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Increasingly, the pharmaceutical industry has been plagued with escalating costs coupled with decreasing productivity, leading to speculation that the pharmaceutical business model as we know it may be broken. It is in this context that many in the industry have been searching for innovative strategies to reduce cost as well as risk. Both phenotypic screening and drug repositioning represent discovery approaches that fit this description. Melior Discovery is unique among drug discovery organizations in its use of an in vivo phenotypic screening platform used to reposition discontinued clinical-stage compounds. The story of Melior's lead candidate, MLR-1023, illustrates this approach. We show that when dealing with “privileged” substrate (discontinued clinical-stage compounds that exhibit good human safety and tolerability characteristics and other favorable drug-like characteristics), an in vivo screening platform, comprising a wide array of animal models of human disease, is ideal. Many years of conducting these screens on hundreds of compounds has shown the frequency with which otherwise unpredicted therapeutic potential is associated with drug targets that were thought to be well-characterized.

Study objective We compare emergency department (ED) operational metrics obtained in the first year of a rotational patient assignment system (in which patients are assigned to physicians automatically according to an algorithm) with those obtained in the last year of a traditional physician self-assignment system (in which physicians assigned themselves to patients at physician discretion). Methods This was a pre-post retrospective study of patients at a single ED with no financial incentives for physician productivity. Metrics of interest were length of stay; arrival-to-provider time; rates of left before being seen, left subsequent to being seen, early returns (within 72 hours), and early returns with admission; and complaint ratio. Results We analyzed 23,514 visits in the last year of physician self-assignment and 24,112 visits in the first year of rotational patient assignment. Rotational patient assignment was associated with the following improvements (percentage change): median length of stay 232 to 207 minutes (11%), median arrival to provider time 39 to 22 minutes (44%), left before being seen 0.73% to 0.36% (51%), and complaint ratio 9.0/1,000 to 5.4/1,000 (40%). There were no changes in left subsequent to being seen, early returns, or early returns with admission. Conclusion In a single facility, the transition from physician self-assignment to rotational patient assignment was associated with improvement in a broad array of ED operational metrics. Rotational patient assignment may be a useful strategy in ED front-end process redesign.

Author(s): Maher, Steven A.; Temkit, M'Hamed; Buras, Matthew R.; McLemore, Ryan Y.; Butler, Rebecca K.; Chowdhury, Yasmynn; Lipinski, Christopher A.; Traub, Stephen J. | Abstract: Introduction: Patients with malignancy represent a particular challenge for the emergency department (ED) given their higher acuity, longer ED length of stay, and higher admission rate. It is unknown if patients with malignancies and hyperlactatemia are at increased risk of mortality. If serum lactic acid could improve detection of at-risk patients with cancer, it would be useful in risk stratification. There is also little evidence that “alarm” values of serum lactate (such as g/=4 mmol/L) are appropriate for the population of patients with cancer. Methods: This was a continuous retrospective cohort study of approximately two years (2012-2014) at a single, tertiary hospital ED; 5,440 patients had serum lactic acid measurements performed in the ED. Of the 5,440 patients in whom lactate was drawn, 1,837 were cancer patients, and 3,603 were non-cancer patients.Cumulative unadjusted mortality (determined by hospital records and an external death tracking system) was recorded at one day, three days, seven days, and 30 days. We used logistic regression to examine the risk of mortality 30 days after the ED visit after adjusting for confounders. Results: In an unadjusted analysis, we found no statistically significant difference in the mortality of cancer vs. non-cancer patients at one day and three days. Significant differences in mortality were found at seven days (at lactate levels of l2 and 4+) and at 30 days (at all lactate levels) based on cancer status. After adjusting for age, gender, and acuity level, 30-day mortality rates were significantly higher at all levels of lactic acid (l2, 2-4, 4+) for patients with malignancy. Conclusion: When compared with non-cancer patients, cancer patients with elevated ED lactic acid levels had an increased risk of mortality at virtually all levels and time intervals we measured, although these differences only reached statistical significance in later time intervals (Day 7 and Day 30). Our results suggest that previous work in which lactate “cutoffs” are used to risk-stratify patients with respect to outcomes may be insufficiently sensitive for patients with cancer. Relatively low serum lactate levels may serve as a marker for serious illness in oncologic patients who present to the ED.

The “rule of 5” has become a mainstay of decision-making in the pharmaceutical industry as well as in nonindustrial (academic and institutional) drug development. However the authors of the original paper never intended for “double cutoffs” to preclude development of new drug leads for parasitic diseases., Graphical abstract Image 1, Highlights • “rule of 5” is a mainstay of decision-making in drug screening efforts. • Acts as an absorption-permeability alert procedure to guide medicinal chemists. • Never intended to apply to parasitic infectious diseases. • Should not impede anti-parasitic drug development.

In a decade with over half a billion dollars of investment, more than 300 chemical probes have been identified to have biological activity through NIH funded screening efforts. We have collected the evaluations of an experienced medicinal chemist on the likely chemistry quality of these probes based on a number of criteria including literature related to the probe and potential chemical reactivity. Over 20% of these probes were found to be undesirable. Analysis of the molecular properties of these compounds scored as desirable suggested higher pKa, molecular weight, heavy atom count, and rotatable bond number. We were particularly interested whether the human evaluation aspect of medicinal chemistry due diligence could be computationally predicted. We used a process of sequential Bayesian model building and iterative testing as we included additional probes. Following external validation of these methods and comparing different machine learning methods, we identified Bayesian models with accuracy comparable to other measures of drug-likeness and filtering rules created to date.

Telemedical physician triage (TPT) is a potential application of telemedicine in the emergency department (ED). We report the technical success, patient satisfaction, and effect on ED throughput metrics (length of stay [LOS] and time to physician evaluation [TPE]) of TPT performed on a mobile platform.Patients underwent standard nursing triage with or without TPT. Technical success is reported as raw data. Patient satisfaction is reported as raw data±standard deviation on a 5-point (low-to-high) scale. LOS and TPE are reported as mean±SD [95% CI] values. Statistical analyses of LOS and TPE are via two-sample t test.One hundred six patients were registered during intervention periods, and TPT was completed in 36 (34%). One hundred ninety-six patients were registered during control periods. The technical success rate was 95%. Average patient satisfaction was 4.7 on a 5-point scale. The primary analysis (106 patients) showed no change in LOS (266±101 [244-288] min versus 258±172 [234-282] min) but a trend toward improved TPE with TPT (35±28 [29-41] min versus 42±31 [38-46] min) (p=0.052). A secondary analysis (36 patients) showed no change in LOS (273±125 [231-316] min versus 258±172 [234-282] min) but improved TPE with TPT (16±15 [11-21] min versus 42±31 [38-46] min) (p0.0001).TPT in the ED on a mobile platform was technically successful, well accepted by patients, and associated with a decrease in TPE but not LOS.

Background Bioassay data analysis continues to be an essential, routine, yet challenging task in modern drug discovery and chemical biology research. The challenge is to infer reliable knowledge from big and noisy data. Some aspects of this problem are general with solutions informed by existing and emerging data science best practices. Some aspects are domain specific, and rely on expertise in bioassay methodology and chemical biology. Testing compounds for biological activity requires complex and innovative methodology, producing results varying widely in accuracy, precision, and information content. Hit selection criteria involve optimizing such that the overall probability of success in a project is maximized, and resource-wasteful “false trails” are avoided. This “fail-early” approach is embraced both in pharmaceutical and academic drug discovery, since follow-up capacity is resource-limited. Thus, early identification of likely promiscuous compounds has practical value. Results Here we describe an algorithm for identifying likely promiscuous compounds via associated scaffolds which combines general and domain-specific features to assist and accelerate drug discovery informatics, called Badapple: bioassay-data associative promiscuity pattern learning engine. Results are described from an analysis using data from MLP assays via the BioAssay Research Database (BARD) http://bard.nih.gov. Specific examples are analyzed in the context of medicinal chemistry, to illustrate associations with mechanisms of promiscuity. Badapple has been developed at UNM, released and deployed for public use two ways: (1) BARD plugin, integrated into the public BARD REST API and BARD web client; and (2) public web app hosted at UNM. Conclusions Badapple is a method for rapidly identifying likely promiscuous compounds via associated scaffolds. Badapple generates a score associated with a pragmatic, empirical definition of promiscuity, with the overall goal to identify “false trails” and streamline workflows. Unlike methods reliant on expert curation of chemical substructure patterns, Badapple is fully evidence-driven, automated, self-improving via integration of additional data, and focused on scaffolds. Badapple is robust with respect to noise and errors, and skeptical of scanty evidence. Electronic supplementary material The online version of this article (doi:10.1186/s13321-016-0137-3) contains supplementary material, which is available to authorized users.

Intellectual property considerations decrease research productivity in subtle and unanticipated ways. Chemical probe exchange between Pharma and academia is hindered by academic IP interests. These are perceived as a subtle nuisance by the academic researcher. Novel ligands for oral targets are historically few and numbers of economically attractive oral drug targets are limited. Economically speculative targets lie in the academic domain but the medicinal chemistry to explore these in a drug discovery sense lies in Pharma and cooperation between the two is hindered by very different academic and Pharma views on chemical quality. Tools and probes for academic target validation can accommodate looser chemical quality criteria as opposed to the very strict chemical quality criteria required in Pharma drug discovery.

Background Although the use of a physician and nurse team at triage has been shown to improve emergency department (ED) throughput, the mechanism(s) by which these improvements occur is less clear. Objectives 1) To describe the effect of a Rapid Medical Assessment (RMA) team on ED length of stay (LOS) and rate of left without being seen (LWBS); 2) To estimate the effect of RMA on different groups of patients. Methods For Objective 1, we compared LOS and LWBS on dates when we utilized RMA to comparable dates when we did not. For Objective 2, we utilized patient logs to divide patients into groups and estimated the effects of the RMA on each. Results Objective 1. LOS fell from 297.8 min pre-RMA to 261.7 min during RMA, an improvement of 36.1 (95% confidence interval 21.8–50.4) min; LWBS did not change significantly. Objective 2. Patients seen and dispositioned by the RMA had an estimated decrease in LOS of 117.8 min (estimated decrease in LOS of 45%), but patients seen by the RMA whose care was transitioned to the main ED had an estimated increase in LOS of 25.0 min (estimated increase in LOS of 8%). Conclusions On a system level, the addition of an RMA shift at a single facility was associated with an improvement in LOS, but not LWBS. On a mechanistic level, it seems that improvements occurred as a result of the rapid disposition component of the RMA rather than placing advanced orders at triage.

Background While epinephrine is the recommended first-line therapy for the reversal of anaphylaxis symptoms, inappropriate use persists because of misunderstandings about proper dosing and administration or misconceptions about its safety. The objective of this review was to evaluate the safety of epinephrine for patients with anaphylaxis, including other emergent conditions, treated in emergency care settings. Methods A MEDLINE search using PubMed was conducted to identify articles that discuss the dosing, administration, and safety of epinephrine in the emergency setting for anaphylaxis and other conditions. Results Epinephrine is safe for anaphylaxis when given at the correct dose by intramuscular injection. The majority of dosing errors and cardiovascular adverse reactions occur when epinephrine is given intravenously or incorrectly dosed. Conclusion Epinephrine by intramuscular injection is a safe therapy for anaphylaxis but training may still be necessary in emergency care settings to minimize drug dosing and administration errors and to allay concerns about its safety.

MLR-1023 [Tolimidone; CP-26154; 2(1H)-pyrimidinone, 5-(3-methylphenoxy)] is an allosteric Lyn kinase activator that reduces blood glucose levels in mice subjected to an oral glucose tolerance test (J Pharmacol Exp Ther 342:15-22, 2012). The current studies were designed to define the role of insulin in MLR-1023-mediated blood glucose lowering, to evaluate it in animal models of type 2 diabetes, and to compare it to the activities of selected existing diabetes therapeutics. Results from these studies show that in an acute oral glucose tolerance test MLR-1023 evoked a dose-dependent blood glucose-lowering response that was equivalent in magnitude to that of metformin without eliciting a hypoglycemic response. In streptozotocin-treated, insulin-depleted mice, MLR-1023 administration did not affect blood glucose levels. However, MLR-1023 potentiated the glucose-lowering activity of exogenously administered insulin, showing that MLR-1023-mediated blood glucose lowering was insulin-dependent. In a hyperinsulinemic/euglycemic clamp study, orally administered MLR-1023 increased the glucose infusion rate required to sustain blood glucose levels, demonstrating that MLR-1023 increased insulin receptor sensitivity. In chronically treated db/db mice, MLR-1023 elicited a dose-dependent and durable glucose-lowering effect, reduction in HbA1c levels and preservation of pancreatic β-cells. The magnitude of effect was equivalent to that seen with rosiglitazone but with a faster onset of action and without causing weight gain. These studies show that MLR-1023 is an insulin receptor-potentiating agent that produces a rapid-onset and durable blood glucose-lowering activity in diabetic animals.

This commentary describes two simple procedures using commercially available software packages that greatly facilitate the creation of and replication of data sets intended for quantitative structure activity relationship (QSAR) and quantitative structure property relationship (QSPR) studies. Used properly, the procedures allow the capture of individual chemical structures from the Chemical Abstracts Service (CAS) SciFinder software in a computer readable format that is recognized by most chemical database and computational calculation software packages. The researcher need not draw in a chemical structure to create a Molecular Design Limited (MDL) mol file, the 2D connection table format most commonly used to create the chemical depiction of compound or drug. The MDL mol format is needed so that properties can be calculated from the chemical structure alone. All that is required is that the compound or drug be located in SciFinder. The procedures are described in considerable detail because the key procedures for capturing structures from Chemical Abstracts Service (CAS) SciFinder through the use of Accelrys’Accord for Excel software are undocumented in either software. Also described is a batch procedure that allows search of CAS SciFinder for the exact chemical structure of up to 25 compounds. Without use of this procedure, Scifinder can only be searched for an exact chemical structure a single compoundat a time using a query consisting of a drawn in structure. Both the single-mode structure retrieval and batch-mode compound search procedures result in very significant time savings to the researcher creating or replicating QSAR/QSPR data sets and likelymay enable structure searches that previously might not have been attempted because of researcher time constraints. These procedures do not affect positively or negatively the cost to the user of the searches against the SciFinder software. These costs are determined by CAS policy, and depend on the numbers of structures/compounds searched. Locating a compound or drug in SciFinder is most accurately done using the CAS Registry Number. The CAS Registry Number uniquely identifies a specific compound and salt form. Older deleted CAS Registry Numbers for a specific compound may be encountered, but a search on the current (or older) CAS Registry Numbers will always bring up the correct compound. If different salt forms of the same compound exist in the CAS databases, they will have different CAS Registry Numbers. By contrast, a search by compound or drug namemay fail. IUPAC names for compounds are of no value in searches against SciFinder because IUPAC Names are not listed in the records. Commonly used drug names work fairly well. However, it is frequent to find variant or misspelled drug names in the scientific literature. A deviation between a search input name and the names stored in CAS databases in only a single letter or number will result in a search failure. Searchesusingdrug tradenames (as invery recent drugs) or company code numbers (as in early discovery stage compounds) fail more frequently than searches using common names.

Olfactory and gustatory hallucinations are not often encountered in the acute care setting but may represent the subtle presenting features of a significant underlying disease process. We describe a patient whose most striking presenting symptoms were of olfactory and gustatory hallucinations and in whom the diagnosis and treatment of a new brain tumor and partial status epilepticus occurred entirely in the emergency department. The lesion was subsequently identified as glioblastoma multiforme involving the hippocampus and amygdala.

Between 2004 and 2008, the US National Institutes of Health Molecular Libraries and Imaging initiative pilot phase funded 10 high-throughput screening centers, resulting in the deposition of 691 assays into PubChem and the nomination of 64 chemical probes. We crowdsourced the Molecular Libraries and Imaging initiative output to 11 experts, who expressed medium or high levels of confidence in 48 of these 64 probes.

A medicinal chemist combines organic synthesis expertise and the ability to optimize chemistry structure-activity relationships (SAR) based on relevant biomedical information so as to achieve project goals. The ability to optimize chemistry SAR consists of both the easier to explain logical stepwise structural modification that is often described by quantitative structure-activity relationships (QSAR) and the more difficult to explain exercise of high-order pattern recognition. Optimizing SAR is full of traps for the unwary. What are the pros and cons of various types of screens Should one believe the screening data How does one optimize against multiple sometimes conflicting properties What types of compounds are worth screening How does one judge the quality of a screening hit Very importantly, drug discovery is a team exercise in which the medicinal chemist plays a key facilitating role. Given good interpersonal skills, the medicinal chemist's training is broad enough to enable cooperative interactions across the whole discovery team. Chemistry pattern recognition is the unique skill that the medicinal chemist contributes to drug discovery. The ability to relate chemistry structure to biological activity and to change chemistry structure so as to change a variety of biomedical parameters in a desired direction leads to the successful “drug hunter.”

The recent outbreak of the Ebola virus in West Africa has highlighted the clear shortage of broad-spectrum antiviral drugs for emerging viruses. There are numerous FDA approved drugs and other small molecules described in the literature that could be further evaluated for their potential as antiviral compounds. These molecules are in addition to the few new antivirals that have been tested in Ebola patients but were not originally developed against the Ebola virus, and may play an important role as we await an effective vaccine. The balance between using FDA approved drugs versus novel antivirals with minimal safety and no efficacy data in humans should be considered. We have evaluated 55 molecules from the perspective of an experienced medicinal chemist as well as using simple molecular properties and have highlighted 16 compounds that have desirable qualities as well as those that may be less desirable. In addition we propose that a collaborative database for sharing such published and novel information on small molecules is needed for the research community studying the Ebola virus.

Strokes in the vertebrobasilar arterial distribution may result in a variety of physical findings and can be challenging to diagnose. We report a case of a 60-year-old woman with infarction of the left midbrain, right pons, and bilateral thalami with physical findings resembling transtentorial herniation.

Hypothermia during brain ischemia can improve neurological outcome. This study tested whether local cranial cooling during the low-flow state of cardiopulmonary resuscitation (CPR) could produce clinically significant cerebral cooling. Ice was applied to the heads and necks of subjects (hypothermia group) with out-of-hospital cardiac arrest (OOHCA) during CPR. Nasopharyngeal and tympanic temperatures were measured as surrogates for cerebral temperature. The rate of cranial cooling in the hypothermia group (-0.06 +/- 0.06 degrees C/min) was not significantly increased compared with a control group without ice (-0.04 +/- 0.07 degrees C/min), although older age was associated with more rapid cranial cooling. Of note, many subjects with OOHCA are already mildly hypothermic (mean cranial temperature= 35.0 +/- 1.2 degrees C) when they are first encountered in the field. This study suggests that brief cranial cooling is ineffective for rapidly lowering brain temperature. However, most cardiac arrest victims are spontaneously mildly hypothermic and preventing rewarming may provide some of the desired benefits of cerebral hypothermia.

61 Background: Patients with cancer often have complex symptoms and morbidity that prompt frequent Emergency Department visits. The length of stay in the ED for cancer patients exceeds that of patients without cancer. Patients with cancer are also more likely to be admitted, but are often discharged within 72h. Protracted ED visits, extensive investigations, and the burdens of even a short admission may be distressing and may not be aligned with patients’ care goals and preferences. Furthermore, the healthcare resources dedicated to these patients is considerable and has economic implications. We recently established a Supportive Care Infusion Center (SCIC), an on-campus outpatient unit where patients can receive treatments for symptom relief and comfort; they are assured integrated palliative care with routine oncologic care. We believe there is a subset of cancer patients who can be safely transferred from the ED to the SCIC for appropriate care. Methods: We are retrospectively evaluating cancer patients admitted through the ED to validate clinical parameters likely to lead to admission, and also identify any differences between patients admitted for 72h. Patients are analyzed based on symptoms, cancer type, prior cancer therapies, performance status, comorbidities, and presence/absence of advance care planning as well as previous contact with Palliative Care. Data are also being gathered on patient outcomes, including mortality within 60d of admission. Results: Previously established indicators predictive of admission included shortness of breath and SIRS criteria, which our current review validates. We also observe that patients admitted for >72h have greater symptom burden and comorbidities and have received multiple lines of therapy. They also less frequently have advance care planning in place. Data analysis is ongoing. Conclusions: There exists a difference between cancer patients admitted >72h and those discharged within 72h. Awareness of these characteristics may lead to improved workflow in the ED. Identifying patients who may be suitable for transfer to an outpatient supportive care unit rather than short-term admission will also facilitate cost-effectiveness. Future direction includes evaluation of outcomes such as mortality, quality of life, and patient-caregiver satisfaction.

Although it is generally safe, there are morbidities associated with home oxygen use. Experience in our burn unit led to an analysis of burn complications from this therapy. A retrospective review of records during a 12-year period identified 23 patients with burns associated with home oxygen use. Average age of the patients was 70 years, with chronic obstructive pulmonary disease the most prevalent indication for use. Concomitant cigarette smoking was the most common inciting mechanism of the burns (70%). Average burn size was 3.9% of total body surface area. Eleven patients presented in the first 10 years of the study period, whereas 12 presented in the last 2 years. We have seen a rise in injuries with the use of home oxygen. The absolute number of injuries sustained is unknown, because many are likely unreported. To decrease the morbidity and costs associated with these injuries, the need for continuing safety education is apparent.

The formation of reactive oxygen species during reperfusion is one trigger for neuronal injury after global cerebral ischemia. Because formation of reactive oxygen species requires delivery of molecular oxygen to ischemic tissue, restricting inspired oxygen during reperfusion may decrease neurological damage. This study examined whether ventilation with room air rather than pure oxygen during resuscitation would improve neurological recovery after cardiac arrest in rats. Adult, male rats were subjected to 8 min of asphyxia resulting in cardiac arrest. During resuscitation, rats were ventilated either with hyperoxia (FiO2 = 1.0) or normoxia (FiO2 = 0.21, room air). Neurobehavioral deficits were scored daily for 72 h after resuscitation, after which brains were collected for histology. Normoxia decreased arterial oxygen content. Other physiological parameters and mortality did not differ between groups. All surviving rats exhibited behavioral and histological signs of brain damage. Neurological deficit scores did not differ between normoxia and hyperoxia conditions at any time point. The number of ischemic neurons in the hippocampus also did not differ between groups. These data indicate neither benefit nor detriment of reducing inspired oxygen concentration during resuscitation from asphyxial cardiac arrest in rats.

NaIoxone is an opioid antagonist used for the reversal of life-threatening opioid overdose. Because naloxone is believed to have few side effects, it is often given liberally even in the absence of absolute indications. The relative safety of prehospital naloxone administration has been rep0rted.l We report two patients in whom the prehospital administration of naloxone unmasked anticholinergic poisoning. PREHOSPITAL CARE Patient 1 was a 46-year-old man who called EMS with a chief complaint of shortness of breath and headache. On arrival, paramedics found the patient conscious and alert with no signs of respiratory distress. The patient stated that he and his girlfriend had been injecting heroin approximately 30 minutes prior to calling EMS. He reported feeling "lightheaded" within minutes of injecting the drug, a feeling that was not consistent with his past experiences with heroin. The patient denied chest pain, fever, headache, recent trauma, weakness, or paresthesias prior to the onset of symptoms. He was not taking any prescription or over-the-counter medications, and had no known allergies. His social history included past heroin and alcohol abuse, as well as prior cocaine use. His vital signs were heart rate (HR) 110 beats/min, respiratory rate (RR) 22 breaths/min, blood pressure (BP) 150/110 mm Hg, and oxygen saturation 99% on room air. EKG monitor revealed sinus tachycardia without ectopy. The patient's breath sounds were clear and equal in all fields. The skin was pale and clammy

© 2014 World Journal of Emergency MedicineBACKGROUND: The use and abuse of designer drugs has been recognized for decades; however there are many derivatives of compounds that make their way into the community. Abuse of compound(s) known on the street as "bath salt" is on the rise.METHODS: We report the case of a 33-year-old man who complained of "flashbacks" and right arm shaking that followed a night of "bath salt" snorting. The active compound methylenedioxypyrovalerone methamphetamine (MDPV) was confirmed; however, analysis of three different "bath salt" products showed difference in their active components.RESULTS: The patient's symptoms remained stable and he was discharged home after observation in the emergency department with instructions to return for any symptom progression.CONCLUSION: Practitioners should be aware of the abuse of the compounds and that not all "bath salt" products contain MDPV.KEY WORDS: Residual neurological defi cits; Methylenedioxypyrovalerone methamphetamine; Emergency Department

Nat. Chem. Biol. 5, 441–447 (2009); published online 17 June 2009; corrected after print 17 June 2009 In the version of this article initially published, the phrase “Though MLI and its pilot phase budget and superficially modest productivity were subject to industrial criticism” originally cited reference 3, but should cite reference 2.

Publisher Summary Gastrointestinal drug is used in treating peptic ulcer disease and other secretory related disorders. The tagamet culminates the search for a safe and effective gastric acid anti-secretory drug. Prostaglandin anti-secretory drug development is hindered by the presence of the side effects. This chapter discusses the developments in understanding the histamine receptors and the pharmacology of histamine antagonists along with progress in prostaglandin research. The gastric acid anti-secretory structure–activity relationships and clinical testing of gastrointestinal peptide hormones are also discussed in the chapter. Tolazoline and the structurally related imidazoline tetrahydrozoline may be histamine (H 2 ) receptor agonists because tolazoline-induced acid stimulation in the dog is blocked by burimamide, metiamide, and cimetidine. Both imidazolines induce characteristic H 2 -agonist effects on isolated guinea pig atria preparations that can be blocked by metiamide. The anti-secretory effect of clonidine in rats is explained by a centrally mediated H 2 -agonist effect that results in acid inhibition. In anesthetized animals, the central effect is masked and only acid stimulation caused by a peripheral H 2 agonist effect is observed. Cimetidine differs from its precursor metiamide by having a cyanoguanidine replace the thiourea moiety found in metiamide. Inhibition of acid output is the key action for H 2 antagonists and in man cimetidine decreases meal-stimulated acid secretion in both healthy volunteers and duodenal ulcer patients. Cimetidine efficacy for treating duodenal ulcer disease appears unrelated to the patients prior to the duration of illness, level of gastric acid secretion, or recurrence record.