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Metformin Liver Toxicity

Metformin (glucophage) Side Effects & Complications

Metformin (glucophage) Side Effects & Complications

The fascinating compound called metformin was discovered nearly a century ago. Scientists realized that it could lower blood sugar in an animal model (rabbits) as early as 1929, but it wasn’t until the late 1950s that a French researcher came up with the name Glucophage (roughly translated as glucose eater). The FDA gave metformin (Glucophage) the green light for the treatment of type 2 diabetes in 1994, 36 years after it had been approved for this use in Britain. Uses of Generic Metformin: Glucophage lost its patent protection in the U.S. in 2002 and now most prescriptions are filled with generic metformin. This drug is recognized as a first line treatment to control blood sugar by improving the cells’ response to insulin and reducing the amount of sugar that the liver makes. Unlike some other oral diabetes drugs, it doesn’t lead to weight gain and may even help people get their weight under control. Starting early in 2000, sales of metformin (Glucophage) were challenged by a new class of diabetes drugs. First Avandia and then Actos challenged metformin for leadership in diabetes treatment. Avandia later lost its luster because it was linked to heart attacks and strokes. Sales of this drug are now miniscule because of tight FDA regulations. Actos is coming under increasing scrutiny as well. The drug has been banned in France and Germany because of a link to bladder cancer. The FDA has also required Actos to carry its strictest black box warning about an increased risk of congestive heart failure brought on by the drug. Newer diabetes drugs like liraglutide (Victoza), saxagliptin (Onglyza) and sitagliptin (Januvia) have become very successful. But metformin remains a mainstay of diabetes treatment. It is prescribed on its own or sometimes combined with the newer d Continue reading >>

Continuation Of Metformin Use After A Diagnosis Of Cirrhosis Significantly Improves Survival Of Patients With Diabetes

Continuation Of Metformin Use After A Diagnosis Of Cirrhosis Significantly Improves Survival Of Patients With Diabetes

Abstract The risks and benefits of metformin use in patients with cirrhosis with diabetes are debated. Although data on a protective effect of metformin against liver cancer development have been reported, metformin is frequently discontinued once cirrhosis is diagnosed because of concerns about an increased risk of adverse effects of metformin in patients with liver impairment. This study investigated whether continuation of metformin after cirrhosis diagnosis improves survival of patients with diabetes. Diabetic patients diagnosed with cirrhosis between 2000 and 2010 who were on metformin at the time of cirrhosis diagnosis were identified (n = 250). Data were retrospectively abstracted from the medical record. Survival of patients who continued versus discontinued metformin after cirrhosis diagnosis was compared using the log-rank test. Hazard ratio (HR) and 95% confidence interval (CI) were calculated using Cox's proportional hazards analysis. Overall, 172 patients continued metformin whereas 78 discontinued metformin. Patients who continued metformin had a significantly longer median survival than those who discontinued metformin (11.8 vs. 5.6 years overall, P < 0.0001; 11.8 vs. 6.0 years for Child A patients, P = 0.006; and 7.7 vs. 3.5 years for Child B/C patients, P = 0.04, respectively). After adjusting for other variables, continuation of metformin remained an independent predictor of better survival, with an HR of 0.43 (95% CI: 0.24-0.78; P = 0.005). No patients developed metformin-associated lactic acidosis during follow-up. Conclusion: Continuation of metformin after cirrhosis diagnosis reduced the risk of death by 57%. Metformin should therefore be continued in diabetic patients with cirrhosis if there is no specific contraindication. (Hepatology 2014;60:200 Continue reading >>

Metformin Effects On The Liver

Metformin Effects On The Liver

Physicians commonly prescribe Metformin if you have Type 2 diabetes and need help controlling your blood sugar. It reduces how much glucose you absorb from food and the amount your liver produces. On rare occasions, however, Metformin causes liver dysfunction and a serious metabolic condition involving the liver. For this reason, physicians exercise caution when prescribing Metformin to patients with liver disease. Video of the Day In healthy individuals, the liver produces glucose to keep blood sugar stable when you haven't eaten for several hours. Uncontrolled glucose production in the liver may cause high blood sugar in individuals with Type 2 diabetes. Researchers discovered that Metformin blocks critical enzymes involved in signaling the liver to produce glucose, thereby decreasing blood sugar levels. Their work was reported in the February 2013 edition of the journal "Nature." Lactic Acid Production Your muscles, brain, skin and other tissues produce a substance called lactic acid. Under normal circumstances, your liver and kidneys remove lactic acid from the blood and convert some of it to glucose. If a life-threatening metabolic condition known as lactic acidosis occurs, lactic acid levels increase faster than the liver can keep up with. Though its mechanism is unclear, Metformin causes lactic acidosis in a small segment -- up to 1 percent -- of patients, according to NYU Langone Medical Center. Almost all reported cases occurred in patients with underlying metabolic issues, such as liver or kidney disease. According to LiverTox, a publication of the U.S. National Library of Science drug database, Metformin may occasionally cause mild liver toxicity, characterized by minor elevations in liver enzymes. It occurs in less than 1 percent of the patients taking Metfo Continue reading >>

Hepatotoxicity Of Antidiabetic Drugs

Hepatotoxicity Of Antidiabetic Drugs

Mary Vagula, PhD Assistant Professor, Biology Department Gannon University Erie, Pennsylvania Assistant Professor Department of Pharmaceutical Sciences Lake Erie College of Osteopathic Medicine Erie, Pennsylvania US Pharm. 2008;33(5)(Diabetes suppl):3-9. Diabetes mellitus is a group of metabolic disorders in which the body does not produce enough or properly use insulin, resulting in hyperglycemia. Two major types of diabetes mellitus are recognized. Type 1, previously known as juvenile diabetes, is the result of the body's failure to produce enough insulin. This type of diabetes is prevalent in 5% to 10% of the diabetic population and is generally diagnosed in children.1 Type 2 diabetes is a result of insulin resistance (a condition in which the body cannot properly use insulin). This type of diabetes is more prevalent and is generally diagnosed in adults. Incidences of diabetes are increasing at epidemic proportions. According to the estimates of the World Health Organization, there are more than 180 million people with diabetes worldwide and this number is likely to more than double by 2030.2 The American Diabetes Association estimates that more than 20 million adults and children in the United States (which accounts for approximately 7% of the U.S. population) have diabetes.3 While more than 14 million patients have been diagnosed with diabetes, over six million individuals are estimated to be unaware of the fact that they have the disease and remain untreated.3 Diabetes-Associated Complications Diabetes is associated with a number of clinical complications such as cardiopathy, nephropathy, and retinopathy. Many individuals are not even aware that they have diabetes until they are diagnosed with one of these complications. Unmanaged diabetes can lead to life-threate Continue reading >>

Protective Effect Of Metformin On Cardiac And Hepatic Toxicity Induced By Adriamycin In Swiss Albino Mice

Protective Effect Of Metformin On Cardiac And Hepatic Toxicity Induced By Adriamycin In Swiss Albino Mice

Protective Effect of Metformin on Cardiac and Hepatic Toxicity Induced by Adriamycin in Swiss Albino Mice Diabetes Mellitus (DM) is a chronic disease that is characterized by deterioration of glycemic control. The disease is known to be caused by imbalance between Reactive Oxygen Species (ROS) and antioxidant defense systems. Hyperglycemia is commonly observed in a wide variety of diseases, including cancer. Although, therapy against glycemic control is used in all these diseases, the diabetic cancer patients are on additional therapy with anticancer drugs. The objective of present study was to investigate if metformin, a very popular antidiabetic agent can avert the cardiac and hepatic toxicity caused by Adriamycin (ADR), which is a commonly used cytotoxic drug. The experimental protocol included oral treatment of mice with different doses (62.5, 125 and 250 mg kg-1 day-1) of metformin for 7 days. Some mice in each group were injected i.p. with ADR (15 mg kg-1), 24 h prior to sacrifice. In each case animals were killed, 24 h after the last treatment, blood sample was collected and plasma was separated for analysis of AST, ALT and CK-MB. Liver and heart from the same animals were excised for analysis of proteins, nucleic acids, MDA and NP-SH. The results obtained revealed that pretreatment with metformin (i) reduced the ADR-induced increase in the concentrations of AST, ALT and CK-MB (ii) protected against the ADR-induced increase of MDA and decrease of DNA and NP-SH in both cardiac and hepatic tissues. These results demonstrate that the treatment with metformin might be useful to protect cardiac and hepatic toxicity. The exact mechanism of action is not known, however; the inhibition of ADR-induced increase of plasma enzymes and MDA and depletion of DNA and NP-SH by m Continue reading >>

Side Effects Of Metformin: What You Should Know

Side Effects Of Metformin: What You Should Know

Metformin is a prescription drug used to treat type 2 diabetes. It belongs to a class of medications called biguanides. People with type 2 diabetes have blood sugar (glucose) levels that rise higher than normal. Metformin doesn’t cure diabetes. Instead, it helps lower your blood sugar levels to a safe range. Metformin needs to be taken long-term. This may make you wonder what side effects it can cause. Metformin can cause mild and serious side effects, which are the same in men and women. Here’s what you need to know about these side effects and when you should call your doctor. Find out: Can metformin be used to treat type 1 diabetes? » Metformin causes some common side effects. These can occur when you first start taking metformin, but usually go away over time. Tell your doctor if any of these symptoms are severe or cause a problem for you. The more common side effects of metformin include: heartburn stomach pain nausea or vomiting bloating gas diarrhea constipation weight loss headache unpleasant metallic taste in mouth Lactic acidosis The most serious side effect metformin can cause is lactic acidosis. In fact, metformin has a boxed warning about this risk. A boxed warning is the most severe warning from the Food and Drug Administration (FDA). Lactic acidosis is a rare but serious problem that can occur due to a buildup of metformin in your body. It’s a medical emergency that must be treated right away in the hospital. See Precautions for factors that raise your risk of lactic acidosis. Call your doctor right away if you have any of the following symptoms of lactic acidosis. If you have trouble breathing, call 911 right away or go to the nearest emergency room. extreme tiredness weakness decreased appetite nausea vomiting trouble breathing dizziness lighthea Continue reading >>

Clarifying Metformin's Role And Risks In Liver Dysfunction.

Clarifying Metformin's Role And Risks In Liver Dysfunction.

Abstract OBJECTIVES: To explore why some clinicians hesitate to use metformin in patients with liver disease and whether routine monitoring of transaminases before and during metformin therapy is substantiated. DATA SOURCES: A Medline literature search was conducted (1966 to June 2008) using the terms metformin, lactic acidosis, liver disease, chronic liver disease, hepatotoxicity, hypoxia, risks, and predisposing factors. DATA SYNTHESIS: Manufacturer prescribing information and some current medical and lay press literature caution against metformin use in patients with liver disease. This recommendation is interpreted variably by different prescribers, with some believing that the caution implies metformin can cause or worsen liver injury. Others believe that liver disease predisposes patients to developing lactic acidosis. A clearer understanding of how and when to screen for liver dysfunction in patients before and during metformin therapy is thus warranted. CONCLUSION: Metformin does not appear to cause or exacerbate liver injury and, indeed, is often beneficial in patients with nonalcoholic fatty liver disease. Nonalcoholic fatty liver frequently presents with transaminase elevations but should not be considered a contraindication to metformin use. Literature evidence of liver disease being associated with metformin-associated metabolic acidosis is largely represented by case reports. Most such patients had cirrhosis and were also actively using alcohol. Patients with cirrhosis, particularly those with encephalopathy, may have arterial hypoxemia, which heightens the risk of developing lactic acidosis. For this reason, identifying patients with cirrhosis before initiating metformin seems prudent. Because cirrhosis can exist in the face of normal liver transaminases, Continue reading >>

Metformin Ameliorates Arsenic Trioxide Hepatotoxicity Via Inhibiting Mitochondrial Complex I

Metformin Ameliorates Arsenic Trioxide Hepatotoxicity Via Inhibiting Mitochondrial Complex I

Cell Death & Disease volume 8, page e3159 (2017) Arsenic trioxide (ATO) is a well-accepted chemotherapy agent in managing promyelocytic leukemia. ATO often causes severe health hazards such as hepatotoxicity, dermatosis, neurotoxicity, nephrotoxicity and cardiotoxicity. The production of reactive oxygen species, (ROS) play a significant role in ATO-induced hepatotoxicity. The oral hypoglycemic drug, metformin, is considered to be a potential novel agent for chemoprevention in the treatment of cancer. Moreover, metformin has also been shown to have hepatoprotective effects. In the present study, we demonstrated that metformin protected normal hepatocytes from ATO-induced apoptotic cell death in vitro and in vivo. Gene expression screening revealed that glucose metabolism might be related to the metformin-induced protective effect on ATO-treated AML12 cells. The metformin-promoted or induced glycolysis was not responsible for the protection of AML12 cells from ATO-induced apoptotic cell death. Instead, metformin increased the intracellular NADH/NAD+ ratio by inhibiting mitochondrial respiratory chain complex I, further decreasing the intracellular ROS induced by ATO. Treatment with low glucose or rotenone, a mitochondrial respiratory chain complex I inhibitor, also protected AML12 cells from ATO-induced apoptotic cell death. We show for the first time that metformin protects the hepatocyte from ATO by regulating the mitochondrial function. With its properties of chemoprevention, chemosensitization and the amelioration of liver damage, metformin has great prospects for clinical application other than type 2 diabetes mellitus (T2DM). Arsenic trioxide (As2O3, ATO) has long been used as a therapeutic agent for certain severe diseases including malaria, syphilis, leukemia, tu Continue reading >>

Metformin

Metformin

DRUG RECORD Introduction Metformin is a first line agent for the treatment of type 2 diabetes that can be used alone or in combination with sulfonylureas, thiazolidinediones or other hypoglycemic agents. Metformin has not been linked to serum enzyme elevations during therapy and is an exceeding rare cause of idiosyncratic clinically apparent acute liver injury. Background Metformin (met for' min) is a biguanine and acts as an insulin sensitizing agent, probably through activation of adenosine monophosphate dependent (AMP) kinase in liver and muscle tissue. Metformin is often associated with weight loss making it a preferred, first line agent for management of overweight patients with type 2 diabetes. Initial concerns about the possibility that metformin (like the related biguanine phenformin) could induce lactic acidosis have been largely resolved, although the agent is contraindicated in patients with renal dysfunction because of this reason and should be used with caution in patients with significant liver disease. Metformin was approved for use in the United States in 1995 and is currently one of the most commonly used drugs for the therapy of diabetes, with more than 30 million prescriptions filled in the United States yearly. Metformin is available in many generic forms in tablets of 500, 850 or 1000 mg, the recommended regimen being to start with 500 or 850 mg once daily and increase based upon tolerance to 1000 to 2550 mg daily taken in two divided doses. Commercial formulations include Glucophage, Glumetza, Fortamet and Riomet. Metformin is also available in extended release formulations and in combinations with sulfonylureas such as glipizide (Metaglip) or glyburide (Glucovance), DDP-4 inhibitors such as alogliptin (Kazano), linagliptin (Jentadueto), saxaglipti Continue reading >>

The Liver Disease Epidemic You Need To Know About

The Liver Disease Epidemic You Need To Know About

Extracts of milk thistle have long been used for liver protection. It is estimated that 30-40% of American liver disease patients use the active ingredient, silymarin.60 Silymarin is itself composed of six major active molecules such as silybin, which are known as flavolignans, with exceptional antioxidant and anti-inflammatory activity.60,61 Modern science is rediscovering the use of milk thistle extracts for reduction of the impact of NAFLD and preventing its progression to NASH. One very effective combination is silymarin plus vitamin E and phospholipids (such as phosphatidylcholine); this approach improves the overall antioxidant activity of the compound.62 In animal studies the combination limited liver depletion of the natural antioxidant glutathione, and reduced mitochondrial stress damage.63 Human trials have shown that a preparation providing 376 mg silybin, 776 mg phosphatidylcholine, and 360 mg vitamin E produces therapeutic effects in patients with a variety of different forms of liver damage, improving insulin resistance, reducing liver fat accumulation, and reducing blood levels of markers of liver scarring.22,23,64 Open studies have shown that silymarin also significantly increased survival rates in patients with alcohol-induced liver cirrhosis.61 Phospholipids—fat molecules with phosphate groups attached—are major constituents of cell membranes in mammals.65 One of the most important phospholipids in humans is phosphatidylcholine (PC), which is available in small amounts in the diet. Higher ratios of PC to other phospholipids in cell membranes help to assure membrane integrity in the face of oxidative and other stresses; they also help limit the progression of NAFLD into NASH.65 A particularly rich source of PC molecules is a mixture called polyenyl Continue reading >>

Metformin

Metformin

Metformin, marketed under the trade name Glucophage among others, is the first-line medication for the treatment of type 2 diabetes,[4][5] particularly in people who are overweight.[6] It is also used in the treatment of polycystic ovary syndrome.[4] Limited evidence suggests metformin may prevent the cardiovascular disease and cancer complications of diabetes.[7][8] It is not associated with weight gain.[8] It is taken by mouth.[4] Metformin is generally well tolerated.[9] Common side effects include diarrhea, nausea and abdominal pain.[4] It has a low risk of causing low blood sugar.[4] High blood lactic acid level is a concern if the medication is prescribed inappropriately and in overly large doses.[10] It should not be used in those with significant liver disease or kidney problems.[4] While no clear harm comes from use during pregnancy, insulin is generally preferred for gestational diabetes.[4][11] Metformin is in the biguanide class.[4] It works by decreasing glucose production by the liver and increasing the insulin sensitivity of body tissues.[4] Metformin was discovered in 1922.[12] French physician Jean Sterne began study in humans in the 1950s.[12] It was introduced as a medication in France in 1957 and the United States in 1995.[4][13] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[14] Metformin is believed to be the most widely used medication for diabetes which is taken by mouth.[12] It is available as a generic medication.[4] The wholesale price in the developed world is between 0.21 and 5.55 USD per month as of 2014.[15] In the United States, it costs 5 to 25 USD per month.[4] Medical uses[edit] Metformin is primarily used for type 2 diabetes, but is increasingly be Continue reading >>

Metformin-induced Hepatotoxicity

Metformin-induced Hepatotoxicity

Metformin is the first choice oral antidiabetic drug for type 2 diabetes and currently the most consumed. Although gastrointestinal intolerance is frequent, metformin-induced hepatotoxicity is rare. Fewer than 10 cases have been reported (1). In all of those cases, metformin was associated with concomitant intake of other potentially hepatotoxic drugs. We present what we feel may be the first documented case of hepatotoxicity due to metformin with no other drug interference. A 61-year-old man was admitted to the hospital with a 3-day history of painless jaundice. He had no history of liver disease or toxic habits and denied previous consumption of drugs or herbal products, but had been taking metformin (1,700 mg/day for 6 weeks) after being diagnosed with type 2 diabetes. Laboratory tests showed a mixed pattern of liver damage (total bilirubin 2.9 mg/dL, direct bilirubin 2.4 mg/dL, aspartate aminotransferase [AST] 290 units/L [≤40], alanine aminotransferase [ALT] 861 units/L [≤35], γ-glutamyltransferase [GGT] 861 units/L [≤35], and alkaline phosphatase [ALP] 622 units/L [≤120]). International normalized ratio and eosinophil counts were normal. Diagnostic work-up ruled out viral hepatitis A, B, and C, as well as autoimmune and metabolic liver disease (negative antinuclear antibodies, anti-mitochondrial antibodies, smooth muscle antibodies, anti-liver/kidney microsomal antibodies; normal ceruloplasmin, α-1 antitrypsin, copper). Abdominal ultrasound and cholangio-MRI showed no pathological findings. The patient refused a liver biopsy. After stopping metformin, the patient's clinical condition progressively improved and liver enzymes normalized in 30 days. He was discharged with only recommendations to modify his lifestyle. Six weeks after discharge, the patient a Continue reading >>

The Liver Disease Epidemic You Need To Know About

The Liver Disease Epidemic You Need To Know About

Metformin Because of the central role of insulin resistance in development of NAFLD and NASH, it makes sense to evaluate insulin-sensitizing drugs for their prevention.36,37 No oral antidiabetic drug has as broad a spectrum of action, and as hefty a safety record, as the drug metformin, which is finding a host of new applications outside of diabetes itself.38,39 Studies of metformin for NAFLD and NASH have multiplied in the past few years with almost uniform success. Metformin in the amount of 500 mg three times daily for 6 months produced dramatic improvements in liver blood flow and velocity as detected by Doppler ultrasound exams.40 A similar dose of metformin (20 mg/kg body weight for one year, or approximately 1,450 mg/day for a 160-pound person) produced reductions in blood markers of liver cell death, though the improvement lasted only 3 months.41 On the other hand, improved insulin sensitivity has repeatedly been shown in patients with NASH and NAFLD who take metformin, and many studies have now shown sustainable improvements in liver chemistry measurements.36,42 And a recent study showed significant reduction in the prevalence and severity of fatty liver after 6 months’ treatment with 850 mg metformin twice daily in obese adolescents, an extremely challenging group of patients.43 Metformin is an ideal drug for combination studies because of its safety and compatibility with other therapies. A 2008 study revealed that the combination of metformin with the potent antioxidant N-acetyl cysteine (NAC) for 12 months improved both liver chemistry results and measurements of insulin resistance.44 Liver tissue evaluated by biopsy also showed improved appearance for the earlier signs of disease. Finally, in 2010 we learned of an entirely new mechanism by which metformi Continue reading >>

Diabetes: How Do I Help Protect My Liver?

Diabetes: How Do I Help Protect My Liver?

If I have diabetes, is there anything special I need to do to take care of my liver? Answers from M. Regina Castro, M.D. You're wise to wonder about steps to protect your liver. Diabetes raises your risk of nonalcoholic fatty liver disease, a condition in which excess fat builds up in your liver even if you drink little or no alcohol. This condition occurs in at least half of those with type 2 diabetes. It isn't clear whether the condition appears more often in people with type 1 diabetes than in the general population because obesity, which is a risk factor, occurs with similar frequency in both groups. Other medical conditions, such as high cholesterol and high blood pressure, also raise your risk of nonalcoholic fatty liver disease. Fatty liver disease itself usually causes no symptoms. But it raises your risk of developing liver inflammation or scarring (cirrhosis). It's also linked to an increased risk of liver cancer, heart disease and kidney disease. Fatty liver disease may even play a role in the development of type 2 diabetes. Once you have both conditions, poorly managed type 2 diabetes can make fatty liver disease worse. Your best defense against fatty liver disease includes these strategies: Work with your health care team to achieve good control of your blood sugar. Lose weight if you need to, and try to maintain a healthy weight. Take steps to reduce high blood pressure. Keep your low-density lipoprotein (LDL, or "bad") cholesterol and triglycerides — a type of blood fat — within recommended limits. Don't drink too much alcohol. If you have diabetes, your doctor may recommend an ultrasound examination of your liver when you're first diagnosed and regular follow-up blood tests to monitor your liver function. Continue reading >>

Metformin-induced Hepatotoxicity

Metformin-induced Hepatotoxicity

Metformin is the first choice oral antidiabetic drug for type 2 diabetes and currently the most consumed. Although gastrointestinal intolerance is frequent, metformin-induced hepatotoxicity is rare. Fewer than 10 cases have been reported (1). In all of those cases, metformin was associated with concomitant intake of other potentially hepatotoxic drugs. We present what we feel may be the first documented case of hepatotoxicity due to metformin with no other drug interference. A 61-year-old man was admitted to the hospital with a 3-day history of painless jaundice. He had no history of liver disease or toxic habits and denied previous consumption of drugs or herbal products, but had been taking metformin (1,700 mg/day for 6 weeks) after being diagnosed with type 2 diabetes. Laboratory tests showed a mixed pattern of liver damage (total bilirubin 2.9 mg/dL, direct bilirubin 2.4 mg/dL, aspartate aminotransferase [AST] 290 units/L [≤40], alanine aminotransferase [ALT] 861 units/L [≤35], γ-glutamyltransferase [GGT] 861 units/L [≤35], and alkaline phosphatase [ALP] 622 units/L [≤120]). International normalized ratio and eosinophil counts were normal. Diagnostic work-up ruled out viral hepatitis A, B, and C, as well as autoimmune and metabolic liver disease (negative antinuclear antibodies, anti-mitochondrial antibodies, smooth muscle antibodies, anti-liver/kidney microsomal antibodies; normal ceruloplasmin, α-1 antitrypsin, copper). Abdominal ultrasound and cholangio-MRI showed no pathological findings. The patient refused a liver biopsy. After stopping metformin, the patient's clinical condition progressively improved and liver enzymes normalized in 30 days. He was discharged with only recommendations to modify his lifestyle. Six weeks after discharge, the patient a Continue reading >>

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