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CPD 70: PARKINSON’S DISEASE Biography - Sinead Ryan graduated from the University of Brighton in 2008, and completed her pre-registration in Chelsea and Westminster Hospital NHS Foundation Trust, London. She worked in a number of clinical positions in London before returning to Ireland in 2011. She completed her higher diploma in community pharmacy from Trinity College Dublin in 2014. Sinead is currently working as a community pharmacist in Limerick.

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PATHOLOGY In idiopathic PD, the progressive degeneration of pigmented neurons in the substantia nigra leads to a pigmented neurones in the substania nigra leads to a deficiency of the neurotransmitter dopamine.1 The resulting neurochemical imbalance in the basal ganglia causes the characteristic signs and symptoms of the illness. In PD, the substantia nigra lobe of the brain undergoes progressive neuronal degeneration; inclusion bodies called Lewy bodies develop. The pathological hallmark of PD is the Lewy body. There is a loss of dopamine and melanin that correlates with cell loss and the degree of akinesia the patient experiences. There is a remarkable degree of “reserve” within the nigrostriatal system, in that up to 80% of dopaminergic neurons are lost before the cardinal clinical features of PD begin to appear. SIGNS AND SYMPTOMS The combination of tremor, rigidity and akinesia develops slowly, over months to several years,

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Parkinson’s disease Parkinson’s Disease (PD) is a chronic, progressive, neurodegenerative condition that generally affects adults in middle to late life and is characterized by bradykinesia, tremor, rigidity, gait disturbances and postural instability.1 Parkinson’s disease is the second most common neurodegenerative disease in the world. It affects 1% of the population over 65 years of age, rising to 2% for those over 80 years. More than 10 million people worldwide are living with Parkinson’s disease. It has a prevalence of 150 per 100,000 under the age of 70 and increasing sharply in those over 70 years. The incidence of PD increases with age, but an estimated 4% of people with PD are diagnosed before the age of 50.1,2 There is a higher prevalence of PD in male patients.3 There is no consistently reliable test that can distinguish PD from other conditions that have similar clinical presentations. The diagnosis is primarily clinical, based on a history and examination.1

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together with changes in posture. Common initial symptoms are tremor and slowness. Limbs and joints feel stiff and they ache. Fine movements become difficult. Slowness causes difficulty rising from a chair or getting into or out of bed. Writing becomes small (micrographia) and spidery. Idiopathic PD is almost always initially more prominent on one side. The diagnosis is usually evident from the overall appearance.  Tremor The characteristic pill-rolling tremor at rest (movements between thumb and forefinger) typically decreases with action. Tremor is often asymptomatic at first.  Rigidity Stiffness develops throughout movements and is equal in opposing muscle groups this is in contrast to the selective increase in limb tone found in other movement disorders. Extrapyramidal rigidity (so-called “lead pipe” and “cog-wheel”) and postural instability are mainstay clinical features of PD.  Akinesia Slowing of movement (bradykinesia) is an additional sign of PD as distinct from rigidity. There is difficulty-initiating movement. There is difficulty initiating movement. Rapid fine finger movements, such as piano playing, become indistinct, slow and tremulous. Facial immobility gives a mask-like appearance. Frequency of spontaneous blinking diminishes, producing a serpentine stare.  Postural and gait changes Stooping is characteristic. Gait becomes unsteady with shuffling and poor arm swinging. The posture is sometimes called simian to describe the ape-like forward flexion, immobility and lack of animation. Balance deteriorates and falls are common in later stages.  Speech Pronunciation is initially a monotone and progresses to tremulous slurring dysarthria, which is the result of akinesia, tremor and rigidity. Eventually, speech may be lost (anarthria).

60 Second Summary Parkinsons Disease (PD) is a progressive neurodegenerative condition resulting from the death of the dopamine containing cells of the substantia nigra. There is no consistently reliable test that can distinguish PD from other conditions that have similar clinical presentations. The diagnosis is primarily a clinical one based on the history and examination. Patients with PD classically present with the symptoms and signs associated with parkinsonism, namely hypokinesia (ie poverty of movement), bradykinesia (ie slowness of movement), rigidity and rest tremor. Currently, there is no cure for PD. Management focuses on relieving the motor and non-motor symptoms of the condition. The treatments for the motor symptoms (for example levodopa, dopamine agonists and monoamine-oxidase B inhibitors) work by increasing dopamine in the central nervous system. In general, selective serotonin reuptake inhibitors (SSRIs) are used to manage depression for patients with PD. Psychosis is usually managed using atypical antipsychotics. Rivastigmine is used first line for the treatment of PD-related dementia. Patients should be counseled on the importance of adherence to PD medications, the possible side effects and possible treatment options available. Patients and caregivers may need to be signposted to supportive services and Parkinson support groups.


CPD 70: PARKINSON’S DISEASE  Cognitive Changes Cognitive decline may occur early in the condition and is rarely absent in advanced disease. Depression is common.  Gastrointestinal and other symptoms These include constipation, sometimes an early symptom, heartburn, dribbling, dysphagia and weight loss. Urinary incontinence is common, especially in men. Skin can be greasy and prone to excessive sweating. PD worsens over the years, beginning as a mild inconvenience but slowly progressing. Remissions are unknown except for rare, remarkable short-lived periods of release. These can occur at times of emotion, fear or excitement, when the sufferer is released for seconds or minutes and able to move quickly. While bradykinesia and tremor worsen, power remains normal until immobility makes its assessment difficult. Patients often complain of limb and joint discomfort. There is no sensory loss. The rate of progression of symptoms is very variable, with a benign form running over several decades. Usually the course is over 10-15 years, with death resulting from bronchopneumonia with immobility and cognitive impairment. DIAGNOSIS There is no definite test to diagnose PD; diagnosis is made by recognizing physical signs and distinguishing idiopathic PD from other Parkinsonian syndromes. Conventional brain imaging is normal initially but atrophy develops over time. Dopamine transporter (DAT) imaging is abnormal but discriminates poorly between PD and other akinetic-rigid syndromes. Patients with suspected PD should be referred to a specialist to confirm the diagnosis; the diagnosis should be reviewed every 6-12 months. “Early PD” refers to PD in patients who have developed functional disability and require symptomatic therapy. “Later PD” refers to PD patients on levodopa who have developed motor complications. DIFFERENTIAL DIAGNOSIS A number of other neurological brain disorders can cause features of PD i.e. slowing, rigidity and tremor seen in idiopathic PD. Examples are Alzheimer’s disease, multi-infarct dementia, repeated head injury and late-effects of severe hypoxia or CO poisoning. Slowing also occurs in hypothyroidism, and in certain forms of depression. Features resembling those of Parkinson’s disease can occur in diseases such as progressive supranuclear palsy and multiple system atrophy, but they do not normally show a sustained response to the drugs used in the treatment of idiopathic PD. SHORT-TERM IMPLICATIONS OF PD In the short-term, the prospect for good symptom control, with minimal impact upon lifestyle, is good in the majority of patients. Although medically, PD may be well controlled in the short-term, the psychological impact of facing a lifelong, chronic, progressive illness cannot be underestimated. Depression is a common yet under-diagnosed facet of PD but it is eminently treatable. A prevalence of 40 to 50 per cent has been suggested for depression in PD, although estimates in various studies vary widely. There is some evidence that depression

in PD represents an endogenous component of the illness, presumably through involvement of monoaminergic systems (serotoninergic, dopaminergic and noradrenergic have all been implicated). In a Global Parkinson’s Disease Survey, a multicentre international study that assessed quality of life in a cohort of 1,000 patients with PD, depression was the primary factor, after motor disability and medication, to have an impact upon the daily life of the patients. LONG – TERM IMPLICATIONS OF PD PD patients and their carers may face a number of problems in the longer term. They include motor deterioration, neuropsychiatric symptoms and autonomic dysfunction. Motor problems evolve at a rate of approximately 10 per cent of patients per year, so that 10 years into the illness, virtually all PD patients will have developed motor fluctuations. For the first four to five year period post diagnosis there is typically a period of good symptom control. At this point it is common for the patient to begin to notice a wearing off of the medication effect before the next dose is due. Increasing the medication leads to peakdose dyskinesias at this stage, which comprise fidgety movements (chorea) or more sustained abnormal muscle contractions and postures (dystonia). As PD progresses over the next few years, the alterations in motor performance becomes more profound and the patient fluctuates between marked dyskinesias and periods of complete immobility. These episodes can occur suddenly and unpredictably and are known as freezing episodes. Falls become more common as the disease advances and, like the freezing episodes, these are difficult to treat.4 TREATMENT Medication therapy does not prevent disease progression, but it improves most patients’ quality of life. While medication alters little, if at all, the natural history of PD, levodopa and /or dopaminergic agonists produce striking initial improvements. Medications are avoided until clinically necessary because of delayed unwanted side effects. In addition, to the difficulties common to other disabling neurological conditions, the management of Parkinson’s disease must take into account the fact that the mainstay of pharmacological treatment, levodopa, can eventually produce dyskinesia and motor fluctuation. Particular care needs to be taken with elderly patients as Antiparkinsonian drugs can cause confusion in the elderly. It is particularly important to initiate treatment with low doses and to increase the dose gradually. Levodopa, dopamine-receptor agonists or monoamine-oxidase-B inhibitors can be administered for initial treatment in early PD. According to the NICE guidelines for PD, it is not possible to identify a universal first-choice drug therapy for patients with early PD. The choice of drug first prescribed should take into account the patients clinical and lifestyle characteristics and patient preference, after the patient has been informed of the short and long term benefits and drawbacks of the drug therapies. Therapy with two or more antiparkinsonian drugs may be necessary as the disease progresses. Most patients eventually require levodopa and subsequently develop motor complications.

LEVODOPA Levodopa has been the gold standard treatment for PD since it was introduced in the 1960s. Having commenced Levodopa treatment, patients experience rapid improvement in their symptoms and quality of life. However, this period is followed by decreased efficacy and levodopa-related motor disturbances, known as dyskinesias. The time this takes to occur can vary from months to years – approximately half of all patients experience dyskinesias after five years of levodopa treatment, and it is suspected that this effect may occur more rapidly in younger patients. Due to this effect, and the availability of other proven first-line options, many clinicians reserve levodopa for later in the course of the disease. Levodopa is initiated at low doses and titrated according to its clinical effect and tolerability. Modified-release preparations of levodopa were developed in an effort to provide more stable plasma levels, thereby reducing motor complications. However, variable absorption means that these advantages have not been realized. Despite this, modified-release preparations have been useful in simplifying drug regimens and providing relief for patients with night-time symptoms. Levodopa can be given in combination with Carbidopa, which prevents the nausea that can be caused by levodopa alone. This combination enables a significantly lower dose of levodopa to be administered and helps reduce the side effects of nausea and vomiting.  Carbidopa/Levodopa: In adult patients Carbidopa 25mg/Levodopa 100mg combination (Sinemet CR®), is prescribed and initially one tablet is taken orally three times a day and is increased by one tablet daily or every other day up to a maximum of eight tablets (200mg Carbidopa) daily. It can be taken with or without food, but high fat meals can delay absorption.7  Carbidopa/Levodopa/Entacapone: In adult patients there are various combinations of Stalevo® Preparations on the market. The dose is titrated to the desired response. The maximum daily amount of tablets varies between the preparations.7 DOPAMINE AGONISTS Dopamine agonists are commonly used as initial treatment of PD when levodopa therapy is delayed (especially for younger patients) and as adjunctive therapy with levodopa in later PD. Dopamine agonists are less effective than levodopa at controlling motor symptoms but are considerably less likely to cause dyskinesia. They have a direct action on postsynaptic dopamine receptors and have been in use since the 1970s. Initial treatment of PD is often with the dopamine-receptor agonists Pramipexole (Mirapexin®), Ropinirole, Rotigotine (Neupro® Transdermal Patch). The ergot-derived dopamine-receptor agonists Bromocriptine, Cabergoline (Dostinex®) and Pergolide are rarely used because they are associated with cardiac valve and pulmonary fibrotic effects. The dopamine-receptor agonists are also associated with more psychiatric side-effects than levodopa. Dopamine-receptor agonists are also used with levodopa in more advanced disease. If a dopamine-receptor agonist is added to


CPD 70: PARKINSON’S DISEASE levodopa therapy, the dose of levodopa needs to be reduced. SPECIAL CONSIDERATIONS - IMPULSE CONTROL DISORDERS Treatment with dopamine-receptor agonists and levodopa is associated with impulse control disorders, including gambling, binge eating and hypersexual urges.5 Some studies suggest it is more common in young males and those with a history of mood disorders, alcohol abuse and obsessive compulsive disorder. There is no evidence that ergot or non-ergot derived dopamine-receptor agonists differ in their propensity to cause impulse control disorders, so switching between dopaminereceptor agonists to control these side-effects is not recommended. If the patient or caregiver notices the development of an impulse control disorder, the dopamine-receptor agonist or levodopa should be withdrawn or the dose reduced until the symptoms resolve. Pharmacists are ideally placed to counsel patients and their caregiver regarding these effects and explain why the decision has been made for the causative medicine to be tapered off or discontinued. MAO-B INHIBITORS Rasagiline (Azilect®) and Selegiline (Eldepryl®) are MAO-B inhibitors. They increase the amount of dopamine at receptors in the striatum by preventing its metabolism. They are used as initial therapy, especially if dopamine agonists should be avoided, or as levodopa-sparing medicines in later disease. Rasagiline is more commonly used because selegiline is associated with hallucinations, insomnia and confusion. When combined with levodopa, selegiline should be avoided or used with great caution in patients with postural hypotension. Both medicines have the potential to interact with many medicines due to their inhibition of monoamine oxidase, which may not be fully selective for MAO-B.

off fluctuations should be monitored in these patients and the control of motor symptoms reviewed. PSYCHOSIS Psychosis can affect between 30 and 40% of PD patients. Psychosis can be triggered by the introduction of new medicines or by changes in the doses of existing anti-Parkinsonian medicines. Therefore, PD therapy should be reviewed for all patients who develop psychosis and the doses reduced where possible. Mild psychotic symptoms in people with PD may not need to be actively treated if they are tolerated by the patient and carer. In PD patients that require treatment atypical antipsychotic medicines (e.g. Clozapine) should be chosen. Typical antipsychotic drugs must not be used because they exacerbate the motor features of PD. DEMENTIA PD related dementia affects 20-40% of patients with PD and the incidence increases by approximately 14% each year for patients aged 70-79 years. Cholinesterase inhibitors are used, as dementia in PD patients is associated with a reduction in cholinergic functioning within the brain. Rivastigmine (Exelon®) is used first line to improve cognition. A significant clinical benefit occurs in approximately 15% of cases. Donepezil (Aricept®) and Galantamine (Reminyl®) have demonstrated some limited efficacy in the management of dementia in PD patients. SLEEP DISTURBANCES Approximately 60 to 90% of PD patients experience sleep disturbances. These can include daytime sleepiness or an inability to sleep at night due to nocturia, tremor or dyskinesia. Depression can also aggravate existing sleep disturbances. Off-label use of Modafinil may provide a therapeutic option for patients with daytime sleepiness.1

BETA-ADRENERGIC ANTAGONISTS (BETA-BLOCKERS)

AUTONOMIC DYSFUNCTION

Beta-adrenergic antagonists may be used in the symptomatic treatment of selected people with postural tremor in PD, but should not be drugs of first choice.

Patients who develop autonomic dysfunction, such as postural hypotension, urinary dysfunction or constipation, should receive symptomatic support.

MANAGING NON-MOTOR SYMPTOMS OF PD Patients with PD can develop non-motor symptoms as the disease progresses. The non-motor features of PD include depression, psychosis, dementia, sleep disturbances and autonomic dysfunction. DEPRESSION Depression has been reported to affect 4050% of patients with PD. However, this may be an underestimate because diagnosing mild depression in patients with PD is complicated by the fact that many of the clinical features of mild depression are also motor features of PD. PD-related depression is generally managed using selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs). The choice of treatment is dependent on patient characteristics and other medicines that the patient is using (e.g. SSRIs can be used for patients receiving rasagiline but TCAs should be avoided). Mood swings and anxiety are possible symptoms of the “off” state of PD. On-

LATER-STAGE DISEASE Over time a patient’s response to initial treatments will decline. When this occurs, patients experience “switching off”, also referred to as “wearing off” or “off time”, as plasma drug concentrations reach a trough (this manifests as akinesia and rigidity). In addition, motor complications, such as dyskinesia and dystonia, occur at peak serum levels. Patients can fluctuate rapidly or erratically between these two states – this is known as the “on-off” phenomenon. Wearing off can be countered by increasing the dose of a patient’s medicines or shortening the interval between doses. However, increasing the dose can induce or worsen motor complications, especially with levodopa. If amendments to dosing regimens fail to correct the problems, combinations of drugs will be necessary. CATECHOL-O-METHYLTRANSFERASE INHIBITORS The catechol-O-methyltransferase (COMT) inhibitors, Entacapone (Comtess®) and Tolcapone (Tasmar®) prevent the peripheral breakdown of levodopa, by inhibiting catecholO-methyltransferase, allowing more levodopa to reach the brain. They are licensed for use as an adjunct to co-beneldopa or co-careledopa for patients with PD who experience ‘end-ofdose’ deterioration and cannot be stabilized on these combinations. The dose of levodopa may need to be reduced when a COMT inhibitor is added because increased levodopa levels can worsen dyskinesia. COMT inhibitors are rarely used with levodopa as initial therapy because the combination has been shown to shorten the time to onset of dyskinesia. COMT inhibitors can worsen dyskinesia, cause abdominal discomfort and colour the urine. Due to risk of hepatotoxicity, Tolcapone should be prescribed under specialist supervision only, when other COMT inhibitors combined with co-beneldopa or co-careldopa have produced an inadequate response. Entacapone is available in a combination product with levodopa and carbidopa (Stalevo®). The use of this product may improve adherence and the range of strengths available enables small adjustments of levodopa dose.

Table 1 Options for initial pharmacotherapy in early PD Initial therapy First-choice Symptom control for early PD option

Risk of side effects Motor Other adverse complications events

Levodopa Yes Good degree Evidence of of symptom control increased motor complications Dopamine Yes Moderate degree Evidence of agonists of symptom control reduced motor complications

Evidence of increased other adverse events

MAO-B Yes Limited degree inhibitors of symptom control

Evidence of reduced motor complications

Evidence of increased other adverse events

Anticholinergics

No

Lack of evidence

Lack of evidence

Lack of evidence

Beta-blockers

No

Lack of evidence

Lack of evidence

Lack of evidence

Amantadine

No

Lack of evidence

Lack of evidence

Lack of evidence

Evidence of increased other adverse events


CPD 70: PARKINSON’S DISEASE ANTIMUSCARINIC DRUGS USED IN PARKINSONISM

with apomorphine should remain under specialist supervision.

Antimuscarinic drugs exert their antiparkinsonian action by reducing the effects of the relative central cholinergic excess that occurs as a result of dopamine deficiency. Antimuscarinic drugs such as Procyclidine (Kemadrin®), Orphenadrine and Trihexyphenidyl can be useful in drug induced parkinsonism, but they are generally not used in idiopathic PD as they are less effective than dopaminergic drugs and they are associated with cognitive impairment. Generally, the use of these drugs is now limited to younger patients with severe tremor and dystonia in their feet, and patients with later-stage disease and dyskinesia (for these patients it is useful because the mode of action does not involve dopaminergic stimulation). There are no important differences between the antimuscarinic drugs, but some patients tolerate one better than another. Procyclidine can be given parenterally and is effective emergency treatment for acute druginduced dystonic reactions. If treatment with an antimuscarinic is ineffective, intravenous diazepam can be given for life-threatening acute drug-induced dystonic reactions.

LEVODOPA INTESTINAL GEL

AMANTADINE

• Counsel patients that the practice of withdrawing patients from their antiparkinsonian drugs (so called ‘drug holidays’) to reduce motor complications should not be undertaken because of the risk of neuroleptic malignant syndrome.

Amantadine is a weak dopamine agonist with modest antiparkinsonian effects. It is mainly used for the management of levodopa-induced dyskinesia. Tolerance to its effects may develop and confusion and hallucinations may occasionally occur. LAST-LINE TREATMENTS Despite optimal management some patients’ disease progresses such that dyskinesia and “off” periods become unmanageable and conventional treatment is ineffective. For such patients, management options could include Apomorphine and Levodopa intestinal gel. APOMORPHINE It is a potent dopamine-receptor agonist that is sometimes helpful in advanced disease for patients experiencing unpredictable “off” periods with levodopa treatment. Treatment

Duodopa is a soluble gel form of levodopa and carbidopa that is administered directly into the duodenum via a percutaneous gastrostomy tube. Because of its expense and the invasive route of administration, the use of Duodopa is limited to those with severe motor fluctuations that are not managed by other drug therapies. PHARMACIST ADVICE • When initiating treatment, patients should be advised about its limitations and possible side effects. About 5-10% of patients when PD respond poorly to treatment.

• The NICE guidelines for PD do not recommend PD patients take Vitamin E or Co-enzyme Q10 as neuroprotective therapy.1 • Patients may need to be signposted to supportive therapies such as occupational therapy, speech and language therapy or physiotherapy services as PD progresses. CLASSICAL FEATURES OF PARKINSON’S DISEASE Bradykinesia Slowness of movement.

• Counsel new patients that treatment is not usually started until symptoms cause significant disruption to daily activities.

Rest Tremor A rhythmic movement with a frequency of 4-6 Hz noticed in patients at rest (the characteristic “pill-rolling movement”).

• Advise patients that Antiparkinsonian drug therapy should never be stopped abruptly as it carries a small risk of neuroleptic malignant syndrome.

Extrapyramidal rigidity An increase in muscle tone, which may be likened to bending a piece of lead piping, often with a superimposed “ratchety” feeling (cogwheel).

• Patients initiating treatments of co-careldopa, co-beneldopa, and dopamine-receptor agonists should be warned of the risk and to exercise caution when driving or operating machinery. Those who have experienced excessive sedation or sudden onset of sleep should refrain from driving or operating machines until these effects have stopped occurring. • NICE guidance recommends “a review of all medication and avoidance of any medication that may affect sleep or alertness, or may interact with other medication (for example, selegiline, antihistamines, H2 antagonists, antipsychotics and sedatives).1

Table 2 Options for adjuvant pharmacotherapy in later PD Adjuvant therapy for later PD

• As patients with PD may develop impaired cognitive ability, a communication deficit and/or depression, they should be provided with both oral and written communication throughout the course of the condition.

First - Symptom control Risk of side effects option choice Motor complications Other adverse events

Dopamine Yes Moderate degree Evidence of reduced agonists of symptom motor complications control

Evidence of increased adverse events

COMT Yes inhibitors

Moderate degree Evidence of reduced of symptom control motor complications

Evidence of increased adverse events

MAO-B Yes inhibitors

Moderate degree Evidence of reduced of symptom control motor complications

Evidence of increased adverse events

Amantadine No

Non-significant result

Evidence of reduced motor complications

Evidence of increased adverse events

Apomorphine No

Limited degree of symptom control

Evidence of reduced motor complications

Evidence of increased adverse events

Postural Instability Usually a late feature of the disease, which comprises impairment of righting reflexes with a tendency to fall. REFERENCES 1. National Institute for Health and Clinical Excellence. Parkinson’s disease: national clinical guidelines for diagnosis and management in primary and secondary care. June 2006. 2. Olanow CW, Stern MB, & Sethi K: The scientific and clinical basis for the treatment of Parkinson disease. Neurology 2009 3. Scottish Intercollegiate Guidelines Network, Diagnosis and pharmacological management of Parkinson’s disease. January 2010. 4. Kostic V, Przedborski S, Flaster E, Sternic N. Early development of levodopa-induced dyskinesias and response fluctuations in young-onset Parkinson’s. Neurology 1991. 5. British National Formulary 67. 6. Monthly Index of Medical Specialities (MIMS). July 2016. 7. Summary of Product Characteristics for all medicines accessed online from: www. medicines.ie September 2016. 8. Dell’Agnello G, Ceravolo R, Nuti A, et al. SSRIs do not worsen Parkinson’s disease: evidence from an open-label, prospective study. Clinical Neuropharmacology 2001. 9. Dunsmure L, Kearney D. Parkinson’s Disease Management. Clinical Pharmacist. December 2011.

Cpd 70 parkinson's disease  
Cpd 70 parkinson's disease  
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