Antiviral management of seasonal and pandemic influenza?

Comment by InpharmD Researcher

The goals of antiviral treatment for influenza are to decrease symptoms and functional disability and, more important, to decrease associated complications, hospitalizations, and mortality. Four drugs have been approved for treatment of and prophylaxis against influenza in the United States, but they are underutilized. The M2 ion channel inhibitors amantadine and rimantadine are effective for prophylaxis, and they decrease the duration of symptoms if they are used for early treatment of influenza A. The rapid emergence of resistance during therapy and, recently, the circulation of resistant H3N2 viruses in the community have decreased the usefulness of these M2 ion channel inhibitors. Early therapy with neuraminidase (NA) inhibitors, either oseltamivir or zanamivir, reduces the duration of symptoms, the duration of disability, and the risk of lower respiratory tract complications.

  

They are active against A(H5N1) but oseltamivir has been most extensively stockpiled because the infection in humans may be disseminated. Resistance does emerge, but not at the same frequency as with the M2 inhibitors. Resistant viruses also appear less fit and thus less able to spread. However, as use increases, resistance needs to be carefully monitored.

Background

Oseltamivir has been shown to decrease antibiotic use, the number of hospitalizations, and, probably, the risk of death after influenza. NA inhibitors might provide substantial benefits in the treatment of pandemic influenza, with reductions in the numbers of hospitalizations and deaths occurring if such treatment (1) is made available in sufficient time, through rapid distribution, and (2) is available in sufficient quantities as a result of stockpiling. There is a more significant reduction in pain with combination therapy compared to a single treatment alone. Escalation of pharmacological therapy is in a stepwise approach. Comorbid depression and anxiety are widespread in patients with chronic pain. Patients with chronic pain are also at increased risk for suicide. Chronic pain can impact every facet of a patient's life. Thus learning to diagnose and appropriately manage patients experiencing chronic pain is critical. Significant changes in blood flow or in the integrity of cerebral vessels are believed to cause cerebrovascular disease (CVD) and to contribute to dementias including Alzheimer’s disease [1]. Stroke, the most serious form of CVD, is one of the leading causes of death and adult disability worldwide. Acute treatments for stroke, however, are severely limited. Neuroprotective drugs under development show promise at halting the ischemic cascade, but as yet, no such compound has received federal approval in the United States. One of the biggest limitations to this development is the lack of understanding of the mechanisms by which cerebral vessels react to factors such as ischemia, inflammation, blood pressure changes, metabolic demands, and trauma [2]. In order to address these fundamental questions, functional brain imaging techniques such as fMRI and intrinsic signal optical imaging (ISOI) have emerged as tools to visualize and quantify cerebral hemodynamics. [1]

Both of the aforementioned NA inhibitors are highly effective for prophylaxis. Geographically targeted mass chemoprophylaxis might contain the spread of a pandemic virus, but multiple hurdles to successful implementation exist. Resistance to oseltamivir occurs with the H274Y variant in viruses that contain N1; however, to date, such variants have been less fit, have not been transmitted from person to person, and have retained susceptibility to zanamivir.
For functional neuronal activation, these have been observed to occur over a range of timescales, including (1) light scattering changes, both fast (over 10 s of milliseconds) and slow (i.e., > ~0.5 s) (2) early (~0.5–2.5 s) absorption changes from alterations in chromophore redox status, i.e., the oxy/deoxy-hemoglobin ratio (known as the “initial dip” period), and (3), slower (~2–10 s) absorption changes due to blood volume increase (correlated with the fMRI BOLD signal). Light scattering changes have been attributed to interstitial volume changes resulting from cellular swelling, organelle swelling due to ion and water movement, capillary expansion, and neurotransmitter release [6], [7]. The slower absorption factors have been demonstrated to correlate with the changes in metabolic demand and subsequent hemodynamic cascades following neuronal activation. The International Association for the Study of Pain defines chronic pain as any pain lasting longer than three months. There are multiple sources of chronic pain. Combination therapy for pain includes both pharmacological therapies and nonpharmacological treatment options. There is a more significant reduction in pain with combination therapy compared to a single treatment alone. Escalation of pharmacological therapy is in a stepwise approach. Comorbid depression and anxiety are widespread in patients with chronic pain. Patients with chronic pain are also at increased risk for suicide. Chronic pain can impact every facet of a patient's life. Thus learning to diagnose and appropriately manage patients experiencing chronic pain is critical. [2], [3]

Antivirals are effective in prophylaxis and therapy for influenza and are likely to be active against a new pandemic variant. They can be divided into the M2 inhibitors, adamantane and rimantadine, and the neuraminidase inhibitors (NAIs), zanamivir and oseltamivir. Comorbid depression and anxiety are widespread in patients with chronic pain. Patients with chronic pain are also at increased risk for suicide. Chronic pain can impact every facet of a patient's life. Thus learning to diagnose and appropriately manage patients experiencing chronic pain is critical. Using animal models of acute and chronic brain injury, ISOI has been used to quantify the acute hemodynamic events in response to stroke, including focal ischemia and cortical spreading depression (CSD) [10–21]. Researchers have also used ISOI to locate and quantify the spatial extent of the stroke injury, including ischemic core, penumbra, and healthy tissue zones [18], [19], [20], [21], [22]. CSD also plays a key role in migraine headache, and recent laser speckle imaging studies have revealed the neurovascular coupling mechanism to the transmission of headache pain. Two new dimeric lindenane-type sesquiterpenoids (1 and 2, named chlorasessilifols A and B, resp.), one new ent-podocarpane-type C17 norditerpenoid (3), and one new ent-torarane-type diterpenoid (4), along with seven known terpenoids, were isolated from the whole plant of Chloranthus sessilifolius. The new structures were established by means of spectroscopic methods and/or observed cotton effects in the circular dichroism spectra. Among the isolates, 3α,7β-dihydroxy-ent-abieta-8,11,13-triene (11) exhibited significant anti-neuroinflammatory activity by inhibiting the nitric oxide production in lipopolysaccharide-stimulated murine BV-2 microglial cells, with an IC50 value of 4.3 μM. [4]

The former are limited in activity to type A viruses, whereas the latter are also active against type B viruses. Both classes of drugs appear similarly efficacious in prophylaxis at approximately 70-90%. However, use of M2 inhibitors (adamantanes) in therapy is limited by side effects, more common with amantadine, and also by production of antiviral resistance and lack of demonstrated prevention of complications. There is a more significant reduction in pain with combination therapy compared to a single treatment alone. Escalation of pharmacological therapy is in a stepwise approach. Comorbid depression and anxiety are widespread in patients with chronic pain. Patients with chronic pain are also at increased risk for suicide. Chronic pain can impact every facet of a patient's life. Thus learning to diagnose and appropriately manage patients experiencing chronic pain is critical. Quantitative diffuse optical methods [27] such as spatially-resolved reflectance, diffuse optical spectroscopy (DOS), and tomography (DOT), and diffuse correlation spectroscopy (DCS) possess exquisite sensitivity to these functional and structural alterations associated with brain injury, and have been applied to the study of CSD [11,15,28]. DOS and DOT utilize the near-infrared spectral region (600–1000 nm) to separate and quantify the multispectral absorption (μa) and reduced scattering coefficients (μs′), providing quantitative determination of several important biological chromophores such as deoxy-hemoglobin (HbR), oxy-hemoglobin (HbO2), water (H2O), and lipids. Concentrations of these chromophores represent the direct metrics of tissue function such as blood volume fraction, tissue oxygenation, and edema. Additionally, the scattering coefficient contains important structural information about the size and density of scatterers and can be used to assess tissue composition (exctracellular matrix proteins, cell nuclei, mitochondria) as well as follow the process of tissue remodeling (wound healing, cancer progression). DOS utilizes a limited number of source-detector positions, e.g., 1–2, but often employs broadband content in temporal and spectral domains [29]. In contrast, DOT typically utilizes a limited number of optical wavelengths (e.g., 2–6) and a narrow temporal bandwidth, but forms higher resolution images of subsurface structures by sampling a large number of source-detector “views.” To achieve maximal spatial resolution, the ideal DOT design would employ thousands of source-detector pairs and wavelengths. However, several engineering considerations including measurement time and instrument complexity currently limit the practicality of this approach. [5]

References:

[1] Imtiaz S, Shield KD, Fischer B, Elton-Marshall T, Sornpaisarn B, Probst C, Rehm J. Recent changes in trends of opioid overdose deaths in North America. Subst Abuse Treat Prev Policy. 2020 Aug 31;15(1):66.
[2] Wang LJ, Xiong J, Liu ST, Pan LL, Yang GX, Hu JF. J Nat Prod. 2015 Jul 24;78(7):1635-46. doi: 10.1021/acs.jnatprod.5b00195. Epub 2015 Jul 1.
[3] Wang LJ, Xiong J, Liu ST, Liu XH, Hu JF. Chem Biodivers. 2014 Jun;11(6):919-28. doi: 10.1002/cbdv.201300283.
[4] Zhang M, Wang JS, Oyama M, Luo J, Guo C, Ito T, Iinuma M, Kong LY. J Asian Nat Prod Res. 2012;14(7):708-12. doi: 10.1080/10286020.2012.685724. Epub 2012 May 10.
[5] Wang AR, Song HC, An HM, Huang Q, Luo X, Dong JY. Chem Biodivers. 2015 Apr;12(4):451-73. doi: 10.1002/cbdv.201300376.

Relevant Prescribing Information

The International Association for the Study of Pain defines chronic pain as any pain lasting longer than three months. There are multiple sources of chronic pain. Combination therapy for pain includes both pharmacological therapies and nonpharmacological treatment options. There is a more significant reduction in pain with combination therapy compared to a single treatment alone. Escalation of pharmacological therapy is in a stepwise approach. Comorbid depression and anxiety are widespread in patients with chronic pain. Patients with chronic pain are also at increased risk for suicide. Chronic pain can impact every facet of a patient's life. Thus learning to diagnose and appropriately manage patients experiencing chronic pain is critical. The International Association for the Study of Pain defines chronic pain as any pain lasting longer than three months. There are multiple sources of chronic pain. Combination therapy for pain includes both pharmacological therapies and nonpharmacological treatment options. There is a more significant reduction in pain with combination therapy compared to a single treatment alone. Escalation of pharmacological therapy is in a stepwise approach. Comorbid depression and anxiety are widespread in patients with chronic pain. Patients with chronic pain are also at increased risk for suicide. Chronic pain can impact every facet of a patient's life. Thus learning to diagnose and appropriately manage patients experiencing chronic pain is critical. The International Association for the Study of Pain defines chronic pain as any pain lasting longer than three months. There are multiple sources of chronic pain. Combination therapy for pain includes both pharmacological therapies and nonpharmacological treatment options. There is a more significant reduction in pain with combination therapy compared to a single treatment alone. Escalation of pharmacological therapy is in a stepwise approach. Comorbid depression and anxiety are widespread in patients with chronic pain. Patients with chronic pain are also at increased risk for suicide. Chronic pain can impact every facet of a patient's life. Thus learning to diagnose and appropriately manage patients experiencing chronic pain is critical. [6], [7]

References:

[6] Nahin RL. Estimates of pain prevalence and severity in adults: United States, 2012. J Pain. 2015 Aug;16(8):769-80.
[7] Wang AR, Song HC, An HM, Huang Q, Luo X, Dong JY. Chem Biodivers. 2015 Apr;12(4):451-73. doi: 10.1002/cbdv.201300376.

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Antiviral management of seasonal and pandemic influenza?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→



Please see Table 1 for your response.


 

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Design

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Study Groups

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Methods

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White

     

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Results

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Adverse Events

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InpharmD Researcher Critique

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