The second Princeton consensus on sexual dysfunction and cardiac risk: new guidelines, new challenges

The second Princeton consensus on sexual dysfunction and cardiacrisk: new guidelines, new challenges

The first PrincetonConsensusConference

was convened in 1999 (1). Its remit was to

evaluate the scientific evidence regarding

sexual activity and cardiac risk with a view

to developing guidelines for advising on

the safety of sexual activity in cardiac

patients and the management of erectile

dysfunction (ED). It established a success-

ful protocol utilised worldwide. As

research progressed and the realisation of

the importance of endothelial dysfunction

and cardiovascular risk factors in the

aetiology of ED became evident the

Second Princeton Consensus Conference

was convened in June 2004 (2). This con-

ference updated the guidelines, developed

new management algorithms, reviewed

the safety of sexual activity and the treat-

ment of EDwith phosphodiesterase type 5

(PDE5) inhibitors and emphasised the

importance of lifestyle intervention in

managing ED. Specifically the importance

of increased physical activity and weight

loss was emphasised with regard to ED

therapy and general cardiovascular risk

reduction.

A follow-up report has focused on

expanding the Princeton II Guidelines

specifically addressing sexual dysfunction

and cardiac risk (3). It establishes the

concept of ED as an early symptom or

harbinger of cardiovascular disease due

to the common risk factors and patho-

physiology secondary to endothelial dys-

function (4). Clear statements follow

with important practical implications:

. ‘‘Any symptomatic man with ED

that does not have an obvious cause

(e.g. trauma) should be screened for

vascular disease and have blood glu-

cose, lipids and blood pressure mea-

surements. Ideally, all patients at risk

but asymptomatic for coronary dis-

ease should undergo an elective exer-

cise electrocardiogram to facilitate

risk stratification.’’

. ‘‘The recognition of ED as a warning

sign of silent vascular disease has led

to the concept that a man with ED

and no cardiac symptoms is a cardiac

(or vascular patient) until proven

otherwise.’’

. ‘‘Studies strongly support the role of

lifestyle factors in the development

and maintenance of ED. Obesity and

lack of exercise have been strongly

implicated in a number of cross-

sectional and longitudinal studies.

Men with ED and other cardiovascu-

lar risk factors, in particular obesity

and sedentary lifestyle, should be

counselled in lifestyle modification.’’

(Perhaps the catchphrase should be

‘‘physically fit ¼ sexually fit’’)

In a short space of time major

advances have been made in both the

treatment and understanding the

pathophysiology of ED and these are

reviewed in the Princeton II papers.

Another publication has recently

added to the overwhelming evidence

that ED predicts subsequent cardiovas-

cular disease (5).

With a lead time of 3-5 years before

the cardiac event there is obviously a

need for a major study to see if

intervention with conventional aggres-

sive cardiac risk reduction will reduce

cardiac morbidity and mortality using

ED as the baseline marker of risk. The

challenge is real – we need to rise to the

challenge because the implications for

improving vascular health and prevent-

ing clinical events are enormous given

the number of men (over 100 million)

with ED worldwide.

Graham Jackson

Editor

REFERENCES

1 DeBusk R, Drory Y, Goldstein I et al.

Management of sexual dysfunction in

patients with cardiovascular disease: the

Princeton consensus panel. Am J Cardiol

2000; 86: 175–81.

2 Kostis JB, Jackson G, Rosen R et al.

Sexual dysfunction and cardiac risk (the

second Princeton consensus conference).

Am J Cardiol 2005; 96: 313–21.

3 JacksonG, Rosen RC, Kloner RA, Kostis JB.

The second Princeton consensus on

sexual dysfunction and cardiac risk: new

guidelines for sexual medicine. J Sex Med

2006; 3: 28–36.

4 Solomon H, Man JW, Jackson G.

Erectile dysfunction and the cardiovas-

cular patient: endothelial dysfunction is

the common denominator. Heart 2003;

89: 251–3.

5 Thompson IM, Tangen CM, Goodman

PJ et al. Erectile dysfunction and sub-

sequent cardiovascular disease. JAMA

2005; 294: 2996–3002.

Pulse pressure and carotid atherosclerosis: an important linkrevisited?

In everyday clinical practice, clinicians

and nurses regularly measure blood pres-

sure and happily express the systolic and

diastolic blood pressures in clinical notes

and bedside charts. The pulse pressure

(PP), which is defined as the difference

between the systolic blood pressure

(SBP) and diastolic blood pressure

(DBP), is not routinely recorded and is

often not given more than a cursory nod

of interest, except by introspective

hypertensionologists and cynical clinical

pharmacologists. This is despite the PP

being an established risk factor for ather-

osclerosis – particularly carotid athero-

sclerosis (CA) – and a role proposed in

the risk stratification of hypertensive

patients (1).

ª 2006 The AuthorsJournal compilation ª 2006 Blackwell Publishing Ltd Int J Clin Pract, February 2006, 60, 2, 127–133

EDITORIAL do i : 10 . 1111 / j . 1368 -5031 . 2006 . 00843 . x

Hypertension is associated with

adverse changes (whether damage or

dysfunction) in the endothelium.

Endothelial damage/dysfunction has

been demonstrated to be a reliable

prognostic indicator of future cardio-

vascular events in hypertension, with

calcium channel blockers and the ACE

inhibitors having significant direct

effects on the endothelium (2).

Although the blood vessels are subject

to high pressures, the complications of

hypertension are paradoxically throm-

botic rather than haemorrhagic (the so-

called ‘thrombotic paradox of hyper-

tension’ or ‘Birmingham paradox’). To

put things even more simply, the blood

vessels in high blood pressure clot,

rather than burst!

Changes in blood flow, vessel wall

and blood constituents are the three

components of the Virchow’s triad for

thrombogenesis. High blood pressure

(particularly SBP and consequently

PP), abnormalities in prothrombotic

factors, endothelial function and plate-

let activation and abnormalities in the

vessel wall, with increased stiffness and

cross-sectional area, are all implicated

in the pathogenesis of atherosclerosis

(3–5). In a study on cardiovascular

remodelling in isolated systolic hyper-

tension (ISH) vs. that in diastolic

hypertension, patients with ISH exhib-

ited greater carotid wall volume and

vascular stiffness, despite similar carotid

mean blood pressure (MBP) in both

groups (6). This was direct evidence of

the hypothesis that increased PP was

related to stroke and total mortality, as

a result of increased arterial stiffness.

Also, there is an association between

PP and carotid remodelling in hyper-

tensives on long-term antihypertensive

treatment, in whom regression of caro-

tid artery wall hypertrophy was depen-

dent upon PP reduction (7).

Nonetheless, PP increases with age

and is strongly related to the early

development of large vessel athero-

sclerosis (8,9). Increased carotid

intima-media thickness (IMT) and car-

otid and/or iliofemoral plaque are

frequent in hypertensive subjects, but

their relationship with PP has been

rarely studied (10). However, some stu-

dies, both cross-sectional and prospec-

tive (8–15), have found an association

between PP and carotid IMT and its

progression, respectively, as sum-

marised in Table 1.

In the current issue of the

International Journal of Clinical

Practice, Su et al. (16) report a positive

relationship between aortic regurgita-

tion (AR) and CA that was attenuated

after controlling for age. PP rises with

age, as does the incidence of AR (some-

thing that is associated with a raised PP

per se). The positive relationship

between AR and IMT (41.4% in sub-

jects with severe AR vs. 26.0% in the

absence of any AR, p ¼ 0.006) was

certainly more impressive than the rela-

tionship to carotid stenosis of �50%

(6.9 vs. 3.3%, p ¼ 0.170). PP was

also found to be associated with thicker

IMT and significant CA. Significant

trends were also noted for common

carotid artery IMT and extra cranial

carotid artery (ECCA) plaque

(p < 0.001). PP, sex (male), age and

smoking had significant risk implica-

tions in hypertensives compared with

normotensives; however, in normoten-

sives, age, smoking and presence of left

ventricular hypertrophy on ECG signif-

icantly increased the risk of CA.

As far as we are aware, only one

previous study (17) has investigated

the signs of atherosclerosis in carotid

and brachial arteries among patients

with AR. This study evaluated the rela-

tionship between AR and atherosclero-

sis by comparing patients with AR and

matched controls with identical cardio-

vascular risk scores and found that the

prevalence of atherosclerosis was greater

in the AR group – this is despite a

significant higher prevalence of smok-

ing in the control group, with other

risk factors between the two groups

relatively identical. IMT was noted to

be significantly greater in the brachial

than in the common carotid arteries, in

the AR group.

The association between PP, AR and

CA is a rather interesting one, with

particular implications in elderly

patients with hypertension and diabetes

mellitus. As noted from the above stu-

dies, a high PP, irrespective of the

cause, does seem to have a direct rela-

tion to the development of athero-

sclerosis. However, whether close

monitoring of PP (in addition to striv-

ing for excellent blood pressure control)

as well as close monitoring of the sever-

ity of AR would have any significant

clinical implications on the progression

of atherosclerosis is yet to be deter-

mined. Another point of interest is to

see whether a reduction in the PP by

tight control of blood pressure, particu-

larly, SBP, strict control of diabetes and

cessation of smoking has any effect on

the progression of atherosclerosis.

Perhaps the time has come for well-

conducted clinical outcome trials that

need to be designed so that cardiovas-

cular endpoints are related to PP reduc-

tion targets. This would give

introspective hypertensionologists, as

well as cynical clinical pharmacologists,

something to think about.

V.J. Karthikeyan

Gregory Y.H. Lip

University Department of

Medicine, City Hospital,

Birmingham B18 7QH, UK

REFERENCES

1 Guidelines Committee. 2003 European

Society of Hypertension–European

Society of Cardiology guidelines for

the management of arterial hyperten-

sion. J Hypertens 2003; 21: 1011–53.

2 Nadar S, Blann AD, Lip GYH.

Antihypertensive therapy and endothe-

lial function. Curr Pharm Des 2004; 10:

3607–14.

3 Lip GYH. Hypertension and the pro-

thrombotic state. J Hum Hypertens

2000; 14: 687–90.

4 Lip GYH, Blann AD, Beevers DG.

Prothrombotic factors, endothelial func-

tion and left ventricular hypertrophy in


128 EDITORIAL

Table 1 Studies examining the relationship between pulse pressure (PP), common carotid artery intima-media thickness (CCA-IMT),

carotid atherosclerosis (CA) and plaque ulceration

Study Number (n) Findings Comments

Matthews et al. (8) 254 healthy postmenopausal

women

Average IMT (0.77 mm),

range (0.60–1.37 mm);

plaque index associated with greater

PP change (odds ratio ¼ 1.47,

p ¼ 0.01) for women with a plaque

score of �2 vs. 1 or 0

Mental stress-induced PP changes

associated with development of early

CA; widened PP, both during stress

and rest, a marker of compromised

vessel wall compliance

Zureik et al. (9) 957 volunteers

(age 59–71 years)

Correlation between PP and

CCA-IMT (OR ¼ 0.20,

p < 0.001); PP and longitudinal

DCCA-IMT (OR ¼ 0.14,

p < 0.001)

PP and CCA-IMT and DPP and

DCCA-IMT positively related

Tartiere et al. (10) 323 hypertensive subjects Diabetes mellitus, controlled

and uncontrolled (p ¼ 0.02),

high CCA-IMT (p ¼ 0.0007)

and high CCA-lumen diameter

(p ¼ 0.01) associated with high

PP. CCA-IMT/radius ratio

associated with BP control and high

PP (p ¼ 0.006)

Cause–effect relationship between PP

and CCA-IMT suggested

Salonen and Salonen (11) 1224 men Age, ambulatory PP (standardised

partial coefficient b ¼ 0.130,

p < 0.0001), cigarette-years

of smoking, serum LDL

cholesterol concentration, history

of ischaemic heart disease,

preexercise systolic blood

pressure and diabetes noted

to be most strongly associated

with CCA-IMT

SBP, PP, smoking and serum LDL

cholesterol levels major risk factors

for increased CCA-IMT

Lassila et al. (12) 200 premenopausal women

(Healthy Women Study)

PP (p � 0.05), LDL cholesterol

and a history of smoking

independently predictive of plaque

and average IMT

Valuable information on CA in

premenopausal women gained

from this study

Lakka et al. (13) 1026 Mean IMT directly related

to an SBP and PP and DSBP(p ¼ 0.005) and DPP (p < 0.001);

Mean SBP and PP directly associated

with DIMT (p < 0.001)

A prospective study that revealed a

reciprocal relationship between BP and

IMT and their increase, thus indicating

a vicious cycle between baseline

BP and IMT in central conduit vessels

Rajala et al. (14) 208 SBP, DBP and PP all positively

correlated with mean and maximal

CCA-IMT (p ¼ 0.008, 0.073

and 0.708, respectively)

High SBP, DBP and PP all noted to

be high risk for severe IMT, particularly

in elderly subjects with diabetes

mellitus and impaired glucose tolerance

Lovett et al. (15) 3007 [from the European

Carotid Surgery Trial (ECST)]

PP, SBP, mean arterial pressure

(MAP), DBP all positively

associated with presence of contra-

lateral carotid bifurcation stenosis. PP,

SBP and MAP positively associated

with ulceration on the symptomatic

side (p < 0.001)

PP strongly associated with plaque

rupture that was severe enough to be

visible on angiography

Su et al. (16) 533 (Chin-Shan Community

Cardiovascular Cohort)

High BP positively associated

with CA (OR 5.0)

Hypertension strongly influences CA

DBP, diastolic blood pressure; SBP, systolic blood pressure.


EDITORIAL 129

isolated systolic hypertension compared

with systolic-diastolic hypertension. J

Hypertens 1999; 17: 1203–7.

5 Nadar S, Lip GYH. Hypertension and

the prothrombotic state. J Am Coll

Cardiol 2003; 41: 1847.

6 Pini R, Cavallini C, Bencini F et al.

Cardiovascular remodeling is greater in

isolated systolic hypertension in older

adults: the Insufficenza Cardiaca negli

Anziani Resienti (ICARE) a Dicomano

Study. J Am Coll Cardiol 2002; 40:

1283–9.

7 Boutouyrie P, Bussy C, Hayoz D et al.

Local pulse pressure and regression of

arterial wall hypertrophy during long

term antihypertensive treatment.

Circulation 2000; 101: 2601–6.

8 Matthews KA, Owens JF, Kuller LH

et al. Stress-induced pulse pressure

change predicts women’s carotid

atherosclerosis. Stroke 1998; 29:

1525–30.

9 Zureik M, Touboul PJ, Bonithon-Kopp C

et al. Cross-sectional and longitudinal

associations between pulse pressure

and common carotid intima-media

thickness in a general population.

The EVA study. Stroke 1999; 30:

550–5.

10 Tartiere JM, Kesri L, Safar H et al.

Association between pulse pressure, car-

otid intima-media thickness and carotid

and/or iliofemoral plaque in hyperten-

sive patients. J Hum Hypertens 2004;

18: 325–31.

11 Salonen R, Salonen JT. Determinants

of carotid intima-media thickness: a

population-based ultrasonography study

in Eastern Finnish men. J Intern Med

1991; 229: 225–32.

12 Lassila HC, Tyrrell KS, Matthews KA

et al. Prevalence and determinants of

carotid atherosclerosis in healthy post-

menopausal women. Stroke 1997; 28:

513–7.

13 Lakka TA, Salonen R, Kaplan GA et al.

Blood pressure and the progression of

carotid atherosclerosis in middle-aged

men. Hypertension 1999; 34: 51–6.

14 Rajala U, Paivansalo M, Laakso M et al.

Associations of blood pressure with car-

otid intima-media thickness in elderly

Finns with diabetes mellitus or impaired

glucose tolerance. J Hum Hypertens

2003; 17: 705–11.

15 Lovett JK, Howard SC, Rothwell PM.

Pulse pressure is independently asso-

ciated with carotid plaque ulceration. J

Hypertens 2003; 21: 1669–76.

16 Su TC, Lee YT, Chien KL et al. Pulse

pressure, aortic regurgitation and caro-

tid atherosclerosis in hypertensives. Int J

Clin Pract 2005.

17 Kervancioglu S, Davutoglu V, Ozkur A

et al. Carotid and brachial intima-media

thickness, arterial diameter and resistiv-

ity indices in aortic regurgitation. Acta

Radiol 2004; 45: 815–8.

Changes in organisation of oxygen therapy in England and Wales

Long-term home oxygen therapy

(LTOT) is the one treatment shown to

improve survival in chronic obstructive

pulmonary disease (COPD) patients

with chronic hypoxia. The two key

studies that underpin this evidence are

over 20 years old; they looked at patients

with chronic hypoxia. In the Medical

Research Council study (1), patients

with hypercapnia and a PaO2 between

5.3 and 8 kPa were given oxygen for

15 h compared with nothing. In the

Nocturnal Oxygen Therapy Trial

(NOTT) (2), the criterion was a PaO2

<7.3 kPa. These studies showed that sur-

vival was improved by oxygen used for at

least 15 h a day, and the NOTT study

showed that overnight use of oxygen was

not sufficient while aiming for 24-h use

proved most beneficial. Subsequent

studies have been able to show an

improvement in health-related quality

of life as well as survival on LTOT (3).

In England and Wales, the organisa-

tion of oxygen use has been fragmented

because blood gas investigations need

to be done in hospital while the pre-

scription of oxygen has been through

general practitioners. Portable oxygen

therapy during exercise has been very

limited because heavy pressurised gas

cylinders have been used rather than

lighter liquid oxygen cylinders. The

whole situation is about to change in

England and Wales, where over 60,000

patients are prescribed home oxygen.

Four suppliers have been selected to

provide an enhanced service ordered

primarily by hospital specialists.

Generally, the criteria for LTOT

have extended beyond COPD in the

original studies to other causes of

chronic hypoxia. However, a number

of studies have shown that the prescrip-

tion of LTOT often does not follow the

current recommendations (4,5).

General practitioners will still be able

to prescribe oxygen, but this will

usually be for short-term relief often

as part of palliative care. Prescriptions

for short-term oxygen therapy are

common but have little scientific evi-

dence to back up their use (6). It tends

to be used before or after exercise or

intermittently in palliative care. The

recommendations are that it is reserved

for those who are otherwise on optimal

therapy and who show an improvement

in breathlessness or exercise tolerance

with intermittent oxygen.

The essential criteria for LTOT

remain the same. Patients should have

chronic hypoxaemia demonstrated while

in a stable state on two occasions at least

3 weeks apart. The PaO2 should be at or

below 7.3 kPa (55 mmHg) while

breathing air or 7.3–8.0 kPa for patients

with polycythaemia or pulmonary

hypertension. Stability at the time of

assessment means that the patient

should be on optimal medical therapy

and free of exacerbation for at least 5

weeks. Arterial gas measurement should

be repeated on the intended oxygen flow

rate to make sure that the PaO2 rises

above 8 kPa without excessive CO2

retention. Saturation alone is not con-

sidered sufficient in most European

countries but can be used as a

The author confirms that he has no conflicts

of interest with regard to the subject of this

article.


130 EDITORIAL

preliminary to blood gas estimation

because PaO2 <8 kPa is not likely to

be associated with a saturation of 93%

or higher. Blood gas estimation should

be repeated at yearly intervals to check

that the flow rate is appropriate. A sig-

nificant minority have improved blood

gas levels at 1 year, which mean that

oxygen can be discontinued at least tem-

porarily with gases repeated at intervals.

Patients who continue to smoke risk

fires and burns from their supplemental

oxygen therapy; hence, oxygen is not

normally prescribed to current smokers.

The opportunities should be taken to

promote smoking cessation.

Ambulatory oxygen should be used to

increase patient mobility and quality of

life. Liquid oxygen will be more easily

available and this allows patients to use a

light cylinder that lasts for several hours

and is portable enough to be carried.

Small compressed gas cylinders are too

heavy to be practical and last less than

2 h. However, liquid oxygen is more

expensive and many patients on LTOT

would not move far outside their homes

even with a portable supply. Therefore,

this should only be prescribed after a

careful evaluation of the mobility of

those on LTOT. For patients not using

LTOT, criteria for ambulatory use

should be a drop in oxygen saturation

on exercise of 4% to <90%, distance

walked or breathlessness improved by

oxygen and the motivation and oppor-

tunity to use it.

LTOT will be prescribed by desig-

nated hospital specialists, usually

respiratory physicians (Figure 1). A

‘Home Oxygen Service Order Form’

will be faxed to one of the four con-

tractors who deal with specified areas.

The equipment can be a choice made

between the contractor and the prescri-

ber. At the same time, the patient

should be informed carefully of the

reasons for the prescription and the

appropriate way to use the equipment.

This information and follow-up are

often best provided through a respira-

tory specialist nurse. The respiratory

specialist nurse should review the

patient at home within 4 weeks; arterial

blood gases should be checked on air

and oxygen at 3 months and then at

least annually. The prediction is that

around 50% of LTOT patients will

need assessment for ambulatory oxy-

gen. It is estimated that this process

will require around 12 h of care and

assessment each year for each LTOT

patient, necessitating the equivalent of

one member of staff for every 100

LTOT patients.

CONCLUS IONS

Changes to the oxygen provision

requirements in England and Wales in

2005 mean a shift in responsibility

from primary to secondary care. It is

an opportunity to ensure that oxygen is

used appropriately and extensively

enough. The greater availability of

liquid oxygen and lightweight portable

cylinders has the potential to improve

the mobility and quality of life of many

patients with chronic respiratory dis-

ease. The challenge for secondary care

is to establish an efficient service to take

on this new organisation and ensure the

effective and efficient use of oxygen at

home in chronic lung disease.

P. John Rees

Senior Lecturer

King’s College School of

Medicine at Guy’s, King’s and

St Thomas’ Hospitals, Guy’s

Hospital, London, UK

REFERENCES

1 Report of the Medical Research Council

Working Party. Long-term domiciliary

oxygen therapy in chronic hypoxic

cor pulmonale complicating chronic

bronchitis and emphysema. Lancet

1981; 1: 681–6.

2 Nocturnal Oxygen Therapy Trial Group.

Continuous or nocturnal oxygen therapy

in hypoxaemic chronic obstructive lung

disease. Ann Intern Med 1980; 93:

391–8.

3 Eaton T, Lewis C, Young P, Kennedy Y,

Garrett JE, Kulbe J. Long-term

oxygen therapy improves health-related

quality of life. Respir Med 2004; 98:

285–93.

4 Shankar P, Muthiah MM. Audit on pre-

scription of long term oxygen treatment.

Clin Perform Qual Health Care 2000; 8:

134–5.

5 Ringbaek TJ, Lange P, Viskum K.

Geographic variation in long-term oxy-

gen therapy in Denmark: factors related

to adherence to guidelines for long-term

oxygen therapy. Chest 2001; 119:

1711–6.

6 Nandi K, Smith AA, Crawford A et al.

Oxygen supplementation before or after

submaximal exercise in patients with

chronic obstructive pulmonary disease.

Thorax 2003; 58: 670–3.

Chronic hypoxaemia with PaO2 <7.3 kPa on two occasions at least 3 weeks apart at least 5 weeks after exacerbation

Assess oxygen flow rate to get PaO2 >8 kPa

Fill in Home Oxygen Service Form

Consider ambulatory oxygenRespiratory specialist nurse visit at 1 month

Low activity Active

Arterial gases on air and oxygen at 3 monthsOxygen at LTOT

flow rate Assess flow rate to keepSaO2 >90% on exercise

Respiratory specialist nurse follow-up

2-month trial

Annual blood gases

Figure 1 Flow chart of the process for the prescription and monitoring of home oxygen


EDITORIAL 131

Rasagiline – is there a place for this drug in managing Parkinson’sdisease?

In this issue of IJCP, Prof. Fabrizio

Stocchi sums up the results of three

studies with a new monoamine B inhi-

bitor, rasagiline, highlighting the signif-

icant results that might guide clinicians

to determine the role of this novel drug

in the management of patients with

Parkinson’s disease (1). It is a second

generation monoamine oxidase B

(MAO-B) inhibitor, introduced after

more than 20 years of the first drug in

this class, selegiline which has faced ups

and downs in its use. Rasagiline is

unique in that its role has been investi-

gated in different stages of Parkinson’s

disease (PD) prior to being introduced

for use. As Prof. Stocchi describes, the

wash-in delayed-start design of

TEMPO study has been the first of its

kind, and the continuing superiority of

the early users of rasagiline over the late

users has been promoted as a disease-

modifying or neuroprotective property

of the drug, perhaps in parallel with the

antiapoptotic activity in in vitro studies.This might be the result of the benefit

of an attempt of early normalization of

dopaminergic transmission as com-

pared with late introduction of drug

therapy, supporting the notion that

late starters never catch up. Previous

studies using functional imaging (2,3)

have not been considered to be repre-

sentative of neuroprotection (4); clin-

ical superiority as shown in TEMPO

might be indicative of neuroprotection,

but there is need for more research on

this principle.

The studies with rasagiline have

produced some results which might

be considered to be unique. In addition

to the possible disease-modifying

property, rasagiline has been shown to

improve quality of life, early morning

akinesia and more significantly the

postural instability and gait disorders

including freezing of gait. These symp-

toms present a challenge in advancing

PD, and any therapeutics in this

direction are welcome to help patients.

Currently available drugs have not

produced evidence for these motor

and non-motor symptoms of PD.

Entacapone has been studied in one of

the studies as a comparative group, but

it has not been able to establish its place

for improving the quality of life (5).

Where would rasagiline fit into the

pharmacotherapy of PD with the

currently available drugs. Levodopa

remains clinically most effective and

rapid acting drug, but its use is still

surrounded by a number of controver-

sies (6). There are proponents both for

its early and delayed use in PD patients.

There is nevertheless a consensus that

the dose of levodopa should be the

minimum possible to ameliorate an

individual patient’s symptoms to

reduce the risk of levodopa-related dys-

kinesia. Early use of dopamine agonists

helps to reduce the risk of dyskinesia

(7). Maintaining a patient at a lower

dose of levodpa with some reference to

the body weight might further help to

reduce dyskinesia (8). Any drug with

levodopa-sparing efficacy while provid-

ing sufficient symptom control is a step

towards achieving a reduction in dyski-

nesia. Rasagiline may be added to the

number of currently available drugs to

reduce the dose of levodopa and thus to

reduce dyskinesia. The design of studies

with rasagiline did not allow a reduc-

tion in the dose of levodopa resulting in

a slight increase in dyskinesia. In clinical

practice, however, the physicians would

aim to reduce the dose of levodopa and

thus able to prevent dyskinesia.

Concern has been raised regarding

the use of MAO-B inhibitors and an

increase in mortality. A meta-analysis

of the use of these drugs in early dis-

ease, however, allayed these concerns

(9), but the recommendation seems to

be that these drugs are safe for use as a

monotherapy in young and generally

well PD patients (10). In practice, the

majority of the PD patients are older

and get frail as the disease advances.

Sixteen of the 17 studies in the meta-

analysis were with selegiline. There are

basic differences between selegiline and

rasagiline; the metabolite of selegiline is

an amfetamine with the potential for

harm, whereas the metabolite of rasagi-

line is an inactive non-amphetamine

substance. This difference is likely to

be clinically significant, but we need

evidence with longer term clinical

studies.

Rasagiline may have a role in

managing Parkinson’s disease patients

across the span of the disease as

monotherapy or adjunct therapy,

and every patient may benefit from

its use at some stage during the

course of the disease. It is unlikely

to replace selegiline or dopamine ago-

nists but may be a better and safer

drug in older and frail patients who

may be at a risk of developing hallu-

cination and confusion which are less

likely with rasagiline. We also watch

with interest further developments in

pharmaco-therapeutics of PD with

the introduction of topical dopamine

agonist, duodenal levodopa and the

new non-dopaminergic therapeutic

concept with Adenosin A2A receptor

antagonist. While the search for novel

agents to improve management of

Parkinson’s disease, aiming to prevent

disease progression, abolish motor

disability and eventually the cognitive

impairment continues, the clinicians

need to use the currently available

agents to the maximum benefit for

an individual patient.

Jagdish C. Sharma

Stroke and Parkinson’s Disease

Services, Sherwood Forest

Hospitals NHS Trust, Newark &

Mansfield Hospitals, Notts, UK

Email: jagdish.sharma@sfh-

tr.nhs.uk


132 EDITORIAL

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EDITORIAL 133

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