How Does Invokana Cause Ketoacidosis?
Invokana (canagliflozin) is a popular diabetes medicationin a new class of drugs called SGLT-2 inhibitors. Manufactured by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, Invokana was the first SGLT-2 inhibitor drug to be FDA approved in 2013. Later, Janssen combined the active ingredient found in Invokana with metformin, another oral diabetes drug, and the combination drug is known as Invokamet. Invokanaand other SGLT-2 inhibitors work by affecting the sodium-glucose-linked transporter 2 (or sodium glucose so-transporter 2 as it is sometimes called) protein located in the duct system of the kidney. The glucose transporters are responsible for reabsorbing glucose back into the kidney. As inhibitors of the SGLT-2 protein, oral medications like Invokana block the reabsorption of glucose into the kidney. Rather than re-enter the kidney, the glucose it taken out and excreted in the urine so it is no longer in the body. Diabetic ketoacidosis (also known as DKA) is caused when ketones are abnormally high in the body, causing harm. Ketones are produced in the body when it is unable to use glucose in the cells and instead breaks down fat as a fuel source for energy. The byproduct of this fat metabolism leads to ketones, and causes the blood to become too acidic. The condition can develop rapidly and can be life-threatening over a short period of time. Initial symptoms of ketoacidosis may include: Feeling lightheaded or on the verge of fainting In type-2 diabetes, the development of ketoacidosis is rare, and the condition is usually seen in type-1 diabetes. Because of this rarity, individuals with type-2 diabetes may not recognize the symptoms. Ketoacidosis can also cause the body to develop other disease conditions, including cardiovascular issues. A dangerously lo Continue reading >>
Do Sglt2 Inhibitors Like Invokana Cause Ketoacidosis?
In an announcement released May 15, the FDA called attention to 20 case reports it had received between March 2013 and June 6, 2014 of 20 persons, most with type 2 diabetes, who had been treated with Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors such as canagliflozin (Invokana), dapagliflozin (Farxiga, Forxiga), and empagliflozin (Jardiance), for an average of 2 weeks, but in some for as much as six months and who had diabetic ketoacidosis. Diabetic ketoacidosis is typically a condition of uncontrolled diabetes seen in type 1 diabetes, or in adolescents with severe type 2 diabetes, with elevated blood glucose and evidence of ketoacidosis with elevated blood or urine ketones and acidosis with a high blood “anion gap,” reflecting the presence of substances called organic anions in the bloodstream. Another unusual feature noted in the FDA release was that blood glucose levels were typically only mildly elevated, below 200 mg/dl. What is ketoacidosis? The body uses insulin not only to move glucose into cells, but also as a signal to increase fat and protein synthesis in fat cells and other body tissues. When a persons who does not have diabetes goes a long period without eating, ketones act as an important source of energy. Their insulin concentrations in blood fall, acting as a negative signal to cause the body to break down fat into fatty acids and protein into amino acids. A subsequent step, also signaled by low levels of insulin, is the further breakdown of fatty acids and the removal of amino groups from certain amino acids to form ketone bodies, particularly an organic acid called beta-hydroxy butyrate, as well as acetoacetic acid, which is less important in ketoacidosis but which is measured in urine ketone test strips. For a diabetic person who has true insu Continue reading >>
What Is Type 2 Diabetes?
INVOKANA® can cause important side effects, including: Amputations. INVOKANA® may increase your risk of lower-limb amputations. Amputations mainly involve removal of the toe or part of the foot; however, amputations involving the leg, below and above the knee, have also occurred. Some people had more than one amputation, some on both sides of the body. You may be at a higher risk of lower-limb amputation if you: have a history of amputation, have heart disease or are at risk for heart disease, have had blocked or narrowed blood vessels (usually in leg), have damage to the nerves (neuropathy) in the leg, or have had diabetic foot ulcers or sores. Call your doctor right away if you have new pain or tenderness, any sores, ulcers, or infections in your leg or foot. Your doctor may decide to stop your INVOKANA® for a while if you have any of these signs or symptoms. Talk to your doctor about proper foot care Dehydration. INVOKANA® can cause some people to become dehydrated (the loss of too much body water), which may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension). You may be at higher risk of dehydration if you have low blood pressure, take medicines to lower your blood pressure (including diuretics [water pills]), are on a low sodium (salt) diet, have kidney problems, or are 65 years of age or older Vaginal yeast infection. Women who take INVOKANA® may get vaginal yeast infections. Symptoms include: vaginal odor, white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese), or vaginal itching Yeast infection of the penis (balanitis or balanoposthitis). Men who take INVOKANA® may get a yeast infection of the skin around the penis. Symptoms include: redness, itching, or swelling o Continue reading >>
Canagliflozin-induced Diabetic Ketoacidosis
Go to: Case Report A 62-year-old woman with type 2 diabetes mellitus, hypertension, gastroesophageal reflux disease, and depression presented with 4 days of nausea, vomiting, and generalized weakness. Her symptoms became progressively worse such that by the day of admission she had decreased appetite, polydipsia, polyuria, and could not walk. The patient denied fever, chills, abdominal pain, diarrhea, or sick contacts. Home medications were atorvastatin, metformin, sucralfate, pioglitazone, canagliflozin, exenatide, omeprazole, fluoxetine, ranitidine, lisinopril, and alprazolam. On physical examination, the patient’s vital signs included a temperature of 38.3°C, blood pressure 134/61, heart rate 107, respiratory rate 24, and oxygen saturation of 100% on 2 liters nasal cannula oxygen. The patient appeared ill and distressed. She had dry mucous membranes, clear lung sounds bilaterally, and her heart was regular without murmurs, gallops, or rubs. Her abdomen was soft and nontender with present bowel sounds. Extremities showed no edema, and she had no focal neurological findings. Laboratory revealed a metabolic acidosis with a pH of 7.08 and anion gap >17. Chemistry panel indicated sodium 134 mEq/L, potassium 5.2 mEq/L, chloride 112 mEq/L, CO2 <5 mEq/L, blood urea nitrogen 22 mg/dL, and creatinine 1.3 mg/dL. Blood glucose was 213 mg/dL, and urinalysis revealed glucose 2+ and ketones 3+. Serum ketones were present at 1:8 dilution, with a lactic acid of 0.8 mmol/L. The patient’s hemoglobin A1C (HbA1c) was 11.1. The patient was admitted to the intensive care unit for severe metabolic acidosis secondary to DKA. Aggressive fluid resuscitation was undertaken and an insulin drip initiated. Within 6 hours, the anion gap metabolic acidosis improved. On further review of her med Continue reading >>
Ketoacidosis Not As Great As Thought In Diabetes Patients Taking Invokana
Home / Resources / Articles / Ketoacidosis Not as Great as Thought in Diabetes Patients Taking Invokana Ketoacidosis Not as Great as Thought in Diabetes Patients Taking Invokana Retrospective cases showed that some patients treated with canagliflozin had severe diabetes ketoacidosis The Food Drug Administration (FDA) had previously reported that Invokana (canagliflozin) had cases of diabetes ketoacidosis (DKA) in type 2 diabetes; however, a recent study done by Janssen Research & Development shows that patients who were taking canagliflozin had lower events of DKA than previously reported. This study was performed in 17,596 patients to demonstrate the severity of diabetes ketoacidosis in type 2 diabetes mellitus patients using canagliflozin. In this trial, there were 12 cases (0.07%) of serious adverse events of DKA and related events were reported. The authors found 4 cases (0.07%) with an incidence rate of 0.522 in patients who were treated with canagliflozin 100 mg, 6 cases (0.11%) with an incidence rate of 0.763 in patients who were treated with canagliflozin 300 mg and 2 cases (0.03%) with an incidence rate of 0.238 of those on comparator; each incidence rate was per one thousand patient-years. Most of those patients who were diagnosed had DKA precipitating factors, including some with type 1 diabetes/latent autoimmune, were on insulin, and blood glucose level were >300 mg/dL (16.7 mmol/L). The authors concluded that, DKA and related events occurred at a low frequency in the canagliflozin type 2 diabetes program, with an incidence consistent with limited existing observational data in the general population with type 2 diabetes. Invokana is beneficial in the management of type 2 diabetes in patients with hypertension and obesity. Use with caution in elderly patien Continue reading >>
Severe Ketoacidosis Associated With Canagliflozin (invokana): A Safety Concern
Case Reports in Critical Care Volume 2016 (2016), Article ID 1656182, 3 pages 1Section of Pulmonary and Critical Care Medicine, Providence Hospital and Medical Center, 16001 W 9 Mile Road, Southfield, MI 48075, USA 2Department of Internal Medicine, Providence Hospital and Medical Center, 16001 W 9 Mile Road, Southfield, MI 48075, USA Academic Editor: Kurt Lenz Copyright © 2016 Alehegn Gelaye et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Canagliflozin (Invokana) is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor that was first introduced in 2013 for the treatment of type 2 diabetes mellitus (DM). Though not FDA approved yet, its use in type 1 DM has been justified by the fact that its mechanism of action is independent of insulin secretion or action. However, some serious side effects, including severe anion gap metabolic acidosis and euglycemic diabetic ketoacidosis (DKA), have been reported. Prompt identification of the causal association and initiation of appropriate therapy should be instituted for this life threatening condition. 1. Introduction More than 5 million patients are admitted annually to intensive care units (ICUs) in the United States. A number of life threatening medical conditions, including diabetic ketoacidosis, can be associated with metabolic acidosis. Metabolic acidosis may also arise from several drugs and toxins through a variety of mechanisms. Since approval of the first-in-class drug in 2013, data have emerged suggesting that Sodium Glucose Transporter-2 (SGLT-2) inhibitors, including canagliflozin, may lead to diabetic ketoacidosis . We pre Continue reading >>
Sglt2 Inhibitors And Diabetic Ketoacidosis: What's Behind The Fda Warning
With commentary by Yehuda Handelsman, MD, FACP, FACE, FNLA, an endocrinologist in private practice in Tarzana, CA, Medical Director and Principal Investigator of the Metabolic Institute of America and President of the American College of Endocrinology People with diabetes who take blood sugar-lowering drugs called SGLT2 inhibitors were recently warned by the U.S. Food and Drug Administration (FDA) that they should watch for signs of a life-threatening condition called diabetic ketoacidosis. canagliflozin (Invokana) dapagliflozin (Farxiga) empagliflozin (Jardiance) as well as the combination pills: canagliflozin plus metformin (Invokamet) dapagliflozin plus metformin extended-release (Xigduo XR) empagliflozin plus linagliptin (Glyxambi). “Diabetic ketoacidosis (DKA) can be deadly,” says Amy Hess-Fischl, MS, RD, LDN, BC-ADM, CDE, an advanced practice dietitian at the University of Chicago Kovler Diabetes Center and a member of EndocrineWeb’s advisory board. “DKA is usually more of a concern for people with type 1 diabetes, but this warning is for people with type 2 diabetes who are taking the SGLT2 inhibitors, as well as people with type 1 diabetes who take these medications off label. DKA — dangerously high acid levels in the bloodstream — happens when your body breaks down fat instead of glucose for energy, releasing acidic compounds called ketones. Early symptoms include thirst, frequent urination and sweet, fruity breath, Hess-Fischl says. You may feel tired and confused, and develop nausea, stomach pain, vomiting and difficulty breathing. “If you notice symptoms, call your doctor immediately. But if you’re vomiting, can’t catch your breath or are concerned, go to the emergency room,” she says. Putting the Risk in Perspective The FDA warning, relea Continue reading >>
Invokana Side Effects
Invokana belongs to a class of drugs known as sodium-glucose cotransporter-2 (SGLT2) inhibitors. These drugs lower blood sugar levels in type 2 diabetes patients, but they may also cause serious side effects like diabetic ketoacidosis (DKA), limb amputations, and kidney problems. Some patients have filed lawsuits against Johnson & Johnson and other drug companies, claiming that drug makers did not sufficiently warn about these side effects. If you or a loved one suffered DKA or kidney problems after taking Invokana or another SGLT2 inhibitor, you may be eligible for a lawsuit. Contact us for a free legal consultation. Diabetic Ketoacidosis (DKA) Diabetic ketoacidosis (DKA) is a severe diabetes complication that occurs when the body produces high levels of blood acids called ketones. Ketones are produced when cells don’t receive the energy they need from glucose and begin to break down fat for energy. Ketone accumulation acidifies the blood and can poison the body. DKA may send the patient into a diabetic coma and can even be fatal. In May 2015, the FDA warned that Invokana and other SGLT2 inhibitors may lead to DKA. In May 2015, the U.S. Food and Drug Administration (FDA) warned that Invokana and other SGLT2 inhibitors may lead to DKA. The FDA based the warning on 20 cases of DKA reported to the agency over a one-year period. This is an unusually high number of cases considering that DKA most commonly occurs in patients with type 1 diabetes. All of the patients required hospitalization and/or a visit to an emergency room. In December 2015, the FDA declared that SGLT2 inhibitors would now be required to carry warnings about the risk of excessive blood acids. The FDA added that the drugs must also warn against serious urinary tract infections. Symptoms of DKA include: N Continue reading >>
Using Invokana To Treat Diabetes Can Lead To Diabetic Ketoacidosis
Millions of people are living with type 2 diabetes in the United States. Depending on the severity of the condition, some patients may need to take medication to control their symptoms and prevent dangerous complications. Unfortunately, however, one such medication used to treat type 2 diabetes has since been linked to the dangerous condition diabetic ketoacidosis. This medication, Invokana, was designed to improve glycemic control and lower blood sugar levels in diabetic patients. It is also accompanied by several potentially harmful side effects. FDA Warning About Ketoacidosis In May of 2015, the U.S. Food and Drug Administration issued a warning with regard to Invokana and Invokamet use. The warning contained the following information: Type 2 diabetes medications Invokana and Invokamet may lead to diabetic ketoacidosis. Patients taking the drugs developed diabetic ketoacidosis in 20 reported cases, with additional reports continuing to unfold. In these cases, the patients needed an emergency room visit or hospitalization. People taking Invokana must be on the lookout for symptoms of ketoacidosis. Some of the symptoms that may arise include difficulty breathing, vomiting, nausea, confusion, unusual fatigue, and abdominal pain. As a result of the warning, many patients who have taken Invokana to treat their diabetes and later developed harmful side effects are pursuing legal action against the drug’s maker. What Is Ketoacidosis? When the body produces high levels of blood acids known as ketones, this is known as diabetic ketoacidosis. This condition develops when the body cannot produce enough insulin. Without sufficient insulin, the body begins to break down fat as fuel instead of sugar. This process then produces a build-up of acids in the bloodstream known as keto Continue reading >>
Diabetes medications like Invokana (canagliflozin) have been linked to ketoacidosis and kidney injuries. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a group of drugs FDA-approved to treat low blood sugar in adults with Type 2 diabetes. The FDA has warned, however, that SGLT2 inhibitors like Invokana can lead to a condition known as diabetic ketoacidosis (DKA), characterized by excessive acid levels in the blood. The FDA has also warned about bone breaks and kidney injuries associated with SGLT2 inhibitors. A number of manufacturers—including Johnson & Johnson, which makes Invokana—sell diabetic medications that are associated with harmful side effects. Hundreds of lawsuits currently await trial against Invokana in federal and state courts. Plaintiffs argue that Janssen Pharmaceuticals (a subsidiary of Johnson & Johnson) misrepresented the risks of the medication and failed to warn patients about Invokana’s side effects. If you suffered an injury caused by Invokana or a similar SGLT2 inhibitor, you may be entitled to compensation. Contact us today for a free legal consultation. Serious Invokana Side Effects Invokana and similar drugs have strong links to ketoacidosis. There is also evidence that the drugs can cause impaired kidney function, heart problems, bone breaks, and other health complications. Ketoacidosis Symptoms of ketoacidosis, as noted by the American Diabetes Association, include: Trouble breathing Nausea Vomiting Abdominal pain Confusion or difficulty concentrating Unusual fatigue or sleepiness Dry or flushed skin Kidney Injuries Adverse event data has also pointed to possible impaired kidney function caused by Invokana and similar drugs. Adverse renal functions associated with these drugs include: Kidney failure Kidney impairment Dehydratio Continue reading >>
Sglt2 Inhibitor Diabetes Drugs May Cause Ketoacidosis: Fda
SGLT2 Inhibitor Diabetes Drugs May Cause Ketoacidosis: FDA The US Food and Drug Administration (FDA) warned today that sodium-glucose cotransporter-2 (SGLT2) inhibitors used to treat type 2 diabetes may lead to ketoacidosis requiring hospitalization. The warning includes the SGLT2 inhibitors canagliflozin (Invokana, Johnson & Johnson), dapagliflozin (Farxiga, AstraZeneca), and empagliflozin (Jardiance, Lilly/Boehringer), as well as three combination products that include an SGLT2 inhibitor: canagliflozin plus metformin (Invokamet, Johnson & Johnson), dapagliflozin plus metformin extended release (Xigduo XR, AstraZeneca), and empagliflozin plus linagliptin (Glyxambi, Lilly/Boehringer). A search of the FDA Adverse Event Reporting System database identified 20 cases of acidosis reported as diabetic ketoacidosis (DKA), ketoacidosis, or ketosis in patients treated with SGLT2 inhibitors from March 2013 to June 6, 2014, the FDA said . Ketoacidosis is not typically observed in patients with type 2 diabetes, the FDA notes, and the DKA case presentations were "atypical in that glucose levels were only mildly elevated at less than 200 mg/dL in some reports, while patients with type 1 diabetes who have DKA typically have glucose levels greater than 250 mg/dL." Signs of ketoacidosis include difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue and sleepiness. "Healthcare professionals should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing these signs or symptoms; discontinue SGLT2 inhibitors if acidosis is confirmed; and take appropriate measures to correct the acidosis and monitor sugar levels," the FDA advises. In Half of Cases, No Triggering Factor for DKA In all cases, a diagnosis of DKA or ketoacidosis wa Continue reading >>
How Does Invokana Cause Ketoacidosis?
Invokana, a popular diabetes medication, has been linked to a number of serious side effects, including ketoacidosis. Invokana belongs to a class of drugs known as sodium-glucose cotransporter-2 (SGLT2) inhibitors. These drugs areused to lower the blood sugar of adult type 2 diabetes patients. Invokana and other medications like it work to lower blood glucose levels by inhibiting some kidney function. Potential side effects of themedication include, but are not limited to: Kidney problems, including kidney failure The FDA has issued a warning about diabetes medication side effects, which has in turn prompted new studies about the drug. A new ketoacidosis study, published in the medical journal Diabetes Care, found that type 1 diabetes patients who take Invokanamay face an increased risk of ketoacidosis. Invokana has only been approved for the treatment of type 2 diabetes, not type 1 diabetes. However, it is often prescribed off-label to patients with type 1 diabetes. The study found that patients taking 100 mg dosage had a 5.4 percent rate of ketone-related Invokana side effects, which included ketoacidosis. Patients taking the 300 mg dosage experienced Invokana side effects at a 9.4 percent rate. It is important to recognize Invokana ketoacidosis symptoms, as they can lead to major health problems. Diabetic ketoacidosis symptoms include: Though the increased risk of ketoacidosis is fairly low, the condition can sometimes result in severe health complications, even involving emergency hospital treatment. Symptoms of ketoacidosis should be taken seriously. After FDA warnings about Invokana side effects, as well as recent studies, many consumers have begun pursuing Invokana lawsuits. Plaintiffs involved in Invokana lawsuits allege that the drugs maker failed to adequatel Continue reading >>
Invokana Ketoacidosis Lawsuit
Our lawyers are investigating Invokana Ketoacidosis Lawsuits on behalf of individuals who took Invokana and suffered from ketoacidosis or any of the following injuries: Heart Attack Stroke Kidney Failure Amputation If you or a loved one took Invokana and suffered a serious side effect you may be eligible for financial compensation through an Invokana Lawsuit. Our lawyers are offering free, no obligation lawsuit evaluations – contact us today to discuss a potential Invokana lawsuit. Over $1 billion in settlements and verdicts for our clients If we don’t win or settle your case, you don’t owe anything 95 years of combined experience Call A Lawyer Now – 888-660-6473 Lawsuits are being filed against Janssen Pharmaceuticals and their parent company Johnson & Johnson, the manufacturers of the diabetes drug Invokana, for failing to warn about several serious and potentially deadly side effects, like ketoacidosis. The FDA has issued several recent warnings about side effects of Invokana, and many people are coming forward after developing ketoacidosis and other serious injuries. Johnson & Johnson marketed Invokana as a safe and effective drug, when in fact it was linked to serious complications. Jennifer Anzo from California filed a lawsuit against Johnson & Johnson after she suffered diabetic ketoacidosis while taking Invokana. She was hospitalized with severe dehydration, severe abdominal pain, low blood pressure, and tachycardia. Anzo claims she would not have used Invokana if she had known about potential side effects. Invokana lawsuits allege that the manufacturer of Invokana: Did not provide enough warnings about the serious side effects Manufactured and marketed Invokana without performing proper testing Misrepresented Invokana’s safety and efficacy through mar Continue reading >>
Three Diabetes Drugs Linked To Ketoacidosis, Fda Warns
NASHVILLE -- Three type 2 diabetes drugs -- canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance) -- may lead to ketoacidosis, the FDA warned today. The sodium-glucose co-transporter-2 (SGLT2) inhibitors are designed to lower blood sugar in patients with diabetes, but the FDA is investigating a connection between the drugs and dangerously high acid levels in the blood. They are also looking at whether changes will need to be made to the prescribing information, they said in the warning, which is posted online. At least two studies presented here at the annual meeting of the American Association of Clinical Endocrinologists have found a connection between the SGLT2 inhibitors and diabetic ketoacidosis (DKA). "Healthcare professionals should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing these signs or symptoms," the FDA said. "Discontinue SGLT2 inhibitors if acidosis is confirmed, and take appropriate measures to correct the acidosis and monitor sugar levels." The signs and symptoms listed included difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue or sleepiness. The FDA is issuing the warning after they searched their database of adverse event complaints, they said in an announcement. From March 2013 to June 2014 there were 20 cases of DKA reported, most of them with type 2 diabetes as the indication. Hospitalization was required in all of the cases, and the median time to onset was 2 weeks after starting the drug. "I would encourage that these cases be studied so we can learn the scenarios behind them so they can be broadcast," said Farhad Zangeneh, MD, medical director of Endocrine, Diabetes and Osteoporosis Clinic, in an interview with MedPage Today. "The important Continue reading >>
Invokana & Ketoacidosis: Fda Takes Action
Introduced to the US market in 2013, Janssen Pharmaceutical’s diabetes drug Invokana met with immediate fanfare. The Johnson & Johnson subsidiary hailed its new product as an “important [and] much-needed” development in the fight against type 2 diabetes. Forbes acclaimed the drug’s “market potential,” while highlighting Invokana’s ability to “attack blood sugar right from the get go.” The US Food & Drug Administration heralded Invokana as an “advance [in] innovation.” Invokana’s market potential was quickly realized, with an estimated 2 million prescriptions written in 2014 alone. But soon after, the FDA would make a troubling announcement: Invokana had been linked to a major health risk. Does Invokana Cause Ketoacidosis? According to an FDA Safety Announcement released on May 15, 2015, Invokana and a number of drugs like it “may lead to ketoacidosis, a serious condition where the body produces high levels of blood acids called ketones that may require hospitalization.” Less than a year later, the agency would turn to concrete action, adding a new warning to Invokana’s label. This major revision instructed physicians to immediately discontinue the drug in patients with signs and symptoms of ketoacidosis. SGLT2 Inhibitors Invokana belongs to a new class of drugs known as SGLT2, or sodium-glucose cotransporter-2, inhibitors. Other products in the class include: Invokamet Farxiga Jardiance Each of these drugs presents a serious risk of ketoacidosis, according to the FDA. To learn more about the agency’s response to Invokana’s potential safety risks, click here. In response to recent developments, patients who experienced ketoacidosis after taking Invokana, many of whom face costly medical bills, lost work and considerable suffering, have b Continue reading >>