Professor Christopher Chapple
email: c.r.chapple@shef.ac.uk

New once daily formulation for trospium in overactive bladder

Aims

To examine the relative efficacy and safety of trospium 20mg bid and 60 mg extended release formulations and position this drug against other antimuscarinic agents

Methods

Data were identified on the pharmacology and pharmacokinetics of trospium chloride. Key publications on trospium 20 mg and 60 mg clinical studies in patients with overactive bladder (OAB) were identified and efficacy and safety compared between these formulations as well as other antimuscarinic agents.

Results

Trospium offers the principal advantage over other antimuscarinic agents that, as it is a quaternary amine, it does not cross the blood-brain barrier and is therefore less likely to cause central nervous system effects observed with several other agents.

Moreover, with its minimal liver metabolisation, independent of the main cytochrome pathways, trospium has a low risk of drug-drug interaction in patients taking multiple pharmacological agents. Trospium 60 mg ER is as effective as trospium 20 mg bid in improving the key outcome parameters associated with OAB, but with a lower rate of dry mouth, the most common side-effect of these agents. Trospium has comparable efficacy and safety to the other antimuscarinic agents currently marketed. Good patient persistence with treatment has been reported with trospium.

Conclusion

There are currently a large number of antimuscarinic drugs on the market without clear evidence to distinguish one agent from another in terms of efficacy provided an adequate dose is used in the clinical setting. The new formulation of trospium is

particularly the elderly where one wants to avoid the potential for cognitive dysfunction.

Review Criteria

'How did you gather, select and analyze the info you considered in your review?'

A medline search was conducted using the key words trospium and incontinence.

Data on all other antimuscarinic agents were based on a comprehensive metaanalysis as well as medline searches on specific adverse events, e.g. cognitive function.

Message for the clinic

'What is the take-home message for the clinician?' Trospium chloride 60 mg ER can be considered a potential addition to the treatment armamentarium for patients with overactive bladder, as it brings with the potential of not crossing the blood brain barrier because of its underlying physico-chemical structure. Further experience is necessary, however, in real life clinical practice as well as results of further controlled studies before more definitive conclusions can be drawn.

Introduction

Overactive bladder (OAB) has been defined by International Continence Society (ICS) as a symptom syndrome comprising "urgency with or without urgency incontinence, usually with frequency and nocturia" [START_REF] Abrams | The standardisation of terminology in lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society[END_REF]. The condition is common and one in six adults is reported as having symptoms of OAB [START_REF] Milsom | How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study[END_REF]. The primary therapies for this condition are non-surgical comprising bladder training, biofeedback, medication and a combination of these options, while the first-line medical therapy for OAB relies on antimuscarinic agents [START_REF] Ouslander | Management of overactive bladder[END_REF]. By blocking the muscarinic M3 receptors, these reduce the symptoms of OAB in part by a direct action on the detrusor muscle (4) as well as potentially affecting the sensory components of the micturition reflex. The widespread occurrence of muscarinic receptors throughout the body, including the central nervous system, eyes, salivary glands, and gastrointestinal tract, however, means that antimuscarinic therapy is associated with a range of adverse effects (AEs). A number of different formulations are available for the various antimuscarinic agents that are currently available. In the past, one such agent, trospium chloride, has been disadvantaged by not being available as a once a day formulation, but this situation has now been resolved by a new 60 mg extended release (ER) formulation. This review examines the background to this compound and draws comparison between the new formulation and the original twice daily preparation, as well as the existing antimuscarinic agents.

Trospium chloride

Pharmacology

Trospium chloride is an antimuscarinic agent indicated for the symptomatic treatment of urgency incontinence and/or increased urinary frequency and urgency and is charged at neutral pH [START_REF] Staskin | Trospium chloride: Distinct among other anticholinergic agents available for the treatment of overactive bladder[END_REF]. Following oral administration, it is absorbed rather slowly, with peak plasma levels reached at 4.5 hours and at 5.0 hours with the IR and ER formulations, respectively [START_REF] Silver | Pharmacokinetics of once-daily trospium chloride 60 mg extended release and twice daily trospium chloride 20 mg in healthy adults[END_REF]; no first-pass effect for systemically absorbed trospium has been observed [START_REF] Sandage | The effect of hepatic disease on the pharmacokinetics of trospium chloride[END_REF][START_REF]Trospium chloride PI[END_REF]. Up to 80% of trospium is excreted unchanged in the urine and metabolism by the cytochrome P450 pathway does not occur [START_REF]Trospium chloride PI[END_REF][START_REF] Schladitz-Keil | Determination of the bioavailability of the quaternary compound trospium chloride in man from urinary excretion data[END_REF], suggesting that no metabolic interactions with other drugs are likely [START_REF]Trospium chloride PI[END_REF].

Antimuscarinic agents interact with muscarinic receptors throughout the body, of which the five known receptor subtypes are all expressed in the central nervous system (CNS) [START_REF] Abrams | Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder[END_REF]. Interactions with the M 1 , M 2 , and M 4 subtypes have each been implicated in cognitive impairment and the M 1 receptor subtype is particularly relevant in this regard [START_REF] Abrams | Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder[END_REF][START_REF] Kay | Antimuscarinic drugs for overactive bladder and their potential effects on cognitive function in older patients[END_REF]. In order to be active within the brain, the individual agent has to cross the blood-brain barrier, either through active transport or passive penetration; the latter is more likely with small hydrophilic molecules. Drugs such as oxybutinin (357 kDA) can readily cross the blood-brain barrier and their subsequent negative effects on cognitive function have been documented [START_REF] Kay | Preserving cognitive function for patients with overactive bladder: evidence for a differential effect with darifenacin[END_REF]. In contrast, data indicate that trospium was less likely to produce CNS AEs than oxybutinin due to its inability to cross the blood brain barrier [START_REF] Pietzko | Influences of trospium chloride and oxybutynin on quantitative EEG in healthy volunteers[END_REF]. Research also suggests that trospium affects general and traffic safety performance to a lesser extent than oxybutinin, tolterodine and propiverine [START_REF] Herberg | General and traffic safety and the effects of incontinence medication: new studies on the safety potential of urological anticholinergics[END_REF]. Further support for the lack of CNS AEs comes from a study by Staskin and Harnett, which showed that trospium did not increase daytime sleepiness or reduce patient alertness [START_REF] Staskin | Effect of trospium chloride on somnolence and sleepiness in patients with overactive bladder[END_REF]. These findings are particularly relevant for the elderly who have cerebrovascular disease or other co-morbidities that alter the permeability of the blood-brain barrier who might be a greater risk of a CNS adverse event.

Efficacy

No head to head studies have been conducted on trospium 20 mg immediate release and the 60 mg ER formulations. Considering the outcomes from individual studies (Table 1) [START_REF] Halaska | Controlled, double-blind, multicentre clinical trial to investigate long-term tolerability and efficacy of trospium chloride in patients with detrusor instability[END_REF][START_REF] Zinner | Trospium chloride improves overactive bladder symptoms: a multicenter phase III trial[END_REF][START_REF] Staskin | Once daily trospium chloride is effective and well tolerated for the treatment of overactive bladder: results from a multicenter phase three trial[END_REF][START_REF] Dmochowski | Trospium 60 mg once daily (QD) for overactive bladder syndrome: results from a placebo-controlled interventional study[END_REF], three key outcome parameters are reported, i.e. reduction in daily incontinence episode rate, daily micturition rate and daily urgency episodes, which show significant improvements with both dosages of trospium over placebo.

No distinction can be observed between the two dosage forms for any of these parameters, albeit, the duration of treatment is longer in one of the lower dosage studies. This latter study actually reports the longest term outcome for trospium 20

mg bid and at 1 year confirms the durability of the therapy.

Additional data on the efficacy of trospium 20 mg bid dosage come from a 3week randomized placebo controlled study of 208 patients with detrusor overactivity [START_REF] Cardozo | Efficacy of trospium chloride in patients with detrusor instability: a placebo-controlled, randomized, double-blind, multicentre clinical trial[END_REF]. Efficacy was based on urodynamic assessments including maximum cystometric bladder capacity, volume at first overactive and maximum contraction, detrusor pressures at different bladder states. Results showed that trospium produced significant improvements in a number of urodynamic parameters (Table 2).

In addition, most patients treated with trospium rated the acceptability of study medication as good or very good; 50% and 37%, respectively compared with 40% and 29%, respectively, with placebo. The pivotal randomized controlled trials on trospium 60 mg ER formulation were conducted in the US and involved over 1000 patients at over 100 sites [START_REF] Staskin | Once daily trospium chloride is effective and well tolerated for the treatment of overactive bladder: results from a multicenter phase three trial[END_REF][START_REF] Dmochowski | Trospium 60 mg once daily (QD) for overactive bladder syndrome: results from a placebo-controlled interventional study[END_REF].

The study by Staskin et al indicated that in addition to the primary efficacy variables shown in Table 2, twice as many patients treated with trospium achieved normalization (no urinary urgency episodes and a daily void frequency of ≤ 8) compared with placebo (20.5% vs. 11.3%; p < 0.01) [START_REF] Staskin | Once daily trospium chloride is effective and well tolerated for the treatment of overactive bladder: results from a multicenter phase three trial[END_REF].There were also significant improvements in other secondary outcome measures (urgency urinary incontinence

[UUI] episodes per week, urgency severity associated with toilet voids, volume voided per void, daily frequency of urgency-associated voids and OAB-SCS). The time to onset of clinical benefit was superior for trospium compared with placebo, with benefits being observed in week 1 of the 12-week study for several of the primary and secondary outcomes. In the Dmochowski et al study, from week 1 significantly more patients were dry in the trospium group than in the placebo group and at week 12 this rose to 36% and 21%, respectively (P < 0.001) [START_REF] Dmochowski | Trospium 60 mg once daily (QD) for overactive bladder syndrome: results from a placebo-controlled interventional study[END_REF]. Similarly, significantly more patients treated with trospium were normalized from week 4 and at week 12, 21% vs. 11% were normalized in the trospium and placebo groups, respectively (P < 0.01).

A post hoc analysis was conducted on pooled data from the two US 12-week, studies rates' following treatment. A further post-hoc analysis on the two studies examined the effects of obesity on outcome. Increased body mass index has been shown to be associated with severity of OAB in a number of studies in both men and women [START_REF] Dallosso | The association of diet and other lifestyle factors with overactive bladder and stress incontinence: A longitudinal study in women[END_REF][START_REF] Dallosso | The association of diet and other lifestyle factors with the onset of overactive bladder: A longitudinal study in men[END_REF]. The analysis showed that trospium was more effective than placebo at reducing the primary endpoints (number of daily voids and UUI; P < 0.0001) and at improving the secondary end-points (percent patients continent and urgency severity; P < 0.0001) for WHO obesity levels I and II.

Safety

Comparison is made in Table 3 of the most frequent AEs reported with the two formulations of trospium [START_REF] Halaska | Controlled, double-blind, multicentre clinical trial to investigate long-term tolerability and efficacy of trospium chloride in patients with detrusor instability[END_REF][START_REF] Zinner | Trospium chloride improves overactive bladder symptoms: a multicenter phase III trial[END_REF][START_REF] Staskin | Once daily trospium chloride is effective and well tolerated for the treatment of overactive bladder: results from a multicenter phase three trial[END_REF][START_REF] Dmochowski | Trospium 60 mg once daily (QD) for overactive bladder syndrome: results from a placebo-controlled interventional study[END_REF]. This shows a lower rate of AEs with the 60 mg ER dose than the 20 mg bid. There was a marked decrease in the incidence of dry mouth with trospium ER; the rates reported for the 20 mg and 60 mg formulations were 21-33% and 8.7-12.9%, respectively. Improved formulations and extended release delivery systems developed for other antimuscarinic drugs have demonstrated an improved therapeutic index, namely by maintaining efficacy but improving the safety profile [START_REF] Van Kerrebroeck | Tolterodine oncedaily: superior efficacy and tolerability in the treatment of the overactive bladder[END_REF]. This is combined with a significantly better improvement in mean number of urgency incontinence episodes per week with the ER formulation. The lower rate of AE has indeed been suggested to be related to the pharmacokinetic profile of this novel formulation; in particular, the systemic exposure to trospium at steady state is lower following administration of the ER formulation, as compared with the IR one, possibly by reducing the chance of reaching the threshold serum level at which AEs occur [START_REF] Silver | Pharmacokinetics of once-daily trospium chloride 60 mg extended release and twice daily trospium chloride 20 mg in healthy adults[END_REF].

A recent open label, non comparative, evaluation study of 12 healthy volunteers, insinuated the ability of trospium extended release to penetrate the blood brain barrier. This looked at serum plasma levels as well as levels in the cerebral spinal fluid at up to 24 hours post dose, when a steady state had been reached at 10 days after starting dosing. All of the volunteers were aged 65-75. No clinically meaningful drug effect was seen after neuro-cognitive measurement and trospium chloride was undetectable to multiple time points in these patients. The study concluded that pharmacological and behavioural results supported a lack of CNS penetration in potentially neuro-cognitively vulnerable elderly people [START_REF] Staskin | Sanctura XR a muscarinic antagonist resists transport (SMART) across the blood-brain barrier (BBB): A prospective, neurocognitive, biodistribution and pharmacokinetic study of extended release trospium chloride (TrCl)[END_REF].

Comparison to other antimuscarinic agents

A meta-analysis was conducted in 2008 on the safety and efficacy of antimuscarinic agents for OAB, which involved an analysis of published randomized controlled trials on drug dosages that were licensed for use in Europe [START_REF] Chapple | The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis[END_REF]. The cutpoint for publication was 18 October 2007. Comparison can now be made to the two RCTs on trospium 60 mg ER that have subsequently been published, namely the studies by Staskin et al [START_REF] Staskin | Once daily trospium chloride is effective and well tolerated for the treatment of overactive bladder: results from a multicenter phase three trial[END_REF] and Dmochowski et al. [START_REF] Dmochowski | Trospium 60 mg once daily (QD) for overactive bladder syndrome: results from a placebo-controlled interventional study[END_REF]. The meta-analysis reported pooled differences in mean change in incontinence episodes of 0.4 to 1.1 episodes per day.

The data on trospium compares favourably with this at 0.5─2.4. Pooled differences for mean change in number of micturitions per day ranged from 0.5 to 1.3 episodes in the meta-analysis compared with 0.3 to 7.9 in the trospium studies. With regard to urgency episodes per day, the trospium studies show a change in rate of 0.3 to 6.7 compared with 0.64 to 1.56 episodes per day in the meta-analysis. These findings suggest that trospium at both dosage forms is as effective as the other antimuscarinic agents available. The safety of trospium is comparable to the other antimuscarinic agents reported in the meta-analysis with the exception of dry mouth where the 8.7% incidence (placebo 3.0%) with the 60 mg ER dosage [START_REF] Staskin | Once daily trospium chloride is effective and well tolerated for the treatment of overactive bladder: results from a multicenter phase three trial[END_REF] was the lowest reported for any oral antimuscarinics.

The efficacy of the antimuscarinics has to be balanced against the sideeffects observed and patient tolerability of these effects. Persistence rates with the different antimuscarinic vary between rates reported in long-term clinical trials and real life situations. Very good long-term persistence has been reported for several antimuscarinic agents including, 75% for trospium at 12 months ( 16), 81% for solifenacin at 40 weeks [START_REF] Haab | Long-term open-label solifenacin treatment associated with persistence with therapy in patients with overactive bladder syndrome[END_REF], 71% for tolterodine at 1 year (28) and 66% for darifenacin at 2 years [START_REF] Haab | Long-term treatment with darifenacin for overactive bladder: results of a 2-year, open-label extension study[END_REF]. In contrast, a much lower rate of 44% has been reported

for real-life prescription renewal for tolterodine ER after 30 days and this reduced to 9% at 1 year [START_REF] Shay | Persistence with overactive bladder pharmacotherapy in a Medicaid population[END_REF]. A more recent report has examined the persistence of antimuscarinics based on a Danish database of reimbursed prescriptions in 2006 in a sample of the population representative of the country as a whole [START_REF] Brostrom | Persistence with antimuscarinic drug use[END_REF]. Results

showed that apart from trospium, all drugs had continuation rates of less than 50% at 6 months, less than 25% at 1 year and less than 10% at 2 years and longer (Fig. 1).

The continuation rates for trospium were 46%, 36%, 22% and 16% at 6 months, 1, 2 and 3 years, respectively. The authors speculated that the higher persistence rates seen with trospium might be due to its lack of interaction with concomitant medications, making it a safer option particularly in the elderly. Factors affecting discontinuation likelihood were gender (men > women), age (young > old), dose (high > low) and previous experience with OAB drugs.

Conclusion

There are currently a large number of antimuscarinic drugs on the market with little clear evidence to distinguish one agent from another in terms of efficacy provided an adequate dose is used in the clinical setting. In particular, this is due to the paucity of head to head clinical studies. The principal difference between compounds relates to pharmacological and pharmacokinetic factors. Another important aspect is ease of administration and the once daily formulations clearly provide additional patient benefit. Trospium, now available as a new once daily formulation, has the added advantage that it does not cross the blood brain barrier, so it may well be beneficial in elderly patients who are at higher risk of potential effects on the CNS. It is unclear as to whether direct excretion of trospium in the urine is relevant to its clinical use, but this certainly may be important in its profile of action. Indeed, it has been suggested [START_REF] Staskin | Once daily trospium chloride is effective and well tolerated for the treatment of overactive bladder: results from a multicenter phase three trial[END_REF][START_REF] Dmochowski | Trospium 60 mg once daily (QD) for overactive bladder syndrome: results from a placebo-controlled interventional study[END_REF] that the relative accumulation of active drug in urine, and its consequent anticholinergic effect exerted on the urothelium (32) , may improve the control of urgency. Future work should include further controlled studies, possibly head-to-head comparisons with other once daily antimuscarinics, in order to provide additional insights into the relative benefits of alternative treatment options.

  as a pharmacological treatment of patients with OAB,

  . Patients were stratified by the mean number of UUI episodes ⁄ day at baseline (1.0, > 1.0-2.0, > 2.0-5.0 or > 5.0). Results showed that baseline UUI levels were inversely correlated with the week 12 percentage of patients continent and that more patients were continent with trospium compared with placebo at all degrees of severity. Complete continence was achieved in 75% of trospium recipients with 1.0 UUI ⁄ day at baseline and 48% of those with > 1.0-2.0 UUIs ⁄ day at baseline indicating that patients with less severe OAB could anticipate higher 'dry

Figure 1 .

 1 Figure 1. Kaplan-Meier plots of persistence with antimuscarinic drugs for the

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Table 1

 1 Efficacy of trospium chloride compared with placebo; results shown represent change from mean baseline values at 12 weeks except where indicated Comparison to placebo: a P ≤ 0.0001; b P < 0.0001; c P = 0.0022; d P < 0.001; e P ≤ 0.001

	Study	Dosage	No.	Incontinence	Micturition/day Urgency
			patients	episodes/day		episodes/day
	Halaska et	20 mg bid	267	-0.5	-7.9	-6.7
	al. 2003 (16)	TC 1
	Zinner et al.	20 mg bid	256	-2.3 a	-0.3 a	-0.3 a
	2004 (17)	TC
		Placebo	256	-1.9	-0.2	-0.1
	Staskin et al.	60 mg ER	292	-2.48 c	-2.81 b	-3.11 b
	2007 (18)	TC
		Placebo	300	-1.93	-1.99	-2.12
	Dmochowski	60 mg ER	267	-2.4 d	-2.5 e	-
	et al. 2008	TC
	(19)	Placebo	276	-1.6	-1.8	-
	1 At week 52

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Table 2

 2 Improvement in urodynamic parameters with trospium 20 mg bid

	Parameter	Mean treatment effect	P value
		compared with placebo
	Max cystometric bladder capacity (ml)	+37.3	0.0054
	Vol at first unstable contraction (ml)	+63.6	0.0015
	Vol at max contraction (ml)	+29.2	0.0113
	Bladder compliance (ml/cmH 2 O)	-1.2	0.1072
	Residual urine (ml)	+5.5	0.0285
	Max detrusor pressure at first unstable	-5.2	0.1278
	contraction (cmH 2 O)

Events with ≥ 3% incidence ; 2 Events with ≥ 1% incidence


Lynn ; Millar

A Mcgreevy

M B Bch

Mb L Millar

Bch

B Murphy

BSc Gw Davison

Md R Brown

Frcs

Donnell Me O'
email: modonnell904@hotmail.com

GB&I) MMedSc MD MFSEM(RCSI&RCPI) MFSEM(UK) MRCSEd 1&3 Dipsem

Mark E O'donnell

The Effect of Sporting Events on Emergency Department Attendance Rates in a District General Hospital in Northern Ireland Authors

Keywords: Attendance Rates, Emergency Department, European Working Time Directive, Sporting Events

Background:

Previous studies have reported a conflicting relationship between the effect of live and televised sporting events on attendance rates to emergency departments (ED). The objectives of this study were to investigate the relationship of major sporting events on emergency department attendance rates and to determine the potential effects of such events on service provision.

Methods:

A retrospective analysis of ED attendances to a district general hospital (DGH) and subsequent admissions over a 24-hour period following live and televised sporting activities was performed over a 5-year period. Data was compiled from the hospital's emergency record books including number of attendances, patient demographics, clinical complaint and outcome. Review patients were excluded. Analysis of sporting events was compiled for live local, regional and national events as well as world-wide televised sporting broadcasts.

Results:

137668 (80445 male) patients attended from April 2002 to July 2007. Mean attendance rate per day was 80 patients (Male=47). Mean admission rate was 13.6 patients per day. Major sporting events during the study period included; Soccer: 4 FA Cup and 1 World Cup (WC) finals; Rugby: 47 Six Nations, 25 Six Nations games involving Ireland, 1 WC Final, 2 WC semi-finals, 2 WC quarter-finals and 4 WC games involving Ireland; and Gaelic Football (GAA): 5 All-Ireland finals, 11 semifinals, 11 quarter-finals and 5 provincial finals. There was a significantly higher patient admission rate during the soccer FA Cup final, rugby 6 nations and games involving Ireland and for GAA semi-and quarter-final games (p=0.001 to 0.01).

There was no difference identified in total attendance or non-admission rates for sporting events throughout the study period. Although there was no correlation identified between any of these sporting events and total emergency department attendances (r<0.15, p>0.07), multinomial logistic regression demonstrated that FA Cup final (p=0.001), Rugby Six Nations (p=0.019), Rugby WC games involving

Conclusion:

This study suggests that live or televised sporting events do not significantly affect ED attendances to a DGH. However, some events appeared to be predictors of patient admission rates. Although it may be beneficial to consider the effect of sporting events on service stratification during these periods, the overall effect is probably minimal and should not create a major concern for future service provision despite the implementation of the European Working Time Directive. World Cup corresponding to a quarter of the total population, and in Ireland, up to half of the population have been estimated to watch world cup soccer matches at any one time. [START_REF] Itv | Rugby World Cup 2003[END_REF][START_REF]Ireland's Top Media Resource. Media Analysis[END_REF] Previous studies have suggested a conflicting relationship between the effect of sporting events and attendance rates in emergency departments (ED), where both live and televised sport have been shown to have significant effects on hospital workload. Miró et al (2000) found a significant decrease in ED use during UEFA Champions League televised soccer matches in Barcelona particularly when the home team were involved. [START_REF] Miró | Football, television and the emergency services[END_REF] American Football's Super Bowl has also been reported to be associated with a reduction in ED attendances. [START_REF] Reich | The Impact of a Major Televised Sporting Event on Emergency Department Census[END_REF] In Buffalo (US), an ED census identified a significant decrease in attendances coinciding with 4 out of 5 Superbowl televised broadcasts during January, between 1988 and 1992, when compared to days without televised coverage during the same month. They found that this relationship was augmented when the local team was a playoff participant. This may be of particular importance to smaller communities, particularly the region surrounding our DGH, which would be considered to have a high interest in local, national and international sporting events. Decreases in ED attendances during a sporting event may be explained by a number of factors including viewing of the event either at home or a licenced premises or actual attendance at the live event itself particularly if it is locally based. This potential for sporting events to affect a local population is an important phenomenon when considering ED attendances to DGHs, particularly if a large sports ground is located nearby. Our ED has a local stadium, located approximately 1.5 miles from the hospital, which has a capacity of 20,000 and hosts some of the Regional Soccer and Gaelic football championship finals. Reis et al (2005) games (those in which the local team was losing and facing likely elimination) were associated with higher ED volumes. [START_REF] Reis | Running outside the baseline: Impact of the 2004 Major League Baseball Postseason on Emergency Department use[END_REF] These results suggested that engagement with televised broadcasts of major events may be one of the factors a patient considers when deciding to seek emergency care. In contrast, Pérez-Ciordia et al (2003) identified that televised soccer games were associated with a greater utilisation of emergency care services in the Spanish population. [START_REF] Pérez-Ciordia | Profile of the Emergency demand and influence of televised soccer games on an extra-hospital center in the Tafalla health care district[END_REF] This may be explained not only by the potential for increased injuries and illnesses secondary to the local population attending the event and watching it in local public places but also due to the influx of visitors to the event from outside the local area.

During the 1998 Soccer World Cup, Mattick (1999) identified a significant increase in attendance rates and workload in an Edinburgh ED during the opening game between Brazil and Scotland. Such an increase may be secondary to either alcohol related medical co-morbidities or injuries sustained as a consequence of assault or other alcohol related violence. Staffing levels in their ED were then increased for subsequent games involving Scotland. However, the initially demonstrated increase in attendance rates was not replicated for the remaining games in the tournament involving Scotland. [START_REF] Mattick | The Football World Cup 1998: An analysis of Related Attendances to an Accident and Emergency Department[END_REF] This study highlights insight into potential difficulties with service provision and variances that may be attributed to sporting events, and it is stressed that service provision decisions should not be dictated by one-off observations and therefore a longer term study is required.

To ensure that necessary staffing levels and facilities are available, it is necessary for all hospitals to analyse their patient workload to prospectively prepare and plan for such local, regional and national sporting events and their emergency sequelae. A greater emphasis on such workload planning and service provision will now occur from August 2009 for all hospitals, particularly smaller DGHs, due to ramifications from the mandatory implementation of the 48-hour working week and further directives defined by the European Working Time Directive (EWTD). [START_REF]European Working Time Directive[END_REF] Daisy Hill Hospital located in Newry City (population 27,430 -2001 census) also covers an extended rural population, often with impaired infrastructure, to a total of 87,058 people (projected total 97,000 in 2013). The department is one of two EDs in the Southern Health and Social Care Trust, which covers an estimated 334,000 local [START_REF]NI Planning Service: District Proposal for Newry City[END_REF] Our ED is located approximately 40 miles from the country's only tertiary referral trauma centre. For comparison, in 2008/9 our ED had 33421 attendances, the trust's other ED had 70015, while the Regional Trauma Centre had 67371 attendances. 10 Although the current literature remains unclear, there is evidence to suggest that major live or televised sporting events could have an effect on ED workload and such reports indicate a need for improved staff planning despite the restrictions of the EWTD. [START_REF] Miró | Football, television and the emergency services[END_REF][START_REF] Reich | The Impact of a Major Televised Sporting Event on Emergency Department Census[END_REF][START_REF] Reis | Running outside the baseline: Impact of the 2004 Major League Baseball Postseason on Emergency Department use[END_REF][START_REF] Pérez-Ciordia | Profile of the Emergency demand and influence of televised soccer games on an extra-hospital center in the Tafalla health care district[END_REF][START_REF] Mattick | The Football World Cup 1998: An analysis of Related Attendances to an Accident and Emergency Department[END_REF] The main objective of this study was to investigate the effect of major sporting events on the ED attendance rates. The outcome of the ED patient attendance was then assessed to determine the effects of subsequent patient admissions on wardbased workload. An analysis of sporting events was then compiled to include live local, regional and national events as well as world-wide televised sporting broadcasts. Major local events were defined as those events which could encompass attendance rates greater than 10,000 such as county-based Gaelic Athletic Association (GAA) events from the All-Ireland Football Championships. National events were defined according to the major sport including European or World Cup Soccer games involving Ireland, GAA All-Ireland Finals (including the quarter-finals, semi-final and finals) and Rugby Six Nations or World Cup events. Major live televised events were described as those shown on prime time terrestrial or satellite television. These figures were then compared with control nights where there was no evidence of a major local, national or televised sporting event.

Data entry was completed on a specially designed Excel database. Descriptive statistics for baseline variables such as patient demographics, attendance rates and clinical outcome were calculated as the mean and standard error of the mean (SEM) or the median and interquartile ranges (IQR). Statistical analysis was performed using the SPSS statistical package (Version 12 SPSS ® inc. Chicago, USA). Independent or paired samples t-tests were used to determine differences between independent or paired variables. Pearson's correlation was used to identify if a relationship existed between ED workload and patient admission rates according to the presence of a major sporting event. Multinomial logistic regression was then performed to determine if certain sporting events could be described as a predictor for patient attendance or hospital admission. All statistical tests were 2-sided and differences were considered significant if the p-value was <0.05. The median attendance rate per day was 80 patients (IQR 71.0-88.0). A significantly higher proportion of male patients attended compared to females (mean attendances per day: 46.8 vs. 33.3, p<0.001) (Figure 1). The mean admission rate was 13.6 patients per day through the study period (Figure 2). The mean attendance rates and total admissions were significantly higher on Mondays, Saturdays and Sundays compared to the other days of the week (p<0.01).

Sporting Event Analysis

Sporting events during the study period included; Soccer: 4 FA Cup and 1 World Cup

Patient episodes vs. Sporting event

There was no correlation identified between any sporting events and total ED attendance (r<0.03, p>0.20). Further separate subgroup analysis according to daily patient totals and the day of the week also demonstrated no correlation between any of these sporting events and total emergency department attendance. However, there was a significantly higher patient admission rate during the soccer FA Cup final (20.8 vs.

13.6, p=0.001), rugby Six Nations (16.0 vs. 13.6, p=0.001) and games involving Ireland (World Cup: 19.3 vs. 13.6, p=0.01 and Six-Nations: 16.3 vs. 13.6, p=0.003) and for GAA All-Ireland semi-final (17.0 vs. 13.6, p=0.01) and quarter-final games (17.0 vs. 13.6, p=0.01). There was no difference identified in total attendance or nonadmission rates from the emergency department for sporting events throughout the study period (Table 1).

Multinomial logistic regression analysis demonstrated that FA Cup final (p=0.001), Rugby Six Nations (p=0.019), Rugby WC games involving Ireland (p=0.003), GAA

DISCUSSION

Although controversial and indeed difficult to effectively determine, we attempted to assess whether live or televised sporting events created a "domino effect" on ED workload in our DGH. Previous research by Farrell et al (2005) have reported that ED attendance rates and subsequent surgical admission rates to a regional paediatric department were not affected by media coverage of soccer events. [START_REF] Farrell | Do Major Televised Events Affect Pediatric Emergency Department Attendances or Delay Presentaton of Surgical Conditions?[END_REF] They suggested that such events do not significantly alter workload and thus negate any amendment to workforce provision in a tertiary referral paediatric centre. Our study concurs with Farrell et al (2005) where we identified no correlation between sporting events and total ED attendance (p>0.20).

However, it remains unclear whether the occurrence of certain sporting events may actually predict total patient admission rates. Multinomial logistic regression demonstrated that FA Cup final, Rugby Six Nations, Rugby WC games involving Ireland, GAA All-Ireland semi-and quarter-finals were predictors of patient admission rates (p<0.019). Although the total number of ED attendances was not significantly affected by major sporting events, we demonstrated that there was an increase in the total number of admissions from such attendances during sporting events which indirectly suggested an increase in overall ED workload (Table 1). A subsequent increase in ward staff duties, with concurrent patient bed requirements, may therefore be attributed to such sporting events.

In our study, a significantly higher proportion of daily ED attendances were male (p<0.001). Murphy et al (2003) also assessed gender demographics during a review of ED attendances and orthopaedic workload in a Dublin hospital during the 2002 World Cup, which involved the home nation, Ireland (who played 4 matches, reaching the final 16 teams in the tournament). [START_REF] Murphy | Ireland in the World Cup: Trauma and Orthopaedic Workloads[END_REF] They noted that the ratio of male to female presentations was 2:1 compared to 1:2 in control years, and that significantly more patients were admitted, referred to orthopaedic and minor trauma clinics and also to general practitioner surgeries during the study period compared to the control period.

In contrast, Cheng et al (2005) identified an inverse gender relationship with a decrease in male and corresponding increase in female usage of the ED during a retrospective review of televised major league baseball competing for the Millennium World Series in the US. [START_REF] Cheng | Major sport championship influence on ED gender census[END_REF][START_REF] Cheng | Major sport championship influence on ED sex census[END_REF] They also reported a significant increase in psychiatric presentations, particularly in female patients. Murphy et al (2003) postulated that major televised sports, particularly when the home nation was involved, had a significant impact on acute hospital services with corresponding increases in ED workload, hospital services and inpatient bed capacity. [START_REF] Murphy | Ireland in the World Cup: Trauma and Orthopaedic Workloads[END_REF] They suggested that future service provision should not only consider admission demographics but also subsequent referral patterns to evaluate additional potential service demand. While the findings of our study were somewhat in agreement, with certain sporting events predicting patient admission rates, the results do not suggest or indicate a need for ED staffing or service provision amendments. It is also thought that the effect of these sporting events on admission rates would not be of sufficient magnitude to suggest a change in shift pattern or service provision on inpatient units, despite the implementation of the European Working Time Directive.

We recognise that our ED has a median attendance rate of 80 patients per day which may be a relatively low number of patients per day in comparison to other EDs in the country. However, our ED functions as more than a minor injuries unit providing a 24-hour service for emergencies and major trauma from a rural area with poor infrastructure, extending a 30-mile radius, for which it is the closest hospital. It is covered by acute surgical, medical and radiological services. The mean attendance rates and total admissions were significantly higher on Saturday, Sunday and Monday compared to the other days of the week (p<0.01).

Sivarajasingam et al (2004) also demonstrated a similar trend with a consistently increased weekend workload during a 5-year review of a Cardiff ED workload in the UK. [START_REF] Sivarajasingam | Relations between violence, calendar events and ambient conditions[END_REF] However, their study suggested that a large proportion of their patients received treatment following violence with a positive association between physical assaults and rugby international games. This contrasts to our study whereby no correlation was identified between any of the sporting events and total emergency department attendance. Cooke et al (1999) assessed the effect of the Euro 1996 International Soccer Competition in the UK on emergency departments in the 3-weeks prior to, during and following the tournament. [START_REF] Cooke | A major sporting event does not necessarily mean an increased workload for accident and emergency departments. Euro96 Group of Accident and Emergency Departments[END_REF] They also identified no significant correlation between the sporting event and ED attendance rates, irrespective of home nation involvement and suggested that additional health service management and staffing measures do not require implementation for such events. Similar to our study they also observed that the day of the week remained an independent predictor of patient variation where Sundays and Mondays were associated with an increased work load.

One of the main strengths of our study was the consecutive assessment of daily records over a period of 5-years with the inclusion of new presentations only.

However, our retrospective study was limited regarding the actual aetiology and mechanism of injuries sustained by each individual attending the ED. Some authors have reported the effect of certain aetiological factors, particularly those ED attendances which were not directly related to a personal involvement in a sporting activity. [START_REF] Mattick | The Football World Cup 1998: An analysis of Related Attendances to an Accident and Emergency Department[END_REF][START_REF] Sivarajasingam | Relations between violence, calendar events and ambient conditions[END_REF][START_REF] O'donnell | The Football World Cup 2002 Analysis of related attendances in an Irish Emergency Department[END_REF][START_REF] Sivarajasingam | Winning, losing, and violence[END_REF][START_REF] Moody | Were attendances to accident and emergency departments in England and Australia influenced by the Rugby World Cup Final 2003?[END_REF] Sivarajasingam et al (2004) described a positive association between physical assaults and rugby international games. [START_REF] Sivarajasingam | Relations between violence, calendar events and ambient conditions[END_REF] Further evidence to support the association between alcohol and sporting related violence has been described by Mattick (1998) of their ED attendances were associated with alcohol ingestion. However, they stated that the actual workload impact to the ED from such attendances was minimal. [START_REF] O'donnell | The Football World Cup 2002 Analysis of related attendances in an Irish Emergency Department[END_REF] Unfortunately due to the nature of our data collection it was not possible to record the reason for ED attendance or the type of admission. We would recommend the consideration of such attendance aetiologies in any future study to determine the relationship between direct and indirect sporting related consultations in the ED and the specialty of subsequent admissions.

A further limitation of our study was the inability to accurately determine the timing of each patient's ED attendance or subsequent admission within the 24-hour period.

Other authors appear to have had similar difficulties with Moody et al (2007) performing a retrospective analysis of the volume and timing of ED attendances during an 18-hour window during the Rugby Wold Cup Final 2003 between New South Wales in Australia and the West Midlands in the UK. [START_REF] Moody | Were attendances to accident and emergency departments in England and Australia influenced by the Rugby World Cup Final 2003?[END_REF] The study time window was then compared with a control period of 18-hours for daily attendances in the 13 preceding 3 years. They identified a reduction in UK ED attendance rates in the hours immediately surrounding the final followed by a subsequent increase in the 12 hours after the game whereas in Australia, a similar reduction in attendance was identified only in the hours leading up to the final. However, such rates quickly returned to normal after the final with no further alteration in attendance rates thereafter. Moody et al (2007) further hypothesised that the difference between the two countries could be related to several reasons, one being postponement of illness presentation until after the match (so as not to be inconvenienced by missing it) and the second being violence and/or alcohol related injuries following celebrations.

The main objective of this study was to investigate the effect of major sporting events on the ED attendance rates and to assess whether the actual sport itself correlates with emergency workloads. While sporting events did not correlate with ED attendance rates we have found that FA Cup final, Rugby Six Nations, Rugby WC games involving Ireland, GAA All-Ireland semi-and quarter-finals were predictors of patient admission rates. These results would not indicate a change in ED staffing or service provision and it is likely that the effect of sporting effects on the admission rate would not be sufficient to suggest a change in service provision on inpatient units.

CONCLUSION

Our study suggests that live or televised sporting events do not significantly affect ED attendances to a DGH. However, some events appeared to be predictors of patient admission rates. Although it may be beneficial to consider the effect of sporting events on service stratification during these periods, the overall effect is probably minimal and should not create a major concern for future service provision. We suggest that this relationship may well be present and even augmented in larger EDs in the region, particularly in larger cities with larger sporting venues.

Assessment of mean patient attendance, admission and non-admission rates from the emergency department according to the presence or absence of the sporting event (mean, SEM and p-value).

Table 2

Multinominal logistic regression analysis for patient attendance, admission and nonadmission rates according to the individual sporting events.

Figure 1

Mean daily total attendance rates to the emergency department for total, male and female patients. Mean daily total attendance rates to the emergency department for total, male and female patients.

  .003), GAA All-Ireland semi-and quarter-finals (p=0.016 & p=0.016) were predictors of patient admission rates.

INTRODUCTION

  Large sporting events have historically led to intense media coverage and huge public interest. Approximately 14.5 million people in the UK watched the 2003 Rugby

  identified an inverse linear dose-response relationship between event magnitude (characterised by television viewing figures) and decreased utilisation of the ED, i.e. the highest

  of the number of ED attendances to a DGH and subsequent admissions over a 24-hour period was completed. Each admission time period was defined as the period between 00.00 and 23:59. Data was collected from the hospital's emergency record books from April 2002 to July 2007, including the number of attendances, patient demographics, clinical complaint and outcome for each 24-hour period. Patients attending specialist or review clinics in the ED were excluded.

  male) patients attended the ED between April 2002 and July 2007.

(

  WC) finals; Rugby: 47 Six Nations, 25 Six Nations games involving Ireland, 1 WC Final, 2 WC semi-finals, 2 WC quarter-finals and 4 WC games involving Ireland; and Gaelic Football (GAA): 5 All-Ireland finals, 11 semi-finals, 11 quarter-finals and 5 provincial finals.

  and O'Donnell et al (2002) from their experience of the 1998 and 2002 Soccer World Cups respectively. 7,17 O'Donnell et al (2002) reported that the majority of ED attendances were related to minor trauma secondary to physical assault sustained during the activity of television viewing either at home or in a licensed (alcohol) premises in Galway during the 2002 Soccer World Cup. Over 50%

Figure 2

 2 Figure 2Mean daily admission and discharge rates from the emergency department.

  Figure 1

  Mean daily admission and discharge rates from the emergency department.146x59mm (300 x 300 DPI)

Page 24 of 26 International Journal of Clinical Practice International Journal of Clinical Practice

	Page 23 of 26		International Journal of Clinical Practice
	SPORT	EVENT	TOTAL	TOTAL PATIENT	TOTAL PATIENTS
	Soccer	FA Cup Final SPORT (n=4) World Cup Final	TOTAL ATTENDANCES ADMISSIONS 0.001 Event ATTENDANCES 0.20 EVENT No p-0.82 0.91	TOTAL PATIENT ADMISSIONS NOT ADMITTED 0.84 Event No p-0.78	TOTAL PATIENTS NOT ADMITTED Event No p-
		(n=1)		Event	value		Event	value	Event	value
	Rugby Gaelic (GAA)	FA Cup Final (n=4) 0.17 World Cup Final World Cup Games Soccer (n=1) World Cup Games involving Ireland (n=4) World Cup Quarter-Final (n=2) Rugby F o r involving Ireland (n=4) World Cup Quarter-Final (n=2) 0.46 World Cup Semi-Final 0.16 F o (n=1) World Cup Final 0.60 r World Cup Semi-Final (n=1) World Cup Final (n=1) 6 Nations (n=47) 6 Nations involving Ireland (n=25) P e e r (n=1) 6 Nations 0.94 P (n=47) 6 Nations involving Ireland (n=25) 0.65 All Ireland Provincial (n=5) 0.20 e e r All Ireland Provincial (n=5) All Ireland Quarter Final (n=11) All Ireland Semi-Final (n=11) Gaelic (GAA) All Ireland Final (n=5) R e 88.5 (6.9) 83.0 (-) 87.8 (6.4) 77.5 (6.5) 67.0 (3.0) 73.0 (-) 81.2 (1.6) 82.0 (1.8) 87.6 (0.8) 82.5 (2.6) 84.0 (2.3) 73.8 (5.1) v i (0.3) 80.0 0.003 0.20 80.0 (0.3) 0.82 80.0 (0.3) 0.24 80.0 (0.3) 0.78 0.18 0.63 0.42 80.0 (0.3) 0.16 80.0 (0.3) 0.59 80.0 (0.3) 0.57 80.0 (0.3) 0.47 0.019 0.69 0.45 80.0 (0.3) 0.20 80.0 (0.3) 0.53 80.0 (0.3) 0.32 80.1 (0.3) 0.29 e w All Ireland Quarter Final (n=11) 0.58 0.016 All Ireland Semi-Final (n=11) 0.34 0.016 All Ireland Final (n=5) 0.29 0.65 R e v i e w	20.8 (1.9) 13.0 (-) 19.3 (2.4) 12.5 (0.5) 15.0 (3.0) 10.0 (-) 16.0 (0.7) 16.3 (1.0) 15.0 (2.0) 17.0 (1.6) 17.0 (1.4) 12.6 (1.0)	13.6 (0.1) 0.68 13.6 (0.1) 13.6 (0.1) 13.6 (0.1) 0.76 0.10 0.78 13.6 (0.1) 13.6 (0.1) 13.6 (0.1) 13.6 (0.1) 0.45 0.73 0.27 13.6 (0.1) 13.6 (0.1) 13.6 (0.1) 13.6 (0.1) 0.79 0.87 0.34	0.001 0.89 0.01 0.72 0.66 0.41 0.001 0.003 0.49 0.01 0.01 0.60	67.8 (5.4) 70.0 (-) 68.5 (4.9) 65.0 (7.0) 66.4 (0.3) 63.0 (-) 9.6 (1.4) 65.7 (1.5) 72.6 (7.1) 65.5 (1.7) 67.0 (2.1) 61.2 (5.8)	66.4 (0.3) 66.4 (0.3) 66.4 (0.3) 66.4 (0.3) 52.0 ).1) 66.4 (0.3) 12.5 (0.3) 66.4 (0.3) 66.4 (0.3) 66.4 (0.3) 66.4 (0.3) 66.4 (0.3)	0.83 0.77 0.74 0.87 0.10 0.78 0.48 0.78 0.26 0.82 0.87 0.34
				O n O n
			International Journal of Clinical Practice l y l y

International Journal of Clinical PracticeInternational Journal of Clinical Practice

ACKNOWLEDGEMENTS

The authors acknowledge Mr Michael McCann, Consultant in Emergency Medicine

for permission to review charts in the emergency department of Daisy Hill Hospital.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest. We certify that we have participated sufficiently in the work of this paper. We have reviewed the final version of the manuscript and approve it for publication. To the best of our knowledge and belief, this manuscript has not been published in whole or in part nor is it being considered for publication elsewhere.

No research funding or external financial support has been provided for this study.

COPYRIGHT STATEMENT

The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the journal's publishing group to permit this article (if accepted) to be published.


MIRCEA; "P. Grigoras
email: grigoras47@yahoo.com

Mircea Grigoras

Loredana Stafie

Article type: MINI-REVIEW Electrically Insulated Molecular Wires

Keywords: supramolecular structures, conducting polymers, macrocyclic compounds, pseudorotaxane and rotaxane architecture, electrically insulated molecular wires supramolecular structures, conducting polymers, macrocyclic compounds, pseudorotaxane and rotaxane architecture, electrically insulated molecular nanowires

This paper is an up-to-date mini-review based on literature data and own results regarding synthesis and properties of conducting (pseudo)rotaxane supramolecular structures.

Conjugated polymers e.g. polyarylene, polyheteroarylene, polyaniline, polyarylenevinylene or polyaryleneimine were used as axle, while the macrocyclic components were cyclodextrins, cucurbiturils, cyclophanes or crown ethers. Properties of the supramolecular structure such as solubility, thermal or chemical stability, conductivity, etc can be drastically modified by inclusion of hydrophobic conjugated polymers inside of the macrocycle, without any chemical modification. For instance, the photophysical properties (i.e., quantum yield of fluorescence and electroluminescence) of the supramolecular structures were enhanced when compared with uninsulated conjugated polymers. The doping process is also affected, because the access of dopant to conjugated chain is limited only to the uncovered domains of conjugated chain.

Introduction

Conjugated polymers and their doped forms have recently attracted tremendous interest due to their potential applications in micro-and nano-electronics and optoelectronics [START_REF]Handbook of Conducting Polymers, 3-rd edition[END_REF]. Their important role in macromolecular chemistry and material science was recognized by awarding the 2000 Nobel Prize in Chemistry "for the discovery and development of conductive polymers" to Professors Alan Heeger and Alan MacDiarmid from USA and Hideki Shirakawa from Japan [START_REF] Shirakawa | The Discovery of Polyacetylene: The Dawning of an Era of Conducting Polymers[END_REF]. Moreover, their applications in organic light emitting diodes (OLED) [START_REF] Walzer | Highly Efficient Organic Devices Based on Electrically Doped Transport Layers[END_REF] and organic field effect transistors (OFET) [START_REF] Sirringhaus | Organic Thin Film Transistors for Large Area Electronics[END_REF] had been reported. Recently, work investigating their use as active elements in solar energy conversion as photovoltaic cells is very encouraging and many efforts have been directed in this field [START_REF] Coakley | Conjugated Polymer Photovoltaic Cells[END_REF]. Unfortunately, due to their intrinsic structure, conjugated polymers are insoluble and non-moldable materials, with poor mechanical and environmental properties and thermal instability. Therefore their technological applications are limited by processing difficulties and in most cases they cannot be transformed into usable forms after synthesis, meaning the desired form for devices has to be obtained directly during the polymerisation process. Electrochemical polymerisation is the best method from this point of view but is limited only to a few monomers and some applications. Various studies have been undertaken to obtain soluble conjugated polymers and overcome these drawbacks by changing the structure of monomers or by the introduction of a bent, crankshaft-shaped, or lateral substituent in the main chain of the polymer [1 and references therein]. Alternatively, the structural irregularities in the main chain of the polymers can be controlled by copolymerization.

All these variations need new monomers, new polymerisation methods and techniques or sophisticated and expensive catalytic systems. Moreover, the increase of solubility by modifying the main chain structure is accompanied in most cases by an alteration of electronic conjugation with resulting effects on electronic and optoelectronic properties.

An alternative strategy for improving conducting polymer processability is to build supramolecular structures by wrapping the polymer into several macrocyclic molecules. This usually involves non-covalent interactions between the linear polymer chain and cyclic component to form a mechanically interlocked molecule such as pseudopolyrotaxane or polyrotaxane [START_REF] Gibson | Catenanes, Polyrotaxanes, Polycatenanes and Related Materials[END_REF][START_REF] Nepogodiev | Cyclodextrin-Based Catenanes and Rotaxanes[END_REF][START_REF] Raymo | Interlocked Macromolecules[END_REF][START_REF] Sauvage | Molecular Catenanes, Rotaxanes and Knots[END_REF][START_REF] Takata | Polyrotaxanes and Polycatenanes: Recent Advances in Synthesis and Applications of Polymers Comprising of Interlocked Structures[END_REF][START_REF] Kim | Cucurbiturils-a New Family of Host Molecules[END_REF][START_REF] Wenz | Cyclodextrin Rotaxanes and Polyrotaxanes[END_REF][START_REF] Harada | Polymeric Rotaxanes[END_REF]. The role of macrocycles is both to insulate the conjugated backbone and to control intermolecular interactions, while the electronic structure of the conjugated core is fully A conducting polymer with (pseudo)rotaxane architecture can be envisioned as an electrically molecular nanowire. It is based on a one-dimensional conjugated macromolecular chain as a good transporter of the charge carriers, electrons and holes, insulated by many macrocycles threaded on it (Figure 1).

< Insert Figure 1 >

To prevent dethreading of the macrocycles, the ends of the linear molecular wire are blocked with bulky groups (stoppers), and the pseudorotaxane is transformed in a rotaxane structure. The conducting macromolecular (pseudo)rotaxanes have been synthesized by three routes [START_REF] Gibson | Catenanes, Polyrotaxanes, Polycatenanes and Related Materials[END_REF]:

(a) monomer polymerization in the presence of a macrocyclic compound, (b) threading of a preformed linear polymer chain through many macrocycles, and (c) polymerisation of a (pseudo)rotaxane monomer.

Depending on the location of the rotaxane/pseudo(rotaxane) unit, polymeric rotaxanes can be divided in two classes: main chain-or side chain polyrotaxanes.

Most of the studies reported so far regarding conducting polymers are focused on the main chain polyrotaxanes using cyclodextrins or cucurbiturils as hosts.

Conjugated polymers

It is known that conducting polymers are insoluble in most organic solvents but their rotaxane structures are soluble in polar solvents (DMF, DMAc, THF, etc) and even in water. The following conjugated polymers were encapsulated in macrocycles: polyheterocycles (polythiophenes and polypyrroles), polyarylenes, polyarylenevinylenes, polyaryleneimines and polyanilines (Figure 2). Heterocyclic polymers, polypyrrole and polythiophene, were synthesized starting from thiophene or pyrrole, either by chemical or electrochemical oxidative polymerization. In some instances, functional derivatives were successfully polymerized via metal-catalyzed polycondensations [START_REF] Jeffries-El | Handbook of Conducting Polymers[END_REF][START_REF] Cho | Recent Advances in Polypyrrole[END_REF]. Polyarylenes [START_REF] Lis | Blue-Emitting Poly(para-Phenylene)-Type Polymers[END_REF], polyarylenevinylenes [START_REF] Grimsdale | Synthesis and Properties of Poly(arylenevinylene)s[END_REF] and polyaryleneimines [START_REF] Grigoras | Imine Oligomers and Polymers[END_REF] are obtained mostly by polycondensation methods. Polyaniline is another well-known conjugated polymer, which can be synthesized as a powder or a thin film with colours depending strongly on the experimental conditions and doping state [START_REF] Gospodinova | Conducting Polymers Prepared by Oxidative Polymerization: Polyaniline[END_REF]. Polyaniline is of particular interest since it is the only conjugated polymer of the above mentioned that is

Macrocyclics as insulating materials

A variety of macrocyclic compounds were tried as shell materials for electrical insulation of conducting polymers. So far, most of the synthesised electrically insulated molecular wires are based on cyclodextrins and cucurbuturils as protecting shell. The chemical structures and average dimensions of cyclodextrins and cucurbiturils are presented in Figure 3 and Table 1.

Cyclodextrins (CDs) are carbohydrate-based cyclic compounds consisting of six, seven or eight α -(1,4)-linked D-glucopyranose units. They have a torus-shaped structure characterized by hydrophobic cavities and are soluble in water and some protic polar solvents. The CDs can form highly stable inclusion complexes by hydrophobic interactions with a variety of organic guests. This is possible because of their accessibility and good water solubility.

< Insert Figure 3 > < Insert Table 1 > Cucurbit[n]urils, abbreviated as CB[n]
, are a family of macrocyclic cavitands that contain n units derived from glycoluril linked by 2n methylene groups derived from formaldehyde and are obtained by acid-catalyzed condensation of glycoluril and formaldehyde. The molecule is like an open-ended pumpkin with a hydrophobic cavity accessible through two polar and identical carbonyl fringed portals. Similar to CDs, CBs have rigid structures and hydrophobic cavities and are useful building blocks of supramolecular structures. Rotaxane, pseudorotaxane and catenane supramolecular assemblies containing CB [START_REF] Gibson | Catenanes, Polyrotaxanes, Polycatenanes and Related Materials[END_REF] and its higher homologues [n= 7,8] as hosts and non-conjugated polymers have been synthesized and studied recently [START_REF] Tuncel | Catalytic Self-Threading: A New Route for the Synthesis of Polyrotaxanes[END_REF][START_REF] Whang | Self-assembly of a Polyrotaxane Containing a Cyclic "Bead" in Every Structural Unit in the Solid State: Cucurbituril Molecules Threaded on a One-Dimensional Coordination Polymer[END_REF][START_REF] Wang | Polycatenated Two-Dimensional Polyrotaxane Net[END_REF][START_REF] Whang | Molecular Necklace: Quantitative Self-Assembly of a Cyclic Oligorotaxane from Nine Molecules[END_REF][START_REF] Park | Designed Self-Assembly of Molecular Necklaces[END_REF][START_REF] Tan | Synthesis and Characterization of Novel Side-Chain Pseudopolyrotaxanes Containing Cucurbituril[END_REF][START_REF] Isobe | Synthesis of Disubstituted Cucurbit[6]uril and Its Rotaxane Derivative[END_REF]. However, unlike CDs, the CB[n] compounds are rarely used in molecular wire synthesis, mainly due to lower solubility in common organic solvents. Their solubility in strongly acidic aqueous solutions limits their use because the synthesis of the conjugated polymers is more difficult in these solvents. However, two conjugated polymers (polyaniline and polyphenylene vinylene) have been used in obtaining of pseudopolyrotaxane structures with CB [START_REF] Gibson | Catenanes, Polyrotaxanes, Polycatenanes and Related Materials[END_REF] or CB [START_REF] Nepogodiev | Cyclodextrin-Based Catenanes and Rotaxanes[END_REF] as macrocycles.

Both polymers can be synthesized in aqueous solution either by oxidative polymerization of aniline [START_REF] Gospodinova | Conducting Polymers Prepared by Oxidative Polymerization: Polyaniline[END_REF] or alkaline modification of polyelectrolyte precursors [START_REF] Grimsdale | Synthesis and Properties of Poly(arylenevinylene)s[END_REF].

The first members of the two macrocyclic clases, α-CD and CB [START_REF] Coakley | Conjugated Polymer Photovoltaic Cells[END_REF], have small internal diameters and the inclusion of aniline, thiophene or pyrrole monomers is difficult to induce due to geometric constrictions.

Other macrocyclics used in synthesis of supramolecular assemblies are presented in Scheme 1.

Scheme 1

Calix[n]arenes, the most accessible type of cyclophanes, are sparingly soluble in some organic solvents and insoluble in aqueous solutions [START_REF] Gutsche | 4. The Synthesis, Characterization of the Calixarenes from p-tert-Butylphenol[END_REF]. The water-soluble calixarenes are obtained by the introduction of anionic (sulfonate) groups on the upper or lower rim, or cationic (ammonium) groups on the upper rim [START_REF] Shinkai | Synthesis and Aggregation Properties of New Water-soluble Calixarenes[END_REF]. Calix[n]arenes possess architecture similar to CDs but have many conformational isomers because of rotational modes of the phenolic unit. Thus, calix [START_REF] Gibson | Catenanes, Polyrotaxanes, Polycatenanes and Related Materials[END_REF]arenes can adopt eight possible conformational forms; cone, partial cone, 1,2-alternate, 1,3-alternate, 1,4-alternate, 1,2,3-alternate, 1,2,4-alternate and 1,3,5-alternate [START_REF] Ikeda | Novel Cavity Design Using Calix[n]arene Skeletons: Toward Molecular Recognition and Metal Binding[END_REF]. This large conformational freedom of calix[n]arenes is a disadvantage in rotaxane synthesis compared to CDs and CBs that have a rigid conformation accessible for guest complexation. The inner cavity of calix [START_REF] Gibson | Catenanes, Polyrotaxanes, Polycatenanes and Related Materials[END_REF]arene has an opening between 2-2.9 Å, while calix [START_REF] Raymo | Interlocked Macromolecules[END_REF]arene in its most expanded conformation (cone) has an opening of 4.5 Å or more in diameter. Therefore, only calix [START_REF] Raymo | Interlocked Macromolecules[END_REF]arenas possess a large enough annulus to allow an organic guest molecule to pass through openings. There are a few reports in literature about the use of calix [START_REF] Gibson | Catenanes, Polyrotaxanes, Polycatenanes and Related Materials[END_REF]arene for synthesis of a rotaxane [33], but a conducting polymer hosted by calixarenes has never been reported. Electron poor macrocycles such as bipyridinium-based tetracationic cyclophane, cyclobis (paraquat-p-phenylene) possess the ability to host electron rich guest in order to form pseudorotaxane and catenanes [START_REF] Nepogodiev | Cyclodextrin-Based Catenanes and Rotaxanes[END_REF][START_REF] Raymo | Interlocked Macromolecules[END_REF][START_REF] Sauvage | Molecular Catenanes, Rotaxanes and Knots[END_REF][START_REF] Dietrich-Buchecker | Interlocked of Molecular Threads: From the Statistical Approach to the Templated Synthesis of Catenands[END_REF].

Recently the encapsulation of thiophene, bithiophene and terthiophene into an electron-poor macrocycles has been reported although in this example the studies on polyrotaxane formation are not described [START_REF] Ikeda | Inclusion complexation of cyclobis(paraquat-p[END_REF].

Other cyclophane or crown ether compounds possessing two p-phenylene groups or a phenanthroline ring linked by (-CH 2 -CH 2 -O-) can be used as receptors for metal-template synthesis of catenanes and rotaxanes [START_REF] Gibson | Catenanes, Polyrotaxanes, Polycatenanes and Related Materials[END_REF][START_REF] Nepogodiev | Cyclodextrin-Based Catenanes and Rotaxanes[END_REF][START_REF] Raymo | Interlocked Macromolecules[END_REF][START_REF] Sauvage | Molecular Catenanes, Rotaxanes and Knots[END_REF][START_REF] Dietrich-Buchecker | Interlocked of Molecular Threads: From the Statistical Approach to the Templated Synthesis of Catenands[END_REF]. For instance, bithiophene-bipyridine and bithiophene-phenanthroline monomers (Scheme 2) have been prepared and used for templatesynthesis of rotaxane monomers with phenanthroline macrocyclic compounds [START_REF] Zhus | Conducting Polymetallorotaxanes: A Supramolecular Approach to Transition Metal Ion Sensors[END_REF][START_REF] Zhu | Conducting Polymetallorotaxanes: Metal Ion Mediated Enhancements in Conducting and Charge Localization[END_REF][START_REF] Vidal | Conjugated Polyrotaxanes Containing Coordinating Units: Reversible Copper (I) Metallation-Demetallation using Lithium Intermediate Scaffolding[END_REF][START_REF] Kern | Transition-Metal-Templateed Synthesis of Rotaxanes and Catenanes: From Small Molecules to Polymers[END_REF]. In the presence of Cu + and Zn 2+ salts, bithiophene monomer and phenanthroline macrocycle form a pseudorotaxane in a high yield. Then, the pseudorotaxane is electropolymerized to form polymetallorotaxane structures or metal-free polyrotaxanes after demetallation (Scheme 3) [START_REF] Zhus | Conducting Polymetallorotaxanes: A Supramolecular Approach to Transition Metal Ion Sensors[END_REF].

Conducting poly(pseudo)rotaxanes

Polypyrroles and polythiophenes

Pyrrole and thiophene are poorly soluble in water but their solublility can be strongly increased by encapsulation inside CDs or hydroxypropyl -CDs. When pyrrole or thiophene was added to a saturated aqueous solution of CD at room temperature and slight heating, the solution became turbid and a crystalline inclusion complex was formed. Guest molecules can be included inside of CDs in two extreme conformations, with polymerisable positions 2,5 (a) perpendicular or (b) parallel on torrus axle (Scheme 4). In the first case, heteroaromatic ring has the polymerisable positions sterically blocked by macrocycle walls and polymerisation is impossible, while for the second case these positions are more accessible.

However, even in the favourable case (b) the monomer is not long enough and the active sites are positioned inside the host. The access of the oxidant in the initiation step or of the monomer molecules in the growing chain step to the aromatic ring is difficult. Therefore an induction period is observed in all oxidative polymerisation of heterocyclics or aniline inclusion products.

In fact, this property of CDs has often been used to protect sensitive drugs, by encapsulation or by time releasing of the drugs.

In the rotaxane synthesis, the guest has to preserve its polymerisation ability and to fit inside the host. Additionally, the guest molecules need to be long enough to contain polymerisable sites outside of the macrocycle to facilitate the polymerisation. Lacaze et al [START_REF] Chane-Ching | Electropolymerization of hydrophobic dipyrrolyls in aqueous medium based on inclusion chemistry[END_REF] reported in 1997 the host-guest complexation of dipyrrolyl monomers with β-CD in aqueous solution. The monomer was modified with aromatic rings linked at N,N' atoms by long and flexible (aliphatic or ethyleneoxide) spacers. Every pyrrole ring was separately encapsulated inside of CD molecules Because the encatennation positions are situated inside of the inner macrocycle cavity, they have hindered access to an oxidant or for electrophillic attack to a neutral molecule. The propagation step is more probable as a result of dissociation of the inclusion adduct. The adduct is in dynamic equilibrium with the host and the guest, and addition to the growing polymer chain is performed outside of the macrocyclic cavity with the participation of free monomers. Thus, the chemical and electrochemical polymerization takes place only with monomers in the decomplexed state and finally polypyrroles without β-CD are obtained (Scheme 5).

Scheme 5

Other heterocycles such as pyrrole and 3,4-ethylenedioxythiophene with α-, βor γ-CD or randomly dimethylated α-, βor γ-CD form 1:1 molar ratio crystalline adducts, with a herringbone fashioned cage-type crystal structure [START_REF] Storsberg | Cyclodextrin in Polymer Synthesis: Supramolecular Cyclodextrin Complexes of Pyrrole and 3,4-Ethylenedioxythiophene and Their Oxidative Polymerization[END_REF]. The chemical oxidative polymerisation of these adducts in water, using K 2 S 2 O 8 or FeCl 3 as oxidants have led to the formation of insoluble polymers. During the polymerisation reaction, because the adduct is decomplexed, CDs remain in solution and insoluble conjugated polymers are obtained [START_REF] Chane-Ching | Electropolymerization of hydrophobic dipyrrolyls in aqueous medium based on inclusion chemistry[END_REF]. However, there are few reports on the synthesis of conducting polymers with pseudorotaxane structures using a 2,2'-bithiophene or 5,5-dibromo 2,2'-bithiophene. These monomers were included inside of CD only in the parallel configuration and are long enough to have encatenation positions outside of the macrocycle. Thus, Lacaze et al. [START_REF] Lagrost | Host-Guest Complexation: a New Strategy for Electrodeposition of Processable Polythiophene Composites from Aqueous Medium[END_REF] have studied the electrochemical polymerisation in aqueous solution of 2.2'-bithiophene hosted inside of hydroxypropyl-β-CD. The complex was soluble in water and a soluble polythiophene with low molecular weight was synthesised. Also, Harada et al. [START_REF] Takashima | Crystal Structure of the Complex of β-Cyclodextrin with Bithiophene and their Oxidative Polymerization in Water[END_REF] have obtained a low molecular weight polythiophene (5000 daltons) within β-CD or modified β-CD by chemical oxidative polymerization in the presence of FeCl 3 as oxidant in aqueous solution. X-ray studies of the crystalline adduct 2,2'-bithiophene/β-CD consistently showed a 3:2 complex, regardless of the molar ratio between guest and host. Two bithiophene The third molecule was easy removed by washing with an organic solvent giving the 1:1 composition between 2,2'-bithiophene and β-CD [START_REF] Lagrost | Host-Guest Complexation: a New Strategy for Electrodeposition of Processable Polythiophene Composites from Aqueous Medium[END_REF]. Conducting pseudorotaxanes were also obtained by including polythiophene or poly(3-methyl)thiophene in the cavity of β-CD [START_REF] Yamaguchi | β-Cyclodextrin Pseudopolyrotaxanes with π-Conjugated Polymer Axels[END_REF].

Synthesis of polythiophenes by polycondensation using bromine-functionalized bithiophenes allowed blocking of the ends with bulky groups preventing the unthreading of macrocycles. The metal-catalysed polycondensation (Yamamoto reaction) of 5,5'-dibromobithiophene/β -CD inclusion adduct followed by the blocking of the bromine ends with 9-bromoanthracene led to a polythiophene with rotaxane structure soluble in water and DMSO (Scheme 7) [START_REF] Boogard | Synthesis of Insulated Single-Chain Semiconducting Polymers Based on Polythiophene, Polyfluorene, and β-Cyclodextrin[END_REF]. Usually, polythiophenes with a polymerisation degree greater than 6 are insoluble in any organic solvents but in this case the molecular weight of the water-soluble polythiophene determined by MALDI TOF method corresponds to a degree of polymerisation of 24. Small angle neutron scattering measurements show that the polymer chains have lengths between 4 and 20 nm, while the maximum coverage with the β -CDs is 60%. This suggests that rest of the macrocycles were de-threaded during the polymerisation step.

Another interesting example was the electrochemical synthesis of insulated nanosized wires and nanodots of polypyrrole or polyaniline using thiolated β-CD modified gold electrodes [START_REF] Lee | Electrochemistry of Conductive Polymers: XXIV. Polypyrrole Films Grown at Electrodes Modified with β-Cyclodextrin Molecular Templates[END_REF][START_REF] Park | Growth and Characterization of Nanosized Structures of Conducting Polymers[END_REF].

Firstly, the whole surface of the electrode was covered with β-CD molecules anchored by covalent linkages and containing seed molecules of pyrrole or aniline in the inner cavity.

Polymerisation started from within the cavities where single nanofibers grown up and are subsequently aligned leading to films with well-oriented morphologies. Sulfonated CDs used in synthesis of polypyrrole play a double role as host and dopant of the conjugated chain [START_REF] Chen | Ordered Conducting Polypyrrole Doped with Sulfopropyl Ether of β-Cyclodextrin[END_REF]. In this case, the presence of sulfonated CDs in the final polymer was evidenced by spectroscopic methods, although the formation of pseudorotaxane structure was not clear demonstrated.

Polyanilines

Only β-CD, CB [START_REF] Gibson | Catenanes, Polyrotaxanes, Polycatenanes and Related Materials[END_REF] and CB [START_REF] Nepogodiev | Cyclodextrin-Based Catenanes and Rotaxanes[END_REF] were used as hosts in synthesis of polyaniline with pseudorotaxane structure.

Polyaniline/ β-CD pseudorotaxanes were synthesised by two ways.

(i) Chemical oxidative polymerisation of aniline/ β-CD [START_REF] Grigoras | Chemical Oxidative Polymerization of β-Cyclodextrin/Aniline Inclusion Complex[END_REF] or N-phenyl-1,4-phenylenediamine/ β-CD [START_REF] Yuan | Preparation of Inclusion Complex between Polyaniline and β-Cyclodextrin[END_REF] inclusion adducts, in aqueous solution using ammonium persulfate as oxidant.

Aniline monomer has a small molecular volume with cross sectional diameter of about 0.4 nm. Therefore, it fits closer in the α-CD cavity and an 1:1 adduct resulted, while in β or γ-CD, two aniline molecules can be included but the resulted adduct is less stable due to higher differences between partner dimensions. Chemical oxidative polymerization of aniline/ β-CD adduct was carried out in aqueous solution in acidic (1M HCl) or neutral medium (pH=7). Polyaniline with pseudorotaxane structure was obtained only at pH=7 while in acidic conditions free PANi emeraldine salt was synthesized [START_REF] Grigoras | Chemical Oxidative Polymerization of β-Cyclodextrin/Aniline Inclusion Complex[END_REF]. The inner surface of the CD's cavity is almost neutral and CDs bind preferentially neutral guest molecules. In acidic conditions, aniline monomer exists predominantly as the anilinium cation carrying a highly hydrophilic -NH 3 (+) group and the aniline/ β-CD inclusion complex dissociates to free partners.

(ii) Inclusion of polyaniline emeraldine base inside β-CD rings. The process was carried out by mixing the two solutions of polymer and β-CD in two miscible solvents [START_REF] Grigoras | Chemical Oxidative Polymerization of β-Cyclodextrin/Aniline Inclusion Complex[END_REF][START_REF] Yuan | Preparation of Inclusion Complex between Polyaniline and β-Cyclodextrin[END_REF][START_REF] Shimomura | Insulation Effect of an Inclusion Complex Formed by Polyaniline and β-Cyclodextrin in Solution[END_REF][START_REF] Yoshida | Inclusion Complex Formation of Cyclodextrin and Polyaniline[END_REF]. A blue precipitate was formed which suggests the formation of the inclusion complex between the two components. Typically, the inclusion of a long linear polymer chain into one or many cyclic molecules is an entropically unfavourable process. However, the hydrophobic interactions, hydrogen-hydrogen and donor-acceptor interactions have promoted the threading of β-CD onto polyaniline when working at lower temperatures (lower than 275 K) [START_REF] Yuan | Preparation of Inclusion Complex between Polyaniline and β-Cyclodextrin[END_REF][START_REF] Yoshida | Inclusion Complex Formation of Cyclodextrin and Polyaniline[END_REF].

Unlike CDs which preferentially host neutral guest molecules, CBs[n] can form very stable hostguest complexes with positively charged molecules, such as anilinium cations or polyanilineemeraldine salt. Therefore, CB[n] can form more stable complexes with anilinium cations than β-CD. This property, together with CB solubility in acidic aqueous solution, could explain why the first insulating molecular wire containing cucurbit [START_REF] Gibson | Catenanes, Polyrotaxanes, Polycatenanes and Related Materials[END_REF]uril has used polyaniline as its conducting core [START_REF] Grigoras | Pseudorotaxanes based on Polyaniline and Cucurbituril[END_REF]. We have synthesized pseudopolyrotaxane polyaniline/ CB [START_REF] Gibson | Catenanes, Polyrotaxanes, Polycatenanes and Related Materials[END_REF] by two methods (Scheme 8):

(i) by chemical oxidative polymerisation of aniline in presence of CB [START_REF] Gibson | Catenanes, Polyrotaxanes, Polycatenanes and Related Materials[END_REF] in acidic aqueous solution using ammonium persulfate as oxidant, and

(ii) by threading the preformed polyaniline chain through the inner cavity of CB [START_REF] Gibson | Catenanes, Polyrotaxanes, Polycatenanes and Related Materials[END_REF]. The second method is entropically unfavorable but is enthalpically driven by noncovalent interactions. The number of macrocycles threaded onto polymer chain could not be estimated by elemental analysis or IR and NMR spectroscopy [START_REF] Grigoras | Pseudorotaxanes based on Polyaniline and Cucurbituril[END_REF].

A polymeric pseudorotaxane based on cucurbit [START_REF] Nepogodiev | Cyclodextrin-Based Catenanes and Rotaxanes[END_REF]uril and polyaniline has been reported by Liu et al. [START_REF] Liu | A Polymeric Pseudorotaxane Constructed from Cucurbituril and Aniline, and Stabilization of Its Radical Cation[END_REF]. Using NMR the authors calculated that every repeating unit contains three aniline units and one CB [START_REF] Nepogodiev | Cyclodextrin-Based Catenanes and Rotaxanes[END_REF] macrocycle, as shown in Scheme 9 [START_REF] Liu | A Polymeric Pseudorotaxane Constructed from Cucurbituril and Aniline, and Stabilization of Its Radical Cation[END_REF]. < Insert Figure 4 > Both samples were synthesised in the same conditions. The widths (ca. 1.5 nm) of PANi/CB [START_REF] Nepogodiev | Cyclodextrin-Based Catenanes and Rotaxanes[END_REF] fibres are consistent with the outer diameter of CB [START_REF] Nepogodiev | Cyclodextrin-Based Catenanes and Rotaxanes[END_REF]. A schematic possible structure of PANi-CB [START_REF] Nepogodiev | Cyclodextrin-Based Catenanes and Rotaxanes[END_REF] is presented in Figure .4,e) [START_REF] Liu | A Polymeric Pseudorotaxane Constructed from Cucurbituril and Aniline, and Stabilization of Its Radical Cation[END_REF]. Therefore, the interchain interactions could be avoided by keeping the chains at a distance determined by the thickness of macrocycles, and the electronic properties could be studied for a single conjugated chain. For the first time, Shimomura et al.

[56] have determined conductivity of a single insulated molecular wire positioned between two electrodes. The wire is based on a polyaniline macromolecule inserted into a CD nanotube followed by doping of PANi with iodine. The value of conductivity (4.10 -2 S.cm -1 ) was smaller than that of the PANi/I 2 film and explained by the low doping level. The doping process is slow for the encapsulated polymer and needs a larger quantity of dopant or the process is limited only to uncovered domains because the dopant molecules do not have free access to the conjugated chain to reduce or oxidise it [START_REF] Shimomura | Insulation Effect of an Inclusion Complex Formed by Polyaniline and β-Cyclodextrin in Solution[END_REF][START_REF] Shimomura | Conductivity measurement of insulated molecular wire formed by molecular nanotube and polyaniline[END_REF]. Other attempts to obtain PPV/CB [START_REF] Nepogodiev | Cyclodextrin-Based Catenanes and Rotaxanes[END_REF] rotaxanes have used the Wessling approach, with pxylylene sulfonium derivatives as intermediates [70]. The formation of a stable inclusion complex between bis-sulfonium salt and CB [START_REF] Nepogodiev | Cyclodextrin-Based Catenanes and Rotaxanes[END_REF] was observed by mass spectroscopy, NMR and UV spectroscopy. It was shown that the phenylene ring is centered in the CB [START_REF] Nepogodiev | Cyclodextrin-Based Catenanes and Rotaxanes[END_REF] cavity. The The ylide precursor of PPV could be encapsulated inside of CB [START_REF] Gibson | Catenanes, Polyrotaxanes, Polycatenanes and Related Materials[END_REF], CB [START_REF] Nepogodiev | Cyclodextrin-Based Catenanes and Rotaxanes[END_REF] and CB [START_REF] Raymo | Interlocked Macromolecules[END_REF] but not inside of CB [START_REF] Coakley | Conjugated Polymer Photovoltaic Cells[END_REF], due to spatial restrictions. However, only ylide-CB [START_REF] Nepogodiev | Cyclodextrin-Based Catenanes and Rotaxanes[END_REF] complex has been transformed to a pseudorotaxane structure. In other cases, the only PPVs without rotaxane structure were obtained, thought to be due to low stability of the complexes. From chemical analysis based on the N content it was assumed that a CB [START_REF] Nepogodiev | Cyclodextrin-Based Catenanes and Rotaxanes[END_REF] macrocycle was threaded at every six phenylene vinylene units. Unfortunately, there are no studies that involve the optical and electronic properties of these materials, especially their use in OLED devices.

Properties and applications

Properties of (pseudo)rotaxanes are dependent on the nature of the two components: the macrocycle and the conjugated polymer. Encapsulation of the conjugated polymer chain by macrocycles has a positive impact on the overall polymer properties. Supramolecular assemblies are more hydrophilic and more chemically, thermally and environmentally stable, properties induced mainly by the macrocyclic component. The solubility of pseudopolyrotaxanes and polyrotaxanes is dependent on both the conjugated polymer and the macrocycle nature and content. The threading of hydrophilic CD macrocycles onto a hydrophobic polymer chain makes the supramolecular assembly soluble in water or organic polar solvents (DMF, DMAc, THF, DMSO), while the conjugated polymer is insoluble in these solvents. The conformation of the polymer chain could also be modified by encapsulation. Polyaniline-emeraldine base has a coil conformation but by its inclusion in CD, the conformation was changed to a rodlike one with extended π-conjugation [START_REF] Yoshida | Inclusion Complex Formation of Cyclodextrin and Polyaniline[END_REF]. The insulating shells have a protective action against different destructive factors (oxygen, UV radiations, thermal degradation, chemical reactants) and confer greater resistance to fluorescence quenching by impurities. The macrocycles have isolated and separated the single polymer chain preventing intermolecular interactions between conjugated chains and the aggregation tendency, avoiding formation of excimers, with visible effects in foto-and electroluminescence properties. Also in polyrotaxanes structures, photo-and electroluminescence efficiency is increased compared to free polymers and blue-shifted emission is observed. The conductivity measurements carried out on a single insulated molecular wire could help to differentiate the contribution of intra-and intermolecular charge transfer. However, these studies are in an incipient stage. There is only a short communication dedicated conductivity investigation of a single conducting polymer chain isolated in a CD nanotube [START_REF] Shimomura | Conductivity measurement of insulated molecular wire formed by molecular nanotube and polyaniline[END_REF].

Conclusions

The building of conducting polyrotaxane structures has emerged from the necessity to improve solubility and processability of conjugated polymers. Despite the progress of recent years in supramolecular chemistry, much remains to be done in this specific domain.

In general, the synthesis of insulated molecular wires is performed by two methods:

-polymerisation of inclusion compounds formed between monomer (as guest) and macrocyclic component (as host), and -threading of the macrocycles onto the preformed conducting polymer.

In both cases the compatibility between the monomer/polymer and macrocycles are crucial in the formation of these structure, as well as the physical interactions between the two partners.

Moreover, the guest has to fit perfectly in the inner cavity of the macrocyclic compounds and to form stable complexes.

  macrocycles have freedom to translate or rotate along or around the polymer backbone without affecting the effective conjugation length.

  aqueous solution. The good solubility of aniline in 1M HCl aqueous solution makes its oxidative polymerization possible in this solvent. In contrast, the water solubility of other monomers (pyrrole, thiophene and their derivatives) is very low but it can be increased by encapsulation in water-soluble macrocyclic compounds such as cyclodextrins (CDs) and crown ethers.< Insert Figure2 >

  Scheme 2

  Scheme 4

  remained free (Scheme 4c). The composition of the inclusion adduct was 1:2.

Page 10 of 50 URL

 50 Scheme 6

  Scheme 7 [ref. 46]

Scheme 8 Page 13 of 50 URL

 850 Scheme 8

Scheme 9 [

 9 Scheme 9 [ref. 55]

< Insert Figure 5 > 4 . 4 .water soluble 1 -

 5441 Scheme 10

Page 17 of 50 URL

 50 Scheme15 [ref. 71]

Figure 2 :

 2 Figure 2: Chemical structure of some conducting polymers used as axles.

Figure 3 :

 3 Figure 3: Chemical and geometrical structure of cyclodextrins and cucurbiturils.

Figure 4 :

 4 Figure 4: AFM images of (a) polyaniline; (b) section analysis of the black line in (a); (c) polyaniline/CB[7]; (d) section analysis of the black image in (c), and (d) possible structure of polyaniline/CB[7]. [Reproduced with permission from ref. 55].

Figure 5 :

 5 Figure 5: STM images of the pseudorotaxane obtained from condensation of β-cyclodextrin/otolidine with β-cyclodextrin/p-phthaldehyde; (a) on a highly ordered pyrolytic graphite; (b) 3D mode of STM image, and (c) the molecular modeling structure of polypseudorotaxane.[Reproduced with permission from ref. 64]

Figure 3 :Figure 4 :Figure 5 :

 345 Figure 3: Chemical and geometrical structure of cyclodextrins and cucurbiturils. 150x150mm (96 x 96 DPI)

  If the dimensions of molecular partners are not correlated, they cannot used in inclusion or polymerization steps also have to be chemically inert for both partners.Control of the degree of insulation of the molecular wire is very difficult, because during the polymerisation or purification steps some macrocycles are unthreaded. The fluorescence quantum yield, electroluminescence efficiency and chemical stability, parameters important for LED applications, are enhanced for encapsulated molecular wires.

	Page 27 of 50	Supramolecular Chemistry
	phenylene) with thiophene, bithiophene and terthiophene. J. Incl. Phenom. Macrocycl [70] Ling, Y.; Kaifer, A.E. Complexation of Poly(phenylenevinylene) Precursors and Monomers
	by Cucurbituril Hosts. Chem. Mater. 2006, 18, 5944-5949
	[71] Corma A., Garcia, H., Montes-Novajas, P. A Pseudopolyrotaxane Consisting in PPV FIGURES
	threaded in Multiple Cucurbiturils. Tetrahed. Lett., 2007, 48, 4613-4617. Figure 1: Structure of insulated organic molecular wires.
	F o F o F o F o F o F o F o F o F o
	r r r r r r r r r
	P P P P P P P P P
	e e r e e r e e r e e r e e r e e r e e r e e r e e r
		R e v i e w R e v i e w R e v i e w R e v i e w R e v i e w R e v i e w R e v i e w R e v i e w R e v i e w
		O n O n O n O n O n O n O n O n O n
		l y l y l y l y l y l y l y l y l y
	form inclusion adducts (linear partner cannot be threaded inside of inner cavity of macrocyclic
	compound), or the inclusion adducts are not stable causing macrocycle dethreading. Another
	requirement is the accessibility of encatennation positions of the monomer included in the cyclic
	compound to initiator or monomer in the polymerization or polycondensation steps. Otherwise,
	polymerisation or polycondensation takes place with free (uncomplexed) monomers. Solvents

URL: http:/mc.manuscriptcentral.com/tandf/gsch Email: suprachem@mail.cm.utexas.edu

Table 1 :

 1 Average dimensions of CD[n]s and CB[n]s

	Macrocycles

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Table 1 :

 1 Average dimensions of CD[n]s and CB[n]s

	Macrocycles

URL: http:/mc.manuscriptcentral.com/tandf/gsch Email: suprachem@mail.cm.utexas.edu Figure 1: Structure of insulated organic molecular wires. 150x150mm (96 x 96 DPI) Page 31 of 50 URL: http:/mc.manuscriptcentral.com/tandf/gsch Email: suprachem@mail.cm.utexas.edu

Figure 2: Chemical structure of some conducting polymers used as axles. 150x150mm (96 x 96 DPI) Page 32 of 50 URL: http:/mc.manuscriptcentral.com/tandf/gsch Email: suprachem@mail.cm.utexas.edu

URL: http:/mc.manuscriptcentral.com/tandf/gsch Email: suprachem@mail.cm.utexas.edu

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Acknowledgments

The authors thank the Romanian National Authority for Scientific Research for financial support (Grant PN II-IDEI-993).

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