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New Drugs Promise Hope This World Sickle Cell Day - News - Nurses Arena Forum

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New Drugs Promise Hope This World Sickle Cell Day by katty : June 19, 2018, 02:20:18 PM
This winter, Shakir Cannon, a 34-year old passionate advocate for sickle cell disease research and education, died unexpectedly from a respiratory infection complicating his sickle cell disease. We knew each other from Twitter and he taught me both about sickle cell and his other strong interest, racial health disparities. It seems fitting to write about Shakir’s lessons and a look ahead at drug development for this rare disease, caused by a genetic mutation, for this World Sickle Cell Day.

One of our shared concerns was pain control. Severe pain in sickle cell occurs when the abnormal red blood cells lose their elasticity, collapsing into the sickle shape and blocking blood vessels, depriving them of oxygen. This results in severe pain, as is seen with gangrene as well.

Repeated episodes of oxygen deprivation (ischemia) can damage organs as well. If this happens to the spleen, the resulting dysfunction and cause increased susceptibility to severe infection and sepsis, especially from two respiratory pathogens,  Streptococcus pneumoniae and Haemophilus influenzae. Before effective vaccines that are now routinely given to young children, these pathogens used to be the major cause of death for young sicklers.

If the sickling strikes the brain, a stroke can occur, as happened with child violin prodigy Caesar Sant. In the lungs, the blockage is similar to a pulmonary embolism, or blood clot to the lung. In the bowel, it can cause dead gut, leading to sepsis as well as excruciating pain. Bone ischemia (lack of oxygen) can result in avascular necrosis, or bone death, and fractures.

Cannon had a stroke at age 3. Since then, he underwent blood transfusions every three weeks. But the transfusions cause a buildup of iron in the blood, and this required nightly subcutaneous injections for chelation therapy, to remove excess iron.

Treatment of pain in Emergency Rooms


Surveys show adults reporting pain on more than 50% of days and children on about 10%. African-Americans with SCD visit an emergency room two to six times more  than those without the disease.

Cannon tweeted, “Every 4 minutes, a Sickle Cell Disease (SCD) patient comes to an American ED for pain management.


Shakir Canon


What happens when a patient with sickle cell shows up in an Emergency Room with severe pain, often described as being akin to passing a kidney stone?

They wait…25% longer, even though their pain is often more severe.

They are often doubted. An emergency room nurse in Georgia told model Constance Bennett, “You’re too pretty to have a disease.”

Once they were believed, women still waited 20 minutes longer to receive pain meds than did men. In another study, patients with kidney stones receives pain meds 30” faster than those with sickle cell, although their pain scores were lower.

Even when they finally receive pain meds, it is likely to be inadequate.  Even with fractures, rather than sickle cell, African-Americans and Hispanics receive far less analgesics.

Opioid crisis


A looming problem is the growing crackdown on narcotic prescriptions.

Per WNYT, there were more than 20,000 deaths due to overdose from prescription pain relievers in 2015 alone.

Many patients with sickle cell disease are young and appear generally healthy, prompting them to be assumed to be drug-seeking rather than truly in pain. In fact, less than 10 percent of people with SCD develop and addiction, similar to that in the general public. Patients with sickle cell often receive an NSAID (non-steroidal anti-inflammatory drug) such as ketoralac (Toradol), which can cause kidney damage, instead of narcotics.

With his typical wry humor, Shakir tweeted, “Today is National Prescription Drug Take Back Day. Sorry, I have Sickle Cell, I will not be participating as I may need them.

Glimmers of progress


Stat New’s Sharon Begley (@sxbegle)  described care of people with SCD bluntly: “The U.S. health care system is killing adults with sickle cell disease.”

There is some encouraging news with, for the first time in decades, progress regarding novel treatments. Much of this is driven by better understanding of molecular biology and physiology, which in turn is resulting in identifying new targets for drugs.

Sickle cell is a genetic disease in which one amino acid, glutamate, is replaced by valine. This caused abnormal hemoglobin, which is what carries vital oxygen in our red blood cells, and these cells collapse, forming the characteristic sickle shape. Instead of being elastic and moving smoothly through our blood vessels, the deformed cells get stuck, blocking blood flow and causing the severe pain as the tissues are suffocated.

Until now, the mainstay of treatment was fluids and transfusions, but repeated blood infusions carries its own risk of immune reactions and iron overload. Hydroxyurea, a chemotherapy drug which increases fetal hemoglobin levels, was the only drug treatment until last year, along with bone marrow transplantation, which is risky and expensive. Gene editing with CRISPR might be able to repair the isolated genetic mutation responsible for SCD.

The first new drug in decades to be approved for treating sickle cell disease is L-glutamine, marketed as Endari by Emmaus Life Sciences. This amino acid is taken by mouth twice daily. Small clinical trials showed a modest reduction in pain (median, 3 vs. 4) and hospitalizations (median, 2 vs. 3), 4.5 day shorter hospital stays, and a greater reduction in acute chest syndrome (9% vs. 23%).

The drug costs $40,000 per year—but Dr. Zaidi notes this is less than a hospitalization.

Other new targets for drugs are well-reviewed by pediatric hematologists Drs. Ahmar U. Zaidi and Matthew Heeney. I like their focus on different mechanisms of action:

—Drugs that induce fetal hemoglobin or modify it to help it better carry oxygen. Intriguingly, studies are looking to repurpose metformin, a widely used drug for diabetes, for this.

—Interfering with the tendency of patients to coagulate blood too readily. Drugs in this class include Rivaroxaban and apixaban, N-Acetylcysteine (used for thinning mucous), heparins and anti-platelet drugs.

—Drugs that cause vasodilation, so that the sickled cells can’t clog the vessels. Besides novel agents, nitrous oxide and magnesium sulfate are two older medicines being looked at for repurposing for SCD.

—Anti-platelet drugs

—Nitric acid pathway stimulators which may help reduce the “stickiness” of the sickled cells to the blood vessel lining (endothelium), as well as other anti-adhesion agents

—Anti-inflammatory drugs. Rather than NSAIDS, statins (Simvastatin and atorvastatin), inhaled anti-asthmatics, and other drugs might have additional value for SCD.

Conclusion


Drug development takes years from identifying a chemical to safety and efficacy testing. The ability to now focus on specific targets in the cascade from the initial genetic mutation that causes sickle cell anemia through the cell deformities to blocking blood vessels, which causes the pain and injury, is an enormous breakthrough in our efforts to treat this devastating disease. For now, we need to focus on the lack of experienced doctors, disparities in access to care and treatment of pain in African-Americans, and the devastating effects the poorly orchestrated “war on drugs” is having on patients with sickle cell disease.

Source: https://www.forbes.com/sites/judystone/2018/06/19/new-drugs-promise-hope-this-world-sickle-cell-day/#7a2b203069ed

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