Tuesday, December 15, 2020

FDA Approves Lampit (nifurtimox) for the Treatment of Chagas Disease in Children

Bayer announced  that  the United States Food and Drug Administration (FDA) has approved Lampit (nifurtimox) for use in pediatric patients (from birth to less than 18 years of age and weighing at least 2.5 kg) for the treatment of Chagas disease (American Trypanosomiasis) caused by Trypanosoma cruzi (T. cruzi).1 Lampit, an antiprotozoal medication will be available in a new, dividable tablet that can be split on the scored lines by hand.1-3 According to prescribing instructions, the tablet is specially formulated to disperse in water, which can aid in the dosing and administration to pediatric patients who may have difficulty swallowing whole or half tablets. 





This indication is approved under accelerated approval based on the number of treated patients who became immunoglobulin G (IgG) antibody negative or who showed an at least 20% decrease in optical density on two different IgG antibody tests against antigens of T. cruzi. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Chagas is an infectious tropical disease that affects an estimated 300,000 people in the U.S.4 The disease is endemic throughout much of Latin America, though it is a growing health concern in the U.S.5,6 Approval of a treatment for pediatric patients is an important milestone.

“Chagas disease can strike at any age, and early detection and treatment are important. This is especially relevant for children,” said Aleksandra Vlajnic, MD, senior vice president and head of Medical Affairs for the Americas at Bayer. “The importance of treating children is a major reason behind Bayer’s collaboration with health authorities to enhance access to Lampit as a means to provide treatment for Chagas disease.”

The FDA approval is based on results from the Chagas disease in children treated with nifurtimoxstudy, the first part of the largest Phase III program ever conducted in pediatric patients for the treatment of Chagas disease.

“In the study, Lampit showed good antiprotozoal activity in patients from 0 to 17 years old,” said Jaime Altcheh, MD, head of the Department of Parasitology and Chagas disease at the Ricardo Gutierrez Children’s Hospital in Buenos Aires, Argentina, and coordinating investigator of the Phase III trial.

The Phase III Lampit study was the first part of a prospective, randomized (to dosing regimen), double-blind evaluation of the efficacy, safety, and pharmacokinetics of nifurtimox in 330 children with Chagas disease.1 The study was conducted at 25 investigational sites in Argentina, Bolivia, and Colombia between 2016 and 2018.7 In the study, 330 pediatric patients with serologic evidence of T. cruzi infection (without Chagas disease-related cardiovascular and/or gastrointestinal symptoms) were randomly assigned in a 2:1 fashion to receive either a 60-day (n=219) or a 30-day (n=111) Lampit treatment regimen, and were followed up for one year after end of treatment.1 The results showed superiority in favor of the nifurtimox 60-day arm compared to the nifurtimox 30-day arm (not an approved dosing regimen). For additional clinical trial information, go to clinicaltrials.gov NCT02625974 and see full prescribing information. 

The study will continue with a second part (Lampit SECURE) to follow patients for an additional three years to confirm efficacy and safety.

Now that Lampit is approved for pediatric use in the U.S., Bayer is working to ensure access to the drug for all patients through retail channels. Commercially insured patients may qualify for a $0 co-pay to help with their out-of-pocket costs. For uninsured patients who cannot afford Lampit, the Bayer U.S. Patient Assistance Foundation, a charitable organization, will help eligible patients obtain the prescription medication at no cost. Restrictions apply. See Program Details for full information. Lampit is not approved in the U.S. for use in adults 18 years of age or older.

https://www.rxlist.com/lampit-drug.htm

Monday, December 14, 2020

Fluvoxamine may prevent serious illness in COVID-19 patients, study suggests: Antidepressant drug repurposed for patients with coronavirus infection




In a preliminary study of COVID-19 patients with mild-to-moderate disease who were attempting to recover in their homes, researchers at Washington University School of Medicine in St. Louis have found that the drug fluvoxamine seems to prevent some of the most serious complications of the illness and make hospitalization and the need for supplemental oxygen less likely.

The study, a collaboration between the university's Department of Psychiatry and Division of Infectious Diseases, involved 152 patients infected with SARS-CoV-2, the virus that causes COVID-19. Researchers compared the outcomes of those treated with fluvoxamine to the outcomes of those given an inactive placebo. After 15 days, none of the 80 patients who had received the drug experienced serious clinical deterioration. Meanwhile, six of the 72 patients given placebo (8.3%) became seriously ill, with four requiring hospitalization.

The study is published online Nov. 12 in the Journal of the American Medical Association.

"The patients who took fluvoxamine did not develop serious breathing difficulties or require hospitalization for problems with lung function," said the paper's first author, Eric J. Lenze, MD, the Wallace and Lucille Renard Professor of Psychiatry. "Most investigational treatments for COVID-19 have been aimed at the very sickest patients, but it's also important to find therapies that prevent patients from getting sick enough to require supplemental oxygen or to have to go to the hospital. Our study suggests fluvoxamine may help fill that niche."

Fluvoxamine is used commonly to treat obsessive-compulsive disorder (OCD), social anxiety disorder and depression. It is in a class of drugs known as selective serotonin-reuptake inhibitors (SSRIs), but unlike other SSRIs, fluvoxamine interacts strongly with a protein called the sigma-1 receptor. That receptor also helps regulate the body's inflammatory response.

"There are several ways this drug might work to help COVID-19 patients, but we think it most likely may be interacting with the sigma-1 receptor to reduce the production of inflammatory molecules," said senior author Angela M Reiersen, MD, an associate professor of psychiatry. "Past research has demonstrated that fluvoxamine can reduce inflammation in animal models of sepsis, and it may be doing something similar in our patients."

Reiersen said the drug's effects on inflammation could prevent the immune system from mounting an overwhelming response, which is thought to occur in some COVID-19 patients who seem to improve after a few days of illness and then worsen. Many of those patients end up hospitalized, and some die.

In an innovative twist to research during the pandemic, the study was conducted remotely. When a symptomatic patient tested positive and enrolled in the study, research staff delivered the medication or inactive placebo to them, along with thermometers, automatic blood pressure monitors and fingertip oxygen sensors.

"Our goal is to help patients who are initially well enough to be at home and to prevent them from getting sick enough to be hospitalized," said Caline Mattar, MD, an assistant professor of medicine in the Division of Infectious Diseases. "What we've seen so far suggests that fluvoxamine may be an important tool in achieving that goal."

For two weeks, subjects took either the antidepressant drug or placebo sugar pills while having daily interactions with members of the research team -- via phone or computer. That allowed patients to report on their symptoms, oxygen levels and other vital signs. If patients suffered shortness of breath or were hospitalized for pneumonia, or their oxygen saturation levels fell below 92%, their conditions were considered to have deteriorated.

"The good news is that not a single person taking the active medication experienced deterioration," Reiersen said. "We believe this drug may be the reason, but we need to study more patients to make sure."

The researchers will begin a larger study in the next few weeks. Lenze, the director of the Healthy Mind Lab at the School of Medicine, is an expert in using mobile and internet technology to conduct clinical trials. He said that although this initial study involved patients in the St. Louis region, the next phase of the research will involve patients from throughout the country.

"We bring the study to the patients, giving them tools to monitor their health at home," Lenze said. "Our hope is that we can keep these patients healthy enough to avoid hospitalization."

This work was supported by the Taylor Family Institute for Innovative Psychiatric Research, the Bantly Foundation, the Center for Brain Research in Mood Disorders at Washington University and the COVID-19 Early Treatment Fund. Additional support from the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH). Grant number UL1 TR002345.




Thursday, November 19, 2020

FDA Approves Zeposia (ozanimod) for Relapsing Forms of Multiple Sclerosis

Myers Squibb Company (NYSE: BMY)  announced that the U.S. Food and Drug Administration (FDA) approved Zeposia (ozanimod) 0.92 mg for the treatment of adults with relapsing forms of multiple sclerosis (RMS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.1 Zeposia, an oral medication taken once daily, is the only approved sphingosine-1-phosphate (S1P) receptor modulator that offers RMS patients an initiation with no genetic test and no label-based first-dose observation required for patients.1,4,5 An up-titration scheme should be used to reach the maintenance dosage of Zeposia, as a transient decrease in heart rate and atrioventricular conduction delays may occur.
Ozanimod.svg

Multiple sclerosis (MS) is a disease in which the immune system attacks the protective myelin sheath that covers the nerves, creating damaging lesions that make it harder for signals to travel between each nerve cell.6,7 This “signal breakdown” can lead to symptoms and relapses.6,8
“With the FDA approval of Zeposia, appropriate patients with relapsing forms of multiple sclerosis will have another oral treatment option with meaningful efficacy to help address the disease’s hallmark relapses and brain lesions,”9 said Samit Hirawat, M.D., chief medical officer, Bristol Myers Squibb. “Zeposia has substantial clinical potential, and we are well positioned with our heritage in transformational science to ensure this innovative compound ultimately benefits as many patients as possible.”
The approval is based on data from the largest pivotal, head-to-head RMS studies with an active comparator to date: the randomized, active-controlled Phase 3 SUNBEAM™ (safety and efficacy of Zeposia versus interferon beta-1a in relapsing multiple sclerosis) and RADIANCE™ (safety and efficacy of the selective sphingosine 1-phosphate receptor modulator Zeposia in relapsing multiple sclerosis) Part B clinical trials of more than 2,600 adults.1,2,3,10 In both trials – as compared to AVONEX® (interferon beta-1a), Zeposia delivered powerful efficacy as measured by annualized relapse rate (ARR), as well as on the number and size of brain lesions.1,2,3
  • Zeposia demonstrated a relative reduction in ARR versus AVONEX of 48% through one year and 38% at two years (absolute ARR of 0.18 versus 0.35 and 0.17 versus 0.28, respectively).1,2,3
  • At one year, treatment with Zeposia reduced the number of T1-weighted gadolinium-enhanced (GdE) brain lesions more than AVONEX (0.16 vs 0.43), a relative reduction of 63%, and reduced the number of new or enlarging T2 lesions (1.47 vs. 2.84), a relative reduction of 48%.1,3
  • At two years, treatment with Zeposia reduced the number of T1-weighted gadolinium-enhanced (GdE) brain lesions more than AVONEX (0.18 vs 0.37), a relative reduction of 53%.1,2 Zeposia also reduced the number of new or enlarging T2 lesions vs AVONEX (1.84 vs 3.18), a relative reduction of 42%.1,2
There was no statistically significant difference in the three-month and six-month confirmed disability progression between Zeposia- and AVONEX- treated patients over two years.1
Zeposia demonstrated acceptable safety and tolerability in the Phase 3 SUNBEAM and RADIANCE Part B trials.1,2,3 Zeposia is contraindicated in patients who in the last six months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III/IV heart failure; patients who have a presence of Mobitz type II second or third-degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial, unless the patient has a functioning pacemaker; patients with severe untreated sleep apnea; and patients taking a monoamine oxidase inhibitor.1 Zeposia is associated with the following Warnings and Precautions: increased risk of infections, bradyarrhythmia and atrioventricular conduction delays, liver injury, fetal risk, increased blood pressure, respiratory effects, macular edema, posterior reversible encephalopathy syndrome, additive immunosuppressive effects from prior immune-modulating treatments, severe increase in disability after stopping Zeposia, and immune system effects after stopping Zeposia.1 Please see Important Safety Information for additional details. The most common adverse reactions (incidence ≥4%) were upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.1


Before initiation of treatment with Zeposia, all patients require assessments including a recent complete blood count including lymphocyte count (within six months or after discontinuation of prior MS therapy), an ECG to determine whether preexisting conduction abnormalities are present, a recent liver function test (within six months), and consideration of current and prior medications, including vaccinations.1 For patients with a history of uveitis or macular edema, an ophthalmic assessment is required.
Treatment for relapsing forms of multiple sclerosis is critical to address this devastating neurological disease.11 I’m excited, with the introduction of Zeposia, I will have a new oral option to offer my RMS patients that has demonstrated efficacy and safety,”1 said Bruce Cree, M.D., Ph.D., M.A.S., professor of clinical neurology, University of California San Francisco (UCSF) Weill Institute for Neurosciences and clinical research director, UCSF MS Center.
“Multiple sclerosis is an unpredictable and often disabling disease that affects nearly one million people in the United States.9,12 Ongoing treatment with disease-modifying therapy can reduce the number of disease attacks,”11 said Bruce Bebo, executive vice president of research, National Multiple Sclerosis Society. “Each person can respond differently to these medications, which is why having treatment options is so important. We are pleased that there will now be another effective treatment option for people with MS.”
As the country’s healthcare system is dealing with the unprecedented COVID-19 pandemic, Bristol Myers Squibb has made the decision to delay commercialization of Zeposia. The Company made the decision based on what’s in the best health interest of our patients, customers and employees. Bristol Myers Squibb will continue to monitor the environment and will partner with the neurology community to inform launch timing.
A Marketing Authorization Application for Zeposia for the treatment of adults with relapsing-remitting multiple sclerosis in the European Union is currently under review with the European Medicines Agency (EMA). A regulatory decision from the EMA is expected in the first half of 2020.
https://en.wikipedia.org/wiki/Ozanimod



FDA Approves Zeposia (ozanimod) for Relapsing Forms of Multiple Sclerosis

Tuesday, November 17, 2020

Kratom Seems Safe for Pain, Anxiety, Opioid Withdrawal



Mitragyna speciosa111.JPG
We know that, Mitragyna speciosa (commonly known as kratom is a tropical evergreen tree in the coffee family native to Southeast Asia. It is indigenous to ThailandIndonesiaMalaysiaMyanmar, and Papua New Guinea, where it has been used in traditional medicines since at least the nineteenth century. Kratom has opioid properties and some stimulant-like effects.
Kratom is used for symptoms of pain, anxiety, depression, and opioid withdrawal, and serious adverse events are uncommon, according to a the results of a survey published online Feb. 3 in Drug and Alcohol Dependence.
Albert Garcia-Romeu, Ph.D., from the Johns Hopkins University School of Medicine in Baltimore, and colleagues conducted a cross-sectional online survey in 2017 involving 2,798 kratom users.


The researchers found that kratom was mainly taken orally in doses of 1 to 3 g (49 percent) and was most commonly used daily (59 percent). Kratom was used for pain, anxiety, and depression (91, 67, and 65 percent, respectively); effectiveness was highly rated. Overall, 41 percent (1,144 individuals) used kratom to stop or reduce prescription or illicit opioid use, with reports of decreased opioid withdrawal and craving in relation to use; continuous abstinence from opioids for more than one year was attributed to kratom use by 411 individuals. Adverse effects of kratom were reported by about one-third of respondents; these adverse effects were mainly rated as mild in severity and lasted ≤24 hours. Only 0.6 percent of participants sought treatment for adverse events. Two percent of participants met criteria for past-year moderate or severe kratom-related substance use disorder.
"Although our findings show kratom to be relatively safe according to these self-reports, unregulated medicinal supplements raise concerns with respect to contamination or higher doses of the active chemicals, which could increase negative side effects and harmful responses," Garcia-Romeu said in a statement.






https://www.sciencedirect.com/science/article/abs/pii/S0376871620300144

https://en.wikipedia.org/wiki/Mitragyna_speciosa





Friday, November 13, 2020

FDA Approves Isturisa (osilodrostat) for the Treatment of Cushing’s Disease

The U.S. Food and Drug Administration today approved Isturisa (osilodrostat) oral tablets for adults with Cushing’s disease who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease. 

Osilodrostat.svg

Cushing’s disease is a rare disease in which the adrenal glands make too much of the cortisol hormone. Isturisa is the first FDA-approved drug to directly address this cortisol overproduction by blocking the enzyme known as 11-beta-hydroxylase and preventing cortisol synthesis.
“The FDA supports the development of safe and effective treatments for rare diseases, and this new therapy can help people with Cushing’s disease, a rare condition where excessive cortisol production puts them at risk for other medical issues,” said Mary Thanh Hai, M.D., acting director of the Office of Drug Evaluation II in the FDA’s Center for Drug Evaluation and Research. “By helping patients achieve normal cortisol levels, this medication is an important treatment option for adults with Cushing’s disease.”
Cushing’s disease is caused by a pituitary tumor that releases too much of a hormone called adrenocorticotropin, which stimulates the adrenal gland to produce an excessive amount of cortisol. The disease is most common among adults between the ages of 30 to 50, and it affects women three times more often than men. Cushing’s disease can cause significant health issues, such as high blood pressure, obesity, type 2 diabetes, blood clots in the legs and lungs, bone loss and fractures, a weakened immune system and depression. Patients may have thin arms and legs, a round red full face, increased fat around the neck, easy bruising, striae (purple stretch marks) and weak muscles.
Isturisa’s safety and effectiveness for treating Cushing’s disease among adults was evaluated in a study of 137 adult patients (about three-quarters women) with a mean age of 41 years. The majority of patients either had undergone pituitary surgery that did not cure Cushing’s disease or were not surgical candidates. In the 24-week, single-arm, open-label period, all patients received a starting dose of 2 milligrams (mg) of Isturisa twice a day that could be increased every two weeks up to 30 mg twice a day. At the end of this 24-week period, about half of patients had cortisol levels within normal limits. After this point, 71 patients who did not need further dose increases and tolerated the drug for the last 12 weeks entered an eight-week, double-blind, randomized withdrawal study where they either received Isturisa or a placebo (inactive treatment). At the end of this withdrawal period, 86% of patients receiving Isturisa maintained cortisol levels within normal limits compared to 30% of patients taking the placebo.
The most common side effects reported in the clinical trial for Isturisa were adrenal insufficiency, headache, vomiting, nausea, fatigue and edema (swelling caused by fluid retention). Hypocortisolism (low cortisol levels), QTc prolongation (a heart rhythm condition) and elevations in adrenal hormone precursors (inactive substance converted into a hormone) and androgens (hormone that regulates male characteristics) may also occur in people taking Isturisa.
Isturisa is taken by mouth twice a day, in the morning and evening as directed by a health care provider. After treatment has started, a provider may re-evaluate dosage, depending upon the patient’s response.
Isturisa received Orphan Drug Designation, which is a special status granted to a drug intended to treat a rare disease or condition.
https://en.wikipedia.org/wiki/Osilodrostat

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FDA Approves Isturisa (osilodrostat) for the Treatment of Cushing’s Disease

FDA Approves Durysta (bimatoprost implant) to Lower Intraocular Pressure In Open-Angle Glaucoma or Ocular Hypertension Patients

Allergan plc (NYSE: AGN), a leading global pharmaceutical company with more than 70 years of heritage in eye care, announced the U.S. Food and Drug Administration (FDA) approval.  With this approval, Durysta becomes the first intracameral, biodegradable sustained-release implant indicated to reduce intraocular pressure (IOP) in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT).


Bimatoprost.png


"Today's FDA approval marks a breakthrough milestone for the glaucoma community and provides a much-needed option for patients challenged with topical drops or needing alternative options," said David Nicholson, Chief Research and Development Officer, Allergan. "At Allergan, our mission is to contribute meaningful strategies that help preserve people's vision, while ensuring that therapies are mindful of the realities of administration and compliance. As a commitment to the ongoing development of this innovation, Allergan has five ongoing Phase 3 studies with Durysta to support further potential FDA label enhancement and rest of the world approvals."

The FDA approval is based on results from the two 20-month (including 8-month extended follow up) Phase 3 ARTEMIS studies evaluating 1,122 subjects on the efficacy and safety of Durysta versus twice daily topical timolol drops, an FDA accepted comparator for registrational clinical trials, in patients with OAG or OHT. In the two Phase 3 ARTEMIS studies, Durysta reduced IOP by approximately 30 percent from baseline over the 12-week primary efficacy period, meeting the predefined criteria for non-inferiority to the study comparator.
"Millions of people are living with glaucoma, one of the leading causes of vision loss; however, new treatment options are needed to help doctors and patients better manage this disease," said Felipe Medeiros , M.D., Ph.D., Distinguished Professor of Ophthalmology and Vice-Chair for Technology, Director Clinical Research Unit, Department of Ophthalmology, Duke University. "The ARTEMIS trials demonstrated that Durysta lowered IOP in patients by approximately 30 percent and demonstrated a duration of effect through the 12-week primary efficacy period. As the first FDA-approved intracameral, biodegradable sustained-release implant providing continuous drug delivery, Durysta has the potential to significantly shift the paradigm for treating glaucoma."
With the launch of Durysta, Allergan proudly expands availability of Allergan EyeCue®, a proven reimbursement service for eye care professionals to facilitate patient benefit verification, savings program enrollment for eligible patients, and prior authorization (PA) assistance for Allergan Eye Care products.

Tuesday, September 15, 2020

New insecticide compounds from plant used for traditional Chinese medicine

For hundreds of years, practitioners of traditional Chinese medicine have used an herb called Stemona sessilifolia as a remedy for parasitic infections, such as those caused by pinworms and lice. Now, researchers reporting in ACS' Journal of Agricultural and Food Chemistry have identified 10 compounds that might be responsible for the herb's effectiveness. But there's a twist: The insecticides are produced by symbiotic microbes that live within the plant's cells -; not by S. sessilifolia itself.
Stemona curtisii CBM.png
Endophytes are microorganisms that live inside plant cells but do not cause apparent disease. Instead, some endophytes help plants survive by enhancing growth, nutrient acquisition, or resistance to drought or pests. Therefore, scientists are investigating endophytes as potential sources of new medicines and agrichemicals. Xiachang Wang, Lihong Hu and colleagues wanted to screen endophytes from S. sessilifolia for insecticidal activity.
To isolate endophytes, the researchers spread fresh, cut-up pieces of S. sessilifolia on agar plates. They then collected the bacteria that grew on the plates, analyzed the DNA and identified the microbes as Streptomyces clavuligerus. Using nuclear magnetic resonance spectroscopy and mass spectrometry, the team purified 10 new compounds from the bacteria with structures similar to a class of insecticides known as pyrroles. Testing the substances on insects revealed that they were strongly toxic to aphids and moderately toxic to spider mites. A bacterial extract containing all of the compounds had greater lethal activity than any compound alone. These substances, or the bacteria that produce them, could be promising new natural pesticides, the researchers say.
The authors acknowledge funding from the National Key R&D Program, the Nature Science Foundation of Jiangsu Higher Education Institutions of China, the Outstanding Scientific and Technological Innovation Team Program of Jiangsu Higher Education Institutions, Jiangsu Provincial "Double Creation Program" and the Priority Academic Program Development of Jiangsu Higher Education Institutions.
https://en.wikipedia.org/wiki/Stemona

Saturday, September 12, 2020

Combined drug treatment for lung cancer and secondary tumors



In continuation of my update on alectiniberlotinib and  osimertinib

Alectinib structure.svg 
                                                                   alectinib

                                                   Erlotinib Structural Formulae.png 
                                                                     erlotinib
                                                  Osimertinib.svg
                                                                             Osimertinib


Researchers at Kanazawa University report in the Journal of Thoracic Oncology a promising novel approach for a combined treatment of the most common type of lung cancer and associated secondary cancers in the central nervous system. The approach lies in combining two cancer drugs, with one compensating for a resistance side effect of the other.

In 20 to 40% of patients with cancer, metastasis (the development of secondary tumors) in the central nervous system (CNS) occurs. CNS metastasis impacts negatively on a patient's quality of life, and is associated with a poor health prognosis. In a form of cancer known as ALK-rearranged non-small-cell lung cancer (NSCLC), CNS metastasis is known to persist when drugs targeting primary tumors are used. Now, Seiji Yano from Kanazawa University and colleagues have investigated the origins for the resistence to such drugs, and tested a new therapeutic strategy on a mouse model.

The researchers looked at the drug alectinib. Although used in standard treatments for advanced ALK-rearranged NSCLC, approximately 20 to 30% of patients treated with alectinib develop CNS metastasis, which is attributed to acquired resistance to the drug.
By treating mice first injected with tumor cells with alectinib daily for 16 weeks, the scientists obtained a mouse model displaying alectinib resistance. By biochemical analyses of the mouse brains, Yano and colleagues were able to link the resistance to the activation of a protein known as epidermal growth factor receptor (EGFR). This activation is, in turn, a result of an increase in production of amphiregulin (AREG), a protein that binds to EGFR and in doing so 'activates' it.
Based on this insight, the researchers tested the effect of administering drugs used for inhibiting the action of EGFR in combination with alectinib treatment. The experiments showed that a combination treatment of alctinib with either erlotinib or osimertinib—two existing EGFR-inibiting drugs—prevented the progression of CNS metastasis, controlling the condition for over 30 days.
The scientists conclude that the combined use of alectinib and EGFR-inhibitors could overcome alectinib resistance in the mouse model of leptomeningeal carcinomatosis (LMC), a particular type of CNS metastasis. Quoting Yano and colleagues: "Our findings may provide rationale for clinical trials to investigate the effects of novel therapies dual-targeting ALK and EGFR in ALK-rearranged NSCLC with alectinib-resistant LMC."
Non-small-cell lung cancer
Non-small-cell lung carcinoma (NSCLC) and small-cell lung carcinoma (SCLC) are the two types of lung cancer. 85% of all lung cancers are of the NSCLC type. NSCLCs are less sensitive to chemotherapy than SCLCs, making drug treatment of the highest importance.
Alectinib is a drug used for treating NSCLC, with good efficiency. However, 20-30% of patients taking the  develop secondary cancer in the central nervous system (CNS), which is associated with an acquired resistance to alectinib. Seiji Yano from Kanazawa University and colleagues have now made progress towards a novel therapy against this resistance: a combination of alectinib with other drugs.
Epidermal growth factor receptor inhibitors
The drugs that Yano and colleagues tested in combination with alectinib on a mouse model were of a type known as epidermal growth factor receptor (EGFR) inhibitors, including osimertinib and erlotinib. Both are being used as medication for treating NSCLC. The former was approved in 2017 as cancer treatment by the U.S. Food and Drug Administration and the European Commission. Yano and colleagues obtained results showing that EGFR inhibitors counteract resistance to alectinib and have therefore potential in novel therapies for NSCLC and secondary cancers in the CNS.
https://medicalxpress.com/news/2017-11-osimertinib-progression-free-survival-asian-egfr-mutated.html

Tuesday, September 8, 2020

Nourianz Approved to Treat 'Off' Episodes in Parkinson Disease

Istradefylline.png
In continuation of my update on Levodopa 
Nourianz (istradefylline) tablets have been approved as an add-on treatment to levodopa/carbidopa for adults with Parkinson disease experiencing "off" episodes, the U.S. Food and Drug Administration announced yesterday.
The drug is available in 20-mg or 40-mg doses, but the maximum recommended dosage in patients taking CYP3A4 inhibitors and those with moderate hepatic impairment is 20 mg once daily. The safety information for Nourianz states that use of the drug should be avoided in these patient populations.
Data from four 12-week placebo-controlled clinical studies demonstrated the effectiveness of Nourianz, a selective adenosine A2A receptor antagonist, in treating "off" episodes in 1,143 PD patients who were receiving treatment with levodopa/carbidopa. Compared with patients who received placebo, patients who received Nourianz experienced a statistically significant decrease in daily "off" time from baseline.
The most commonly reported adverse reactions with Nourianz included dyskinesia, dizziness, constipation, nausea, hallucination, and insomnia. The FDA noted that physicians should monitor patients for the development or progression of dyskinesia while taking Nourianz. A reduction in dosage or stoppage of Nourianz should be considered in the case of hallucinations, psychotic behavior, or impulsive/compulsive behavior. Nourianz should not be used during pregnancy, and women with childbearing potential should use contraception during treatment.
https://pubchem.ncbi.nlm.nih.gov/compound/Istradefylline#section=2D-Structure          https://en.wikipedia.org/wiki/Istradefylline
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Saturday, August 22, 2020

Tramadol Linked to Increased Hip Fracture Risk in Adults Aged ≥50


In continuation of my update on Tramadol

Tramadol as a racemic mixture.svg

For older adults, initiation of tramadol is associated with an increased risk for hip fracture compared with initiation of codeine, ibuprofen, and other commonly used nonsteroidal anti-inflammatory drugs, according to a study published online Feb. 5 in the Journal of Bone and Mineral Research.
Jie Wei, Ph.D., from Central South University in Changsha, China, and colleagues examined the association between tramadol and the risk for hip fracture among individuals aged 50 years or older without a history of hip fracture, cancer, or opioid use disorder. Five sequential propensity score-matched cohort studies were assembled, including participants initiating tramadol (146,956 participants) or one of the following: codeine (146,956 participants), naproxen (115,109 participants), ibuprofen (107,438 participants), celecoxib (43,130 participants), or etoricoxib (27,689 participants).
The researchers identified 518 hip fractures in the tramadol cohort and 401 in the codeine cohort (3.7 versus 2.9/1,000 person-years) during one-year follow-up (hazard ratio, 1.28 for tramadol versus codeine). Hip fracture risk was higher in the tramadol cohort compared with the naproxen (2.9 versus 1.7/1,000 person-years; hazard ratio, 1.69), ibuprofen (3.4 versus 2.0/1,000 person-years; hazard ratio, 1.65), celecoxib (3.4 versus 1.8/1,000 person-years; hazard ratio, 1.85), and etoricoxib (2.9 versus 1.5/1,000 person-years; hazard ratio, 1.96) cohorts.
"Considering the significant impact of hip fracture on morbidity, mortality, and health care cost, our results point to the need to consider tramadol's associated risk of fracture in clinical practice and treatment guidelines," the authors write.


https://asbmr.onlinelibrary.wiley.com/doi/10.1002/jbmr.3933

https://en.wikipedia.org/wiki/Tramadol












Tramadol Linked to Increased Hip Fracture Risk in Adults Aged ≥50 

Thursday, July 9, 2020

A single dose of magic mushroom compound reduces anxiety and depression among cancer patients

Kekulé, skeletal formula of canonical psilocybin

In continuation of my update on psilocybin
Magic mushrooms are wild or cultivated mushrooms containing psilocybin, which is a naturally occurring hallucinogenic and psychoactive compound. A single dose of psilocybin provides long-term relief of anxiety and depression in cancer patients, a new study found.
A team of researchers at the New York University Grossman School of Medicine has found that a one-time, single dose of psilocybin, the compound found in psychedelic mushroom or magic mushroom, combined with psychotherapy, has been linked to a marked improvement in existential and emotional distress in patients with cancer. The drug’s effect has persisted for nearly five years after administration.
The study, published in the Journal of Psychopharmacologyhighlights the efficacy of psilocybin in reducing anxiety levels and depression in cancer patients. Patients with cancer who received the compound reported reductions in anxiety, depression, demoralization, hopelessness, and death anxiety nearly five years after receiving a single dose of the drug and psychotherapy.

Psilocybin effects

Psilocybin is a known hallucinogenic substance commonly found in mushrooms growing in South America, Mexico, Europe, and the United States. A schedule-I controlled substance, the compound has a high potential for abuse. However, people use it as a recreational drug, and over the past years, studies have analyzed its potential for medical purposes.
The compound has both positive and negative effects. It has been studied to relieve symptoms of anxiety and depression but has been known to trigger psychotic episodes. The drug has long been used recreationally due to its hallucinogenic effects, which work by altering a person’s perception, thoughts, and feelings.

Promising results

In the current study, the researchers conducted a long-term within-subjects follow-up analysis of self-reported symptomatology among 15 participants, who agreed to participate at an average of 3.2 to 4.5 years, following the administration of psilocybin.
The researchers noted that among the participants, about 60 to 80 percent of them had met the criteria for clinically significant anxiolytic or antidepressant responses after 4.5 years after receiving the drug. Further, 71 to 100 percent attributed positive life changes, thanks to the combination of psilocybin and psychotherapy treatment, rating it among the most spiritually significant and personally-meaningful experiences in their lifetime.


“These findings suggest that psilocybin-assisted psychotherapy holds promise in promoting long-term relief from cancer-related psychiatric distress. Limited conclusions, however, can be drawn regarding the efficacy of this therapy due to the crossover design of the parent study,” the researchers wrote on the paper.
“Nonetheless, the present study adds to the emerging literature base suggesting that psilocybin-facilitated therapy may enhance the psychological, emotional, and spiritual well-being of patients with life-threatening cancer,” they added.
The authors said psilocybin shows promise as an important tool for enhancing psychotherapy’s efficacy and eventually, providing relief for symptoms of anxiety and depression.  While the exact mechanism on how psilocybin works are not fully understood, the researchers believe the drug makes the brain more receptive to new thought patterns and ideas.


It is also believed that the compound targets a brain network, called the default mode network, which becomes activated when individuals perform mind wandering and self-reflection. These activities aid in making sense of oneself and a sense of coherent narrative identity.
In most people with anxiety and depression, the said network becomes excessively active and has been tied to feelings of worry, rigid thinking, and rumination. The compound appears to work to shift the activity in the network, allowing people to have a broader perspective of their lives and behaviors.
The team plans to further conduct additional studies with bigger trials in patients who belong to diverse ethnic and socioeconomic populations. Also, they hope to conduct more studies on patients with advanced cancer-related psychiatric and existential distress.
https://journals.sagepub.com/doi/abs/10.1177/0269881119897615?journalCode=jopa&
https://en.wikipedia.org/wiki/Psilocybin

Wednesday, July 8, 2020

Plant flavonols significantly reduce Alzheimer’s risk

A new study published in the journal Neurology in January 2020 concludes that increasing the intake of plant flavonols steeply reduces the risk of Alzheimer’s dementia (AD) by up to a half. In other words, AD could be prevented in many people simply by regularly eating and drinking more foods containing these compounds such as tea, oranges, and broccoli.

Alzheimer’s disease

AD is a progressive brain disorder in which the individual loses cognitive skills, including memory and thinking skills, and the ability to perform simple tasks. It is by far the leading cause of such disorders and affects over 5 million Americans.
One study was carried out on over 900 people, who were part of a community-wide ongoing larger research project called the Rush Memory and Aging (MAP) Project. These participants were assessed yearly for their neurologic health and dietary patterns, for an average of 6 years, but some for as long as 12 years. The average age was 81 years, and 3 out of 4 were female.

The findings

In the first study, 220/921 participants developed AD during the study. The risk of AD fell with a greater intake of flavonols. This finding held good even after the researchers adjusted for other health-associated factors – because those with the highest total flavonol intake were also the best educated, most active and took part in more cognitive activities. They also accounted for genetic factors like the presence of the APOE4 gene, and for cardiovascular risk factors that could influence the risk of AD, such as diabetes mellitus, history of heart attack, or stroke, or hypertension.
When classified into five groups based on decreasing flavonol intake, the participants in the first group (highest intake) consumed over 15 mg of flavonols a day. Compared to those in the lowest fifth (about 5 mg a day), these individuals showed an approximately 50% reduction in AD risk.
In concrete terms, 28 of 186 patients in the highest-intake group developed AD, vs. 54 of 182 in the lowest-intake group.
With respect to individual flavonols, kaempferol intake was linked to a reduction of almost 50%, and both myricetin and isorhamnetin by 40% each. A fourth flavonol, called quercetin, had no noticeable effect on AD risk.
Participants with the highest flavonol intake drank about one cup of black tea a day. Kale, and about a glass of red wine each day, could also supply flavonols.

Sources of flavonols

Kaempferol is richly present in green leafy vegetables, including spinach, broccoli, beans, tea and kale – and also in tea. Isorhamnetin-rich foods include olive oil, red wine, pears and tomato sauce. Myricetin is found in tea, kale, oranges, tomatoes and red wine.
Researcher Thomas Holland says, “More research is needed to confirm these results, but these are promising findings. Eating more fruits and vegetables and drinking more tea could be a fairly inexpensive and easy way for people to help stave off Alzheimer's dementia.”

Implications

Many scientists disagree with the emphasis on flavonols. Though these were thought to have antioxidant activity in the body, this theory was discredited many decades earlier. Antioxidant activity ceases when they are ingested and subjected to the activity of enzymes in the digestive tract.
They point out that flavonols are found in many plants, fruits and vegetables, which have been associated with good health for centuries. Nutritionists say that the AD-delaying effects of such foods are likely due to other plant chemicals which are relatively more abundant. On the other hand, taking flavonol pills or tea extracts is unlikely to produce the same healthful effect, and overdoses could be counterproductive.
This is not to say that eating more flavonol-rich foods or drinking a cup of black tea in the morning would hurt, since any foods containing these chemicals would also contain many more healthful compounds including vitamins, minerals and plant fiber. Holland makes a valid point with his conclusion: “'With the elderly population increasing worldwide, any decrease in the number of people with this devastating disease, or even delaying it for a few years, could have an enormous benefit on public health.”
https://n.neurology.org/content/early/2020/01/29/WNL.0000000000008981

Tuesday, July 7, 2020

New compound prevents amyloid formation to fight Alzheimer’s disease

It is known that Alzheimer’s disease is caused by the formation of amyloid plaques and tau tangles in the brain. A novel compound shows promise in preventing amyloid formation, fighting Alzheimer’s disease development.
Graphical abstract: Substrate interaction inhibits γ-secretase production of amyloid-β peptides
       


Alzheimer’s disease (AD) is the most common form of dementia, affecting about 50 million people worldwide. In the United States, 5.5 million people are living with neurodegenerative diseases, making it the 6th leading cause of death in the country.
AD is caused by the abnormal build-up of proteins, amyloid, and tau, in and around the brain. These proteins form plaques and tangles in brain cells, leading to memory loss and other symptoms. Abnormal proteins form toxic clumps, dubbed as fibrils, inside the brain, affecting brain regions that are vital for brain processes.
In the study published in the journal Chemical Communications by the Royal Society of Chemistry, reveals that the new compound, known as “C1”, can prevent the enzyme gamma-secretase from producing amyloids.

What is the role of C1?

Amyloid fibrils are made of peptide amyloid-beta, produced when certain enzymes make cuts to the amyloid precursor protein, which is found in the brain cell membrane. A type of covalent gamma-secretase inhibitor, the compound works by blocking the active site of the enzyme, hence, preventing the formation of amyloid.
The team of researchers at the Center for Biotechnology and Interdisciplinary Studies (CBIS) at Rensselaer Polytechnic Institute noted that there were samples of gamma-secretase inhibitors in the past, but these failed since they have severe side effects. What happened is, the inhibitors used stopped all the functions of gamma-secretase.
“Our compound binds to the cleavage site of the precursor protein instead of the enzyme itself, which may avoid many problems associated with traditional enzyme inhibitors,” Chunyu Wang, a professor of biological sciences and author of the study, said.
The team started to screen drugs to determine a potential compound that can target the amyloid precursor protein substrate, blocking the gamma-secretase activity that is tied to amyloid production. Using a computer model, they tested millions of compounds in the hopes of finding the one that can show promise in battling Alzheimer’s disease.


Though there were several candidates found, C1 showed high accuracy and effectiveness in cell cultures and test tubes. The patent for the compound is still pending but the researchers hope that the new drug can be studied more to determine its efficacy in people at a high risk of developing Alzheimer’s disease.

Implications of the compound

The discovery of the novel compound can pave the way for the development of new drugs that can prevent and treat Alzheimer’s disease. The new approach targets the disease, based on tis principal pathology.
Currently, there is no cure for Alzheimer’s disease and the treatment revolves around providing a safe environment for patients. Therapy is also effective in providing support, but scientists are racing to finally find a medicine for the condition.

What is Alzheimer’s disease?

Alzheimer’s disease is a type of dementia, which is a neurodegenerative disease. The disease is irreversible and progressive, which means that it worsens over time. The condition affects brain sections responsible for memory, thinking skills, and cognitive ability. In time, the symptoms worsen, often causing the inability to carry out the simplest tasks or activities of daily living.
The disease first appears in people who are in their mid-60s but can emerge earlier in some cases. Scientists don’t fully understand the exact cause of Alzheimer’s disease, but it may be a combination of various factors. These include age, since older adults are mostly affected, and hereditary because it can run in families. There is also evidences that changes in the brain starting even years before the start of the symptoms may have occurred.

https://pubs.rsc.org/en/Content/ArticleLanding/2020/CC/C9CC09170J#!divAbstract