The whole subject has become highly charged and politicised. Disease-toxicity interactions may well be relevant. Malaria and malarial fever have independent effects on the QT interval and heart rate [ 90 ], although the heart is relatively spared even in severe malaria [ 91 ]. It is unclear whether the mechanism for the cardiotoxic hydroxychloroquine-azithromycin interaction is explained only by TdP or whether there is a febrile illness interaction.
It remains to be seen whether patients receiving high-dose chloroquine or hydroxychloroquine for COVID will have more or fewer arrhythmias or other adverse cardiovascular effects than those not receiving 4-aminoquinoline drugs. This is best assessed from RCTs. The evidence reported to date is reassuring. Hypokalaemia is a consistent feature of chloroquine poisoning [ 93 ].
Monitoring for cardiovascular adverse events QRS widening, QT prolongation, arrhythmias and modifiable risk factors i. Chloroquine and hydroxychloroquine improve glycaemic control in type 2 diabetes and may occasionally cause hypoglycaemia [ 94 — 96 ]. Several factors contribute: stimulation of insulin secretion, reduced insulin degradation, and increased receptor binding. Pruritus is particularly troublesome in dark-skinned patients and may be dose limiting [ 96 ]. Itching is described as a widespread prickling sensation mostly affecting the palms, soles, and scalp, which starts within 6 to 24 hours and may last for several days.
It can be very distressing. Antihistamine treatment is not usually very effective [ 97 ]. Hydroxychloroquine may be associated with less itching. Very rarely, chloroquine may cause an acute and self-limiting neuropsychiatric reaction [ 58 , 61 ].
Chloroquine and hydroxychloroquine have also been associated with keratopathy, ciliary body dysfunction, and lens opacities. Half are asymptomatic, but some patients may complain of photophobia, visual halos around lights, and blurred vision. Hydroxychloroquine has been considered slightly less toxic to the retina than chloroquine, although with sensitive techniques, retinal damage is evident earlier than appreciated previously [ , ]. Myopathy is rare at the doses used in antimalarial prophylaxis.
Long-term high dose use in rheumatological conditions may cause skeletal or cardiac myopathy. Less common cutaneous side effects include lightening of skin colour, various rashes, photoallergic dermatitis, exacerbation of psoriasis severe psoriasis is probably a contraindication , bullous pemphigoid, exfoliative dermatitis, pustular rash, skin depigmentation with long-term use , and hair loss [ 61 ].
Contrary to some recent reports, chloroquine and hydroxychloroquine do not cause oxidant haemolysis in glucosephosphate dehydrogenase G6PD deficiency [ ].
Slight increases in methaemoglobin concentrations follow chloroquine administration in NADH methaemoglobin reductase deficiency [ ], but otherwise the 4-aminoquinolines do not cause methaemoglobinaemia. Both drugs have some inhibitory activity on these enzymes, but this has not led to clinically significant pharmacokinetic interactions. Renal tubular secretion of chloroquine involves the multidrug and toxin extrusion protein 1 MATE1 , so concomitant administration of MATE1 inhibitors would be expected to reduce renal elimination, but no clinically significant consequences have been reported.
Displacement from tissue binding sites may occur, and this probably explains the moderate elevation in primaquine concentrations when coadministered with chloroquine [ 25 ]. Chloroquine and hydroxychloroquine both inhibit P-glycoprotein P-gp efflux pumps and so may increase cyclosporine and digoxin levels.
Cimetidine, but not ranitidine, reduces chloroquine clearance. The main drug-drug interactions causing concern are pharmacodynamic interactions with other hERG channel blocking QT prolonging drugs—notably, azithromycin, which has been coadministered commonly with high-dose hydroxychloroquine or chloroquine in COVID treatment and clearly augments QT prolongation [ 52 , 78 , ].
Individually, azithromycin use may carry a greater risk of TdP than chloroquine or hydroxychloroquine. Lignocaine or mexiletine may be used to reduce excessively prolonged QT intervals and reduce the TdP risk. Chloroquine and hydroxychloroquine are dangerous in overdose [ 47 , 93 , — ]. In self-poisoning, nausea, vomiting, diplopia, hypoacusis, and dysphoria are sometimes followed by tremors, athetoid movements, dysarthria, difficulty swallowing, lethargy and drowsiness, and then seizures, coma, hypotension, hypokalaemia, arrhythmias, and ventricular fibrillation.
The lethality of chloroquine in overdose is over six times higher than with other drugs [ ]. Outcome is dependent on the dose retained, the blood concentrations that result, and the delay in reaching supportive intensive care.
Both drugs are absorbed extensively by activated charcoal, which can be used to limit further absorption. In overdose, a variety of arrhythmias have been observed, including sino-atrial and atrioventricular block, bundle branch block, and different ventricular arrhythmias including TdP. Hypokalaemia, resulting from intracellular accumulation, is an important complication, an indicator of prognosis, and a contributor to arrhythmias [ 93 ].
It has been suggested that diazepam is a specific antidote [ ] for chloroquine poisoning, but more recent studies do not support a specific role for this drug above good haemodynamic and ventilatory support [ , ]. There is a loose relationship between the self-administered chloroquine dose and the resulting blood concentrations. Mortality is proportional to peak blood concentrations. Hypotension, arrhythmias, coma, and acute respiratory distress syndrome ARDS all contributed to death.
Several patients presented with cardiac arrest, and in some others this occurred after thiopental administration preceding intubation. Clinical evidence of pulmonary oedema was usually absent on admission. In the patients who developed ARDS, it occurred a mean of 17 hours after admission to the intensive care unit [ ]. The plasma potassium concentration on admission correlated inversely with QRS widening and QT prolongation.
Good intensive care with prompt management of hypokalaemia were important contributors to survival [ — ]. Patients given large amounts of potassium should be monitored carefully for later rebound hyperkalaemia.
There is less information on hydroxychloroquine in overdose, but the complications and the management are similar. Chloroquine and hydroxychloroquine should be stored in secure containers out of reach of children. Chloroquine should not be prescribed to patients with a history of suicide or those who have suicidal ideas. Whole-blood chloroquine concentrations were measured by UV-spectrophotometry, which did not distinguish the parent compound from the desethylated metabolites.
Admission whole-blood chloroquine concentrations varied from 1. Raw data used to produce this image are provided in S1 File. We simulated treatment of adult patients with a loading dose of four tablets of hydroxychloroquine sulphate each tablet contains mg salt, equivalent to mg base or chloroquine phosphate each tablet contains mg salt, equivalent to mg base at time 0 and 6 hours, followed by a maintenance dose of two tablets twice daily starting 12 hours after the first dose , for a total treatment duration of 7 or 10 days Fig 4.
For a detailed description of the pharmacokinetic modelling, see S2 Text. The reported in vitro values [ 29 , 54 ] were assumed to correspond to total plasma values and scaled to whole blood using a reported blood-plasma ratio of for chloroquine [ 13 , ] and for hydroxychloroquine [ 38 ], resulting in a putative in vivo blood EC 50 value of 3.
However, only the free fraction of drug can distribute to the site of action i. These are of uncertain relevance to antiviral activity in-vivo. To evaluate exposure and peak whole-blood concentrations in relation to body weights 40—90 kg , we simulated three different dosing strategies shown in S2 Fig :. Flat dosing 1 consisted of the 7-day treatment scenario described above loading dose four tablets twice, maintenance doses two tablets 12 hourly.
As expected, weight-based loading and maintenance dosing are preferable, particularly in underweight or overweight patients. Whole-blood exposure and peak concentrations at different body weights 40—90 kg were simulated using a weight-based loading dose of three to five tablets S5 Fig followed by a flat maintenance dose of one tablet daily Fig 5 for 3 months. These show expected exposures, as in the treatment of rheumatological conditions, which are well below those associated with cardiovascular safety concerns, although it remains to be seen if these levels are effective in the prevention of COVID These EC 50 estimates derived from in-vitro studies are of uncertain relevance to antiviral activity in-vivo.
Both acute treatment and prophylactic therapy were simulated, assuming no adjustment in loading dose. An alternative dosing of half the maintenance dose in patients with severe renal impairment is shown S6 Fig. Whole-blood chloroquine exposure was similar in patients with adequate renal function and renal impairment in short-course treatments of 7 or 10 days. Dose adjustment will not be needed in these patients.
Exposures are significantly higher in patients with renal impairment receiving prophylactic treatment.
It is uncertain whether this requires dose modification. Despite the enormous usage of chloroquine in malaria and hydroxychloroquine in rheumatological conditions for over half a century, their clinical pharmacology is not well understood. There are several confusing aspects to their pharmacological assessment. First, dosing is sometimes reported as base equivalent usually in malaria and sometimes as salt rheumatological conditions. Of the 49 different chloroquine or hydroxychloroquine treatment regimens under evaluation for COVID on clinicaltrials.
Second, the measurement of these drugs in plasma and blood samples is complicated by extensive binding to platelets, leukocytes, and to a lesser extent, erythrocytes and in malaria, concentration within malaria parasites. Third, they have complex pharmacokinetic properties characterised by an enormous total apparent volume of distribution and very slow terminal elimination such that blood concentration profiles in acute illness are determined by distribution rather than elimination.
Finally, there are still considerable uncertainties about their mode of action. The moderate inhibitory activity of chloroquine and hydroxychloroquine against the SARS-CoV-2 virus in vitro suggests that if there is any benefit from these medicines, it is likely to require high concentrations of free drug in blood to drive high concentrations in the infected respiratory epithelium. The concentration-effect relationships derived from in vitro studies suggest only partial antiviral effects at best as shown in Fig 4 and S6 Fig.
We assume that the cytosolic concentrations of the drugs in the respiratory epithelium will be in dynamic equilibrium with the free fraction in plasma. We know from the treatment of life-threatening infections that the earlier in the evolving disease process that pathogen multiplication is inhibited, the better is the outcome. This argues for achieving high blood concentrations of chloroquine or hydroxychloroquine as soon as possible in the clinical trials, but this has to be balanced against the potential for serious toxicity.
Provided that there is not a significant drug-disease interaction, these doses evaluated in the two largest RCTs are predicted to be relatively safe see simulated profiles in Fig 4. Both of these trials have stopped recruitment to the hydroxychloroquine arm because of a lack of evidence for benefit in severe COVID Elsewhere, clinical trials have evaluated smaller doses. For prevention or prophylaxis, where the viral burden is much lower, the daily doses being evaluated are similar to those widely recommended and generally very well tolerated in rheumatological conditions [ 37 , 62 , — ].
Giving these drugs to a seriously ill patient gives the impression that something potentially beneficial is being done. And if these drugs do work, then lives would have been saved, and individuals at risk would have been protected.
We outline the arguments against recommending this position from the evidence-based medicine perspective that has largely replaced opinion-based medical decision-making. Today, although we now know that hydroxychloroquine is not beneficial in severe disease, we do not know if giving chloroquine or hydroxychloroquine for the prevention or early treatment of COVID is better, or worse, than nothing.
Publications on COVID are appearing at a rate of hundreds per day, but the only convincing and actionable evidence from large RCTs has come from the RECOVERY trial, which stopped its hydroxychloroquine and lopinavir-ritonavir arms because of lack of efficacy and stopped its dexamethasone arm because of life-saving benefit in patients receiving oxygen or being ventilated.
There is also weak evidence that hydroxychloroquine does not work in postexposure prophylaxis, although relatively small but potentially valuable benefits cannot be ruled out by these moderately sized studies [ , ]. Lack of benefit in hospitalised patients has been extrapolated to lack of any preventive or therapeutic benefit, which is unjustified. Considering the use of chloroquine and hydroxychloroquine in prevention, we are clearly still in a position of substantial uncertainty, awaiting the results of large and definitive studies.
These randomised trials are now under substantial threat, as some regulatory agencies have actively stopped ongoing studies, and media opinion, fuelled by a steady stream of observations, cautions, claims, and counterclaims [ ], has turned against these highly politicised medicines. Recommending or banning the use of chloroquine or hydroxychloroquine before their safety and efficacy have been well characterised compromises these critical randomised trials, and it violates the generally accepted principle of recommending or proscribing interventions only after there is sufficient evidence of their safety and efficacy [ ].
Chloroquine and hydroxychloroquine are not harmless [ 71 ]. Even though we do not know whether they are harmful or beneficial overall in the prevention or treatment of COVID, many countries now recommend them for treatment, and seven countries covering one-fifth of the world's population have recommended them for prophylaxis in high-risk groups.
In contrast, a minority of countries actively promote inclusion of treated patients in clinical trials [ , ]. A national recommendation based on inadequate evidence is irresponsible, and it gives the public the wrong message.
This could also lead to widespread self-medication. Fatal self-poisonings have already been reported from unsupervised self-medication of chloroquine and hydroxychloroquine in several countries [ ]. Recommending valuable drugs for unproven indications wastes valuable resources, damages health, and compromises finding effective medicines.
People are likely to assume that recommended drugs do work and, in the context of preventive use, will believe they are protected and therefore may not take other necessary precautions or adhere to other public health measures. Taking drugs is easier than complying with public health measures such as physical distancing and wearing protective equipment.
In addition, the high demand for these currently unproven drugs has put patients at risk who legitimately need them for treatment for other conditions such as SLE and rheumatoid arthritis. Shortages have already occurred and prices have risen markedly, leaving these vulnerable groups to suffer unnecessarily [ ]. It could also encourage unscrupulous manufacturers to make falsified chloroquine and hydroxychloroquine [ ].
Well-conducted, large, and definitive RCTs are needed [ ], but they are not being sufficiently promoted or supported. Premature national recommendations for chloroquine and hydroxychloroquine use or unjustified regulatory statements indicating that these drugs are ineffective in prevention or early treatment have both compromised clinical trials to determine their benefit [ ] and made recruitment into these trials more difficult.
Several trials have stopped prematurely. In this context, sick patients potentially enrolling in RCTs and their relatives will want to know why they are being denied treatments advocated or recommended elsewhere or conversely given treatments that have been recommended against. Also, potential participants in pre- or postexposure trials may opt for self-medication rather than join the trials.
This jeopardises the substantial uncertainty between whether to recommend the drug or not that justifies randomised trials, at least in the eyes of the public.
Recommending chloroquine and hydroxychloroquine for widespread prophylaxis use is not the same as getting approval for unproven drugs for compassionate use. Unjustified recommendations based on opinion or politics rather than evidence undermines public trust in the regulation of the pharmaceutical industry, and it goes against the carefully developed drug approval and regulatory mechanisms established over a generation to protect public safety.
Measured whole-blood concentration data showing the long terminal elimination of chloroquine top and hydroxychloroquine bottom. Top panel: Measured profiles following , , and mg base single oral chloroquine doses reproduced from [ 14 ]. Bottom panel: Measured profiles in one individual following mg hydroxychloroquine base intravenous infusion solid circles and mg base infusion hollow squares , reproduced from [ 30 ].
The inset in the bottom panel shows the first hours after drug administration. This is reproduced with permission from the authors [ 14 , 30 ]. AUC, area under the whole-blood concentration-time curve from time zero to 1 month after the last dose; C MAX , maximum concentration. AUC, area under the concentration-time curve from time zero to 1 month after the last dose; C MAX , maximum concentration.
Simulated whole-blood concentration-time profiles of chloroquine left column and hydroxychloroquine right column for 7-day treatment regimens top two panels , day treatment regimens middle two panels , and day prophylaxis regimens bottom two panels.
The simulations are based on [ ]. The black dashed lines indicate the maximum mean concentrations. Allometric scaling of body weight was added. We thank Jean-Luc Clemessy and Frederic Baud for providing us with the original data from the chloroquine self-poisoning studies. Funding: The authors received no specific funding for this work.
Summary points Chloroquine and hydroxychloroquine have been used for over 60 years in the treatment of malaria, amoebic liver abscess, and several rheumatological conditions, but their clinical pharmacology is not well understood.
COVID is a new potential indication, although these drugs have only moderate in vitro activity against the SARS-CoV-2 virus and there is no convincing evidence at this time of significant clinical efficacy. The free plasma concentrations that drive potentially serious adverse reactions hypotension, cardiac conduction disturbances, delayed ventricular repolarization, and neurotoxicity are determined largely by distribution processes. Hydroxychloroquine was slightly safer than chloroquine in preclinical testing and is considered better tolerated over the long term.
Both drugs are dangerous when overdosed, and parenteral administration needs careful control. There are different salts, each with a different base equivalent. This has led to confusion and sometimes mistakes in dosing. As different salts are available in different places, malaria treatment is usually recommended in terms of base equivalent. Tablets of the two most widely available forms, chloroquine diphosphate mg salt and hydroxychloroquine sulphate mg salt, both contain mg base. The pro-arrhythmic and anti-arrhythmic effects of chloroquine and hydroxychloroquine have been poorly characterised, although the majority of evidence for current regimens is very reassuring.
Arrhythmia risks have been inferred from QT prolongation rather than observed. We used available pharmacokinetic information from healthy volunteers, the treatment of malaria, the chronic treatment of rheumatological conditions, and the toxicokinetics of chloroquine in self-poisoning to predict exposures and safety margins in the high-dose COVID prevention and treatment regimens that have been evaluated. These regimens are predicted to have reasonable safety margins.
Using lower doses risks failing to identify any putative benefit in this potentially lethal infection. Large, well-conducted randomised clinical trials with appropriate monitoring are required to determine if chloroquine and hydroxychloroquine have preventive or treatment efficacy in COVID and acceptable safety. Current recommendations for their use outside of clinical trials are not justified at this time. Introduction Chloroquine [7-chloro[4- diethylamino methylbutyl]amino] quinoline is a 4-aminoquinoline compound discovered in Germany in as part of a research programme to develop new antimalarial drugs [ 1 , 2 ].
Download: PPT. Clinical pharmacokinetics Even in the s, when drug measurement was in its infancy, it was clear that the 4-aminoquinolines had unusual pharmacokinetic properties [ 2 ]. Fig 2. Example of a general whole-blood or plasma concentration-time profile for chloroquine or hydroxychloroquine. Antiviral and antimalarial activities The 4-aminoquinolines inhibit the pH-dependent steps of replication of a broad range of viruses including flaviviruses, retroviruses, and coronaviruses [ 29 , 50 — 54 ].
Toxicity Chloroquine and hydroxychloroquine are generally well tolerated. Chloroquine poisoning Chloroquine and hydroxychloroquine are dangerous in overdose [ 47 , 93 , — ]. Fig 3. Dosing simulations of chloroquine and hydroxychloroquine Treatment simulations We simulated treatment of adult patients with a loading dose of four tablets of hydroxychloroquine sulphate each tablet contains mg salt, equivalent to mg base or chloroquine phosphate each tablet contains mg salt, equivalent to mg base at time 0 and 6 hours, followed by a maintenance dose of two tablets twice daily starting 12 hours after the first dose , for a total treatment duration of 7 or 10 days Fig 4.
Fig 4. Pharmacokinetic treatment profiles for a typical kg adult. Prophylactic treatment simulations Whole-blood exposure and peak concentrations at different body weights 40—90 kg were simulated using a weight-based loading dose of three to five tablets S5 Fig followed by a flat maintenance dose of one tablet daily Fig 5 for 3 months.
Fig 5. Pharmacokinetic prophylactic profiles of chloroquine and hydroxychloroquine. Discussion Despite the enormous usage of chloroquine in malaria and hydroxychloroquine in rheumatological conditions for over half a century, their clinical pharmacology is not well understood. The case for evaluating large doses in COVID The moderate inhibitory activity of chloroquine and hydroxychloroquine against the SARS-CoV-2 virus in vitro suggests that if there is any benefit from these medicines, it is likely to require high concentrations of free drug in blood to drive high concentrations in the infected respiratory epithelium.
They can also include swelling of your tongue, mouth, or throat, which can cause trouble breathing. Call your doctor right away if you have an allergic reaction to Skyrizi. Skyrizi is prescribed to treat moderate to severe plaque psoriasis in some adults. Plaque psoriasis is an autoimmune disorder. It causes thick, red or dark-colored patches of skin on the elbows, knees, lower back, and scalp. As an autoimmune disorder, plaque psoriasis is caused by your immune system attacking your own cells.
Skirizi works by attaching to certain immune system proteins. This helps to ease swelling that leads to plaque psoriasis lesions on your skin. These include your overall health and any medical conditions you may have. These and other factors to consider before taking Skyrizi are described below. Taking medications, vaccines, foods, and other things with a certain drug can affect how the drug works.
These effects are called interactions. Before taking Skyrizi, be sure to tell your doctor about all medications you take including prescription and over-the-counter types. Also describe any vitamins, herbs, or supplements you use. Your doctor or pharmacist can tell you about any interactions these items may cause with Skyrizi. Live vaccines are made from live forms of a virus. Skyrizi can lower your ability to fight infections. So if you get a live vaccine, you may be more likely to get the infection the vaccine was meant to protect you from.
Skyrizi may not be right for you if you have certain medical conditions or other factors that affect your health. Talk with your doctor about your health history before you take Skyrizi.
Factors to consider include those in the list below. Tuberculosis TB. Your doctor will order a TB test for you before you start taking Skyrizi. Allergic reaction. Ask your doctor what other medications are better options for you.
Active infection or a history of reoccurring infections. And be sure to tell your doctor right away if you get an infection while taking this drug.
This might change in the future, though. In fact, studies are looking at using Skyrizi for this condition. Both Skyrizi and Humira are injections used to treat plaque psoriasis in adults. Humira is also prescribed to treat other conditions in adults and children.
However, Skyrizi and Humira each contain different active drugs. Skyrizi contains the active drug risankizumab-rzaa. Humira contains the active drug adalimumab. Both Skyrizi and Humira come as a solution inside prefilled syringes. But Humira is also available in a vial and in a prefilled pen. Yes, Skyrizi is a type of biologic drug. Biologic drugs are made from parts of living organisms.
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However, if you have severe symptoms, immediately call or your local emergency number or go to the nearest emergency room. Swallow it whole to avoid exposure to a potentially fatal dose. If you need surgery, tell the surgeon ahead of time that you are using this medicine. You may need to stop using the medicine for a short time. Do not stop using this medicine suddenly after long-term use , or you could have unpleasant withdrawal symptoms. Ask your doctor how to safely stop using the medicine.
Store at room temperature away from moisture and heat. Keep track of the amount of medicine used from each new bottle. Oxycodone is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription. Do not keep leftover acetaminophen and oxycodone pills or liquid. Ask your pharmacist where to locate a drug take-back disposal program. If there is no take-back program, flush any unused pills or liquid medicine down the toilet. Never crush or break an acetaminophen and oxycodone pill to inhale the powder or mix it into a liquid to inject the drug into your vein.
Since this medicine is used for pain, you are not likely to miss a dose. Skip any missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose. Seek emergency medical attention or call the Poison Help line at An overdose can be fatal, especially in a child or other person using this medicine without a prescription.
Overdose symptoms may include slow breathing and heart rate, severe drowsiness, muscle weakness, cold and clammy skin, pinpoint pupils, and fainting.
The first signs of an acetaminophen overdose include loss of appetite, nausea, vomiting, stomach pain, sweating, and confusion or weakness. This medicine may impair your thinking or reactions. Avoid driving or operating machinery until you know how this medicine will affect you. Dizziness or severe drowsiness can cause falls or other accidents.
Ask a doctor or pharmacist before using any other cold, allergy, pain, or sleep medication. Acetaminophen sometimes abbreviated as APAP is contained in many combination medicines.
Taking certain products together can cause you to get too much acetaminophen which can lead to a fatal overdose. Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. In rare cases, acetaminophen may cause a severe skin reaction that can be fatal.
This could occur even if you have taken acetaminophen in the past and had no reaction. Like other narcotic medicines, oxycodone can slow your breathing. Death may occur if breathing becomes too weak. Seek medical attention right away if you have symptoms of serotonin syndrome, such as: agitation, hallucinations, fever, sweating, shivering, fast heart rate, muscle stiffness, twitching, loss of coordination, nausea, vomiting, or diarrhea.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. Narcotic opioid medication can interact with many other drugs and cause dangerous side effects or death. Be sure your doctor knows if you also use:.
This list is not complete. Other drugs may interact with acetaminophen and oxycodone, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide. Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed. Every effort has been made to ensure that the information provided by Cerner Multum, Inc.
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