11 comments

  1. 1.
    •Hypothesis: H2 receptors are the receptors involved in non-H1 histamine responses.
    •Conclusion: Burimamide is a H2- receptor antagonist that can antagonize responses to histidine (such as gastric acid secretion) in which mepyramine (H1- receptor antagonist) cannot

    2.
    •Good controls and test groups within the experimental design
    •For figures 1 and 6, I appreciate the writers for including two sets of information as it was important to include, but it could have been presented in a different way as the figures were a little cluttered
    •All other figures/tables/corresponding summaries were straightforward and well organized/labeled/designed
    •Writers included statistical analysis
    •The methods and results were not separated into sections like we normally see in more recent papers, but I actually think this allowed for a more straightforward paper.
    •I would have liked to have seen some images or diagrams of the some of the methods used, but I recognize this as an older paper
    •Some of their data was not shown

    3.
    •The overall conclusions is well supported by the results
    •Future directions were not specifically mentioned
    •It is good that the writers mentioned that the analysis of actions of burimamide on gastric secretion cannot be used to analyze anti-inflammatory actions, so it is unsure whether they are due to H2- receptor antagonism. This could be a future direction

  2. • Hypothesis: The H2 receptor on parietal cells signals to increase gastric acid secretion. The use of H2 antagonists prove the inhibition of H2 alleviates GI distress though gastric acid release. 1st development of H2 receptors, then go into how antagonism of the receptor decreases gastric acid section in many different animal models and experiments
    Methods:
    • Use of classic h receptor blocker: mepyramine, burimamide: both used to clearly explain antagonism of the H2 receptor decreases acid secretion
    • Uses of different animals, a bit inconsistent but also taking the time period into consideration is needed
    • Could have at least picked similar enough animals, but randomly using guinea pigs, then rats, then dogs? Do they just use whatever animal they can get a hold of?
    • Used burimamide: actually has higher affinity for H3 receptors compared to H2
    • Structure of paper not used to comparing it to papers now, methods are almost woven in with the results and not as clearly laid out
    Results:
    • Overall I think this paper is well laid out, and thoughtful organization of the figures makes a good story throughout the paper
    • figure 1: activity of histamine derivatives
    • Table 1: showing results of assays used on different animal tissue, appreciate that significance was ran
    • Figure 2: really clearly laid out, clearly shows antagonism of H2 receptor well, in comparison directly to histamine
    • Figure 3: a bit unclear, not sure why need both figure 2 and 3? They are both showing the same thing but just transformed differently?
    • Table 2, Table 3: clearly shows that this is tissue specific H1 receptor that is ilium specific, rate of dissociation showing that burimamide does dissociate over time
    • Figure 4: very well done, clearly shows acid secretion done through measuring pH
    • Figure 5: using dog, don’t love the inconsistency between animal models, but overall shows wider relevance? Clear use of burimamide inhibits H+ output and production of gastric acid
    • Figure 6: like that they include human volunteers to the study, shows clinical relevance.
    o Clearly shows the use of burimamide inhibits acid secretion
    Discussion: does identify that there has been argument in the past that histamine is not involved in gastric acid secretion, but this paper does a good job to add more to the hypothesis that histamine does play a role in gastric acid secretion through gastrin-mediated release of histamine.
    • I wish it was elaborated on a bit more, but also I take into consideration the time period of this paper and discussions and future directions were less reflected on.
    • Overall I think this paper did a really good job with clearly showing the use of H2 activation for gastric acid release, as well as showing how an antagonist like burimamide and mepyramine can be used to unveil the functionality of the differing histamine receptors
    Overall Conclusion: activation of H1 and H2 is done through direct act of histamine. Gastrin formation and release activates histamine release, that then activates H2 cells to increase gastric acid secretion.

  3. The goal of this paper was to identify receptors that mediated histamine’s actions on the stomach, heart rate and uterine contractions and identify antagonists to these actions. They defined burimamide as an H2 receptor antagonist. Based on several results (inhibition of pentagastrin- and food-stimulated secretion indistinguishable from histamine secretion) this paper indicates that histamine and gastrin activities are coupled.

    2. Critically review the Methods and Results, including appropriateness of methods, rigor (e.g. controls, data analysis), and whether results are substantiated by the data provided.

    • They didn’t really clearly identify an “n” and didn’t really talk about how big or what parts of the tissues they were testing were.
    o Unclear whether it was a section or a whole vessel.
    o In the “Histamine Receptors and Mammalian Gastric Secretion” section they did give an “n”
    • Figures 2 and 3 were clear and easy to follow.
    • The tables were also pretty clear and well-organized.
    • I thought the authors gave good explanations and rationales for experiments throughout the various sections of the paper.
    • Overall, Figure 4 was not very easy to read and the explanation wasn’t very clear either.
    o Not sure how this figure gave them Ka and Kb like mentioned?
    • The authors seemed to change between organisms for different studies but didn’t ever talk about why really.
    o I assume it could be because of what resources they had available to them but if there was another reason for this I wish they would have said what it was.
    • Overall I liked how the authors organized this paper.

    3. Critically review the Discussion/Conclusions. Topics for evaluation include relevance of the findings to literature in the field, whether results support the overall conclusion, and possible future directions.

    • The summary and conclusions section was succinct and to the point, and covered most of the data mentioned in the paper.
    • They didn’t talk about any physiological relevance I thought, although they did mention studies in-progress involving humans.
    • At first glance, I thought this paper was going to be confusing, but actually found it to be organized and easy to follow, but did wish they had talked a little more in the beginning or at the end about clinical relevance and why this data matters in the grand scheme of public health.
    o That could have been a future direction for them.

  4. 1. The authors hypothesized that stimulation of a non-H1 receptor (later termed H2), contributed to the secretion of acid by the stomach, increased heart rate, and inhibition of contractions in the uterus. The authors’ results supported their hypothesis that H2 receptors exist in different tissue, and are activated by different compounds than H1. They also identified the compound burimamide as a competitive antagonist at the H2 receptor.

    2. • Using the two different tissue setups to isolate the two different receptor subtypes is a clever idea
    • Since this isn’t the typical paper setup of intro, methods, results, conclusion, discussion, quite a few details and rationale of the methods felt left out. For instance,
    o In Fig 1, how did they decide to test these histamine derivatives? What doses of each compound are they using?
    o Dependent measure for Fig 1 and Table 1 is relative activity to histamine. What exactly are they measuring? Force of contraction, number of contractions, pH, volume of acid secretion? Receptor binding? It is unclear unless you are familiar with their previous work or these types of assays.
    • Good control in Table 1 of testing the triazole analog of histamine to show nonsignificant variability within and between groups
    • Great use of classic pharmacological manipulations and applied receptor theory
    o Very clear indication from dose-response curve (Fig 2) and Schild plot (Fig 3) that burimamide is a competitive antagonist
    • Good control showing that burimamide does not block effects of isopraline (because it acts at catecholamine B-receptors) or histamine H1 agonists
    o In the discussion it says that large doses of burimamide did block effects of isopraline and H1 agonists though. Is the main conclusion here that it has much lower affinity for H1 than H2?
    • Clear evidence that burimamide is inhibiting histamine and pentagastrin-stimulated gastric secretion both in vitro and in vivo and in humans. However, they did not show their negative results where burimamide allegedly failed to inhibit vagally-stimulated secretion.
    3. • Overall, did a good job of tying their findings to the literature in the field and future directions for this work.
    • Mentioned future directions of investigating H2 involvement in cardiovascular system, and potential combination of burimamide and mepyramine to give full antagonization of histamine effects.
    • Failed to mention what an H2 antagonist be clinically useful for. Seems like for GERD or heartburn.
    • As a reader I would have appreciated more explanation of why they think burimamide inhibits histadine and pentagastrin-induced acid secretion but not vagal-stimulated secretion. It seems like the H2 receptor would be a common downstream target for all those pathways.

  5. Hypothesis of this paper was that there are Histamine 2 (H2) receptors that are activated by histamine but mepyramine (antihistaminic drug) cannot antagonized. Conclusion of this paper was that histamine also acts through H2 receptors and H2 receptor can be antagonized using burimamide (H2 antagonist). Other histamine induced through H1 receptor can be blocked by mepyramine.
    They discussed their next step as they moved forward with it. Figure 1 has a lot of information on it and adding a key on the side to indicate what color represents what would’ve been better than explaining everything on the description. Also, they talk about significant difference of data and its visibly clear, but a significance label (*) would’ve been appropriate as well as adding P values to show significance. For table 1, they talk about 2-methylhistamine greatest contribution to heterogeneity X2 comes from the “between-groups” differences and its due to high activity on atrial assay, but table one shows relatively lower activity of 2-methylhistamine on atrial assay. For results, they made the conclusion and basically discussed it and then moved on to the next experiment. They have done pharmacology trials on healthy human volunteers, but they just left it at “details will be published later”. I think including the details in the paper is appropriate.
    Although there wasn’t a discussion section, they discussed the results right after providing them which was interesting. The conclusion and summary was short and simple. They didn’t really talk about a hypothesis to support it at the end. It was really interesting to see a summary section at the end. I think the reading can be confusing and that might be one reason for them to include a summary section.

  6. 1. Summarize the hypothesis and major conclusion in no more than four lines.
    Histamine is responsible for varied effects, and use of an H1 antagonist had shown that another class of histamine receptors exist that are responsible for histamine’s effects on acid secretion in the stomach (that didn’t respond to H1 antagonism). In vivo assays suggest that burimamide functionally inhibits H2 receptors, reducing gastric acid secretion.

    2. Critically review the Methods and Results, including appropriateness of methods, rigor (e.g. controls, data analysis), and whether results are substantiated by the data provided.

    Given the various locations of H2 receptor activity, I think it was critical that Black/Duncan conducted assays in several tissue locations across several mammalian phyla in examining the effects and specificity of mepyramine (H1) and burimamide (H2). I particularly found the use of a pentagastrin-based system of testing [human] H2 antagonism on gastric secretion interesting. I found that it nicely complimented the burimamide assay conducted using dogs given tinned meat. Due in part to the changes in publishing since this paper came out, I would like to see a more complete out methods section (Ex. What anesthetics were used for these preparations?).

    3. Critically review the Discussion/Conclusions. Topics for evaluation include relevance of the findings to literature in the field, whether results support the overall conclusion, and possible future directions.
    Very important paper, not just in finding treatments for acid reflux/over-secretion of acid (cimetidine), but the characterization of a new histamine receptor opened the doors to new methods and understanding of endogenous histamine signaling. Black and Duncan et, al did tremendous work especially given the available tools, further research would/could focus on better H2 antagonists (reverse agonists) (better SAR/quant tools helped this along)

  7. 1. Summarize the hypothesis and major conclusion in no more than four lines.
    The group hypothesized that the discovery of an H2-recceptor antagonist may be beneficial in helping to resolve the physiology of histamine and gastrin. They concentrated on the classification and specific blockade of mepyramine-insensitive receptors. They found that mepyramine is an H1-receptor antagonist and burimamide is an H2-receptor antagonist.
    2. Critically review the Methods and Results, including appropriateness of methods, rigor (e.g. controls, data analysis), and whether results are substantiated by the data provided.
    I believe this paper is outdated for the purpose of this class. The paper does not have a separate methods section. They explained their experiments while presenting their results. They neglected to mention the effects of burimamide on gastric secretion evoked by feeding examined in every dog. For their clinical studies, they had 2 human volunteers, this isn’t enough for a sufficient sample size.
    3. Critically review the Discussion/Conclusions. Topics for evaluation include relevance of the findings to literature in the field, whether results support the overall conclusion, and possible future directions.
    They don’t have a separate discussion section. However, they have a summary and conclusion section, which is helpful to the reader. It’s very hard to critique a section that isn’t given a section. However, they put the results, discussion and their conclusion all in the same section. It would have been better if they separated these sections.

  8. 1. Summarize the hypothesis and major conclusion in no more than four lines.
    The focus of the study was to classify and specify the blockade of the receptors involved in mepyramine-insensitive histamine responses. Through the study, the investigators concluded that mepyramine is an H1-receptor antagonist and burimamide is an H2-receptor antagonist, which antagonizes histamine responses ike acid gastric secretion.

    2. Critically review the Methods and Results

    Identification of H2-Receptors
    • Good idea using 3 non-H1 systems (gastric acid secretion, contraction frequency of atrium, contractions of uterine horn) and 2 H1 receptor systems (contraction of ileum and contraction of stomach)
    • Could explain how tissues were isolated or gathered
    • Would have liked an explanation as to why they used the different isomers of histamine
    o The differences obviously made a difference noticing the significant values
    H2-Receptor Antagonists
    • Good reasoning that compounds could inhibit gastric secretion not specifically through H2-receptor antagonism
    • Mentioned that an ideal solution was not found for problems associated with long time-cycles and washout of antagonists
    o It getting more tissue samples not an option or would this not help?
    o Was it really satisfactory?
    Burimamide
    • Using dose-response curves and using burimamide and histamine in conjunction on rat uterus, can provide reasoning that burimamide is a competitive antagonist to histamine and it can be surmounted
    • Potential inhibitors were given through IV injections
    o Varied histamine infusion rate was done to control for the mean response
    o What is the maximum response? How is that calculated or visualized?
    • Further explained additional evidences to explain the relationship between H2-receptor antagonism and inhibition of histamine-stimulated gastric secretion
    o Specificity of the inhibition of secretion
    o Comparison of H2-receptor antagonist potencies of compounds with corresponding activities as inhibitors
    o Calculation of regression between plasma concentration of burimamide and DR-1
    • Noticed that burimamide can inhibit histamine-stimulated but not vagally-stimulated secretion

    3. Critically review the Discussion/Conclusions.
    • Concluded that burimamide was a specific competitive antagonist of H2-receptors and noticed no significant interactions with catecholamine beta-receptors, histamine H1 receptors, or acetylcholine (muscarinic) receptors
    • Also noticed that burimamide inhibits pentagastrin-stimulated acid secretion but cholinergic secretion is unaffected
    • Proposes that the actions of gastric are somehow coupled to those of histamine

  9. 1.

    The major goal of the article is with the classification and specific blockade of the receptors involved in non H1 histamine responses. The conclusion is burimamide can antagonize responses to histamine which is not blocked by Mepyramine, an H1 antagonist. Histamine activates H2, and responses can be completely blocked by H1 and H2. Burimamide inhibits penta-gastrin stimulated acid secretion.

    2.

    – When identifying the receptor, how much of each compound was given?
    – Control curve was the secretory response immediately before injection
    – Where is the dose response curve for the gastric secretion experiment?
    – Good to confirm that gastrin was not being interfered with from H2 block
    – Mentions how much penta-gastrin was given per minute but I do not see how long it was given for
    – Was there a sex difference in any of the animals?

    3.

    – Future studies and possible errors in the experiment
    – No real discussion section would like to see it separated into separate sections so it is easier to read this is a personal preference
    – Clinical implications are significant but not discussed in the paper

  10. They hypothesized that histamine was acting via a non-H1 (H2) receptor to illicit response in gastric acid secretion as this response was not blocked by a known H1 antagonist mepyramine.

    2. Methods and Results

    • Lacks a true methods section
    • Interesting choice of whole tissue vs some receptor ligand binding assay
    • Utility of multiple model organisms
    • Tyrode and McEwen solution formulation not given, and reasons used
    • Large sample sizes
    • Good use of various statistical approaches
    • All male animals
    • Use of human subjects good but very small sample
    • Use of pA2 values to determine competitive antagonists
    • Use of chi-square test of heterogeneity to determine relationship among species and tissues

    3. Discussion/Conclusions.

    Overall, this paper is able to make pivotal conclusions in terms of the role of histamine and histamine antagonists in the production of gastric acid. They were able to demonstrate that burimamide can antagonize response to histamine which was not blocked by H1 antagonist mepyramine. They also showed that histamine activates H2 receptors to produce gastric acid. They also showed that histamine’s effects on the heart could be modified through combination therapies indicating localization of different receptors and responses in different tissue types. The authors, however, could be more thorough in their explanation of methods and materials used throughout the paper to avoid problems when trying to reproduce their findings.

  11. 1. I did not find a clear hypothesis from this paper, but the paper was primarily focused on the effects of antihistamine drugs like Mepyramine and Burimamide on Histamine receptors.
    – The paper concluded that Mepyramine is an H1-receptor antagonist while Burimamide is a H2-receptor antagonist.
    – Burimamide alone antagonizes histamine stimulated gastric acid secretion by activating H2-receptors.
    – Histamine reponses that are partially antagonized by Mepyramine alone can be fully antagonized with a combination of Mepyramine and Burimamide. Additionally, Burimamide inhibits pentagstrin-stimlated acid secretion.

    2. When the author talks about using “three non-H1 systems”, why do they use different animals for each test, such as measuring gastric acid secretion and contraction frequency?
    – Fig.1 provided a clear understanding of which histamine derivatives displayed the most activity, especially the chemical structure providing a further comprehensive display of what a specific derivative has in terms of chemical structure.
    – In fig. 4, the figure was confusing to understand, while I get that it was plotting rat gastric acid secretion by pH, I believe using a different graph would have been a better solution in displaying their findings.
    – Overall the methods presented what the author’s aims were, finding the effects of Histamine and the H2-receptor antagonists effects.

    3. I appreciate the fact the study had pharmacological trials on healthy human volunteers and that they would get the details in the future, which shows the future clinical implications about this study.
    – The findings from this study and the conclusion reinforce the overall direction of finding the effects of histamine and H2-receptor antagonists and their effects.
    – A future direction they could have tested would have been using H2-receptor partial agonists and comparing the effects to H2-receptor agonists and H2-receptor antagonists.

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