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Excellent Paper

A Systematic Review of Gastric Acid-Reducing Agent-Mediated Drug–Drug Interactions with Orally Administered Medications

In this comprehensive review, 121 individual medications were found to clinically meaningfully interact with ARAs. Thirty-eight medications were identified to have a mechanism of interaction that was gastric pH dependent, and 83 medications were found to interact with ARAs with a non-gastric pH-mediated interaction (CYP/transporter/chelation/urine alkalization…

While mitigation strategies for introducing an ARA (perpetrator) and a substrate medication together are described in this review, it is also important to re-evaluate therapy changes when ARA (perpetrator) doses are decreased or stopped.

For some medications, mitigation strategies recommended in prescribing information when H2RAs are perpetrators of a clinically meaningful gastric pH-dependent interaction are often inconsistent and sometimes debatable based on their pharmacodynamic properties. H2RA activity can persist for up to 12 h, with peak acid suppression occurring around 2 h."

Acid Reducing Agent ARA
H2 Receptor Antagonists H2RA
Drug to Drug Interaction DDI

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Ultrasensitive to some meds? Benadryl make you hyper? You may be an ultra metabolizer.

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Paradoxical Excitation on Diphenhydramine May Be Associated with Being a CYP2D6 Ultrarapid Metabolizer: Three Case Reports

https://www.researchgate.net/profile/Jose_De_Leon/publication/5623615_Paradoxical_Excitation_on_Diphenhydramine_May_Be_Associated_with_Being_a_CYP2D6_Ultrarapid_Metabolizer_Three_Case_Reports/links/5614055408aed47facee01e9/Paradoxical-Excitation-on-Diphenhydramine-May-Be-Associated-with-Being-a-CYP2D6-Ultrarapid-Metabolizer-Three-Case-Reports.pdf

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“Baby’s Got Her Blue Gene’s On”

How you deal with medication. Over 90 percent of medication metabolization, sensitivity reactions and drug to drug interaction is controlled by the P450 enzymes.

"Cytochrome P450 enzymes are essential for the metabolism of many medications.

Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6.

Genetic variability (polymorphism) in these enzymes may influence a patient’s response to commonly prescribed drug classes, including beta blockers and antidepressants.

Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures. Interactions with warfarin, antidepressants, antiepileptic drugs, and statins often involve the cytochrome P450 enzymes.

Knowledge of the most important drugs metabolized by cytochrome P450 enzymes, as well as the most potent inhibiting and inducing drugs, can help minimize the possibility of adverse drug reactions and interactions.

Although genotype tests can determine if a patient has a specific enzyme polymorphism, it has not been determined if routine use of these tests will improve outcomes."

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Amazing Progress in CAR-T evolution. Victories. #MDAnderson

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Introduction: An increasing number of patients present with multiple symptoms affecting many organs including the brain due to multiple mediators released by mast cells. These unique tissue immune cells are critical for allergic reactions triggered by IgE, but are also stimulated (not activated) by immune, drug, environmental, food, infectious, and stress triggers, leading to secretion of multiple mediators often without histamine and tryptase. The presentation, diagnosis and management of the spectrum of mast cell disorders is very confusing. As a result, specialists have recently excluded neuropsychiatric symptoms, and made the diagnostic criteria stricter, at the expense of excluding most patients.

Areas covered: A literature search was performed on papers published between January 1990 and November 2018 using MEDLINE. Terms used were activation, antihistamines, atopy, autism, brain fog, heparin, KIT mutation, IgE, inflammation, IL-6, IL-31, IL-37, luteolin, mast cells, mastocytosis, mediators, myalgic encephalomyelitis/chronic fatigue syndrome, mycotoxins, release, secretion, tetramethoxyluteolin, tryptase.

https://sci-hub.se/https://www.tandfonline.com/doi/abs/10.1080/1744666X.2019.1596800?journalCode=ierm20

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McCardio Infarction, Ventricular McFibrilation?

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Potential role of the common food additive manufactured citric acid in eliciting significant inflammatory reactions contributing to serious disease states: A series of four case reports

About 99 percent of all commercial Citric Acid (MCA) is manufactured by fermenting enhanced Aspergillus Niger fungi in shallow pans by feeding it fruit juice, molasses, and sugars. About 60 percent of total production is in China.

The Citric acid is harvested by a thermal cooking, sulfuric acid, separation, solidification, crystallization, and purification process. This results in a white crystalline powder.

“After fermentation, A. niger is physically removed, usually by filtration, and citric acid is isolated by precipitation of the fermentation mix with calcium hydroxide (lime) to generate calcium citrate salt. Subsequent treatment with sulphuric acid yields the citric acid product.”

The authors postulate that some residual fragments of the biological waste or interleukin immunomodulators may survive the high temperature purification and result in stimulation of some patients immune system as an allergic response.

" We recognize the limitations of the level of evidence from our four case reports.

We cannot conclusively affirm that Manufactured Citric Acid (MCA) is the causative factor in the subjects’ inflammatory symptoms.

However, our findings demonstrate a significant likelihood that MCA may be the culprit and are suggestive of valid concerns which warrant proper double blind studies to determine presence or absence of harm.

Additional research is mandatory to evaluate the potential of MCA to cause inflammatory symptoms in the body, or to contain Aspergillus proteins or by-products from the manufacturing process which may be inflammatory with repetitive exposure.

We conclude that there is enough anecdotal data to support the need for thorough evaluation of the safety and risks associated with the ubiquitous use of the currently manufactured citric acid in our foods, beverages and other ingested substances, and to ensure that the final product is highly purified, non-inflammatory and void of pro-inflammatory contaminants."

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Mast Cells…Mold fighting superheroes

The contribution of mast cells to bacterial and fungal infection immunity

"It is well-known that mast cells are significantly involved in IgE-mediated allergic reactions, but because of their location, it has also been long hypothesized that mast cells can act as sentinel cells that sense pathogens and initiate protective immune responses. By using mast cell or mast cell protease deficient murine models, recent studies by our groups and others indicate that mast cells have pleiotropic regulatory roles in immunological responses against pathogens.

In this review, we discuss studies that demonstrate that mast cells can either promote host resistance to infections caused by bacteria and fungi or contribute to dysregulated immune responses that can increase host morbidity and mortality.

Overall, these studies indicate that mast cells can influence innate immune responses against bacterial and fungal infections via multiple mechanisms.

Importantly, the contribution of mast cells to infection outcomes depends in part on the infection model, including the genetic approach used to assess the influence of mast cells on host immunity, hence highlighting the complexity of mast cell biology in the context of innate immune responses"

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Intestinal Mucosal Mast Cells: Key Modulators of Barrier Function and Homeostasis

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If you start getting push back from your physicians, this is why. I would reccomend to spend some time to fully digest and understand this as the "New’ Definition of MCAS. I think Dr Theorades and Dr Butterfield and others are pushing back but, the tryptase mafia is currently winning.

https://www.jacionline.org/article/S0091-6749(19)31116-9/fulltext

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The Circadian Clock Drives Mast Cell Functions in Allergic Reactions

" A multitude of immunological processes have been shown to be linked to the biological clock or to function under the control of circadian rhythms.

Steroid levels, for example, are known to naturally cycle with the circadian clock whereby the feedback loop, which controls the release of cortisol is most apt to respond to synthetic corticosteroid treatment in the morning rather than at other times of day giving way to the inclusion of timing in the treatment of various conditions, a term known as chronotherapy or chronomedicine.

Mast cells, which serve as key effector cells in allergic disease were shown to be under control of the SCN and to have a circadian expression and release of their mediators in response to activation.

Being ubiquitously distributed throughout connective and mucosal tissues and near blood vessels, mast cells are uniquely able to affect other immune cells and serve as a transition point from innate to adaptive immune response (46, 62). Hence, disrupted mast cell clocks could impair the subsequent adaptive immune responses and trigger or fortify allergic symptoms.

Allergic conditions such as asthma or allergic rhinitis have historically shown circadian bias as the severity of symptoms is exacerbated between midnight and morning time and exhibits prominent 24-h variation (12, 13).

Mast cells are known to have multiple immunoregulatory functions through the release of their mediators, such as histamine, leukotrienes, cytokines, chemokines and proteases and also serve as the key drivers of long-term pathophysiological changes associated with chronic allergic responses (14, 15).

As they are the main effector cells in allergy, the rhythmicity of mast cells has also come under investigation. For example, in some of the earlier findings, serum mast cell tryptase and plasma histamine levels were shown to be lower in the afternoon but peaked during night (18, 19).

Histamine levels are another potent downstream target. Allergic symptoms exacerbate during nighttime and plasma histamine levels exhibit nocturnal peaks.

In mastocytosis patients, peak levels of plasma histamine were observed in the early morning with the lowest in the afternoon (19). Interestingly, circadian variations of plasma histamine levels were diminished in mast cell-deficient mice reconstituted with Clock-mutated BMMCs demonstrating the influence of the mast cell clock (37). "

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Analysis of plasma histamine levels in patients with mast cell disorders

“Data in four patients with mastocytosis demonstrated a diurnal variation in plasma histamine, with the highest values observed in the early morning (approximately 2:00 A.M.) and the lowest values in the afternoon (approximately 2:00 P.M.).”

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Regulation of plasma histamine levels by the mast cell clock and its modulation by stress

Scientific Reports volume 7, Article number: 39934 (2017)

At steady state, plasma histamine levels exhibit circadian variations with nocturnal peaks, which is implicated in the nighttime exacerbation of allergic symptoms. However, the regulatory mechanisms are largely unexplored. This study determined how steady-state plasma histamine levels are regulated and affected by environmental factors.

In humans, plasma histamine levels increase in the early hours of the morning in healthy volunteers or asthmatic patients7,8,9,10. Although still controversial10, these nocturnal peaks in steady-state plasma histamine levels are implicated in the nighttime exacerbation of asthma symptoms7,9. In any case, there has been little information about the precise mechanisms that regulate plasma histamine levels at steady state.

In mammals, the circadian clock system consists of the central oscillator, located in the suprachiasmatic nucleus (SCN) of the hypothalamus, and peripheral oscillators in virtually all cell types, including mast cells.

Our findings indicate that mast cells are the main cell type responsible for maintaining plasma histamine levels in mice at steady state (Fig. 1). This notion may be supported by a number of clinical reports showing that patients with mastocytosis have higher plasma histamine levels than normal subjects and exhibit a diurnal variation in plasma histamine levels35,36.

Because histamine in plasma is rapidly metabolized (~5 minutes)37, we assume that plasma histamine levels at steady state largely reflects constitutive release of histamine from tissue mast cells into the circulation.

Stressful conditions predispose humans to allergic reactions39,40,41. Given that baseline plasma histamine levels were correlated with the degrees of mast cell–mediated allergic reactions (Fig. 5), we speculate that stressful conditions might influence the degree of mast cell–mediated allergic reaction, at least in part by affecting the mast cell clock–dependent regulation of plasma histamine levels. It will be thus interesting to investigate whether not only sub-acute restraint stress but also chronic stress (e.g. a range of social and psychosocial stress) can critically modulate the mast cell clock–dependent regulation of plasma histamine levels and affect temporal profiles or intensity of mast cell–mediated allergic reactions.

We showed previously that the extent of IgE-mediated degranulation in mast cells exhibits temporal variations with peaks in the resting phase, dependent upon circadian regulation of FcεRI expression and signaling by mast cell clock activity21,44. These findings suggest that the mast cell clockwork temporally gates mast cell responses to IgE, thereby causing the nighttime exacerbation of IgE-/mast
cell–mediated allergic symptoms44.

This study suggests that circadian regulation of plasma histamine levels by the mast cell clockwork may also be associated with temporal or stress-induced variations in allergic reactions. Hence, the current findings provide another layer of complexity underlying the temporal regulation of allergic reaction.

In summary, the mast cell–intrinsic clock plays a predominant role in circadian regulation of steady-state plasma histamine levels in mice, which can be modulated by stress.

Additionally, this mechanism may be associated with the nighttime- or stress-induced variations of allergic symptoms.

To the best of our knowledge, this is the first study to reveals a regulatory mechanism of plasma histamine levels at steady state and its possible roles in the pathologies of allergy.

https://www.nature.com/articles/srep39934

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The Circadian Clock Drives Mast Cell Functions in Allergic Reactions.
Christ P1,
Sowa AS1,
Froy O2,
Lorentz A1

"Experiments of our group showed that human intestinal mast cells produce a circadian release of de novo synthesized cysteinyl leukotrienes and pre-stored histamine upon IgE-mediated activation (25, 26).

Moreover, stimulation at different time points via FcεRI resulted in rhythmic interleukin (IL)-13 and IL-6 cytokine mRNA expression in BMMCs. FcεRI α chain mRNA and protein levels displayed a circadian pattern, which could explain the circadian oscillation of cytokine production in response to activation via FcεRI (26).

We subsequently found that the phosphorylation of the signaling molecule extracellular-signal regulated kinase 1/2 (ERK1/2) in response to FcεRI crosslinking showed circadian rhythms (28). ERK1/2 plays a major role in cytokine expression, degranulation, and arachidonic acid metabolism in mast cells (29).

Thus, the clock affects activation of signaling molecules, such as ERK1/2, and thereby the functionality of mast cells resulting in circadian production and release of mediators.

The impact of the clock on the reactivity of mast cells may explain how mast cells can contribute to the circadian variation of allergic symptoms.

Histamine levels are another potent downstream target. Allergic symptoms exacerbate during nighttime and plasma histamine levels exhibit nocturnal peaks. In mastocytosis patients, peak levels of plasma histamine were observed in the early morning with the lowest in the afternoon (19).

The circadian clock modulates a multitude of human conditions including asthma and allergy although the cellular mechanisms regulating the clock are still under investigation.

Mast cells, which serve as key effector cells in allergic disease were shown to be under control of the SCN and to have a circadian expression and release of their mediators in response to activation.

Being ubiquitously distributed throughout connective and mucosal tissues and near blood vessels, mast cells are uniquely able to affect other immune cells and serve as a transition point from innate to adaptive immune response (46, 62).

Hence, disrupted mast cell clocks could impair the subsequent adaptive immune responses and trigger or fortify allergic symptoms."

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ROBERTS CONFERENCE PRESENTATION:
METAL HYPERSENSITIVITY AND ORTHOPAEDIC IMPLANTS
CRAIG A. RINEER, MD
BRIGHAM AND WOMEN’S HOSPITAL

http://www.orthojournalhms.org/volume7/pdfs/ms19.pdf

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Mast cells mediate acute inflammatory responses to implanted biomaterials

Liping Tang, Timothy A. Jennings, and John W. Eaton
https://www.pnas.org/content/95/15/8841

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"This paper presents FDA’s review of currently available scientific information related to metals and their uses in medical implants, with focus on how metal materials are impacted by a physiological environment, expected and potential immune system responses to the metal associated with an implant, as well as subsequent clinical manifestations.

It is the result of a collaborative effort amongst subject matter experts (SMEs) gathered from across the Center for Devices and Radiological Health (CDRH), the organization within the FDA that is charged with regulating medical devices.

Just as importantly, this paper identifies where gaps exist in the scientific evidence related to immunological responses to metal-containing implants, and where opportunities for further research exist and will serve as a starting point for a public discussion on November 13 and 14, 2019 as part of an advisory panel meeting.2

The paper focuses on those metals and alloys which are commonly used in the medical device industry for implants."

https://www.fda.gov/media/131150/download

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