
cystitis and pyelonephritis in women: A 2010 Update
by the Infectious Disease Society of America and the
European Society for Microbiology and Infectious
Diseases. Clinical Infectious Diseases 2011:52(5):
e103-e120.

Journal of the Malta College of Pharmacy Practice

11

Metformin revisited
an old drug with
a new beginning
Sandro Vella

MD, MSc (Roehampton), MRCP (UK)

Consultant Physician, Diabetologist and Endocrinologist, Mater Dei Hospital, Malta


Visiting Assistant Lecturer, Department of Medicine, University of Malta Medical School, Malta
Email: svell11@um.edu.mt
Educational aims
To highlight the mechanism of action of metformin
To identify metformins role as an oral glucose lowering agent with favourable
pleiotropic effects on cardiovascular outcomes.
To discuss potential new roles for this drug in type 1 diabetes, as well as in the fields
of obstetrics and gynaecology, nephrology, hepatology and oncology
To discuss the cost-effectiveness and safety of metformin pharmacotherapy, with
particular reference to established prescription guidelines
Key words
metformin - diabetes - cardiovascular - pregnancy - cancer
Abstract

Acting as a weak activator of AMP-activated protein kinase,


metformin has established itself as a cost-effective first line agent
in the management of type 2 diabetes (T2DM). Besides slowing
progression to this condition, its use is associated with improved
survival and lower rates of myocardial infarction in T2DM, as well
as benefits in stable patients with heart failure. Metformin may
play a valuable role in early nephropathy, non-alcoholic fatty liver
disease and as adjunct therapy in type 1 diabetes. It is increasingly
advocated in patients with gestational diabetes and polycystic ovary
syndrome. Its role as an anti-cancer agent remains controversial.
Abbreviations
AMP adenosine monophosphate
AMPK AMP-activated protein kinase
ATP adenosine-5-triphosphate
BMI body mass index
DARTS Diabetes and Audit in Research Tayside Scotland
DPP Diabetes Prevention Programme
eGFR estimated glomerular filtration rate
HbA1c glycosylated haemoglobin
HF heart failure
HOME Hyperinsulinaemia: the Outcome of its Metabolic
Effects
IGT impaired glucose tolerance
MIG Metformin in Gestational Diabetes

12

mTOR mammalian Target Of Rapamycin


NAFLD non-alcoholic fatty liver disease
NASH non-alcoholic steatohepatosis
OCT1 organic cationic transporter 1
OR Odds ratio
PRESTO Prevention of Restenosis with Tranilast and
its Outcomes
QALY quality-adjusted life year
RR relative risk
T1DM type 1 diabetes mellitus
T2DM type 2 diabetes mellitus
UKPDS United Kingdom Prospective Diabetes Study

Journal of the Malta College of Pharmacy Practice

Introduction
Derived from the French Lilac plant Galega
Officinalis, metformin (N,N-dimethylimidodicarbonimidic diamide) has widely established
itself as a safe as well as clinically effective oral glucose lowering agents. Used for
55 years in the United Kingdom (although
for only the last eighteen years or so in
the United States),1-3 this drug has been
virtually uniformly advocated as a first line
agent in the management of type 2 diabetes
(T2DM) by local, national and international
treatment guidelines. This review will seek
to address the evidence underpinning its
widespread use in T2DM patients, as well
as potentially exciting new roles in type 1
diabetes (T1DM) and beyond.
Pharmacology
Perhaps surprisingly, the mechanism of
action of metformin had remained obscure
until relatively recently. This biguanide is
now recognised as a weak activator of an
important, ubiquitous, phylogenetically conserved serine/threonine protein kinase called
AMP-activated protein kinase (AMPK).4 Acting as a gauge of systemic and cellular energy status, AMPK is activated by an increase
in intracellular adenosine monophosphate /
adenosine-5-triphosphate (AMP/ATP) ratio,
and serves to protect cellular functions under
energy restricted conditions by switching
from an anabolic to a catabolic state. The
latter is achieved through phosphorylation
of key metabolic enzymes and transcription
factors/co-activators modulating gene expression.5 Following hepatic uptake through
the organic cationic transporter 1 (OCT1),6
metformin exerts additional specific and
AMPK independent inhibition of complex 1
of the respiratory chain,7 leading to an acute
and transient inhibition of gluconeogenesis,
as well as an inhibition of key gluconeogenic
enzymes.8, 9 AMPK activation also reduces
hepatic lipogenesis through phosphorylation
and inactivation of acetyl-Co-A carboxylase
4
while suppressing lipogenic genes such as
fatty acid synthase.10
Cost effectiveness
Data from the Diabetes Prevention Programme (DPP) suggests that metformin is
cost-effective in individuals below the age
of 65. Intervening with this drug over a
lifetime is expected to prevent diabetes in
8%, delay onset of T2DM by 3.4 years, increase life expectancy by 0.2 year and reduce
the cumulative incidence of coronary artery
disease, stroke, amputation, end-stage renal
Issue 19 Summer 2013

disease and blindness by 2%, 3%, 16%, 17%


and 16% respectively.11 The estimated cost
per quality-adjusted life year (QALY) gained
for (generic) use of metformin over a lifetime
is $1755 compared to placebo.11
Metformin in pre-diabetes and obesity
The DPP reported that metformin prescribed
at a dose of 850mg twice daily decreased
progression from impaired glucose tolerance
(IGT) to diabetes by 31% over three years.
Benefits were greater in patients with a body
mass index (BMI) exceeding 35 kg/m2 (mean
reduction of 53%) compared with those
whose BMI ranged between 22 and 30 kg/
m2 (mean reduction 3%). Metformin therapy
was as effective as lifestyle intervention in
younger individuals and those with a higher
BMI.12 These effects appear to be durable, as
demonstrated in the ten-year follow-up data
of the DPP, resulting in comparable diabetes
incidence rates between metformin-treated
individuals and those adopting intensive
lifestyle interventions.13
Metformin in type 2 diabetes
The United Kingdom Prospective Diabetes
Study (UKPDS) was the first major study to
suggest a cardiovascular benefit in T2DM.
Randomising 1704 overweight T2DM patients
to initial treatment with metformin (342
patients), sulphonylurea or insulin (951
patients), or dietary measures alone (411
patients), metformin therapy (but not sulphonylurea/insulin therapy) was associated
with a 32% lower incidence of any diabetes
related endpoint (micro- and macrovascular)
(p = 0.002), 42% fewer diabetes related
deaths (p = 0.017), 36% lower all cause mortality (p = 0.011), and 39% fewer myocardial
infarctions (MIs) (p = 0.010).14 These effects
persisted after 10 years of follow-up (risk
reductions of 21% for any diabetes related
end-point (p = 0.01), 33% for myocardial
infarction (p = 0.005), and 27% for death
from any cause (p = 0.002), despite the fact
that differences in glycaemic control (as assessed by glycosylated haemoglobin [HbA1c]
levels) were no longer evident after one year
of follow-up.15 These potential cardiovascular benefits in high risk patients with T2DM
have been corroborated by subgroup analyses
of other trials, such as the Prevention of
Restenosis with Tranilast and its Outcomes
(PRESTO) trial. In a retrospective review of a
subgroup of 1997 participants with diabetes
who had undergone a percutaneous coronary
intervention, those treated with metformin
(with or without additional therapy, n = 887)
Issue 19 Summer 2013

were at a significantly lower risk of death


(OR 0.39 [95% CI 0.19, 0.77]; p = 0.007)
and myocardial infarction (OR 0.31 [95% CI
0.15, 0.66]; p = 0.002) compared with those
treated with insulin and /or sulphonylurea (n
= 1110).16 Data from the Diabetes and Audit
in Research Tayside Scotland (DARTS) study
reported that mortality was significantly
lower after five years among drug-naive
T2DM patients initially treated with metformin compared with a sulphonylurea.17 McAfee
et al reached similar conclusions, reporting a
23% reduction in the composite endpoint of
myocardial infarction and coronary artery revascularisation in metformin treated patients
compared with sulphonylurea therapy after
five years of follow-up.18 Use of metformin in
higher risk T2DM patients with heart failure
was associated with a significant reduction
in all-cause hospitalization at one year (OR
0.85 [95% CI 0.76, 0.95]; p = 0.004) compared with non-sensitisers (sulphonylureas,
non-sulphonylurea insulin secretagogues,
alpha glucosidase inhibitors or insulin) in a
systematic review and meta-analysis of eight
controlled studies.19 In a similar vein, Eurich
et al reported that metformin monotherapy
in this setting translates into a lower risk
of mortality (HR 0.70 [95% CI 0.54, 0.91])
as well as a lower risk of the composite
outcome of deaths or hospitalization (HR
0.83 [95% CI 0.70, 0.99]) compared to
sulphonylurea therapy.20 In a retrospective
study of 8063 insulin-treated patients with
no prior history of heart failure (HF), Nichols
et al, reported that metformin therapy
reduced the congestive HF rate ratio to 0.63
(95% CI 0.37, 1.07), a development which
is particularly desirable given that initial
insulin therapy was associated with a higher
incidence of HF.21
Is there a role for adjunct metformin in
type 1 diabetes?
An ever increasing proportion of T1DM
patients harbour a phenotypic and metabolic
profile typical of patients with the metabolic
syndrome. Indeed insulin resistance has
been shown to accelerate progression to
macrovascular and microvascular outcomes
in T1DM.22 These observations generated
considerable interest in a potential role for
adjunct metformin, also given that achieving tight glycaemic control is particularly
challenging in this setting, particularly with
its attendant risk of hypoglycaemia. Data
from the Hyperinsulinaemia: the Outcome of
its Metabolic Effects (HOME) study was reassuring, albeit comparing outcomes in 390

insulin treated T2DM patients randomised


to treatment with metformin or placebo
therapy and followed up for 4.3 years. Use of
this biguanide led to significant reductions
in body weight (-3.07 kg [range -3.85 to
-2.28]; p<0.001), HbA1c (mean -0.4% [95%
CI = -0.25, -0.55]; p < 0.001) and insulin
requirements (mean -19.63 IU/day [95% CI
= -14.36, -24.91]; p < 0.001). Additionally,
metformin was reported to decrease macrovascular morbidity and mortality (HR 0.61
[95% CI = 0.40, 0.94]; p = 0.02), an effect
that was partly explained by the difference
in weight.23 While prospective data remains
scanty, a formal meta-analysis of available
studies published by the undersigned suggested that use of adjunct metformin use in
T1DM is associated with a significant reduction in total daily insulin dose (6.6 units /
day; p < 0.001), albeit no improvement in
glycaemic control.24
Polycystic ovary syndrome and gestational
diabetes
Affecting at least 5-15% of women of childbearing age, insulin resistance is a hallmark
(though not imperative feature) of this
condition characterised by hyperandrogenism, hirsutism, acne, menstrual irregularities
and infertility. A meta-analysis of 31 clinical
trials demonstrated that metformin therapy
may increase ovulation, improve menstrual
cyclicity and reduce serum androgen levels
in these patients.25 A recently published systematic review of metformin use in pregnant
women with the polycystic ovary syndrome
reported lower pooled risks of early pregnancy loss (OR 0.32; [95% CI 0.19, 0.55]),
gestational diabetes (OR 0.37; [95% CI 0.25,
0.56]), pre-eclampsia (OR 0.53; [95% CI
0.30, 0.95]) and preterm delivery (OR 0.30
[95% CI 0.13, 0.68]).26 Current guidelines
tend to advocate a role for metformin in
the management of gestational diabetes.2, 27
Despite concerns that metformin crosses the
placenta, two meta-analyses (one in women
prescribed metformin monotherapy, and the
other recruiting women using metformin
and/or a sulphonylurea) have not reported
an increase in congenital malformations
or neonatal deaths 28, 29. The Metformin in
Gestational Diabetes (MIG) trial reported
no significant difference in the composite
neonatal outcome of neonatal hypoglycaemia, respiratory distress, need for phototherapy, birth trauma, 5-minute Apgar score
< 7, or prematurity), albeit higher rates of
preterm births and less weight gain among
the 363 patients treated with metformin (

Journal of the Malta College of Pharmacy Practice

13

Practice points
Metformin is a cheap, effective first line oral glucose lowering agent, that has
proven to be cost-effective in type two diabetes patients aged below the age of 65
years.
Metformin has been shown to delay or prevent progression to diabetes, improve life
expectancy, and reduce the cumulative incidence of macrovascular and microvascular
complications in diabetes.
Prescribed in the right setting, metformin decreases heart failure incidence, and
improves outcomes in established heart failure patients with type 2 diabetes
Risks of metformin-associated lactic acidosis remain low provided that this
biguanide is prescribed outwith clinical scenarios associated with hypoxia or
a tendency for acidosis (such as sepsis, acute heart failure, cardiogenic shock,
respiratory failure).

supplemental insulin) compared to patients


randomised to insulin therapy (n = 370).30 A
recently published, albeit smaller (n = 94),
trial largely showed that metformin improved
glycaemic control (lower mean glucose levels
throughout the day), with the added advantages of less weight gain and lower rates
of neonatal hypoglycaemia compared with
insulin therapy.31
Metformin and cancer
Data from several studies suggests that metformin use is associated with significantly
lower incidence rates across multiple cancers. Two meta-analyses, integrating results
from several observational and randomised
controlled trials, reported relative risks of
0.69 (95% CI 0.61, 0.79) 32 and 0.67 (95%
CI 0.53, 0.85) 33 respectively. While impressive, such results should be interpreted with
caution, given the inherent limitations of
observational studies, and the potential
of including studies with immortal time
bias. At least one study employing statistical techniques which avoided immortal
time bias reported no association between
metformin use and cancer incidence.34 At a
cellular level, the anti-neoplastic action of
metformin appear to be mediated by both
AMPK-dependent and -independent mechanisms, leading to an inhibition of the cell
cycle (through a reduction in cyclin D1 level)
and mammalian Target Of Rapamycin (mTOR)
signalling, a stimulation of the p53/p21 axis,
and a suppression of fatty acid synthesis, angiogenesis, inflammation, hyperinsulinaemia
and prevalent insulin growth factors.35
Metformin and non-alcoholic fatty liver
disease
The majority of patients with T2DM are
characterised by non-alcoholic fatty liver
disease (NAFLD) and up to 50% may develop
14

non-alcoholic steatohepatosis (NASH), a harbringer of cirrhosis. Metformin prescription


in patients with NAFLD may translate into a
reduction in plasma aminotransferases, albeit
without evidence of improvement in liver
histology. 36-38
Metformin and nephropathy
Metformin should be prescribed with caution
in individuals with an estimated glomerular
filtration rate (eGFR) ranging between 30
and 45 mls/min/1.73m2 and is absolutely
contraindicated if eGFR <30 mls/min/1.73m2.
Nonetheless, data from animal models
suggests that metformin pharmacotherapy
ameliorates tubular injury associated with
hyperglycaemia (partly by reducing oxygen
consumption and hypoxia-inducible factor- 1 expression) 39 as well as reactive
oxygen species-mediated lipotoxicity of renal
podocytes.40 Both mechanisms underpin
the development of diabetic nephropathy.
Additionally, data from murine models suggests that metformin reduces cystic growth
in autosomal dominant polycystic kidney
disease.41 Such promising roles remain to be
confirmed in clinical studies.
Adverse effects
A Cochrane review has largely dispelled the
myth that the benefits of metformin may be
offset by an unacceptably high risk of lactic
acidosis. Indeed, the authors reported no
additional risk of developing this complication in prospective comparative trials or
from observational cohort studies, provided
metformin is prescribed in the appropriate
setting.42 To this effect, use of this oral glucose lowering agent is not recommended in
acute situations associated with hypoxia or a
tendency for acidosis (such as sepsis, acute
heart failure, cardiogenic shock, respiratory
failure) as well as in moderate to severe

Journal of the Malta College of Pharmacy Practice

renal impairment (as outlined earlier).


Gastro-intestinal adverse effects (bloating,
diarrhoea, abdominal cramps, flatulence) are
best avoided if metformin is dosed gradually
over a few days to weeks. Tolerability may
be improved by switching to an extended
release formulation.43 Vitamin B12 deficiency is a recognised, albeit rare, adverse
effect, and should be borne in mind in patients with macrocytic anaemia, peripheral
neuropathy and cognitive impairment.44,45
Conclusion - the way forward
Metformins pivotal role in the management
of T2DM is clearly established, and likely
to remain undisputed, at least in the near
future. Available evidence suggests that it
is safer than initially thought, particularly
if prescribed in the right clinical setting.
A better understanding of the mechanisms
underpinning its diverse actions at a cellular level, particularly in humans, is likely
to unravel exciting new roles for this cheap,
widely prescribed, biguanide.
References
1. NICE clinical guideline 87. NICE clinical guideline
87. Type 2 diabetes: the management of type
2 diabetes London: National Institute for
Health and Clinical Excellence 2009 [accessed
30/04/2013]. Available from: www.nice.org.uk.
2. SIGN 116. Management of diabetes. A national
clinical guideline Edinburgh: Scottish
Intercollegiate Guidelines Network; 2010
[accessed 30/04/2013]. Available from: www.sign.
ac.uk.
3. Global Guideline for Type 2 Diabetes Brussels,
Belgium International Diabetes Federation 2012
[accessed 30/04/2013]. Available from: www.idf.
org.
4. Zhou G, Myers R, Li Y, Chen Y, Shen X, FenykMelody J, et al. Role of AMP-activated protein
kinase in mechanism of metformin action. J Clin
Invest. 2001;108(8):1167-74.
5. Viollet B, Guigas B, Leclerc J, Hebrard S, Lantier
L, Mounier R, et al. AMP-activated protein kinase
in the regulation of hepatic energy metabolism:
from physiology to therapeutic perspectives. Acta
Physiol (Oxf). 2009;196(1):81-98..
6. Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S,
Castro RA, et al. Effect of genetic variation in the
organic cation transporter 1 (OCT1) on metformin
action. J Clin Invest. 2007 May;117(5):1422-31.
7. Stephenne X, Foretz M, Taleux N, van der Zon
GC, Sokal E, Hue L, et al. Metformin activates
AMP-activated protein kinase in primary human
hepatocytes by decreasing cellular energy status.
Diabetologia. 2011 Dec;54(12):3101-10.
8. Foretz M, Hebrard S, Leclerc J, Zarrinpashneh
E, Soty M, Mithieux G, et al. Metformin inhibits
hepatic gluconeogenesis in mice independently of
the LKB1/AMPK pathway via a decrease in hepatic
energy state. J Clin Invest. 2010 Jul;120(7):235569. PubMed PMID: 20577053.

Issue 19 Summer 2013

9. Miller RA, Birnbaum MJ. An energetic tale of


AMPK-independent effects of metformin. J Clin
Invest. 2010 Jul;120(7):2267-70. PubMed PMID:
20577046.
10. Foretz M, Carling D, Guichard C, Ferre P, Foufelle
F. AMP-activated protein kinase inhibits the
glucose-activated expression of fatty acid synthase
gene in rat hepatocytes. J Biol Chem. 1998 Jun
12;273(24):14767-71.
11. Herman WH, Hoerger TJ, Brandle M, Hicks K,
Sorensen S, Zhang P, et al. The cost-effectiveness
of lifestyle modification or metformin in
preventing type 2 diabetes in adults with
impaired glucose tolerance. Ann Intern Med.
2005;142(5):323-32.
12. Knowler WC, Barrett-Connor E, Fowler SE, Hamman
RF, Lachin JM, Walker EA, et al. Reduction in
the incidence of type 2 diabetes with lifestyle
intervention or metformin. N Engl J Med.
2002;346(6):393-403.
13. Diabetes Prevention Program Research Group,
Knowler WC, Fowler SE, Hamman RF, Christophi
CA, Hoffman HJ, et al. 10-year follow-up of
diabetes incidence and weight loss in the Diabetes
Prevention Program Outcomes Study. Lancet.
2009;374(9702):1677-86.
14. UK Prospective Diabetes Study (UKPDS) Group.
Effect of intensive blood-glucose control with
metformin on complications in overweight
patients with type 2 diabetes (UKPDS 34). Lancet.
1998;352(9131):854-65.
15. Holman RR, Paul SK, Bethel MA, Matthews DR,
Neil HA. 10-year follow-up of intensive glucose
control in type 2 diabetes. N Engl J Med. 2008 Oct
9;359(15):1577-89.
16. Kao J, Tobis J, McClelland RL, Heaton MR, Davis
BR, Holmes DR, Jr., et al. Relation of metformin
treatment to clinical events in diabetic patients
undergoing percutaneous intervention. Am J
Cardiol. 2004 Jun 1;93(11):1347-50, A5.
17. Evans JM, Ogston SA, Emslie-Smith A, Morris
AD. Risk of mortality and adverse cardiovascular
outcomes in type 2 diabetes: a comparison
of patients treated with sulphonylureas and
metformin. Diabetologia. 2006;49(5):930-6.
18. McAfee AT, Koro C, Landon J, Ziyadeh N, Walker
AM. Coronary heart disease outcomes in patients
receiving antidiabetic agents. Pharmacoepidemiol
Drug Saf. 2007;16(7):711-25.
19. Eurich DT, McAlister FA, Blackburn DF, Majumdar
SR, Tsuyuki RT, Varney J, et al. Benefits and harms
of antidiabetic agents in patients with diabetes
and heart failure: systematic review. BMJ. 2007 Sep
8;335(7618):497.
20. Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT,
Johnson JA. Improved clinical outcomes associated

Issue 19 Summer 2013

with metformin in patients with diabetes and heart


failure. Diabetes Care. 2005 Oct;28(10):2345-51.
21. Nichols GA, Koro CE, Gullion CM, Ephross SA,
Brown JB. The incidence of congestive heart failure
associated with antidiabetic therapies. Diabetes
Metab Res Rev. 2005 Jan-Feb;21(1):51-7.
22. McGill M, Molyneaux L, Twigg SM, Yue DK. The
metabolic syndrome in type 1 diabetes: does it
exist and does it matter? J Diabetes Complications.
2008 Jan-Feb;22(1):18-23.
23. Kooy A, de Jager J, Lehert P, Bets D, Wulffele
MG, Donker AJ, et al. Long-term effects of
metformin on metabolism and microvascular
and macrovascular disease in patients with type
2 diabetes mellitus. Arch Intern Med. 2009 Mar
23;169(6):616-25.
24. Vella S, Buetow L, Royle P, Livingstone S,
Colhoun HM, Petrie JR. The use of metformin in
type 1 diabetes: a systematic review of efficacy.
Diabetologia. 2010;53(5):809-20.
25. Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH.
Insulin-sensitising drugs (metformin, rosiglitazone,
pioglitazone, D-chiro-inositol) for women with
polycystic ovary syndrome, oligo amenorrhoea
and subfertility. Cochrane Database Syst Rev.
2012;5:CD003053.
26. Zheng J, Shan PF, Gu W. The efficacy of metformin
in pregnant women with polycystic ovary
syndrome: a meta-analysis of clinical trials. J
Endocrinol Invest. 2013; in press.
27. NICE Clinical Guidline 63. Management of Diabetes
and its complications from pre-conception to the
postnatal period: The National Centre for Health
and Clinical Excellence; 2008 [updated March 2008
(last modified July 2008)]; (accessed 30/04/2013).
Available from: guidance.nice.org.uk/cg63.
28. Gutzin SJ, Kozer E, Magee LA, Feig DS, Koren G.
The safety of oral hypoglycemic agents in the
first trimester of pregnancy: a meta-analysis.
The Canadian journal of clinical pharmacology
200;10(4):179-83.
29. Gilbert C, Valois M, Koren G. Pregnancy outcome
after first-trimester exposure to metformin: a
meta-analysis. Fertil Steril. 2006;86(3):658-63.
30. Rowan JA, Hague WM, Gao W, Battin MR, Moore
MP, MIG trial investigators. Metformin versus
insulin for the treatment of gestational diabetes. N
Engl J Med. 2008;358(19):2003-15.
31. Spaulonci CP, Bernardes LS, Trindade TC, Zugaib M,
Vieira Francisco RP. Randomized trial of metformin
vs insulin in the management of gestational
diabetes. American journal of obstetrics and
gynecology 2013; in press.
32. Decensi A, Puntoni M, Goodwin P, Cazzaniga
M, Gennari A, Bonanni B, et al. Metformin and
cancer risk in diabetic patients: a systematic

review and meta-analysis. Cancer Prev Res (Phila).


2010;3(11):1451-61.
33. Noto H, Goto A, Tsujimoto T, Noda M. Cancer risk
in diabetic patients treated with metformin: a
systematic review and meta-analysis. PLoS One.
2012;7(3):e33411.
34. Azoulay L, DellAniello S, Gagnon B, Pollak M,
Suissa S. Metformin and the incidence of prostate
cancer in patients with type 2 diabetes. Cancer
Epidemiol Biomarkers Prev. 2011;20(2):337-44.
35. Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz
M, Andreelli F. Cellular and molecular mechanisms
of metformin: an overview. Clin Sci (Lond).
2012;122(6):253-70.
36. Haukeland JW, Konopski Z, Eggesbo HB, von
Volkmann HL, Raschpichler G, Bjoro K, et al.
Metformin in patients with non-alcoholic fatty
liver disease: a randomized, controlled trial. Scand
J Gastroenterol. 2009;44(7):853-60.
37. Duseja A, Das A, Dhiman RK, Chawla YK, Thumburu
KT, Bhadada S, et al. Metformin is effective in
achieving biochemical response in patients with
nonalcoholic fatty liver disease (NAFLD) not
responding to lifestyle interventions. Ann Hepatol.
2007;6(4):222-6.
38. Rakoski MO, Singal AG, Rogers MA, Conjeevaram
H. Meta-analysis: insulin sensitizers for the
treatment of non-alcoholic steatohepatitis. Aliment
Pharmacol Ther. 2010 Nov;32(10):1211-21.
39. Takiyama Y, Harumi T, Watanabe J, Fujita Y, Honjo
J, Shimizu N, et al. Tubular injury in a rat model
of type 2 diabetes is prevented by metformin: a
possible role of HIF-1alpha expression and oxygen
metabolism. Diabetes. 2011;60(3):981-92.
40. Louro TM, Matafome PN, Nunes EC, da Cunha FX,
Seica RM. Insulin and metformin may prevent renal
injury in young type 2 diabetic Goto-Kakizaki rats.
Eur J Pharmacol. 2011;653(1-3):89-94.
41. Takiar V, Nishio S, Seo-Mayer P, King JD, Jr., Li H,
Zhang L, et al. Activating AMP-activated protein
kinase (AMPK) slows renal cystogenesis. Proc Natl
Acad Sci U S A. 2011;108(6):2462-7.
42. Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk
of fatal and nonfatal lactic acidosis with metformin
use in type 2 diabetes mellitus. Cochrane Database
Syst Rev. 2006 (1):CD002967.
43. Jabbour S, Ziring B. Advantages of extendedrelease metformin in patients with type 2 diabetes
mellitus. Postgrad Med. 2011 Jan;123(1):15-23.
44. Liu KW, Dai LK, Jean W. Metformin-related vitamin
B12 deficiency. Age Ageing. 2006;35(2):200-1.
45. Pierce SA, Chung AH, Black KK. Evaluation of
vitamin B12 monitoring in a veteran population
on long-term, high-dose metformin therapy. Ann
Pharmacother. 2012;46(11):1470-6.

Journal of the Malta College of Pharmacy Practice

15

matter is urgent, they may contact the


Medicines Authority directly.
The role of the Medicines Authority is
to provide an assessment and communicate
between suppliers of medicinal products,
the regulatory authorities and the users.
Where a defective medicine is considered to
present a risk to public health, the marketing
authorisation holder, the manufacturer
or wholesale dealer as appropriate, is
responsible for recalling the affected
batch(es) or, in extreme cases, removing all
batches of the product from the market. The
Medicines Authority will normally support
this action by the issue of a drug alert
notification to healthcare professionals.

Medicinal product quality


defects reporting
Karl De Marco

B.Pharm (Hons)

Medicines Inspector
Inspectorate and Enforcement Directorate, Medicines Authority
Email: karl.de-marco@gov.mt
Introduction
One of the ways in which the Medicines
Authority protects public health is by
minimising the risk to patients arising from
the distribution of defective medicinal
products. It achieves this by managing an
assessment and communications system,
between suppliers of medicinal products, the
regulatory authorities and the users including
patients, and when required oversees the
removal of the defective medicinal products
from the local market.
Holders of a manufacturers, importers
and wholesale dealers licence are obliged
to report to the Medicines Authority any
defect in a medicinal product handled under
their authorisation that could result in a
recall or abnormal restriction in supply. This
includes possibly faulty manufacture, product
deterioration, detection of falsified medicines

16

or any other serious quality problems with a


product.
Reporting of suspected product quality
defects
Reports of suspected defects may also be
sent to the authorities by other competent
authorities, healthcare professionals and
members of the general public.
If a member of the general public has
reason to believe that their medicine is not
of an acceptable quality, they should, in the
first instance, consult with their doctor or
pharmacist who may then decide to refer
the matter to the Medicines Authority, since
the doctor or pharmacist may be in a better
position to provide prompt advice and/
or reassurance to the patient. However, if
it is not possible to speak to a doctor or
pharmacist and the patient feels that the

Journal of the Malta College of Pharmacy Practice

Product recalls
A product recall is defined as the retrieval
from the marketplace of a batch or batches
of any medicinal product which is/are the
subject of a quality defect.
Product recalls are categorised according
to the potential impact of the issue giving
rise to the need for a recall, on patients
and public health. There are three classes of
recalls:
Class I recalls generally for critical
quality defect issues.
These are recalls which result
fromquality defects of medicinal
products which are potentially lifethreatening or could cause a serious risk
to health;
Class II recalls generally for major
quality defect issues.
These are recalls due to quality
defects which could cause illness or
mistreatment but are not Class I;
Class III recalls generally for minor
quality defect issues.
These are recalls due toquality defects
which are not likely to pose a significant
hazard to health but where a recall has
been initiated for other reasons.
In the case of Class I and Class II recalls,
the Medicines Authority will notify regulators
in other countries using the European Rapid
Alert System.
Reporting of suspected quality defects
Suspected quality defects can be reported by
using the Medicinal Product Defect Reporting
Form.
Email: inspectorate.adm@gov.mt
Tel: 00356 2343 9000
medicinesauthority.gov.mt/recallsrapidalerts

Issue 19 Summer 2013

Asian Mosquito Tiger:


a nuisance, threat or both?
Tanya Melillo

MD MSc(HSM)Dip (HSM)

Consultant in Public Health


Head of Infectious Disease Prevention and Control Unit
Department of Health Promotion and Disease Prevention, Msida
Email: tanya.melillo@gov.mt
Educational aims
To identify diseases caused by the Asian Mosquito Tiger
To highlight methods of preventing bites
To familiarise with ways of minimising mosquito proliferation
Key words
Mosquito, Asian Mosquito Tiger, mosquito borne diseases, Dengue, Chikungunya
Abstract

Asian Mosquito Tiger or Aedes Aldopictus is a mosquito which


reached the Maltese Islands towards the end of summer of 2009 and
has since spread and proliferated all over Malta and Gozo.
It is a nuisance because of its ferocious biting on humans but it
can also be a carrier of a number of diseases which may eventually
be introduced to our islands causing outbreaks and resulting in
a negative impact on our tourism and jeopardizing agricultural
development resulting in major economic consequences.
Issue 19 Summer 2013

The local situation


In the beginning of September 2009, Dr
Paul Gatt, an entomologist, discovered the
first Aedes (stregomyia) Aldopictus (Skuse)
mosquito (Insecta Diptera Culicidae) in Malta
in Mellieha. The presence of this mosquito
in Malta added to the total mosquito
fauna documented in Malta, which now
incorporates all of the subfamily Culicinae.2,3
The Aedes Aldopicutus, popularly known as
the Asian Mosquito Tiger originated from the
forests of Southeast Asia where it was found
to breed mainly in rotting tree holes.4 It was
first described by Skuse (1984)5 in India but
has since found its way all over the world
due to its ability to breed successfully in
both natural and artificial habitants since
it requires only a small amount of water to
breed.
A second record of the same species was
confirmed by Dr J Buhagiar during the period
of September and October of the same year
in Marsascala.6 With two sightings in two
different localities of the same mosquito
which was previously never documented, the
likely conclusion was that this mosquito had
finally reached our shores during the summer
of 2009.
Both Gatt and Buhagiar postulated
that the likely mode of how this mosquito
reached our shores was from Italy due to
the large amount of sea traffic and close
proximity between Italy/Sicily and Malta.
On a daily basis, the Malta Freeport acts as
a transhipment centre in the Mediterranean
where large volumes of containers arrive,
in addition there is a daily ferry link
between Malta and Sicily, where there is
a large flow of vehicles, both private and
commercial which cross over between May
and November, a large number of cruise
liners touring the Mediterranean, stop for
a day at Valletta Grand Harbour. The Aedes
Aldopictus mosquito inhabits large parts
of Italy and Sicily and Italy is in fact the
country most infested with this mosquito in
all of Europe.1,6,10
During the winter of 2009/2010,
surveillance was conduted to investigate
the mosquitoes presence and behaviour
following its discovery and to see whether
the species would survive our winter. 7 Larvae
and pupae were found to develop in the
ovitraps throughout the winter and a few
adult mosquitoes were also observed.
The results obtained from this
surveillance confirmed that Malta had the
ideal climate conditions during the winter
months to allow the mosquito to develop

Journal of the Malta College of Pharmacy Practice

17

both in the egg and larvae stage with the


development of the adult form once Spring
arrives.7
A steering committee between the
Infectious Disease Prevention and Control
unit (ICDU) and the Institute of Earth
Systems within the University of Malta
was set up to develop a strategy for the
surveillance of Aedes Aldpoictus in Malta.
The insects distribution on the Maltese
islands since reaching our shores was
monitored throughout a whole year from
September 2010 up to September 2011 using
ovitraps placed in potential introduction
sites and within localities that harbour
potential habitats for the species. The
Maltese islands were geographically split into
7 regions and ovitraps were placed in each
region.
Every week they were checked for eggs
and larvae. Scientific data was gathered from
the ovitraps placed. The results following
a full year monitoring showed that the
mosquito proliferated and spread across all
of Malta and was found in all regions except
Gozo, but was then confirmed in December
2011. These results were also confirmed by
reporting of public sightings during the same
year whereby the general public was asked
to provide information to IDCU if they were
bitten by the mosquito and to also provide
specimens of the mosquito when possible. 9
The Asian Mosquito Tiger
It is a striking mosquito approximately
2-10mm in length, characterised by its black
and white striped legs and small black and
white body. The head consisting of eyes
and a pair of long segmented antennae, is
responsible for receiving sensory information
and for feeding. The antennaes role is used
to detect host odours.
It typically flies and feeds during the
daytime unlike other mosquitoes. Aedes
albopictus feeding peaks in the early morning

(dawn) and late afternoon (dusk). It is an


opportunistic and aggressive biter with a
wide host range including man, domestic
and wild animals.10 Since it has a short flight
range (around 200m), it tends to remain
close to its breeding site. The male has a
short life expectancy but the female can
live from 3 weeks to 3 months. Water is the
essential element for mosquito development
because the female lays her eggs just above
the surface of the water.11,12
Life cycle
The female mosquito, after birth, looks for
a male to mate. Mating occurs soon after
emergence during a swarm flight. Once this
is done, which only occurs once in their life,
the female looks for a blood meal which is
necessary to fertilise its eggs. About four
or five days after feeding on blood, the
female mosquito lays her eggs just above the
surface of standing water.
Around 150 to 250 eggs are laid per
oviposition (egg-laying event). Each female
can have 1 to 4 ovipositions. When rain
covers the eggs with water, the larvae
hatch. The active reproductive period occurs
from late Spring (May) to early Autumn
(October).10,12
Eggs are laid singly on the sides of
water-holding containers such as tyres,
animal watering dishes, birdbaths, flowerpots
and natural holes in vegetation.10 They are
black and oval with a length of 0.5 mm. Eggs
can withstand desiccation for up to one year.
Larval emergence occurs after rainfall
raises the water level in the containers. The
eggs may require several submersions before
hatching. Larvae development takes 3-8

Figure 2: Adult Asian Tiger Mosquito,


Aedes albopictus (Skuse).

Photograph: Michele M. Cutwa, University of Florida

Figure 1: Adult Asian Tiger Mosquito,


Aedes albopictus (Skuse).
Photograph: J.L. Castner, University of Florida

Figure 3: Larva of the Asian Tiger


Mosquito, Aedes albopictus (Skuse).

Photograph : Michele M. Cutwa, University of Florida

weeks and adults can live for a period of 3


weeks to 3 months.10,13
Asian Tiger Mosquitoes spend the
winter in the egg stage, hatching into
larvae when the eggs get covered with
water in the spring. The larvae feed on
small bits of debris and bacteria in the
water. Its life cycle is closely associated
with human habitat, and it breeds in
containers with standing water.14
Asian Tiger Mosquitoes are known
to be attracted to carbon dioxide, dark
clothing, perspiration, and particular
odours.14
Female mosquitoes hunt their blood
host by detecting organic substances
such as carbon dioxide and 1-octenol-3ol produced from the host. Some persons
are preferred to others by mosquitoes and
that is why some are bitten while others
are not. This is due to the smells produced
by the victims sweat which attracts the
mosquito because of the proportions
of carbon dioxide, octenol and other
compounds that make up body odor.28
Medical significance
Aedes albopictus is a known competent
vector for at least 22 Arboviruses.15
These include Dengue, Chikungunya, West
Nile fever, Yellow fever and Japanese
Encephalitis. It can also transmit
Dirofilariasisi to dogs. In order for the
mosquito to be able to transmit infections,
it has to be carrying the pathogen within
itself first and then through biting its
host, it transmits the virus, causing the
host to develop the viral illness.
The two most likely viral illnesses
transmitted by Aedes Aldopictus within the
Mediterranean region are:
Chikungunya
Dengue

18

Journal of the Malta College of Pharmacy Practice

Issue 19 Summer 2013

Chikungunya virus is a member of the


genus alphavirus. It is spread by the bite
of an infected mosquito. The incubation
period is between 2-12 days but usually
occurs within 3-7 days. It can cause a
debilitating illness and is characterised by
fever, headache, fatigue, nausea, vomiting,
muscle pain, rash and joint pain. Acute
Chikungunya fever can last from a few days
to a few weeks but some patients have
prolonged fatigue or develop incapacitating
joint pains or arthritis which lasts for weeks
or months.16
Dengue is an acute febrile viral
disease caused by Flavivirus serotpyes. It
presents with sudden fever for 2-7 days
together with two or more of the following:
intense headache, retro-orbital pain,
myalgia, arthralgia, rash or haemorrhage
manifestation. Anorexia, nausea, vomiting
and persistent abdominal pain may also be
present.
Some patients with dengue fever go
on to develop a severe and sometimes
fatal form of the disease called Dengue
Haemorrhagic Fever. This is characterised
by a fever and evidence of haemorrhagic
manifestations. The symptoms of infection
usually begin 4-7 days post being bitten and
last between 3-10 days.17
Ways to prevent being bitten
Minimise the time spent outdoors
between dawn and dusk when the
mosquito is most active.
Be sure that doors and windows have
screens fitted tightly.
Where possible wear socks, shoes, long
trousers and long sleeved shirts when
outdoors for long periods of time.
Clothing should be made of tightly
woven materials to keep the mosquitoes
away from the skin.
Use mosquitoes netting when sleeping
outdoors and to protect infants in
prams, pushchairs when outdoors.
When it is necessary to be outdoors,
apply insect repellent as indicated on
the products label. The more DEET (N,Ndiethyl-m-toluamide) a product contains,
the longer the repellent can protect
against bites. However, concentrations
higher than 50 percent do not increase
the length of protection. For most
situations, 10 -20% DEET is adequate.
Apply to clothes when possible, and
sparingly to exposed skin if the label
permits. Consult a physician before using
repellents on young children.
Issue 19 Summer 2013

Use fans as mosquitoes are weak fliers


and a strong winds produced by a fan not
only keeps them from away but diffuses
chemical cues they use to locate blood
meals.
Note that insect light traps (bug
zappers) or sound devices do little to
reduce the number of biting mosquitoes
in an area.
Spraying your backyard with an
insecticidal fog or mist is effective only
for a short time. Mosquitoes will return
when the spray dissipates.18
Ways to control mosquitoes
All mosquitoes need water in order to
reproduce. Each female mosquito may lay as
many as 200 eggs that will transform into
larvae and then into adults.
Therefore the control of these mosquitos
should be aimed at destroying the places
where they lay their eggs which are never far
from where people are being bitten.
Remove all water filled containers like
flower pots, old buckets, food containers
and tires.
Keep mosquitoes from breeding in birds
baths, pet water dishes and paddling
pools by emptying them at least every 3
days.
Any puddles, inlets to sewers and
drainage systems should be drained not
to allow water to stagnate fro more than
3 days.
Gutters should be kept clean from fallen
leaves and other debris so that water
does not collect in them.
Man made outdoor features especially
fish ponds should contain fish like gold
fish, carp or killifish as these feed on the
mosquitos immature stages.
Litter can also hold rain water and
should be removed.
Any standing water in catchment basins
etc that cannot be drained must be
regularly treated with properly labelled
insecticides.
Always place a tight lid on containers
used for water storage like water tanks
In cases where fish cannot be kept in
open water reservoirs or wells, they need
to be covered.
Swimming pools must be maintained
with regular chlorine or emptied if not
is use.
Do not leave toys in the garden which
can store rain water
Protect boats and vehicles from rain with
tarps that do not accumulate water.19, 20

Treatment when bitten


Once bitten, the clinical manifestation is
characterised by an area of erythema around
the bite, pruritus and moderate to extensive
swelling of the area. This is largely due
to a local chemical cellulites rather than
hypersensitivity caused by the contact of the
mosquitos saliva with human skin.
It is recommended that a cold compress
is applied initially followed by an antiseptic
cream. Oral antihistamines should be given
and if gross swelling is present, topical and/
or oral corticosteroid might be indicated
following specialist advice. Antibiotics
should not be prescribed as the bites are
not infected. If evidence of secondary
bacterial infections develops characterised
by pain, tenderness, pus and an extension
of the erythema beyond the bite, than an
oral antibiotic primarily aimed against staph
aureus and strep.pyogenes should be given.
Topical antibiotics should be avoided. 21
Conclusion
The Asian Mosquito Tiger will use almost
any container that holds enough water to
complete its life cycle including flower pots,
tin cans, plastic buckets, cemetery urns and
discarded tyres. Control is difficult because a
proportion of mosquitoes still deposits their
eggs in natural containers like tree holes
which are impossible to eliminate. However
the reduction of container breeding sites has
shown to be an effective way for people in
the community to manage its control near
where they live. 22
The discovery of Aedes Aldopictus in
Malta is of public health importance because
it is a competent vector which can result
in spread of diseases like Dengue and
Chikungunya. Since it is now established
locally, the risk of the mosquito becoming
infected and starts transmitting disease
locally increases. Outbreaks of Chikungunya
occurred in Italy in Taranto in 2007 23 in La
Reunion in France in 2010 24 while cases of
Dengue have occurred in Croatia and France
in 2010. An outbreak of Dengue occurred
in Madeira, Portugal between October and
December of 2012 following the discovery
of two cases of autochthonous Dengue virus
infections with over 1,357 cases of Dengue
fever-the first sustained transmission of
disease since the last outbreak in Greece in
1927. 25
Outbreaks of mosquito borne disease
have a considerable economic impact.
A cost illness analysis performed on the
Chikungunya epidemic in La Reunion island

Journal of the Malta College of Pharmacy Practice

19

(2005-2006) where 204,000 cases were


infected, estimated the total cost of medical
expenses at 42.0 million Euro, of which 60%
were direct medical costs and 40% to disease
related loss of productivity.26
The most effective means of vector
control is environmental management
with the aim to modify or manipulate
environmental factors with the view to
prevent and reduce vector propagation
and human-vector-pathogen contact. The
methods involved will include improving
the water supply and storage, solid waste
management and modification of man-made
larval habitats. Chemical control using
insecticides and also biological control
using biocides or larvivorous fish are used to
destroy larvae.27
Control measures would need to be
applied throughout the whole year since
the mosquito continues to breed locally
throughout the whole year but can be most
effective during the winter period during
larvae development. Adult biting activity
in winter is very low so the potential
transmission of Arboviruses will take place
during the period of May and November
when adult mosquitoes are present in large
numbers.

3.

4.

5.
6.

7.

8.

9.

10.

11.

12.

References
1.

2.

20

Gatt P. First record of Aedes ( stregomyia)


aldopcitus ( Skuse) (Diptera Culicidae) in Malta.
European Mosquito Bulletin 2009: 27, 56-64.
Gatt P. Mosquitoes from the Maltese island: new
records and observations. Boll. Soc. Ent. Ital.,
Genova 1996:128 (1): 77 84.

13.

14.

Gatt P. Culex Perexiguus Theobald ( Dipter:


Culicidae) a mosquito species new to the Maltese
fauna. European Mosquito Bulletin 2009: 27, 7-9.
Reinert JF. & Harbach RE. Generic changes
affecting European aedine mosquitoes with a
checklist of species. European Mosquito Bulletin
2005: 19, 1-4.
Skuse FA. The banded mosquito of Bengal.
Indian Museum Notes 1984: 3(5), 20.
Buhajar JA. A second record of Aedes
(stregomyia) aldopcitus ( Dipteria Culicidea) in
Malta. European Mosquito Bulletin 2009: 27,
65-67.
Gatt P, Francis S and Cassar, L.F. Aedes
(stregomyia) aldipictus ( Skuse) (Diptera
Culicidae) in Malta-the first winter. European
Mosquito Bulletin 2010: 28, 225-229.
Schaffner, F, Gatt, P, Spiteri, G, Melillo, T and
Zeller, H. Mosquitoes in Malta: preliminary
entomological investigation and risk assessment
for vector borne diseases. Bulletin of the
Entomological society of Malta 2010: Vol 3:
41-54.
Melillo, T. Report on one year surveillance on
Asian mosquito tiger in Malta. 2011. (Internal
Department of Health Report Malta unpublished)
Hawley WA. 1988. The biology of Aedes
albopictus. Journal of the American Mosquito
Control Association (1998) Supplement 1. p.
1-40.
Centers for Disease Control. Current trends
update: Aedes albopictus InfestationUnited
States. Morbidity and Mortality Weekly Report
1987: 36: 769-773.
Cutwa MM, OMeara GF. An identification guide
to the common mosquitoes of Florida. http://
fmel.ifas.ufl.edu/key/ (accessed 19 October
2011).
OMeara GF. The Asian tiger mosquito in Florida.
EDIS 1997. http://edis.ifas.ufl.edu/MG339
(accessed 21 January 2004).
WHO, The mosquitoes and the community. A
World Health Organisation Report 2003.

Journal of the Malta College of Pharmacy Practice

15. Gratz, N. Critical review of the vector status


of Aedes aldopictus, medical and Veterinary
Entomology. 2004:18,215-27.
16. CDC-Chikungunya fact sheet http:www.cdc.gov/
chikungunya (accessed 5th June 2013).
17. CDC-Dengue fact sheet http://www.
cdc.gov/dengue/resources/30Jan2012/
albopictusfactsheet.pdf (accessed 5th June
2013).
18. CDC. Travellers information on prevention of
mosquitoes bites http://wwwnc.cdc.gov/travel/
yellowbook/2012/chapter-2-the-pre-travelconsultation/protection-against-mosquitoesticks-and-other-insects-and-arthropods
(accessed 5th June 2013).
19. CDC-Dengue vector control http:www.cdc.gov/
dengue/resources/Vectorcontrolsheetdengue.pdf
(accessed 5th June 2013).
20. CDC-Dengue http:www.cdc.gov/dengue/
entomologyecology/index.html (accessed 5th
June 2013).
21. National antibiotic Committee, Malta. Guidelines
for the management of mosquito bites.2011.
22. Dame D, Fasulo TR. Mosquitoes. Public Health
Pesticide Applicator Training Manual 2003.
http://entomology.ifas.ufl.edu/fasulo/vector/
(accessed 21st January 2004).
23. Angelini R, Finarelli AC, Angelini P, Po C. et
al. An outbreak of Chikungunya fever in the
province of Ravenna, Italy. Euro surveillance
2009:12(36).
24. Borgherini G, Poubeau P, Staikowsky F et al.
Outbreak of Chikungunya on Reunion Island.
Clinical Infectious Diseases 2007: 44 (11);14011407.
25. ECDC mission report on Dengue outbreak in
Madeira, Portugal October-December 2012.
26. 26. CDC Guidelines for the surveillance of
invasive mosquitoes in Europe, 2012
27. WHO, control on vector borne diseases, World
Health organisation Report 2003
28. Hallem EA, Fox N, A.; Zwiebel LJ, Carlson JR.
Olfaction: Mosquito receptor for human-sweat
odorant. Nature 2004: 427 (6971): 212213.

Issue 19 Summer 2013

The pill in the future pharmacological contraception


in science fiction
Victor Grech MD, PhD (Lond.), PhD (Melit), FRCPCH, MRCP(UK), DCH
Clare Vassallo B.A. (Gen.), B.A. (Hons) PhD (Bologna)
3
Ivan Callus B.Ed. (Hons), B.A. (Hons) (Lond.), M.A., Ph.D. (Cardiff)
1
2

Consultant Pediatrician (Cardiology) and Associate Professor of Paediatrics. Humanities and


Medical Science Programme, University of Malta
Email: victor.e.grech@gov.mt
2
Senior Lecturer, Translation and Interpreting Studies, University of Malta.
Email: clare.vassallo@um.edu.mt
3
Associate Professor and Head, English Language Dept, University of Malta.
Email: ivan.callus@um.edu.mt
1

Key words
Birth control, Forecasting
Abstract

Contraception dates back to Mesopotamian times. Science


fiction (SF) has utilised many contraceptive plot devices
and this paper will explore these stratagems from the
pharmacological point of view. It will be shown that the oral
contraceptive pill and the contraceptive implant were both
predicted in SF as well as other forms of contraception of
which we only, as yet, have tantalising research possibilities.

Issue 19 Summer 2013

Introduction
Birth control is a wide term that includes
techniques and methods that that can be
utilised in order to prevent fertilisation
or to terminate pregnancy. These
include contraception (the prevention of
fertilisation), contragestion (the prevention
of implantation of the blastocyst) and
abortion (the removal or induced expulsion
of the developing fetus from the uterus).
Contraception methods are various and
include barrier methods (such as condoms
or diaphragms) and hormonal contraception
which may be oral or parenteral.
Birth control is well documented in
ancient Mesopotamia and Egypt and this
includes the description of contraceptive
pessaries with ingredients that included
acacia gum, a natural spermicidal that is
currently utilised in contraceptive jellies.1
Plants (such as Silphium, Asafoetida, willow,
date palm, pomegranate, pennyroyal,
artemisia, myrrh, rue and Queen Annes
lace (Daucus carota)) containing natural
contraceptive and/or abortifacient agents
were used from about the seventh century BC
in ancient Greece.1
Science fiction (SF) is a specific genre of
English literature. Actually defining SF is an
endlessly challenging and disputatious task,
one that has been deemed impossible since
SF is the literature of change, it changes
even as one tries to define it.2 Thus the
slogan on the masthead of the first issue of
Amazing Stories, the earliest SF magazine
(1926): Extravagant Fiction Today, Cold Fact
Tomorrow.3
A reasonable and widely accepted
definition of SF from the multitude available
is that of Suvin, that SF is the literature
of cognitive estrangement,4 a literature
with a wide spectrum or spread of literary
subject-matter, running from the ideal
extreme of exact recreation of the authors
empirical environment to exclusive interest
in a strange newness, a novum.4 Suvin
elaborates further, stating that SF takes off
from a fictional (literary) hypothesis and
develops it with extrapolating and totalizing
(scientific) rigor.4 Suvin ably summarises:
SF is, then a literary genre whose necessary
and sufficient conditions are the presence
and interaction of estrangement and

Journal of the Malta College of Pharmacy Practice

21

cognition, and whose main formal device is


an imaginative framework alternative to the
authors empirical environment.4
SF has utilised many contraceptive
plot devices and this paper will explore
these stratagems from the pharmacological
point of view. This work arises from a Ph.D.
dissertation dealing with the wider topic of
infertility in SF.5
Contraception
Natural methods
Voluntary infertility is used to prevent
overpopulation on the island of Parz in the
far future in One Million Centuries (1967)
where a delicious, naturally occurring fruit
severely curtails libido, ensuring that few
children are born.6
The oral contraceptive pill
Many texts, such as The Twilight of Briareus
(1974) mention the pill in everyday use,7
but earliest mention of the equivalent of
an oral contraceptive pill appears to have
been in Brave New World (1932) where
procreation and sex are completely divorced.
Sex is solely procreational and safeguarded
from conception in fertile women by the
permanent and regulation carriage of a
supply of contraceptives on a fashion
accessory known as a Malthusian belt, which
they are conditioned to wear from birth.8
More urgently, the pill may be used
where it is crucial to avoid pregnancy, such
as in astronaut crews. Titan (1979) empowers
female astronauts with monthly implants
and ever-wear diaphragms.9 Contraception
for spaceship crews is also outlined in
The Wind People (1959) wherein artificial
gravity conditions are said to completely
preclude female crew conception but have
no effect on libido or potency, and this
effect wears off after approximately three
months. Automatic contraception is naturally
a desired side effect of interstellar travel
and on long planet layovers between trips,
spaceship crews are routinely administered
a contraceptive drug called anticeptin to
further continue to prevent pregnancies.10
Likewise, in Luna One (1973), women
who form part of the first moon colony
are given a contraceptive pill called P-C
pill.11 On a different tack, in the interest of

22

cementing friendship between the various


branches of the armed forces, in Short in
the Chest (1954), sex between men and
women is by roster, with women taking an
oestric drug in order to increase libido,
and men take the equivalent priapic, with
contraception ensured through women also
taking an anti-concipient.12
Contraceptive Patch
In The Eleventh Commandment (1962),
anti-contraceptive matters are taken even
further when the Vatican is vaporised in
a nuclear exchange and a new pontiff is
chosen from among the American cardinals
resulting in a schism, with the establishment
of an eleventh commandment: be fruitful
and multiply and replenish the Earth,
and contraception is made illegal. The
protagonist, a human colonist from Mars,
visits Earth and wears a contraceptive patch,
but this fails, and the reason given is that
the higher gravity of Earth rendered the
patch ineffective.13
Contraceptive Implants
Islands of Tomorrow (1994) depicts humans
travelling back in time and abducting
humans into the future for breeding
purposes, and one of the women has a
contraceptive implant and hence, initially,
fails to become pregnant.14
In A Reasonable World (1991), the impact
of a totally foolproof contraceptive leads
to the development of sexual intercourse
as a performance art form.15 In the Group
(1973) extrapolates the consequences of
such technology into entertainment, where
sexual experiences (including the input of
all senses) during copulation are transmitted
through technological means to the rest of
the members of an entire group, a group that
is dispersed around the world.16
The state subversion of population
control into eugenics is also used in the
Known Space stories. In this future, complete
contraceptive birth control is achieved by
the annual subcutaneous administration
of a crystalline drug, a crucial system in
the heavily overpopulated dystopia that
comprises this future Earth.17
A greater level of detail with regard to
population control in the closed environment

Journal of the Malta College of Pharmacy Practice

that constitutes a huge spaceship is given


in Paradises Lost (2002),18 where conshots
are given to both genders by the medical
staff, and individuals who fail to show up
for their shots are tracked down by the
ships authorities. Exempt individuals include
postmenopausal females, sterilised crew
and those who are strict homosexuals or
who have taken a pledge of strict chastity.
The intention to conceive must be formally
declared beforehand by both partners, and
each individual is only allowed to have
one child. Irregular or extra pregnancies
are stopped by a morning after drug or by
forcible termination and indeed, in White
Mars (1999), the perils of inadequate
contraception are shown when stranded
colonists run out of contraceptives.19
More practically, in the Vorkosigan
novels, women who have had a contraceptive
implant wear a distinguishing earring
to state that they are consenting and
contraceptive-protected adults.20
Iatrogenic chemical infertility
Widespread infertility may be a completely
accidental and involuntary iatrogenic event
in SF, a flawed cure as depicted in The
Douglas Convolution (1979) and its sequels,
set in a 22nd century Earth suffering from
widespread female infertility brought on by
the use of a contraceptive agent.21 Similarly,
in The Wind Obeys Lama Toru (1967), fertility
and sterility drugs act and counteract,
driving human population levels up and
down in a chaotic fashion.22 Likewise, in
They Shall Not Die (1939), a drug is available
that prevents all disease but sterilises all
those who take it.23
Deliberate and widespread state-induced
infertility
Benefits (1979) traces the progress
from state benefits for mothers to an
overpopulation-prevention program, with
the state ultimately dumping a universal
contraceptive in drinking water, a drug
which, when combined with the antidote
that is given to approved mothers, proves
to be a potent mutagen.24 An identical
population-control strategy is mentioned
in The Year of the Comet (1955), where an
anti-fertility agent is added to drinking

Issue 19 Summer 2013

water, which, however, is said to have up to


two percent mortality, with the majority of
deaths conveniently being women, further
reducing the populations reproductive
potential.25
Chemical infertility inflicted on animals
In Auto da fe (1966), a future humanity
modifies dogs, giving them intelligence,
speech, the ability to walk upright and
lengthening their lifespan to some five
centuries. However, these gifts come at a
price in that the story depicts the worlds
last dog among a troupe of bitches, and their
fertility is at a complete standstill because
of contraceptive drugs that are dripped into
their food at the behest of the last surviving
human.26
Aliens
In the Star Trek episode The Mark of Gideon
(1969), the Enterprise crew discover a grossly
overpopulated planet. Captain Kirk suggests
to the rulers that his United Federation of
Planets would be willing to provide any kind
of contraceptive devices that the populace
would need.27
Contraception failure
Contraceptive failure is not uncommon in
SF television series, and in the Farscape
episode Natural Election (2002),28 one of
the protagonists, a military peacekeeper,
becomes pregnant, and the only positive
aspect is that the possibility of an arrested
pregnancy is mentioned, implying that
pregnancy may be temporarily suspended and
gestation later resumed. However, the nature
of any contraception used in this society is
not discussed. The scenario posed in the Star
Trek Deep Space Nine episode The Dogs of War
(1999) is even more implausible as one of
the protagonists finds herself pregnant since
her partner forgot to take his birth control
injection, and yet both are meant to be
taking their injections.29
Discussion
The daily contraceptive pill was developed in
1951 by Djerassi and colleagues, earning him
the 1973 National Medal of Science,30 and
the concept of the pill itself appears to have
been first mentioned in SF in 1932, twenty

Issue 19 Summer 2013

years earlier. It is typical of medicine that a


Nobel prize was also given to the scientists
to who made great inroads into infertility
treatment.31
Contraceptive implants were utilised
in SF in the 1970s, prefiguring the actual
development of long-acting implantable
contraceptive agents, such as Norplant
(developed in 1991 with a pregnancy rate of
<1% over a five-year period) by twenty years.
Injectable depot contraceptive hormones
are now available for both sexes.32,33 With an
estimated 60% of all unplanned pregnancies
in the developed world occurring in women
using some form of birth control, it is
anticipated that this range of options will
provide more effective contraception, albeit
without preventing sexually transmitted
diseases due to the lack of the barrier nature
of these systems. Some American states
are actually attempting to persuade certain
sectors of the populace to implant such
agents in order to curb the population growth
of the underprivileged.34
Interestingly, there are also several
naturally occurring candidate compounds
that could be added to food or drink in order
to induce infertility or produce outright
sterility. For example, the short term, oral
administration of an aqueous or chloroform
extract of Carica papaya seed has been shown
to induce complete and reversible sterility
in male rats and rabbits with no effect on
libido, and this has been attributed to a
decline in sperm motility and alteration in
sperm morphology, as well as to reduced
contractile response of the vas deferens, the
conduit by which sperm is ejaculated out of
the testis.35,36
This brief sampling of SF stories
demonstrates a typical and important
property of the genre: the ability to predict
the future, if for no other reason, then
through the sheer multitude of stories and
the inevitability of such narratives prefiguring
future turns of events. In this way, SF
prepares us for future shock, which has been
described as a time phenomenon, a product
of the greatly accelerated rate of change in
society the dizzying disorientation brought
on by the premature arrival of the future.
It may well be the most important disease
of tomorrow.37 It is also simultaneously

evident that SF also offers inspiration to


would-be inventors, spurs on technological
progress.38
The genre also continually inflicts a
reality-test on itself, and does not break
with the Aristotlean admonition that
we must presuppose many things that
accord with our highest hope, although
the existence of none of them must be
impossible.39 This returns us to back to
the concept of novum in SF, in this case,
a chemical contraceptive agent, a novel
scientific/technological plot device that is
validated by cognitive logic, that is, made
to appear scientifically plausible, thereby
making an SF narrative not only possible
but also plausible.
References
1.

2.

3.
4.
5.

6.
7.
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12.
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14.
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17.
18.

Riddle John M. Contraception and Abortion


from the Ancient World to the Renaissance.
London: Harvard University Press; 1994.
Pohl F. The Study of Science Fiction: A Modest
Proposal. Science Fiction Studies 1997: 24:
11-16.
Gernsback H. A New Sort of Magazine. In:
Amazing Stories, April 1926.
Suvin D. On the Poetics of the Science Fiction
Genre. College English 1972:34: 372-382.
Grech V. Infertility in Science Fiction.
University of Malta. 2011 (Unpublished
Doctoral Thesis).
Lupoff RA. One Million Centuries. New York:
Lancer Books, Inc; 1967.
Cowper R. Twilight of Briareus. New York: The
John Day Company; 1974.
Huxley A. Brave New World. London: Chatto &
Windus; 1932.
Varley J. Titan. London: Futura; 1979.
Bradley MZ. The Wind People. If. February
1959.
Taves E. Luna One. Galaxy. July 1973.
St. Clair M. Short in the Chest. Fantastic
Universe. July 1954.
Del Rey L. The Eleventh Commandment. New
York: Ballantine Books; 1962.
Busby FM. Islands of Tomorrow. New York: Avon
Books; 1994.
Knight D. A Reasonable World. New York: Tor
Books; 1991.
Silverberg R. In the Group. In: Unfamiliar
Territory. New York: Charles Scribners Sons;
1973.
Niven N. Protector. New York: Ballentine Books;
1978.
Le Guin UK. Paradises Lost. In: The Birthday
of the World: and Other Stories. Scranton:
HarperCollins; 2002.

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23

19. Aldiss B., Penrose R. White Mars, or, The Mind


Set Free: A 21st-Century Utopia. London: Little,
Brown & Co.; 1999.
20. McMaster Bujold L. A Civil Campaign. New York:
Baen Books; 1999.
21. Llewellyn E. The Douglas Convolution.New York:
DAW Books Incorporated; 1979.
22. Lee T. The Wind Obeys Lama Toru. Bombay:
Khrishna S. Kurwar; 1967.
23. Parkinson HF. They Shall Not Die. London:
Constable and Company Ltd.; 1939.
24. Fairbairns Z. Benefits. London: Virago; 1979.
25. Christopher J. The Year of the Comet. London:
Michael Joseph; 1955.
26. Knight D. Auto da fe. In: Turning On. New York:
Ace; 1966.

24

27. Taylor J. The Mark of Gideon. In: Star Trek The


Original Series. January 1969.
28. Watson I. Natural Election. In: Farscape. July
2002.
29. Brooks A. The Dogs of War. In: Star Trek Deep
Space 9. May 1999.
30. Djerassi C. et. Al. Delta 4-19-nor-17alphaethinylandrosten-17beta-ol-3-one and Process.
1556:United States; Patent 2744122.
31. Steptoe PC, Edwards RG. Birth After the
Reimplantation of a Human Embryo. Lancet
1978:2:366.
32. Johansson ED et. Al. Future Developments in
Hormonal Contraception. Am J Obstet Gynecol
2004:190:69-71
33. Kamischke A, Nieschlag E. Progress Towards
Hormonal Male Contraception. Trends Pharmacol
Sci 2004:25:49-57.

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34. Moseley CA, Beard MT. Norplant: Nursings


Responsibility in Procreative Rights. Nursing and
Health Care 1994:6:294-7.
35. Chinoy NJ, George SM. Induction of Functional
Sterility in Male Rats by Low Dose Carica
papaya Seed Extract Treatment. Acta Europaea
Fertilitatis 1983:14: 425-32
36. Lohiya NK et al. Reversible Contraception with
Chloroform Extract of Carica papaya Linn. seeds
in Male Rabbits. Reprod. Toxicol. 1999:13:59-66.
37. Toffle A. Future Shock New York: Random House;
1970.
38. Parrinder P. Learning From Other Worlds.
Liverpool: Liverpool University Press; 2000.
39. Aristotle. Politics. Books VII and VIII. 7.

Issue 19 Summer 2013

Hypopituitarism:
a review on the diagnosis
and management of
central hypoadrenalism and
hypothyroidism
Mark Gruppetta

MD, MRCP(UK)

Department of Medicine, Faculty of Medicine and Surgery, University of Malta, Msida, Malta;
Department of Medicine, Mater Dei Hospital, Msida, Malta.
Email: mark.gruppetta@gov.mt
Educational aims
To identify best practices in the management of patients who have central
hypoadrenalism and/or hypothyroidism
To outline the necessary tests needed for the diagnosis of central hypoadrenalism and
hypothyroidism
To understand the rationale for supplementation therapy with glucocorticoids and
thyroxine
To better appreciate the role of patient education and proper advice as an essential
part of management
To highlight the monitoring requirements needed for proper titration of
supplementation dosages
Key words
Hypopituitarism, central hypoadrenalism, secondary hypothyroidism, TSH deficiency,
ACTH deficiency.
Abstract

A variety of conditions can result in hypopituitarism and this article


focuses on the diagnosis, treatment and management of central
hypoadrenalism and hypothyroidism. Central hypoadrenalism, if
untreated, can potentially prove to be fatal and thus it is imperative
that a timely diagnosis is done and life long supplementation
instituted. Different glucocorticoid supplementation regimes
together with possible side effects are discussed. Life long thyroxine
replacement is needed for central hypothyroidism. Particular aspects
regarding the diagnosis and management of central hypothyroidism
are tackled. Important elements in the management of these patients,
so as to ensure suitable supplementation are proper clinical and
biochemical monitoring together with effective patient education.
Issue 19 Summer 2013

Introduction
The pituitary gland is situated at the
base of the brain and is divided into the
anterior and posterior lobes. The anterior
pituitary is responsible for the synthesis and
secretion of adrenocorticotropic hormone
(ACTH), thyroid-stimulating hormone
(TSH), luteinizing hormone (LH), folliclestimulating hormone (FSH), growth hormone
(GH) and prolactin. It has a crucial role in
the control of the hypothalmo-pituitaryadrenal axis through its secretion of ACTH,
released under the influence of hypothalamic
corticotropin-releasing hormone (CRH),
ACTH being responsible for the control of
cortisol secretion by the adrenals. Control of
thyroid hormone production by the thyroid
through the secretion of TSH, released under
the influence of hypothalamic thyrotropinreleasing hormone (TRH) is another key
role of the anterior pituitary. Partial or
complete insufficiency of anterior pituitary
hormone secretion termed hypopituitarism
may result from pituitary or hypothalamic
disease. A variety of conditions can result
in hypopituitarism besides developmental
and genetic causes, including various
tumours such as pituitary adenomas
and craniopharyngomas, head trauma,
irradiation, pituitary infarction, empty
sella syndrome and infiltrative diseases. In
acquired hypopituitarism, failure of pituitary
hormones usually follows a particular order
with loss of GH first, followed by LH and
FSH, than TSH and lastly ACTH. This order
may reflect their relative importance for
survival and in fact the more severe clinical
condition occurs with ACTH deficiency
which if left untreated can be fatal.1 This
review will focus on the diagnosis and
management of ACTH and TSH deficiencies
(central hypoadrenalism and hypothyroidism
respectively).
Central hypoadrenalism
Diagnosis of central hypoadrenalism
Since serum cortisol levels usually reach a
peak value at about 0800h, a level less than
100nmol/L at this time is taken to mean
that there is cortisol deficiency.2 Levels
of serum cortisol taken at other times of
the day are not very significant in terms
of the diagnosis of hypoadrenalism. Hence
a number of dynamic function tests have
been devised to assess whether a patient
can mount a suitable elevation in serum
cortisol in response to stress as happens
physiologically in a normal person. The
test which has been available for many

Journal of the Malta College of Pharmacy Practice

25

years and still considered to be the gold


standard is the insulin tolerance test (ITT)
in which an insulin dose is given to induce
a hypoglycaemic episode and repeated
measurements of serum cortisol are taken.3
Due to the nature of the test, it needs to
be carried out under medical supervision
and has some important contraindications
such as a history of epilepsy, ischaemic
heart disease or cardiac dysrhythmias. A
peak value of 550nmol/L or above has to be
achieved for the test to indicate adequate
cortisol stress response.1 A test which is
simpler and shorter to do and for most cases
provides adequate results which correlate
well with an ITT, is the short synachten test
(SST). In this test 0.25mg of ACTH[1-24]
[tetracosactrin (Synacthen)] are injected
intramuscularly (i.m.) or intravenously (i.v.)
and serum cortisol levels are measured at
0, 30 and 60 minutes. Since the use of the
SST for evaluation of central hypoadrenalism
works on the principle that adrenal
glucocorticoid producing cells will have their
cortisol producing ability attenuated as a
result of chronic ACTH deficiency, there is
a time lag until this develops and thus this
test should not be used to assess patients in
their early stages after a pituitary insult.4,5
Another alternative test which could be
used when an ITT is contraindicated, is the
glucagon test where 1mg of glucagon is
injected subcutaneously and measurements
of serum cortisol are carried out every half
hour for 4 hours.1,6-8
Treatment of central hypoadrenalism
In the acute setting when central
hypoadrenalism is present or suspected,
the treatment of choice is hydrocortisone
given through the i.v. or i.m. route.
Before administering the first dose of
hydrocortisone, if possible a serum sample
for estimation of cortisol level is taken.
Usually the dose is 100mg every 6-8 hours,
together with i.v. saline infusion. After
24 hours the dose of hydrocortisone can
be reduced to 50mg 6 hourly and then,
if clinically tolerated, changed to oral
hydrocortisone.1,9
Long term treatment involves lifelong
supplementation of glucocorticoids.
Previously most patients used to be given
hydrocortisone 20mg as soon as they
wake up and 10mg in the late afternoon.
Following studies10 that determined that
the average daily dose of cortisol secreted
is 5.7mg/m2 per day or 9.9 2.7 mg/day,
which is equal to a daily delivered dose of
26

15-20mg, usual supplementation dosages


were revised down to this level. With
the knowledge that mimicking the normal
circadian cortisol rhythm has proven to be
very difficult, different approaches were
adopted by various experts: either starting
with a twice daily dose of hydrocortisone and
if on clinical assessment, the patient is still
feeling unwell going up to thrice daily dosing
or advocating that the replacement dose of
hydrocortisone be divided into 3 doses from
the start with typical dosages being a 10mg
dose taken on rising, 5mg at midday and
5mg in the early evening.1,11-13 Some experts
advocated that this thrice daily regime be
further fine tuned by adopting a weight
adjusted dosage.11 It is important to note
that the first morning dose of hydrocortisone
is best taken as soon as the patient wakes
up with a glass of water and the last dose
should be taken in the late afternoon rather
than the evening to prevent unphysiological
high levels of cortisol in the evening and
possibly insomnia.1,12 Studies on the relation
between hydrocortisone dosage and healthrelated quality of life suggest that a twice
daily regimen is superior to a once daily
dose and perhaps a thrice daily better than
twice daily although the evidence here is
not as strong.12,13 In a large study14 on
2424 hypopituitary patients of whom 1186
were on hydrocortisone, it was shown that
while patients who were on hydrocortisone
had higher levels of total cholesterol,
triglycerides, HbA1c and a higher waist
circumference, compared to ACTH-sufficient
patients, those who were taking a dose of
hydrocortisone less than 20mg/day did not
have statistically significant differences in
the metabolic parameters mentioned when
compared to patients who had an intact
hypothalamic-pituitary-adrenal axis. To
try to mimic the physiological cortisol
circadian rhythm better, modified release oral
formulations of hydrocortisone are currently
being developed. The total replacement
dose needed might be less for those patients
who have some residual pituitary function as
evidenced by a subnormal peak response on
a stimulation test but a normal basal level
of cortisol. Some patients would even just
require steroid cover for periods of increased
stress.1 Mineralocorticoid replacement (Ex.
Fludrocortisone) is not needed in central
hypoadrenal patients.
An important dimension of the
assessment of proper glucocorticoid
replacement treatment is regular clinical
assessments aiming to highlight symptoms/

Journal of the Malta College of Pharmacy Practice

signs of under or over treatment, although


one has to appreciate that minor degrees
of over/under treatment might prove very
difficult to diagnose on clinical grounds.12,13
In this context the role and value of cortisol
day curves is debated by various experts,
though they may have a role in monitoring
adequate replacement and avoiding over
treatment of patients1 or in those who are
on other drugs which interfere with the
metabolism of hydrocortisone.13 Another
method advocated by some experts to help
assess adequate glucocorticoid replacement
is taking a serum cortisol level 4 hours
after ingestion and comparing this level to
a dosing nomogram.11 Although the effect
on bone mineral density of patients who are
on glucocorticoid is debatable, there are
some studies which suggest a lower bone
density in such patients particularly in postmenopausal women. Hence it is reasonable
to suggest that patients are to be kept on
the lowest dose of hydrocortisone possible
and have their bone mineral density followed
up.12,13
An important dimension in the
management of patients who are
glucocorticoid deficient is their education.
Patients who are on replacement steroids are
advised to carry a Steroid Card with them at
all times and emphasis made on the fact that
they should not stop taking this treatment
unless advised otherwise by their doctor. On
a practical level, patients should be advised
to think ahead so that they do not run out
of the replacement steroid tablets. They are
also provided with a phial of hydrocortisone
100mg to be available for administration in
emergency settings and adequately educated
on how this is given if the need arises.
These patients are advised that they should
double their usual dose of hydrocortisone
if they have a major stressful event such
as a febrile illness unless they are severely
ill when they might need hydrocortisone
administration through the i.v. route.1,9,12
Central hypothyroidism
Diagnosis of central hypothyroidism
The biochemical diagnosis of central
hypothyroidism is done when a low
thyroxine (T4) level is noted together with
an inappropriately normal or low TSH level.
It is worth noting that tri-iodothyronine
(T3) levels often remain within normal
limits even when T4 levels are low and
thus the measurement of its level might
not be helpful for diagnosis. A high index
of suspicion should be maintained in
Issue 19 Summer 2013

4.

Key points
A combination of basal serum cortisol levels and various dynamic function tests
have been devised to establish whether a patient has an adequately functioning
hypothalamo-pituitary-adrenal axis.
Typical daily glucocorticoid supplementation dose is 15-20mg hydrocortisone divided
into twice or thrice daily doses.
The first morning dose of hydrocortisone is best taken when the patient wakes up
and the last dose should be taken not later than in the late afternoon.
Vital to educate patients on the importance of drug compliance and what to do
during major stressful events.
Biochemically patients with central hypothyroidism have low thyroxine levels with
an inappropriately normal or low TSH level.
Serum TSH level is not a good indicator of adequate thyroxine supplementation
dosages in central hypothyroidism and changes in dose should be done according to
serum thyroxine levels and on clinical grounds.
those patients who have conditions which
could result in hypopituitarism and thus
central hypothyroidism, such as a history of
pituitary tumours, previous cranial irradiation
or cranial injuries.15,16
Treatment of Central Hypothyroidism
The treatment of central hypothyroidism
is life long thyroxine. It is important to
ascertain before starting T4 treatment in a
patient, that the possibility of coexistent
hypoadrenalism has been excluded or if
present is adequately replaced since it
is well known that T4 increases cortisol
clearance and thus an adrenal crisis
might be precipitated in patients who are
cortisol deficient. Usually it is advisable
to start with low doses of T4 such as 2550g daily and than titrating the dose
every few weeks until the correct dose is
found. Elderly patients and those with a
history of ischaemic heart disease deserve
special attention in titrating the dose of
T4. Several drugs including iron, calcium,
mineral supplements, aluminium hydroxide
and sucralfate are known to interfere with
T4 absorption. Adverse reactions to T4
treatment have to do with over replacement
of T4 and thus will include symptomatic or
subclinical thyrotoxicosis. It is important
to note that in central hypothyroidism
TSH levels cannot be used as an indicator
of correct dosage as is done in primary

Issue 19 Summer 2013

hypothyroidism since the TSH response is


inappropriate. Thus changes in dosages
should be done on clinical grounds and
according to serum T4 levels, aiming to
keep these in the upper half of the normal
reference range.15,16
Conclusion
While not very common, hypopituitarism,
especially central hypoadrenalism and
hypothyroidism need to be promptly
diagnosed and appropriately treated. While
aiming to restore normal physiological
hormonal levels, a structured monitoring
system, both clinically and biochemically is
needed to determine the most appropriate
drug supplementation dosages for a
particular patient. Patient information is a
key component of the management of these
patients in order to ensure drug treatment
compliance and minimise potential problems.

2.

3.

6.

7.

8.

9.

10.

11.

12.

13.

References
1.

5.

Grossman AB. The Diagnosis and Management of


Central Hypoadrenalism. J Clin Endocrinol Metab.
2010: 95:48554863.
Jones SL, Trainer PJ, Perry L, Wass JA, Bessser
GM, Grossman A. An audit of the insulin
tolerance test in adult subjects in an acute
investigation unit over one year. Clin Endocrinol
(Oxf). 1994: 41: 123128.
Plumpton FS, Besser GM. The adrenocortical
response to surgery and insulin-induced
hypoglycaemia in corticosteroid-treated and
normal subjects. Br J Surg. 1969: 56:216-219.

14.

15.
16.

Stewart PM, Corrie J, Seckl JR, Edwards CR,


Padfield PL. A rational approach for assessing
the hypothalamo-pituitary-adrenal axis. Lancet
1988: 1:12081210.
Mukherjee JJ, de Castro JJ, Kaltsas G, Afshar F,
Grossman AB, Wass JA, Besser GM. A comparison
of the insulin tolerance/glucagon test with the
short ACTH stimulation test in the assessment
of the hypothalamo-pituitary-adrenal axis
in the early post-operative period after
hypophysectomy. Clin Endocrinol (Oxf) 1997:
47:5160.
Littley MD, Gibson S, White A, Shalet SM.
Comparison of the ACTH and cortisol responses
to provocative testing with glucagon and
insulin hypoglycaemia in normal subjects. Clin
Endocrinol (Oxf). 1989: 31:527533.
Leong KS, Walker AB, Martin I, Wile D, Wilding
J, MacFarlane IA. An audit of 500 subcutaneous
glucagon stimulation tests to assess growth
hormone and ACTH secretion in patients with
hypothalamicpituitary disease. Clin Endocrinol
(Oxf). 2001: 54 463468.
Berg C, Meinel T, Lahner H, Yuece A, Mann K,
Petersenn S. Diagnostic utility of the glucagon
stimulation test in comparison to the insulin
tolerance test in patients following pituitary
surgery. Eur J Endocrinol. 2010: 162:477482.
Stewart PM. The Adrenal Cortex. In: Kronenberg
HM, Melmed S, Polonsky KS, Larsen PR, editors.
Williams Textbook of Endocrinology. 11th ed. pp.
479-485. Philadelphia: Saunders; 2008.
Esteban NV, Loughlin T, Yergey AL, Zawadzki
JK, Booth JD, Winterer JC, LoriauxDL. Daily
cortisol production rate in man determined by
stable isotope dilution/mass spectrometry. J Clin
Endocrinol Metab. 1991: 72:3945.
Mah PM, Jenkins RC, Rostami-Hodjegan A,
Newell-Price J, Doane A, Ibbotson V, Tucker
GT. Ross RJ. Weight-related dosing, timing and
monitoring hydrocortisone replacement therapy
in patients with adrenal insufficiency. Clin
Endocrinol (Oxf). 2004: 61: 367375.
Crown A, Lightman S. Why is the management
of glucocorticoid deficiency still controversial:
a review of the literature. Clin Endocrinol (Oxf).
2005: 63:483492.
Debono M, Ross RJ, Newell-Price J. Inadequacies
of glucocorticoid replacement and improvements
by physiological circadian therapy. Eur J
Endocrinol. 2009: 160:719729.
Filipsson H, Monson JP, Koltowska-Haggstrom
M, Mattsson A, Johannsson G. The impact
of glucocorticoid replacement regimens
on metabolic outcome and comorbidity in
hypopituitary patients. J Clin Endocrinol Metab.
2006: 91:39543961.
Roberts CG, Ladenson PW. Hypothyroidism.
Lancet. 2004: 363:793803.
Ascoli P, Cavagnini F. Hypopituitarism. Pituitary.
2006: 9:335342.

Journal of the Malta College of Pharmacy Practice

27

The extemporaneous
compounding of paediatric
medicines at Mater Dei Hospital
Antonella Aquilina

B. Pharm (Hons), MSc Clin (Aberdeen)

Pharmacist, Compounding Section, Pharmacy Department


Mater Dei Hospital, Msida MSD 2090, Malta
Email: antonella.a.aquilina@gov.mt
Educational aims



To gain further knowledge about extemporaneous compounding of medicines


To highlight the importance of extemporaneous preparations in paediatric use
To appreciate the need for the extemporaneous compounding of medicines locally
To showcase the extemporaneous preparatory service provided at Mater Dei Hospital

Key words
extemporaneous, compounding, off-licence preparation

Extemporaneous compounding is defined as the preparation,


mixing, assembling, packaging and labelling of a medicinal
product based on a prescription order from a licensed
practitioner for the individual patient.1 The lack of commercially
available formulations for patients with specific needs poses a
challenge to making medicines available to what are considered
to be the most vulnerable patients.2 This qualifies as off-license
use of a medicine, whereby a licensed medicine is reformulated
into a preparation that is acceptable/appropriate for the patient.
28

Journal of the Malta College of Pharmacy Practice

Introduction
Children, especially the younger age groups,
may require age-appropriate formulations
allowing both safe and accurate dose
administration.3 Lack of appropriate studies
preclude most medications from being labelled
for use in paediatric patients.4 In order to
improve the health of children in Europe
without subjecting children to unnecessary
trials, or delaying the authorisation of
medicinal products for use in adults, the
European Unions Paediatric Regulation came
into force in 2007.5
Since licensed medicines represent
the gold standard for quality, safety and
efficacy, the underlying general rule is that
a licensed preparation is always preferable
to a compounded one. Medicines are
given a license, now called a marketing
authorisation, if the pharmaceutical company
has demonstrated the quality, efficacy and
safety of the medicine as recommended in the
Summary of Product Characteristics (SmPC)
when given in the dose and for the disease
and age group recommended. The Standing
Committee on Medicines has stated that in
paediatric practice, the informed use of some
unlicensed medicines or licensed medicines
for unlicensed applications is necessary. 6
There are circumstances in which there
is no licensed product or alternative which
fully meets the clinical needs of a particular
patient and therefore it becomes necessary to
extemporaneously prepare a limited quantity
of a custom-made product for an individual
patient.7 Between 15 and 80% of all medicines
used in hospitalised children have either not
been licensed at all (unlicensed) or are used
outside the specification terms of the product
license (off-license).8
Extemporaneous compounding of
medicines carries significant risk, as the risks
of using unlicensed medicines are combined
with inherent risks associated with the
pharmaceutical compounding process.7 The
risk for the patient is that total accuracy and
uniformity of the dose can never be assured
and the risk for the operator is that he/she
is being exposed to the chemicals whilst
reconstituting a preparation. Extemporaneous
compounding is defined as the preparation,
mixing, assembling, packaging and labelling
of a medicinal product based on a prescription
order from a licensed practitioner for the
individual patient.1 At Mater Dei Hospital,
the extemporaneous compounding service
caters for both children and adults, to
both in- and out-patients and liaises with
clinicians, pharmacists and nursing stuff to
Issue 19 Summer 2013

ensure seamless care. Since the majority


of medicines are prepared for paediatric
patients, this article will focus on this
category of patients.
Extemporaneous medicines can range
from oral formulations such as suspensions
and solutions, sachets, mouthwashes to
topical formulations such as creams and
ointments. Examples range from captopril
suspension for cardiovascular disease to
controlled medicines such as clobazam
sachets, both for use in paediatric patients.
Oral liquid medicines are commonly prepared
extemporaneously because of a relative lack
of licensed formulations for children who
are unable to swallow tablets or capsules,
or for whom the required dose is less than a
single tablet or capsule. 7 A large proportion
of extemporaneous compounding lies in
converting capsules and tablets to oral
liquids or powders. Others are made from the
bulk active ingredient, such as oseltamivir
powder to prepare oseltamivir phosphate
solution.
It can be noted that most medications
are marketed without adequate studies
and availability of appropriate dosages for
infants and children.9 Even medications
such as phenobarbital and spironolactone,
which have been approved for use in
paediatric patients, are not available in an
appropriate dosage form for this category of
patients. One of the aims of extemporaneous
compounding is making medicines available
to paediatric patients.10
Legal considerations
Extemporaneous compounding of medicines
is usually not covered by the manufacturer in
the products SmPC. An off-license form must
be filled in by the prescriber every time there
is a new request for an extemporaneous
formulation, wherein the prescriber takes
full responsibility for the clinical use of the
preparation. This should accompany every
new prescription. At MDH, off-license forms
can either be departmental (e.g. caffeine
citrate oral liquid is used by Neonatal and
Paediatric Intensive Care Unit (NPICU) in
neonates for respiratory distress syndrome)
or patient-specific (e.g. sildenafil suspension
for pulmonary hypertension in paediatrics)
and are downloadable from the hospital
intranet via the following link: http://
www.kura.gov.mt/infocentre/forms/result.
asp?keys=off-license&SearchMonth=&Searc
hYear=. A database of off-license medicinal
products is kept by Quality Assurance (QA)
section within the Pharmacy Department.
Issue 19 Summer 2013

The role of QA is to ensure that services and


medicinal products provided/supplied by
the Pharmacy Department are of the quality
required for their intended use.
Key points for consideration prior to
compounding
The following alternatives should be
considered before extemporaneous
compounding is undertaken:
1. Soluble or dispersible tablets may be a
useful and convenient alternative to the
preparation of liquid extemporaneous
products. Some tablets can be dispersed
or crushed and information on this aspect
can be obtained from the Medicines
Information Section within MDH. In this
case, the dose should be prepared and
administered immediately. In general
compressed tablets or tablets which are
scored or just film coated can be crushed
whereas modified release tablets cannot.
2. If a particular medicine is not available
as a liquid formulation, another medicine
from the same therapeutic classification
may well be used, such as the use of a
less potent steroid rather than diluting a
potent one.
3. Using a suitable preparation intended
for a different route of administration,
for example, using an injectable solution
orally.
4. Use of a specials preparation
manufactured in licensed premises
(Specials are medicines made in larger
volumes by a licensed manufacturer).9
Stability
When evaluating the stability of a
formulation, its chemical, physical and
microbiological stability must be considered.1
It is highly important that the storage
conditions stated on the label are adhered
to. Even where a given formulation has
been shown to achieve suitable physical,
chemical and microbiological stability,
the bioavailability and palatability of the
preparation may be unproven.
Very few extemporaneous preparations
are supported by any data to demonstrate
a suitable absorption profile and/
or bioequivalence with a licensed
preparation. Other issues include concerns
about inadequate access to equipment
and materials needed to provide a safe
extemporaneous dispensing service and the
highest possible quality products.
In order to limit degradation and
spoilage, products are given a maximum

shelf-life of 28 days, unless the product is


not chemically stable, whereby the shelf-life
is then given according to the stability of
the respective product.7 Stability studies for
extemporaneous preparations are usually
conducted over small periods of time.
Lack of stability data limits many
medicines from being made available for
use in paediatrics. The armamentarium of
formulations available for extemporaneous
compounding relies heavily on the
availability of stability data and the
ingredients required for compounding.
A systematic approach to compounding at
Mater Dei Hospital
Non - sterile extemporaneous
preparations must always be compounded
upon receipt of a prescription i.e. on
demand.
If a worksheet for the formulation
requested is not available and a
licensed product or alternative cannot
be found, an appropriate formulation
must be researched. The details of the
new formulation are presented to the
prescriber who endorses it.
A new worksheet and label must then
be prepared. The master worksheets are
then approved by the Quality Assurance
section and endorsed by the Head of
Pharmacy. A request for inclusion of the
new extemporaneous formulation in the
hospital formulary should also be filled
in. The original master work sheets are
stored by Quality Assurance section
which is also responsible for uploading
a secured electronic version on the
intranet. A separate set of worksheets
and labels are drawn up for every
preparation compounded (i.e. patientspecific).
All pharmacists and pharmacy technicians
receive training which is certified by
Quality Assurance prior to starting duties
within the Compounding Section. All the
compounding steps are double-checked
by a pharmacist before a preparation is
released for use.
Premises
At MDH, extemporaneous medicines are
prepared in a clean controlled environment
containing equipment required for
extemporaneous compounding such as a
fume cupboard and a powder-containment
cabinet for personnel protection from fumes
and aerosols generated during compounding.
Personnel must don the prescribed garments

Journal of the Malta College of Pharmacy Practice

29

Key Points
Extemporaneous compounding is the preparation, mixing, assembling, packaging
and labelling of a medicinal product based on a prescription order from a licensed
practitioner for the individual patient.1
The extemporaneous compounding of medicines, involving the alternation of a
licensed formulation, is off-license unless it is clearly indicated in the Summary of
Product Characteristics (SmPC) of the product that the extemporaneous process can
be performed.
Extemporaneous preparations have a limited shelf life.
A licensed, commercially available preparation is always preferable and in its
absence, if possible, a licensed alternative should be sought.
Extemporaneous preparations are patient-specific.

before entering the clean area i.e. mob hat,


gloves, overshoes, plastic overcoat and a
facial mask for males.

group purchasing and cost reduction, in


order to solve the compounding problems
of hospital pharmacies. 10

Final comment
The pharmaceutical industry is expected
to develop and market dosage forms which
are suitable for children, hence relieving
the hospital pharmacy from the burden of
preparing extemporaneous preparations.
However, it remains to be discussed whether
this is a realistic expectation. Manufacturers
would have to produce formulations that
have a limited shelf life, since many existing
medicines are intrinsically unstable in any
aqueous vehicle, which is possibly the only
acceptable formulation for paediatric oral
administration. The manufacturer would
be placed at a financial disadvantage,
considering the small size of the paediatric
healthcare market and the economic push for

Conclusion
The aim of extemporaneous compounding
is that of meeting the therapeutic
needs of vulnerable patients, especially
the paediatric population, as a last
resort in the absence of a marketed
licensed preparation. Prescribers are
encouraged to use their clinical judgment
when recommending extemporaneous
formulations to their patients, and should
monitor for safety and efficacy throughout
treatment. With the the resulting aim of
preparing appropriate dosage forms for
paediatric use, a significant responsibility
in a pharmacists work remains the
compounding of extemporaneous
formulations.

30

Journal of the Malta College of Pharmacy Practice

Acknowledgements
The author would like to thank Mr Mario
Barbara, Senior Pharmacist, Quality
Assurance for reviewing the document.
References
1.

Shargel L. et al. Comprehensive Pharmacy


Review. Third Edition. USA: Lippincott Williams
and Wilkins; 1997.
2. Jew R, Mullen R, Soo-Hoo W. Extemporaneous
Formulations. Bethesda: American Society of
Health-System Pharmacists, Inc.; 2003.
3. European Medicines Agency. Pediatric
Formulations. [Internet]. Available from: http://
www.ema.europa.eu/ema/index.jsp?curl=pages/
regulation/general/general_content_000045.
jsp&mid=WC0b01ac05800260a6 (accessed 6th
June 2013).
4. Taketomo C, Hodding J, Kraus D. Pediatric and
Neonatal Dosage Handbook. Nineteenth Edition.
USA: American Pharmacists Association , 2012.
5. European Medicines Agency. Medicines for
Children. [Internet]. Available from: http://
www.ema.europa.eu/ema/index.jsp?curl=pages/
special_topics/general/general_content_000302.
jsp&mid=WC0b01ac058002d4ea (accessed 6th
June 2013).
6. Royal College of Paediatrics and Child Health.
Medicines for Children. London: Hobbs the
Printers Limited; 2003.
7. Jackson M and Lowey A. Handbook of
Extemporaneous Preparation. London:
Pharmaceutical Press; 2010.
8. Marriot J et al. Pharmaceutical Compounding
and Dispensing. Second Edition. London:
Pharmaceutical Press; 2010.
9. Costello I. et al. Paediatric Drug Handling.
London: Pharmaceutical Press; 2007.
10. Nahata M, Pai V and Hipple T. Pediatric Drug
Formulations. Fifth Edition. USA: Harvey
Whitney Book Company; 2004.

Issue 19 Summer 2013

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For further information please refer to the full summary of
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Journal of the Malta College of Pharmacy Practice

31

PANADOL ADVANCE

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up to

than standard paracetamol tablets1

PANADOL ADvANce with Optizorb technology delivers significantly faster


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PANADOL ADvANce disintegrates significantly
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Standard paracetamol

PANADOL ADVANCE

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The same trusted suitability of PANADOL


in an advanced formulation.2,3
Wont harm the stomach.4
*Representation of actual gamma scintigraphy images of paracetamol in the
gastrointestinal (GI) tract.
References
1. Wilson CG, Clarke CP, Starkey YY, Clarke GD. Comparison of a novel fast-dissolving acetaminophen tablet formulation
(FD-APAP) and standard acetaminophen tablets using gamma scintigraphy and pharmacokinetic studies [Epub ahead of print
January 11, 2011]. Drug Dev Ind Pharm. 2. GSK. Data on file. Bioequivalence Studies A1900260, A1900265. 3. Clarke GD,
Adams IM, Dunagan FM. Using suitability profiles to better inform consumers choice of commonly used over-the-counter
analgesics. Int J Pharm Pract. 2008;16(5):333-336. 4. Singh G. Gastrointestinal complications of prescription and
over-the-counter nonsteroidal anti-inflammatory drugs: a view from the ARAMIS database. Arthritis, Rheumatism,
and Aging Medical Information System. Am J Ther. 2000;7(2):115-121.

Provides fast, effective


and suitable pain relief
32

Journal of the Malta College of Pharmacy Practice

076-12 Prepared September 2012

Issue 19 Summer 2013