COVID-19: Separating Infected Mothers from Newborns: Weighing the Risks and Benefits

By Melissa Bartick, MD, MS, FABM
March 31, 2020

Current guidelines around whether infected mothers with COVID-19 should be separated from their newborn infants are conflicting. While the current guidelines for COVID-19 allow breastfeeding, this is not being clearly conveyed in the media. Reportedly, many US hospitals are routinely separating infected mothers from their newborns. Separation makes establishing breastfeeding difficult, even if breastfeeding is allowed and encouraged. The virus has not been found in breastmilk in limited studies of it1 and the related virus that causes SARS,1,2 but it’s not known with absolute certainty that the virus is not transmitted through breastmilk. The March 28 announcement of the death of an Illinois infant of undisclosed age may raise anxiety. Continue reading “COVID-19: Separating Infected Mothers from Newborns: Weighing the Risks and Benefits”

Ravulizumab: Is it the Ultimate Treatment for Atypical Uremic Syndrome?

By Rohit Jain, B. Pharmacy, MBA, PGDBM, LL.B, DCR
January 23, 2020

Atypical hemolytic uremic syndrome (aHUS) is a rare, serious, and progressive condition characterized by thrombocytopenia, hemolytic anemia, and renal failure. The condition occurs in both children and adults. In almost half of all the cases, the patient suffers from end-stage renal disease due to damage to tiny blood vessels in the kidney. Unlike typical hemolytic uremic syndrome (tHUS) which is related to Shiga-like toxin (E. coli), aHUS is associated with prolonged and uncontrolled activation of the complement system. Comparatively 10 times less common than tHUS, the incidence of aHUS is about 1 in 500,000 people in the United States1.

In October this year, USFDA had approved ravulizumab for the treatment of adults and pediatric patients one month of age and older with the atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). The approval is with the limitation that this drug should not be used in Shiga toxin E. coli related hemolytic uremic syndrome. The drug was also approved in 2018 by USFDA in the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH). Ravulizumab, a long-acting C5 complement inhibitor, is approved for the first time in pediatric patients2.

Administration of ravulizumab is through intravenous injection and it is available as a single-dose vial containing 300 mg ravulizumab-cwvz at a concentration of 10 mg/mL. The drug prevents the generation of the terminal complement complex C5b9 by specifically binding to the complement protein C5 with high affinity.

Recent Studies

The efficacy of ravulizumab was evaluated through two open-label, single-arm studies3. One study, ALXN1210-aHUS-311, enrolled adult patients and the other study, ALXN1210-aHUS-312, enrolled pediatric patients. Important inclusion criteria in both the studies were evidence of hemolysis such as elevated serum lactate dehydrogenase (LDH) and platelet count ≤150 x 109/L.

In the study involving adults, analysis of efficacy was done on 56 patients. Complete thrombotic microangiopathy response was observed in 54% of the patients during the initial evaluation period of 26 weeks. There was an increase in mean platelet count to 240.34 ×109/L at Day 8 from 118.52 × 109/L at baseline. The platelet count remains above 227 × 109/L in the initial evaluation period of 26 weeks. There was an increase in mean eGFR from 15.86 to 51.83 indicating an improvement in the renal function, and 76.8% of the patients experience normalization in LDH level indicating a reduction in hemolysis.

Fourteen patients were enrolled in the study on pediatric patients. In 71% of the patients, there was complete thrombotic microangiopathy (TMA) response. Improvement in renal function was noted as there was an increase in eGFR from 28.4 at baseline to 108.0 by 26 weeks. An increase in mean platelet count from 60.50 × 109 /L at baseline to 296.67 × 109/L at day 8 was observed. The platelet count remained above 296 × 109/L throughout the initial evaluation period. Reduced hemolysis was observed in 85.7% of patients as normalization of LDH was observed in these patients.

Eculizumab is the first and the only other drug approved by USFDA for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. Although there is no head-to-head study available to compare the efficacy of eculizumab and ravulizumab in the treatment of aHUS, a comparison can be done based on their respective pharmacokinetic data and dose frequency.

Comparing Ravulizumab to Eculizumab

The terminal half-life of ravulizumab is approximately fourfold longer as compared to eculizumab. The elimination half-life of eculizumab is approximately 270 hours to 375 hours while ravulizumab has an elimination half-life of approximately 51 days indicating a longer duration of action. The immediate, complete, and sustained action of ravulizumab is due to 4-amino substitutions in the FC regions and complimentary-determining regions. The prolonged effect of ravulizumab as compared to eculizumab is also obvious from the dose frequency.  While eculizumab is generally required to be administered every 2 weeks, the administration frequency of ravulizumab is 8 weeks.

A study comparing the safety and efficacy of ravulizumab and eculizumab in the treatment of paroxysmal nocturnal hemoglobinuria (PNH) concluded that both ravulizumab and eculizumab were well tolerated. The same study concluded that switching of patients with PNH from eculizumab to ravulizumab may reduce the occurrence of breakthrough hemolysis, improved quality of life, reduced treatment burden, and increased retention of long-term therapy4.

Author’s Conclusion

Ravulizumab is better than eculizumab, at least in terms of patient compliance and frequency of administration.

References:

  1. https://ghr.nlm.nih.gov/condition/atypical-hemolytic-uremic-syndrome#statistics (Accessed on December 07th, 2019).
  2. https://www.medscape.com/viewarticle/920120 (Accessed on December 07th, 2019).
  3. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761108s001lbl.pdf (Accessed on December 07th, 2019).
  4. Austin G. Kulasekararaj, Anita Hill, Scott T. Rottinghaus et al. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor–experienced adult patients with PNH: the 302 study. Blood. 2019 Feb 7; 133(6): 540–549.

 

Rohit JainRohit Jain is a medical writing expert, medico-marketing trainer, and patent specialist who has written various medical articles covering different therapeutic areas. He is a registered patent agent in India and is currently pursuing a Masters in Pharmacy. He has more than a decade of experience in the pharmaceutical industry and as an avid reader, his interests include reading about the latest research in the medical and pharmaceutical arenas.

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The Emergence of NK Cell-Based Treatment in Cancer Immunotherapy

By Olivier Lucar
August 20, 2019

The 2018 Nobel Prize in Physiology or Medicine was awarded to James Alison and Tasuku Honjo for their groundbreaking work on cancer therapy targeting the inhibition of immune checkpoints (IC), proteins that negatively regulate the immune response. Their work was groundbreaking because it opened a new powerful tool for the cure of cancer—immunotherapy (Fritz J. et Lenardo M., 2019).

The Cancer Revolution

At the beginning of cancer research, the immune system was not considered an important actor in cancer pathogenesis. But, in fact, the tumor microenvironment is Continue reading “The Emergence of NK Cell-Based Treatment in Cancer Immunotherapy”

How CAR-T Cell Therapy is Impacting Solid Tumor Cancer Research

By David Haas
Wednesday June 5, 2019

Treatment options available to cancer patients have both improved and grown over the past decade. The development of personalized medicine has enabled patients to seek a new route, tailoring their treatments specifically to their situations. One outcome of this unique treatment approach is the development of CAR-T (chimeric antigen receptor T) cell therapy (see: Taking Personalized Medicine to a New Level: CAR-T Cell Therapy). Continue reading “How CAR-T Cell Therapy is Impacting Solid Tumor Cancer Research”

AAO-HNS Releases New Guidelines on Tonsillectomy in Children

By Eric Gantwerker MD, MMSc (MedEd), FACS
May 23, 2019

Recently the American Academy of Otolaryngology-Head and Neck Surgery updated their clinical practice guidelines (CPG) on Tonsillectomy in Children (Mitchell et al., 2019). As more studies are published, a periodic review of the literature is necessary.  The last CPG was released in 2011 (Baugh et al., 2011). Since that time 2,190 studies have been indexed in PubMed under the search term “pediatric sleep apnea” with over half of those occurring just since 2016 (1140) (“US National Library of Medicine – NCBI PubMed,” n.d.). Continue reading “AAO-HNS Releases New Guidelines on Tonsillectomy in Children”

Do Large Clinical Trials Adequately Consider Individual Patient Physiology? Debating The RELIEF Study

By Michael Keane, BMBS, FANZCA and Shashikanth Manikappa, MD, DNB, FANZCA
February 21, 2019

Patient safety requires a well-informed debate about the rationale of large, randomized controlled trials (RCTs) and whether, by their very nature, they can adequately consider the unique physiology of every individual patient. 

RCTs must be reproducible; the fundamental premise of any scientific experiment. In their day-to-day practice, clinicians must, therefore, be willing to reproduce the same treatment of individual patients’ physiology. If clinicians would treat individual patients (including physiological outliers) differently to that in which individual patients were treated in a trial, then that trial data becomes meaningless to their practice.  Continue reading “Do Large Clinical Trials Adequately Consider Individual Patient Physiology? Debating The RELIEF Study”

WAKE-UP Time for Thrombolysis in Acute Stroke?

By Martina McGrath, MD
October 30, 2018

MRI thrombolysis for stroke of unknown time of onset

Current clinical guidelines recommend thrombolysis in acute stroke where patients present within 4.5 hours of onset of symptoms. However, for up to a quarter of patients, the time of symptom onset is unknown as they wake from sleep with neurological deficits.1 Such patients frequently do not meet criteria for therapies such as thrombolysis or mechanical thrombectomy.

Prior studies have suggested a particular pattern may be seen on an MRI of the brain in the early hours following stroke onset; a visible ischemic lesion on diffusion-weighted imaging along with the lack of a hyperintense signal in the same area on fluid-attenuated inversion recovery (FLAIR). The benefit of aggressive stroke intervention in patients with the combination of unknown time of symptom onset and this particular signal mismatch on MRI brain scans is unknown. Continue reading “WAKE-UP Time for Thrombolysis in Acute Stroke?”

Worldwide Trends in HIV Vaccine: Are We There Yet?

By Olivier Lucar
October 16, 2018

Chronic HIV infection remains a major public health issue. According to 2017 data from UNAIDS, there are still 36.9 million HIV-positive individuals worldwide, including 1.1 million in the USA, of whom 1 in 7 are unaware of their status. HIV infection usually has a slow and paucisymptomatic infectious development, which makes recognition of infection difficult and leads to its persistence. HIV disproportionately affects individuals in less developed countries and can only be treated with multiple expensive drugs, the availability of which depends on the country. Furthermore, despite the phenomenal progress in anti-HIV drug efficacy (leading to sustained undetectable levels of viral load), long-term infection and treatment are associated with other comorbidities from cardiovascular diseases to certain cancers (Taiwo et al., 2013). The search for therapeutic or prophylactic vaccines remains the best option to fight HIV and prevent its permanent development. Continue reading “Worldwide Trends in HIV Vaccine: Are We There Yet?”

Use of Guideline-Recommended Medical Therapy in Patients with Heart Failure

By Connor Emdin
September 26, 2018

Over the past thirty years, survival after the diagnosis of heart failure has improved, with five-year mortality falling from 57% in 1979 to 1984 to 48% in 1996 to 2000.1 Much of this reduction in mortality has been due to the development of novel therapeutics for treatment of heart failure.2 Large randomized clinical trials have demonstrated that angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), angiotensin receptor neprilysin inhibitors (ARNIs), beta-blockers (BBs) and mineralcorticoid receptor antagonists (MRAs) all reduce the risk of death and re-hospitalization among patients with heart failure with reduced ejection fraction (HFrEF).2 Current guidelines strongly recommend that all eligible patients with HFrEF be treated with a combination of these agents.2 Continue reading “Use of Guideline-Recommended Medical Therapy in Patients with Heart Failure”

Restrictive versus Liberal Fluid Therapy in Abdominal Surgery

By Connor Emdin
August 28, 2018

Abdominal surgery can result in significant fluid loss, arising from multiple sources, including fasting prior to surgery, evaporation during surgery, from blood loss and from other sources.1 Traditionally, individuals undergoing abdominal surgery received liberal fluid resuscitation (up to 7L on the day of surgery) which frequently exceeded their losses and led to weight gain of 3-6kg.2 Excessive fluid loading can lead to elevated rates of postoperative heart failure, arrhythmias, and wound infection due to local tissue edema, and in small clinical trials, restrictive hydration strategies (targeting net zero fluid balance) have been associated with fewer complications than liberal fluid replacement.3 Consequently, clinical guidelines now recommend more restrictive fluid therapy for abdominal surgery.4,5 Continue reading “Restrictive versus Liberal Fluid Therapy in Abdominal Surgery”