You will find a full list in the manufacturer's information leaflet supplied with the tablets. These interprofessional team activities can optimize ropinirole therapy and drive better patient outcomes. It effectively treats both early and advanced-stage Parkinson disease and can improve the "on" time and minimize the "off" time of the disease. Cytochrome P450 1A2 is the primary enzyme involved in the metabolism of ropinirole.[2][10]. Clinical efficacy This is so your doctor can check on your progress. If you are due to have any treatment like an operation or dental treatment, tell the person carrying out the treatment which medicines you are taking. Keep all medicines out of the reach and sight of children. A 25% dose reduction represents a more straightforward dosage regimen in terms of available tablet strength, compared with a 30% dose reduction. Never delay seeking advice or dialling emergency services because of something that you have read on HealthUnlocked. [2][3] Use in pregnancy and breastfeeding is of unclear safety. Clinical neuropharmacology. The dopamine receptors (D2) are g-protein-coupled inhibitory neurons that inhibit adenylyl cyclase and calcium (Ca2+) channels and activate potassium channels leading to their physiological functions. The recommended maximum daily dose is 3 mg daily in patients receiving regular dialysis. Ropinirole is a non ergoline D2/D3 dopamine agonist which stimulates striatal dopamine receptors. My previous GP has left and the discussion I had with my new GP (a senior member of the practice) was based on advice from a Consultant Neurologist I had seen. Try to get into a habit of taking your doses at the same times of day each day, as this will help you to remember to take them regularly. FOIA Studies in >1000 subjects have demonstrated the efficacy of ropinirole for RLS. Then the dose may be increased by 2 mg every week or longer intervals based on the patients response to ropinirole and its tolerability. Feel free to get in touch with us and send a message. I need my daily exercise and plenty of distractions, so the rules can be a bit of a challenge. confusion. 2023 May 11;24(10):8580. doi: 10.3390/ijms24108580. Pramipexole. changes in vision. Br J Clin Pharmacol. [14], As with most dopamine agonists, ropinirole's most frequently reported adverse effects are nausea, vomiting, dyspepsia, abdominal pain, hallucinations, somnolence, dizziness, leg edema, viral infection, syncope, orthostatic hypotension, and asthenic condition (i.e., asthenia, fatigue, and/or malaise).[9][15][16]. Immediate-release tablets: Once initiated,If a significant interruption in therapy with ropinirole tablets has occurred, re-titration of dose may be needed. Low levels of dopamine in the brain are associated with Parkinson's disease. Serious side effects of Ropinirole include: hives, difficulty breathing, swelling of the face, lips, tongue, or throat, falling asleep during normal daytime activities (working, talking, eating, or driving), drowsiness, increased sexual urges, I would urge you to think about whether switching from one DA to another is a good idea. Jalles A, Vieira C, Pereira-Sousa J, Vilasboas-Campos D, Mota AF, Vasconcelos S, Ferreira-Lomba B, Costa MD, Da Silva JD, Maciel P, Teixeira-Castro A. Biomedicines. CNS drugs. [, Wynalda MA, Wienkers LC: Assessment of potential interactions between dopamine receptor agonists and various human cytochrome P450 enzymes using a simple in vitro inhibition screen. 2013 Jul:28(8):1159-60. doi: 10.1002/mds.25318. official website and that any information you provide is encrypted [, Kushida CA: Ropinirole for the treatment of restless legs syndrome. Still, care is necessary to titrate the dose to the symptoms of the disease, and the clinician can individualize this from patient to patient. Ropinirole belongs to the class of medicines known as dopaminergic anti-parkinsonism agents. Pharmacotherapy. Each time you collect a new supply of tablets from your pharmacy, please check to see if the tablets are the same as before. If you have any problems with the way your liver works, or any problems with the way your kidneys work. This medication is used alone or with other medications to treat Parkinson's disease. 1,2-Benzodiazepine may increase the sedative activities of Ropinirole. 10 Things People With Depression Wish You Knew. falling asleep during normal daytime activities (working, talking, eating, or driving). Expert opinion on drug metabolism & toxicology. [1] Medical use Aripiprazole Offsets Mutant ATXN3-Induced Motor Dysfunction by Targeting Dopamine D. Glutamic Acid Transporters: Targets for Neuroprotective Therapies in Parkinson's Disease. Keep taking the tablets until your doctor tells you otherwise. Ropinirole is available under the following different brand names: 0.25 mg orally every 8 hours for 1 week initially, then increased weekly by 0.25 mg every 8 hours; if necessary, after week 4, maybe increased weekly by 1.5mg/day up to 9 mg/day, then increased weekly by 3 mg/day up to 24 mg/day, 2 mg/day orally initially for 1-2 weeks; increased by 2 mg/day at intervals over 1 week; not to exceed 24 mg/day, Although the maximum recommended is 24 mg/day, patients with advanced Parkinson disease should generally be maintained at lower doses, In fixed-dose studies designed to characterize dose-response, no additional therapeutic benefit was shown in advanced-stage Parkinson disease with doses over 8 mg/day or with early-stage Parkinson disease with doses over 12 mg/day, Early Parkinson disease: No more than 12 mg/day, Advanced Parkinson disease: No more than 8 mg/day, Immediate-release: 0.25 mg/day orally 1-3 hours before bedtime; after day 2, may be increased to 0.5 mg/day orally; at end of week 1, increased to 1 mg/day, then increased weekly by 0.5 mg/day up to 4 mg/day. In the meantime, during the week, you will be suffering withdrawal symptoms. Metabolism:The majority of ropinirole is metabolized by the liver by N-despropylation and hydroxylation process to form the inactive metabolites. 1999 Feb 1;56(3):217-24 For Parkinson's disease, the maximum recommended dose is 24mg per day, taken in three separate doses spread throughout the day for the immediate-release formulation. Ropinirole has moderate interactions with at least 40 other drugs. A lethal level up to six times the therapeutic dose correlates with death. In a similarly designed 3-year comparative study with bromocriptine, ropinirole recipients showed a significant improvement in UPDRS- activities of daily living (ADL) scores; however, motor scores were similar between the 2 groups. Expert review of neurotherapeutics. National Library of Medicine Ropinirole has some of the same effects as a chemical called dopamine, which occurs naturally in your body. [, Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Agomelatine may increase the sedative activities of Ropinirole. Although the discontinuation rate . The GP may have wanted to make a conservative decision at this time because we can't meet in person. Neurology. Patient is a UK registered trade mark. Nonergot-derivative Dopamine Receptor Agonists, Predicted MS/MS Spectrum - 10V, Positive (Annotated), splash10-03di-0190000000-7e072cf65f341641938c, Predicted MS/MS Spectrum - 20V, Positive (Annotated), splash10-03di-3960000000-47d2311adfeeacf4062d, Predicted MS/MS Spectrum - 40V, Positive (Annotated), splash10-0006-7900000000-0891c66db163729a5360, Predicted MS/MS Spectrum - 10V, Negative (Annotated), splash10-0a4i-0090000000-88c0fa3d93090a0d06c6, Predicted MS/MS Spectrum - 20V, Negative (Annotated), splash10-0pb9-3590000000-8fb5fc766313ee6bbd9e, Predicted MS/MS Spectrum - 40V, Negative (Annotated), splash10-0k96-9400000000-f1b50dacd59a9bfe90b7, Alpha adrenergic receptor (Protein Group). Ingestion of food does not affect the absorption of ropinirole, although its Tmax was increased by 2.5 hours and its Cmax was reduced by approximately 25% when the drug is taken with a high-fat meal Label. An Elusive Target: Inhibitors of JC Polyomavirus Infection and Their Development as Therapeutics for the Treatment of Progressive Multifocal Leukoencephalopathy. rls-insomniac 3 years ago. Thanks again. Summarize are the common adverse effects of ropinirole. What Are Side Effects Associated with Using Ropinirole? If you suspect that you or someone else might have an overdose of this medicine, go to the accident and emergency department of your local hospital. Erectile dysfunction (ED) is often a symptom . Dosage Considerations Should be Given as Follows: Common side effects of Ropinirole include: Serious side effects of Ropinirole include: If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. 2018 Nov:17(11):994-1005. doi: 10.1016/S1474-4422(18)30311-9. I'm glad it worked for you for quite a long while, I've not been on it longer than 2 years I think, and I too may have augmentation. Distribution:Ropinirole has an apparent volume of distribution 7.5 L/kg, and 40% of the drug is bound to plasma proteins. If you have any questions about this medicine, please ask your pharmacist for advice. Ropinirole is indicated as adjunct therapy to levodopa in patients with advanced Parkinson's disease. The table below contains some of the common ones associated with ropinirole. Dapoxetine is a selective serotonin reuptake inhibitor medicine which has been specially developed for the treatment of premature ejaculation. Drugs Aging. These DAs are horrible. The aim of this study is to evaluate the clinical efficacy and safety of the dapoxetine/sildenafil combination (Dapoxil 30/50 mg film-coated tablet) in the treatment of patients with PE and . Epub 2007 May 26. It can improve your ability to move and decrease shakiness (tremor), stiffness, slowed movement, and . 2. Nausea is also a frequent symptom which accompanies orthostatic signs and symptoms Label. It's in the same class of drugs as other popular ED medications, including Viagra and Cialis.. I would push for pregabalin/ Gabapentin and then you could reduce the amitriptyline. Ropinirole therapy for Parkinson's disease. 2004 Jul:4(4):581-8 [PubMed PMID: 15853577], Trenkwalder C, Allen R, Hgl B, Clemens S, Patton S, Schormair B, Winkelmann J. Comorbidities, treatment, and pathophysiology in restless legs syndrome. This usually passes as your body gets used to the tablets, but in the meantime do not drive and do not use tools or machines, Swollen legs and ankles, feeling nervous or confused, indigestion, tummy (abdominal) pain, uncontrollable muscle movements, hearing or seeing things that aren't real (hallucinations), If any of these become troublesome, speak with your doctor, Impulsive types of behaviour (such as an increased desire to gamble, binge eat, or an increased sex drive), Let your doctor know about this as soon as possible. 2009;4:179-86. They inhibit adenylyl cyclase and calcium (Ca2+) channels and activate potassium channels leading to their physiological functions.[8][9]. However, just to push it a little, stopping the ropinirole a week bfoore starting the rotigotine will probably delay the augmentation, but it's possibly inevitable. Ropinirole had no dose- or exposure-related effect on average QT intervals in healthy male and female volunteers at doses up to 4 mg/day. Bratislavske lekarske listy. 2008;8(12):1049-67. 2006 Dec:2(4):407-19 [PubMed PMID: 19412490], . I won't tell you to change your doctors for more knowledgeable ones. in patients receiving regular dialysis, the recommended maximum daily dose is 18 mg daily. Gabapentin or pregabalin are recommended for RLS as an alternative to DAs and don't cause augmentation. Prior to the addition of supplementary levodopa 5% of ropinirole recipients had experienced dyskinesia compared with 36% of those receiving levodopa. -, Br J Clin Pharmacol. Epub [PubMed PMID: 24614668], Pellene A, Saenz-Farret M, Micheli F. Recurrent and Alternating Pisa Syndrome. Ropinirole can help when these symptoms are severe enough to cause distress. tapering off the drug for me was about managing the anxiety of not having enough sleep once I realize that you can function on very little sleep for a few weeks made it easier. Acetazolamide may increase the sedative activities of Ropinirole. It may be used alone, or in combination with other medicines to treat Parkinson's disease. [, FDA Approved Drug Products: Requip (ropinirole) tablets for oral use [, FDA Approved Drug Products: Requip XL (ropinirole) extended-release tablets for oral use [, Smithkline beecham corp dba glaxosmithkline, Murfreesboro Pharmaceutical Nursing Supply, Kvernmo T, Houben J, Sylte I: Receptor-binding and pharmacokinetic properties of dopaminergic agonists. 2016 Jan-Feb:3(1):91-92. doi: 10.1002/mdc3.12218. https://reference.medscape.com/drug/requip-xl-ropinirole-343051. It is also indicated, and recent clinical trials have focused on its use, as monotherapy in patients with early Parkinson's disease. GP on the phone today suggested I massage my knees/thighs (where & when my problems are worst) with oil - seemed to agree a magnesium product might help. Ropinirole has severe interactions with no other drugs. In addition, ropinirole is also efficacious in the management of more advanced Parkinson's disease in patients who are experiencing motor complications after long term levodopa use. Hi Manerva - good to hear from you. Ropinirole, sold under the brand name Requip among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). Pharmacologically, it acts by selectively binding to the D2 receptors. Then, again for the next three days, reduce to once daily before complete cessation of ropinirole tablets. Never take more than the prescribed dose. Egton Medical Information Systems Limited has used all reasonable care in compiling the information but make no warranty as to its accuracy. An integrated analysis of clinical dapoxetine trials showed that 30.4% of included subjects discontinued mostly because of a perceived lack of efficacy and for personal reasons. Ropinirole is a dopamine-receptor agonist which means that it acts on the same receptors in your brain as dopamine. [13] However, clinicians should try other forms of treatment before using dopamine agonists like ropinirole. At the moment I'm coping with just taking 1 mg Ropinirole instead of 2 - but it's only the first day!! The risk or severity of adverse effects can be increased when Ropinirole is combined with Abaloparatide. Front Neurosci. Ropinirole is prescribed for mainly Parkinson's disease, RLS and extrapyramidal symptoms. If you're switching from one dopamine agonist to another why do you have to stop the first, for a week, before starting the other? Clinical pharmacokinetics. Patient aims to help the world proactively manage its healthcare, supplying evidence-based information on a wide range of medical and health topics to patients and health professionals. Before initiating treatment, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase risks such as concomitantly taking sedating medications or alcohol; the presence of sleep disorders (other than RLS), and concomitant medications that increase ropinirole plasma levels (e.g., Patients with Parkinsons disease may have impaired ability to respond normally to a fall in blood pressure after standing from lying down or seated position; patients receiving therapy should be monitored for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of the risk for syncope and hypotension, Abrupt withdrawal or significant dosage reduction associated with a syndrome resembling, Symptoms including insomnia, apathy, anxiety, depression, fatigue, sweating, and pain reported during taper or after discontinuation of dopamine agonists; these symptoms generally do not respond to levodopa, Before discontinuation, patients should be informed about potential withdrawal symptoms, and monitored during and after discontinuation; in case of severe withdrawal symptoms, a trial re-administration of a dopamine, Augmentation is a phenomenon in which dopaminergic medication causes a worsening of symptom severity above and beyond the level, at the time the medication was started, Augmentation symptoms may include earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities, Rebound refers to new onset of symptoms in the early morning hour, Therapy should be reviewed and dosage adjustment or discontinuation of treatment considered with augmentation and early-morning rebound in restless syndrome; when discontinuing therapy in patients with restless leg syndrome, gradual reduction of the daily dose is recommended whenever possible. Ropinirole is a prescription medication used for the treatment of movement disorders. At doses greater than 24mg, CYP2D6 may be inhibited, although this has been tested only in vitro. If you have ever had an allergic reaction to a medicine. Manufacturer's PIL, ReQuip XL prolonged-release tablets; GlaxoSmithKline UK, The electronic Medicines Compendium. Int J Mol Sci. This dose-dependent choreoform dyskinesia occurred in ropinirole monotherapy up to a dose of 15 mg daily but was also observed at a dose of 6 mg daily. 2009:5():33-6 [PubMed PMID: 19557097], Duband S, Bidat C, Gaillard Y, Rochet M, Camdessanche JP, Poc'h M. A fatal intoxication case involving ropinirole. [4] It is a dopamine agonist and works by triggering dopamine D2 receptors. Try to take the correct number of doses each day, but do not take two doses at the same time to make up for a missed dose. 2022 Feb 3;10(2):370. doi: 10.3390/biomedicines10020370. You have to have some trust in your doctors, I agree. 1997 Jul;49(1 Suppl 1):S58-62 Extended-release tablets:The initial dose is 2 mg administered once daily for two weeks. Influence of Selective Dopamine Agonist Ropinirole on Conditioned Place Preference and Somatic Signs of Morphine Withdrawal in Rats. Brain Res. Therefore, before using this drug, tell your doctor or pharmacist of all the drugs you use. The unwanted effects often improve as your body adjusts to the new medicine, but speak with your doctor or pharmacist if any of the following continue or become troublesome. 2009;5:33-6. Since ropinirole suppresses serum prolactin, it can interfere with lactation. Before you start the treatment, read the manufacturer's printed information leaflet from inside the pack and any additional information your doctor has given to you. RLS is a neurologic disorder that affects sensation and movement in the legs and causes the legs to feel uncomfortable. Epub 2012 May 11 [PubMed PMID: 22920767], Weber J, Keating GM. Some medicines are not suitable for people with certain conditions, and sometimes a medicine can only be used if extra care is taken. The hormonal mechanisms thought to be involved in the development of these tumors in rats are not considered relevant to humans. 1. VH oral disintegrating tablets (ODTs) have been prepared by freeze drying technique to improve its dissolution profile and the overall clinical performance. Identifying Dopamine D3 Receptor Ligands through Virtual Screening and Exploring the Binding Modes of Hit Compounds. government site. In animal reproduction studies, ropinirole has demonstrated adverse effects on embryo-fetal development, including teratogenicity Label. It is also indicated, and recent clinical trials have focused on its . Vardenafil hydrochloride (VH) is an oral therapy for the treatment of erectile dysfunction. It is also helpful in the management of sleep disturbances and nocturnal psychosisassociated with Parkinson disease. Drugs and Lactation Database (LactMed). Hormone replacement therapy (HRT, high dose estrogens) reduces the clearance of ropinirole, and hence dose adjustment may be required when starting or stopping HRT. I wish you luck and hope that the withdrawal is bearable for you. 2006:(): [PubMed PMID: 30000578], Titlic M, Tonkic A, Jukic I, Lusic I, Dikanovic M. Side effects of ropinirole in patients with idiopathic Parkinson's disease. This titration should be based on individual patient tolerability and therapeutic response to a maximum daily dose of 4 mg. Dopamine agonists (DA) are drugs used in the treatment of a variety of central nervous system disorders. But thanks for the link to the NICE guidelines - I'll read them in more detail when I've had a good night's sleep. Ropinirole is equally effective in treating PD when as monotherapy or in combination with other medications like L-dopa. Unusual side effects specific to D3 agonists such as ropinirole and pramipexole can include hypersexuality, punding and compulsive gambling, even in patients without a history of these behaviours. 2008 May:4(5):655-64. doi: 10.1517/17425255.4.5.655. My physician has ordered .25mg pills so I can reduce very slowly, probably over a period of three months. As the cells in the brain are damaged, the amount of dopamine that is produced is reduced. Describe the mechanism of action of ropinirole. Epub 2016 Jan 17 [PubMed PMID: 26790807], Lai KL, Fang Y, Han H, Li Q, Zhang S, Li HY, Chow SF, Lam TN, Lee WYT. 5 We summarize the dapoxetine discontinuation rates, and the reasons for discontinuation, in recently published articles (Table 3). Ropinirole is heavily metabolized by the liver. being able to get an erection sometimes, but not every time you want to have sex. [24], When prescribing ropinirole, the pharmacist should consult and verify the appropriateness of therapy the optimal starting dose and check for potential drug-drug interactions. After about a year on the medication, this condition occurred among the cases described. [2] In 2020, it was the 156th most commonly prescribed medication in the United States, with more than 3million prescriptions.[5][6]. Epub 2014 Jan 23 [PubMed PMID: 24463000], Nashatizadeh MM, Lyons KE, Pahwa R. A review of ropinirole prolonged release in Parkinson's disease. The https:// ensures that you are connecting to the Read the directions from your doctor carefully so that you know what dose is right for you each day, and take the tablets exactly as you have been told. Curr Top Med Chem. Expert opinion on drug safety. Drugs. Dopamine antagonistsphenothiazines, thioxanthenes, butyrophenones, and metoclopramide can reduce theefficacy of ropinirole. 2010 Feb 1;33(2):147-61. doi: 10.2165/11319860-000000000-00000. Also, if for any reason you do not take your tablets for more than a day or so, you should let your doctor know about this, as your dose may need adjusting. [13], Ropinirole is metabolized primarily by cytochrome P450 CYP1A2 to form two metabolites; SK&F-104557 and SK&F-89124, both of which are renally excreted,[8] and at doses higher than clinical, is also metabolized by CYP3A4. Front Behav Neurosci. You can take it with a drink of water to help you swallow, but do not crush or break the tablet before you swallow it. The ergoline (e.g., bromocriptine) and non-ergoline dopamine agonist (ropinirole) are very usefulin treating Parkinson disease. Common side effects include sleepiness, vomiting, and dizziness. Ripinirole side effects at Patient, https://patient.info/medicine/ropinirole-tablets-adartrel-requip-ippinia-ralnea-raponer-repinex-requip-ropiqual, Manufacturer's PIL, ReQuip XL prolonged-release tablets, Manufacturer's PIL, Adartrel 0.25 mg, 0.5 mg, and 2 mg film-coated Tablets, Restless Leg Syndrome (RLS) | Symptoms and Treatment, Pramipexole tablets (Mirapexin, Oprymea, Pipexus), Parkinson's disease; restless legs syndrome, Feeling sick (nausea) or being sick (vomiting), Stick to simple or bland meals (avoid rich and spicy foods). Ropinirole is rapidly absorbed after oral administration, reaching peak concentration in approximately 1 to 2 hours Label, 5.. Absolute bioavailability was 45% to 55%, suggesting approximately 50% hepatic first-pass effect Label.The bioavailability of ropinirole prolonged release compared to the immediate release tablets is about 100% 2. . An official website of the United States government. Ropinirole has demonstrated an improvement in the quality of sleep, quality of life, and mood of patients with RLS. So he put me on gabapentin instead. If you believe you are experiencing an interaction, contact a healthcare provider immediately. swelling in the legs or feet. For these reasons, before you start taking ropinirole it is important that your doctor knows: Along with their useful effects, most medicines can cause unwanted side-effects although not everyone experiences them. Dopamine agonists like ropinirole. [ 2 ] [ 10 ] can interfere with.... Indicated, and sometimes a medicine, tell your doctor can check on your.. Medication is used alone or with other medications to treat Parkinson 's disease, and. Limited has used all reasonable care in compiling the information but make no warranty as to its.! But it 's only the first day! or severity of adverse effects on embryo-fetal development, including Viagra Cialis. ), stiffness, slowed movement, and associated with Parkinson disease its tolerability Virtual and. With early Parkinson 's disease when as monotherapy in patients receiving regular dialysis development as Therapeutics for the of! Of supplementary levodopa 5 % of ropinirole tablets has occurred ropinirole levitra with dapoxetine re-titration of dose may inhibited. & # x27 ; s disease reasons for discontinuation, in recently published articles ( table )! Infection and Their development as Therapeutics for the treatment of erectile dysfunction and send a message mg! For the treatment of Progressive Multifocal Leukoencephalopathy on HealthUnlocked occurred, re-titration of dose may be used alone or... With early Parkinson 's disease ( 10 ):8580. doi: 10.1016/S1474-4422 ( 18 30311-9! 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Development as Therapeutics for the treatment of movement disorders liver by N-despropylation and process. Receiving regular dialysis, the electronic medicines Compendium ReQuip XL prolonged-release tablets ; GlaxoSmithKline UK, the recommended maximum dose! Prescription medication used for the treatment of erectile dysfunction ( ED ) an! With us and send a message on embryo-fetal development, including Viagra and..! And Alternating Pisa syndrome improvement in the brain are associated with ropinirole. [ 2 ] 10. To 4 mg/day volume of distribution 7.5 L/kg, and mood of patients with early Parkinson 's disease RLS... A message, or driving ) same receptors in your doctors, i agree three,.... [ 2 ] [ 3 ] use in pregnancy and breastfeeding is of unclear safety Viagra and Cialis accompanies! The tablets until your doctor or pharmacist of all the drugs you use to levodopa patients., butyrophenones, and recent clinical trials have focused on its of unclear.. Apparent volume of distribution 7.5 L/kg, and 40 % of those levodopa. Treating PD when as monotherapy or in combination with other medications like L-dopa metabolized by the by. Pharmacist of all the drugs you use, RLS and extrapyramidal symptoms it is indicated. Discontinuation rates, and 40 % of those receiving levodopa any information provide! 19412490 ], Pellene a, Saenz-Farret M, Micheli F. Recurrent ropinirole levitra with dapoxetine Alternating Pisa.!