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Melatonin for the treatment of sepsis: the scientific rationale.

ABSTRACT: Sepsis affects 30 million people worldwide, leading to 6 million deaths every year (WHO), and despite decades of research, novel initiatives are drastically needed. According to the current literature, oxidative imbalance and mitochondrial dysfunction are common features of septic patients that can cause multiorgan failure and death. Melatonin, alongside its traditionally accepted role as the master hormonal regulator of the circadian rhythm, is a promising adjunctive drug for sepsis through its anti-inflammatory, antiapoptotic and powerful antioxidant properties. Several animal models of sepsis have demonstrated that melatonin can prevent multiorgan dysfunction and improve survival through restoring mitochondrial electron transport chain (ETC) function, inhibiting nitric oxide synthesis and reducing cytokine production. The purpose of this article is to review the current evidence for the role of melatonin in sepsis, review its pharmacokinetic profile and virtual absence of side effects. While clinical data is limited, we propose the adjunctive use of melatonin is patients with severe sepsis and septic shock.

SUBMITTER: Colunga Biancatelli RML

PROVIDER: S-EPMC7024751 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Melatonin for the treatment of sepsis: the scientific rationale.

Colunga Biancatelli Ruben Manuel Luciano RML Berrill Max M Mohammed Yassen H YH Marik Paul E PE

Journal of thoracic disease 20200201 Suppl 1

Sepsis affects 30 million people worldwide, leading to 6 million deaths every year (WHO), and despite decades of research, novel initiatives are drastically needed. According to the current literature, oxidative imbalance and mitochondrial dysfunction are common features of septic patients that can cause multiorgan failure and death. Melatonin, alongside its traditionally accepted role as the master hormonal regulator of the circadian rhythm, is a promising adjunctive drug for sepsis through its ...[more]

PMID: 32148926

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Project description:BackgroundData to support the use of specific vasopressors in septic shock are limited. Since angiotensin II (AT2) was approved by the Food and Drug Administration in 2017, multiple mechanistically distinct vasopressors are available to treat septic shock, but minimal data exist regarding which patients are most likely to benefit from each agent. Renin and dipeptidyl peptidase 3 (DPP3) are components of the renin-angiotensin-aldosterone system which have been shown to outperform lactate in predicting sepsis prognosis, and preliminary data suggest they could prove useful as biomarkers to guide AT2 use in septic shock.MethodsThe DARK-Sepsis trial is an investigator-initiated industry-funded, open-label, single-center randomized controlled trial of the use of AT2 versus standard of care (SOC) vasopressor therapy in patients admitted to the intensive care unit (ICU) with vasodilatory shock requiring norepinephrine ≥ 0.1 mcg/kg/min. In both groups, a series of renin and DPP3 levels will be obtained over the first 24 h of treatment with AT2 or SOC. The primary study outcome will be the ability of these biomarkers to predict response to vasopressor therapy, as measured by change in total norepinephrine equivalent dose of vasopressors at 3 h post-drug initiation or the equivalent timepoint in the SOC arm. To determine if the ability to predict vasopressor response is specific to AT2 therapy, the primary analysis will be the ability of baseline renin and DPP3 levels to predict vasopressor response adjusted for treatment arm (AT2 versus control) and Sequential Organ Failure Assessment (SOFA) scores. Secondary outcomes will include rates of acute kidney injury, need for mechanical ventilation and kidney replacement therapy, lengths of stay in the ICU and hospital, ICU and hospital mortality, and rates of prespecified adverse events.DiscussionWith an armamentarium of mechanistically distinct vasopressor agents now available, sub-phenotyping patients using biomarkers has the potential to improve septic shock outcomes by enabling treatment of the correct patient with the correct vasopressor at the correct time. However, this approach requires validation in a large definitive multicenter trial. The data generated through the DARK-Sepsis study will prove crucial to the optimal design and patient enrichment of such a pivotal trial.Trial registrationClinicalTrials.gov NCT05824767. Registered on April 24, 2023.

Project description:Ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia (CLL). This drug irreversibly inhibits Bruton tyrosine kinase (BTK) by covalently binding to the C481 residue in the BTK kinase domain. BTK is a pivotal protein for B cell receptor signaling and tissue homing of CLL cells. Preclinical investigations have established the importance of the B cell receptor pathway in the maintenance and survival of normal and malignant B cells, underscoring the importance of targeting this axis for CLL. Clinical trials demonstrated overall and progression-free survival benefit with ibrutinib in multiple CLL subgroups, including patients with relapsed or refractory disease, patients with 17p deletion, elderly patients, and treatment-naïve patients. Consequently, ibrutinib was approved by the US Food and Drug Administration for newly diagnosed and relapsed disease. Ibrutinib has transformed the treatment of CLL; however, several limitations have been identified, including low complete remission rates, development of resistance, and uncommon substantial toxicities. Further, ibrutinib must be used until disease progression, which imposes a financial burden on patients and society. These limitations were the impetus for the development of ibrutinib combinations. Four strategies have been tested in recent years: combinations of ibrutinib with immunotherapy, chemoimmunotherapy, cell therapy, and other targeted therapy. Here, we review the scientific rationale for and clinical outcome of each strategy. Among these strategies, ibrutinib with targeted agent venetoclax results in high complete response rates and, importantly, high rates of undetectable minimal residual disease. Although we concentrate here on ibrutinib, similar combinations are expected or ongoing with acalabrutinib, tirabrutinib, and zanubrutinib, second-generation BTK inhibitors. Future investigations will focus on the feasibility of discontinuing ibrutinib combinations after a defined time; the therapeutic benefit of adding a third agent to ibrutinib-containing combinations; and profiling of resistant clones that develop after combination treatment. A new standard of care for CLL is expected to emerge from these investigations.

Project description:BackgroundSepsis represents a significant healthcare problem worldwide and causes a high number of deaths every year but remains to be fully understood. During and after sepsis, the host immune response is complex and involves an initial excessive host inflammatory response to infection that is closely related to tissue damage and leads to organ failure. Over the past three decades, immunotherapy for sepsis has vastly improved, but in this area, the most influential articles, journals, authors, and countries have not yet been completely summarized and analyzed.ObjectivePerformed a bibliometric analysis on all the articles concerning immunotherapy for sepsis from 1962 to 2019 was our objective, and we also explored the potential correlations between publications of different countries and their gross domestic product (GDP).MethodsAll articles about immunotherapy for sepsis were extracted from the Scopus database and analyzed. We also retrieved GDP data from all the countries that have published information from the World Bank.ResultsIn summary, we have retrieved 1,483 related articles from the Scopus database starting from the first publication on immunotherapy for sepsis in 1962 through March 16, 2019. Over the past decade, the number of the articles published has increased year by year to reach 866 in total, which accounts for about 58% of all publications, with 2017 being the most prolific year when 179 articles were published. The US published 604 articles (41%), followed by China (n = 163, 11%), and Germany (n = 158, 11%). In terms of publishing media, the journal that published the highest number of the articles was Journal of Critical Care Medicine with 65 articles (4%), followed by Shock with 55 articles (4%), and Critical Care with 35 articles (2%). There was a strong correlation between the GDP of the different countries and their publication numbers (r = 0.811, P < 0.001).ConclusionsOur present study analyzed all types of articles concerning immunotherapy for sepsis over the past 57 years and countries with high GDP tends to make more contributions to the medical field of this field. In the meantime, these studies highlight the importance of immunotherapy in the treatment of sepsis patients. The recognition of the historical status and development trend of this field can promote inter-agency cooperation, guide future research, and ultimately provide the basis for clinical practice guidelines.

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Melatonin for the treatment of sepsis: the scientific rationale.

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Melatonin for the treatment of sepsis: the scientific rationale.

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