Ronald J. Tallarida

Temple University, Filadelfia, Pennsylvania, United States

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Publications (224)506.39 Total impact

  • Christopher S. Tallarida · Ronald J. Tallarida · Scott M. Rawls
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    ABSTRACT: Background: The Drug Enforcement Agency estimates that 80% of cocaine seized in the United States contains the veterinary pharmaceutical levamisole (LVM). One problem with LVM is that it is producing life-threatening neutropenia in an alarming number of cocaine abusers. The neuropharmacological profile of LVM is also suggestive of an agent with modest reinforcing and stimulant effects that could enhance cocaine's addictive effects. Methods: We tested the hypothesis that LVM (ip) enhances the rewarding and locomotor stimulant effects of cocaine (ip) using rat conditioned place preference (CPP) and locomotor assays. Effects of LVM by itself were also tested. Results: LVM (0-10 mg/kg) produced CPP at 1mg/kg (P<0.05) and locomotor activation at 5mg/kg (P < 0.05). For CPP combination experiments, a statistically inactive dose of LVM (0.1 mg/kg) was administered with a low dose of cocaine (2.5 mg/kg). Neither agent produced CPP compared to saline (P > 0.05); however, the combination of LVM and cocaine produced enhanced CPP compared to saline or either drug by itself (P < 0.01). For locomotor experiments, the same inactive dose of LVM (0.1mg/kg, ip) was administered with low (10 mg/kg) and high doses (30 mg/kg) of cocaine. LVM (0.1 mg/kg) enhanced locomotor activation produced by 10mg/kg of cocaine (P < 0.05) but not by 30 mg/kg (P>0.05). Conclusions: LVM can enhance rewarding and locomotor-activating effects of low doses of cocaine in rats while possessing modest activity of its own.
    No preview · Article · Feb 2015 · Drug and Alcohol Dependence
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    ABSTRACT: Cannabinoid and opioid agonists can display overlapping behavioral effects and the combination of these agonists is known to produce enhanced antinociception in several rodent models of acute and chronic pain. The present study investigated the antinociceptive effects of the nonpsychoactive cannabinoid, cannabidiol (CBD) and the µ-opioid agonist morphine, both alone and in combination, using three behavioral models in mice, to test the hypothesis that combinations of morphine and CBD would produce synergistic effects. The effects of morphine, CBD, and morphine/CBD combinations were assessed in the following assays: (a) acetic acid-stimulated stretching; (b) acetic acid-decreased operant responding for palatable food; and (c) hot plate thermal nociception. Morphine alone produced antinociceptive effects in all three models of acute nociception, whereas CBD alone produced antinociception only in the acetic acid-stimulated stretching assay. The nature of the interactions between morphine and CBD combinations were assessed quantitatively based on the principle of dose equivalence. Combinations of CBD and morphine produced synergistic effects in reversing acetic acid-stimulated stretching behavior, but subadditive effects in the hot plate thermal nociceptive assay and the acetic acid-decreased operant responding for palatable food assay. These results suggest that distinct mechanisms of action underlie the interactions between CBD and morphine in the three different behavioral assays and that the choice of appropriate combination therapies for the treatment of acute pain conditions may depend on the underlying pain type and stimulus modality.
    Full-text · Article · Dec 2014 · Behavioural Pharmacology
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    ABSTRACT: More than 90% of individuals who use cocaine also report concurrent ethanol use, but only a few studies, all conducted with vertebrates, have investigated pharmacodynamic interactions between ethanol and cocaine. Planaria, a type of flatworm often considered to have the simplest ‘brain’, is an invertebrate species especially amenable to the quantification of drug-induced behavioral responses and identification of conserved responses. Here, we investigated stereotypical and environmental place conditioning (EPC) effects of ethanol administered alone and in combination with cocaine. Planarians displayed concentration-related increases in C-shaped movements following exposure to ethanol (0.01–1%) (maximal effect: 9.9 ± 1.1 C-shapes/5 min at 0.5%) or cocaine (0.1–5 mM) (maximal effect: 42.8 ± 4.1 C-shapes/5 min at 5 mM). For combined administration, cocaine (0.1–5 mM) was tested with submaximal ethanol concentrations (0.01, 0.1%); the observed effect for the combination was enhanced compared to its predicted effect, indicating synergism for the interaction. The synergy with ethanol was specific for cocaine, as related experiments revealed that combinations of ethanol and nicotine did not result in synergy. For EPC experiments, ethanol (0.0001–1%) concentration-dependently increased EPC, with significant environmental shifts detected at 0.01 and 1%. Cocaine (0.001–1 μM) produced an inverted U-shaped concentration-effect curve, with a significant environmental shift observed at 0.01 μM. For combined exposure, variable cocaine concentrations (0.001–1 μM) were administered with a statistically ineffective concentration of ethanol (0.0001%). For each concentration of cocaine, the environmental shift was enhanced by ethanol, with significance detected at 1 μM. Cocaethylene, a metabolite of cocaine and ethanol, also produced C-shapes and EPC. Lidocaine (0.001–10 μM), an anesthetic and analog of cocaine, did not produce EPC or C-shaped movements. Evidence from planarians that ethanol produces place-conditioning effects and motor dysfunction, and interacts synergistically with cocaine, suggests that aspects of ethanol neuropharmacology are conserved across species.
    No preview · Article · Sep 2014 · Alcohol
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    ABSTRACT: A multi-mechanistic approach offers potential enhancement of analgesic efficacy, but therapeutic gain could be offset by an increase in adverse events. The centrally acting analgesic tapentadol [(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines μ-opioid receptor (MOR) agonism and neuronal noradrenaline reuptake inhibition (NRI), both of which contribute to its analgesic effects. Previously, isobolographic analysis of occupation-effect data and a theoretically equivalent methodology determining interactions from the effect scale demonstrated pronounced synergistic interaction between the two mechanisms of action of tapentadol in two models of antinociception (low-intensity tail-flick and spinal nerve ligation). The present study investigated the nature of interaction of the two mechanisms on a surrogate measure for gastrointestinal adverse effect (inhibition of gastrointestinal transit). Dose-response curves were generated in rats for tapentadol alone or in combination with the opioid receptor antagonist, naloxone, or the α2 -adrenoceptor antagonist, yohimbine, to reveal the effect of tapentadol based upon MOR agonism, NRI, and combined mechanisms. The dose-effect curve of tapentadol was shifted to the right by both antagonists, thereby providing data to distinguish between MOR agonism and NRI. Analysis revealed a simple additive interaction between the two mechanisms on this endpoint, in contrast to the synergistic interaction previously demonstrated for antinociception. We believe this is the first published evaluation of mechanistic interaction for a surrogate measure of adverse effect of a single compound with two mechanisms of action, and the results suggest that there is a greater separation between the analgesic and gastrointestinal effects of tapentadol than expected based upon its analgesic efficacy.
    No preview · Article · Sep 2014 · European journal of pain (London, England)
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    ABSTRACT: Chronic pain is a highly prevalent medical problem in the United States. Although opioids and serotonin-norepinephrine reuptake inhibitors (SNRIs) have demonstrated efficacy for relief of chronic pain, each has risks of adverse events in patients. Because of the risk of opioid abuse and addiction, combinations reducing opioid requirements are particularly valuable. Opioid and SNRI agents relieve pain by different pathways; concurrent use of each agent separately offers many potential benefits: complementary and possibly synergistic analgesic efficacy, separate titrations of opioid and SNRI effects, and the reduction of opioid requirements. However, few clinical studies have investigated the ideal ratios for combinations of opioids and SNRIs. A number of factors affect whether specific combinations have additive, synergistic, less than additive efficacy, or increase adverse events in patients, including general pharmacokinetic considerations, the potential for pharmacodynamic drug interactions, dose, and timing. Because there is little clinical evidence guiding combination therapy with separate opioid and SNRI agents, using single-molecule agents provides safe and effective therapy and should be the first option presented to patients. The use of empiric combinations of separate opioid and SNRI combinations needs to be considered in light of clinical cautions, including the lack of published evidence to guide dose conversion from any opioid to tramadol or to tapentadol, and vice versa; the need to avoid combinations with known drug interactions; and the need to titrate the dose when adding an SNRI to an opioid, and vice versa.
    No preview · Article · Jul 2014 · Postgraduate Medicine

  • No preview · Article · Mar 2014 · Journal of Pharmacology and Experimental Therapeutics
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    ABSTRACT: Levamisole is estimated by the Drug Enforcement Agency (DEA) to be present in about 80% of cocaine seized in the United States and linked to debilitating, and sometimes fatal, immunologic effects in cocaine abusers. One explanation for the addition of levamisole to cocaine is that it increases the amount of product and enhances profits. An alternative possibility, and one investigated here, is that levamisole alters cocaine's action in vivo. We specifically investigated effects of levamisole on cocaine's stereotypical and place-conditioning effects in an established invertebrate (planarian) assay. Acute exposure to levamisole or cocaine produced concentration-dependent increases in stereotyped movements. For combined administration of the two agents, isobolographic analysis revealed that the observed stereotypical response was enhanced relative to the predicted effect, indicating synergism for the interaction. In conditioned place preference (CPP) experiments, cocaine produced a significant preference shift; in contrast, levamisole was ineffective at all concentrations tested. For combination experiments, a submaximal concentration of cocaine produced CPP that was enhanced by inactive concentrations of levamisole, indicating synergism. The present results provide the first experimental evidence that levamisole enhances cocaine's action in vivo. Most important is the identification of synergism for the levamisole/cocaine interaction, which now requires further study in mammals.
    No preview · Article · Jan 2014 · Neuropharmacology
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    ABSTRACT: Tapentadol is a Mu Opioid Receptor (MOR) agonist and Norepinephrine reuptake inhibitor (NRI) with established efficacy in neuropathic pain in patients and intrinsic synergistic interaction of both mechanisms as demonstrated in rodents. In diabetic mice, we analyzed the central antihyperalgesic activity, the occurrence of site-site interaction as well as the spinal contribution of opioid and noradrenergic mechanisms in a hot plate test. Tapentadol (0.1-3.16 μg/animal) showed full efficacy after i.t. as well as after i.c.v. administration (ED50 0.42 μg/animal i.t., 0.18 i.c.v.). Combined administration of equi-analgesic doses revealed spinal-supraspinal synergy (ED50 0.053 i.t.+i.c.v.). Morphine (0.001-10 μg/animal) also showed central efficacy and synergy (ED50 0.547 i.t., 0.004 i.c.v., 0.014 i.t.+i.c.v.). Supraspinal potencies of tapentadol and morphine correlated with the 50-fold difference in their MOR affinities. In contrast, spinal potencies of both drugs were similar and correlated with their relative systemic potencies (ED50 tapentadol 0.27, morphine 1.1 mg/kg i.p.). Spinal administration of the opioid antagonist naloxone or the α2 adrenoceptor antagonist yohimbine prior to systemic administration of equi-analgesic doses of tapentadol (1 mg/kg, i.p.) or morphine (3.16 mg/kg, i.p.) revealed pronounced influence on opioidergic and noradrenergic pathways for both compounds. Tapentadol was more sensitive towards both antagonists than was morphine, with ID50 values (i.t.) of 0.75 and 1.72 ng/animal naloxone and 1.56 and 2.04 ng/animal yohimbine, respectively. It is suggested that the antihyperalgesic action of systemically administered tapentadol is based on opioid spinal-supraspinal synergy as well as intrinsic spinally mediated MOR-NRI synergy.
    No preview · Article · Sep 2013 · Journal of Pharmacology and Experimental Therapeutics
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    ABSTRACT: Current formulations of methylphenidate (MPH) used in treatment of attention-deficit/hyperactivity disorder (ADHD) result in significantly different bioavailability of MPH enantiomers. Daytrana(®), a dl-MPH transdermal patch system, produces higher levels of l-MPH than when dl-MPH is administered orally (e.g., Ritalin(®)). One potential limitation of increased l-MPH was indicated in a preclinical study showing l-MPH may attenuate effects of d-MPH. The objective of the study was to investigate the interactive effects of MPH enantiomers by (1) assessing drug effects via a preclinical model of "impulsivity" and (2) performing a quantitative dose equivalence analysis of MPH enantiomer interactions. Sprague-Dawley rats were trained to emit either of two responses, one producing an immediate food pellet, the other producing four pellets delivered at increasing delays (0, 8, and 32 s). The percent selection of the larger food amount was graphed as a function of delay with the area under the curve (AUC) assessed. Increases in AUC are consistent with decreases in "impulsivity" (i.e., selection of the smaller, immediate over the larger, delayed reinforcer). Systemic administration of dl-MPH and d-MPH dose-dependently increased AUC, while l-MPH, morphine, and pentobarbital did not alter AUC. An analysis based upon dose equivalence indicated that dl-MPH produced additive effects that were not different from that predicted from effects of the enantiomers administered alone. The present results indicate pharmacologically selective effects in that only drugs prescribed for the treatment of ADHD symptoms decreased a measure of "impulsivity" and that l-MPH likely does not attenuate or enhance the effects of d-MPH in the current delay-discounting task.
    Full-text · Article · Aug 2013 · Psychopharmacology
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    R J Tallarida · U Midic · N S Lamarre · Z Obradovic
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    ABSTRACT: What is known and objective: Individuals who abuse drugs usually use more than one substance. Toxic consequences of single and multi-drug use are well documented in the Treatment Episodes Data Set that lists drug combinations that result in hospital admissions. Using this list as a guide, we focused our attention on combinations that result in the most hospital admissions and searched the PubMed database with the objective of determining the number of such publications and, in particular, those that used the term synergism in their titles or abstracts. Comment: Using the search criteria produced an extensive list of published articles. However, a further intersection of the search terms with the term isobole revealed a surprisingly small number of literature reports. What is new and conclusion: Because the method of isoboles is the most common quantitative method for distinguishing between drug synergism and simple additivity, the small number of investigations that actually employed this quantification suggests that the term synergism is not properly documented in describing the toxicity among abused substances. The possible reasons for this lack of quantification may be related to a misunderstanding of the modelling equations. To help rectify this possible hurdle to understanding and clinical utility, the theory and modelling are discussed here.
    Preview · Article · Apr 2013 · Journal of Clinical Pharmacy and Therapeutics
  • Neil S Lamarre · Robert B Raffa · Ronald J Tallarida
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    ABSTRACT: Background: Cocaine has long been known to increase blood pressure, but the degree and mechanism of vasoconstricting action remain poorly understood. Here we examine the interaction between cocaine and alpha-adrenoceptor agonists, with the action of reuptake inhibition minimized. Methods: Cocaine was administered to isolated rings of rat thoracic aorta, alone and in combination with three different adrenoceptor agonists: phenylephrine, methoxamine, and norepinephrine. Synergy analysis begins with the predicted additive effect of the combination of two agonists, based upon dose equivalence theory. This case where one agonist (cocaine) has no effect when administered alone requires only a t-test to demonstrate that a departure from additivity has occurred. Results: At doses where cocaine alone produced no vasoconstriction, it potentiated the vasoconstriction produced by all three alpha agonists, a clear indication of synergism between cocaine and these agents. Higher doses of cocaine in combination with alpha adrenoceptor agents gave an inverted-U shaped (hormetic) dose-effect curve, i.e., dose-related relaxation at higher doses. The hormetic dose-effect relation was analyzed using computational methodology based on dose equivalence to derive the unknown second component of action that causes relaxation. Conclusions: Cocaine exhibits both vasoconstricting and vasorelaxant effects. This relaxing component, possibly related to activation of myosin light chain phosphatase, was quantified as a dose-effect curve. Most important is the synergism between cocaine and alpha-adrenoceptor stimulation which cannot be explained as an action due to reuptake inhibition, and has not been previously described.
    No preview · Article · Dec 2012 · Drug and alcohol dependence
  • Ronald J Tallarida
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    ABSTRACT: The isobole is well established and commonly used in the quantitative study of agonist drug combinations. This article reviews the isobole, its derivation from the concept of dose equivalence, and its usefulness in providing the predicted effect of an agonist drug combination, a topic not discussed in pharmacology textbooks. This review addresses that topic and also shows that an alternate method, called "Bliss independence," is inconsistent with the isobolar approach and also has a less clear conceptual basis. In its simplest application the isobole is the familiar linear plot in cartesian coordinates with intercepts representing the individual drug potencies. It is also shown that the isobole can be nonlinear, a fact recognized by its founder (Loewe) but neglected or rejected by virtually all other users. Whether its shape is linear or nonlinear the isobole is equally useful in detecting synergism and antagonism for drug combinations, and its theoretical basis leads to calculations of the expected effect of a drug combination. Numerous applications of isoboles in preclinical testing have shown that synergism or antagonism is not only a property of the two agonist drugs; the dose ratio is also important, a fact of potential importance to the design and testing of drug combinations in clinical trials.
    No preview · Article · Apr 2012 · Journal of Pharmacology and Experimental Therapeutics
  • Robert B Raffa · Ronald J Tallarida · Robert Taylor · Joseph V Pergolizzi
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    ABSTRACT: INTRODUCTION: Pain is a large and growing medical need that is not currently being fully met, primarily due to the shortcomings of existing analgesics (insufficient efficacy or limiting side-effects). Better outcomes might be achieved using a combination of analgesics. The ratio of the combinations matters and should therefore be evaluated using rigorous quantitative and well-documented analysis. AREAS COVERED: Advances have been made in understanding the normal physiology of pain processing, including the pathways and neurotransmitters involved. Insight has also been gained about physiological processes that can lead to different 'types' of pain and the transition from acute to chronic pain conditions. This 'multimechanistic' nature of most pains is better matched using a 'multimechanistic' rather than 'monomechanistic' analgesic approach. Such an approach - and the experimental design and data analysis to assess optimal combinations - is described and discussed. EXPERT OPINION: There are sound pharmacologic, as well as practical, reasons for using combinations of drugs to treat pain. Compared with single agents, they offer a potential better match to the underlying pain physiology and thus greater efficacy or reduced side effects. The optimal efficacy and side-effect ratio must be determined in a scientifically rigorous manner.
    No preview · Article · Mar 2012 · Expert Opinion on Pharmacotherapy
  • Ronald J Tallarida · Neil Lamarre · Robert B Raffa
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    ABSTRACT: PK/PD modeling is enhanced by improvements in the accuracy of its metrics. For PK/PD modeling of drugs and biologics that interact with enzymes or receptors, the equilibrium constant of the interaction can provide critical insight. Methodologies such as radioliogand binding and isolated tissue preparations can provide estimates of the equilibrium constants (as the dissociation constant, K value) for drugs and endogenous ligands that interact with specific enzymes and receptors. However, an impediment to further precision for PK/PD modeling is that it remains a problem to convert the concentration of drug in bulk solution (A) into an estimate of receptor occupation, since A is not necessarily the concentration (C) of drug in the biophase that yields fractional binding from the law of mass action, viz., C/(C + K). In most experimental studies A is much larger than K, so the use of administered instead of biophase concentration gives fractional occupancies very close to unity. We here provide a simple way to obtain an estimate of the factor that converts the total drug concentration into the biophase concentration in isolated tissue preparation. Our approach is an extension of the now classic 'null method' introduced and applied by Furchgott to determination of drug-receptor dissociation constants.
    No preview · Article · Mar 2012 · Pharmaceutical Research
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    Ronald J. Tallarida · Uros Midic · Neil S. Lamarre · Zoran Obradovic
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    ABSTRACT: It is well known that individuals who abuse drugs usually use more than one substance. Toxic consequences of single and multiple drug use are well documented in the Treatment Episodes Data Set that lists combinations that result in hospital admissions. Using this list as a guide, we focused our attention on combinations that result in the most hospital admissions and searched the PubMed database to determine the number of publications dealing with these toxic combinations. Of special interest were those publications that looked for or used the term synergism in their titles or abstracts, a search that produced an extensive list of published articles. However, a further intersection of these with the term isobole revealed a surprisingly small number of literature reports. Because the method of isoboles is the most common quantitative method for distinguishing between drug synergism and simple additivity, the small number of investigations that actually employed this quantitation suggests that the term synergism is not properly documented in describing the toxicity among these abused substances. The possible reasons for this lack of quantitation may be related to a misunderstanding of the modeling equations. The theory and modeling are discussed here.
    Preview · Article · Feb 2012
  • L Ramoz · S Lodi · P Bhatt · A.B. Reitz · C Tallarida · R.J. Tallarida · R.B. Raffa · S.M. Rawls
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    ABSTRACT: Psychoactive bath salts (also called meph, drone, meow meow, m-CAT, bounce, bubbles, mad cow, etc.) contain a substance called mephedrone (4-methylcathinone) that may share psychostimulant properties with amphetamine and cocaine. However, there are only limited studies of the neuropharmacological profile of mephedrone. The present study used an established invertebrate (planarian) assay to test the hypothesis that acute and repeated mephedrone exposure produces psychostimulant-like behavioral effects. Acute mephedrone administration (50-1000 μM) produced stereotyped movements that were attenuated by a dopamine receptor antagonist (SCH 23390) (0.3 μM). Spontaneous discontinuation of mephedrone exposure (1, 10 μM) (60 min) resulted in an abstinence-induced withdrawal response (i.e. reduced motility). In place conditioning experiments, planarians in which mephedrone (100, 500 μM) was paired with the non-preferred environment during conditioning displayed a shift in preference upon subsequent testing. These results suggest that mephedrone produces three behavioral effects associated with psychostimulant drugs, namely dopamine-sensitive stereotyped movements, abstinence-induced withdrawal, and environmental place conditioning.
    No preview · Article · Jan 2012 · Neuroscience

  • No preview · Article · Jan 2012 · Pharmacology & Pharmacy
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    Ronald J Tallarida
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    ABSTRACT: Two or more drugs that individually produce overtly similar effects will sometimes display greatly enhanced effects when given in combination. When the combined effect is greater than that predicted by their individual potencies, the combination is said to be synergistic. A synergistic interaction allows the use of lower doses of the combination constituents, a situation that may reduce adverse reactions. Drug combinations are quite common in the treatment of cancers, infections, pain, and many other diseases and situations. The determination of synergism is a quantitative pursuit that involves a rigorous demonstration that the combination effect is greater than that which is expected from the individual drug's potencies. The basis of that demonstration is the concept of dose equivalence, which is discussed here and applied to an experimental design and data analysis known as isobolographic analysis. That method, and a related method of analysis that also uses dose equivalence, are presented in this brief review, which provides the mathematical basis for assessing synergy and an optimization strategy for determining the dose combination.
    Preview · Article · Nov 2011 · Genes & cancer
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    Neil S Lamarre · Tom Parry · Ronald J Tallarida
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    ABSTRACT: In this communication we show that the same principle that underlies the use of the isobolograph for assessing agonist interactions also leads to a method for analyzing the opposing effects of a single agonist. This is the principle of dose equivalence whose application is illustrated here and applied to the endothelium-dependent relaxing component of two putative vasoconstrictor peptides. These studies, employing angiotensin II and endothelin-1, were conducted with isolated preparations of rat aorta that were measured for agonist-induced isometric tension development in both endothelial-denuded and -intact vessels. The dose-effect relation of the relaxing component of each agonist, which should not be calculated from simple effect subtraction, was derived by the method described here.
    Full-text · Article · Sep 2011 · European journal of pharmacology
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    ABSTRACT: Good surgical outcomes depend in part on good pain relief, allowing for early mobilization, optimal recovery, and patient satisfaction. Postsurgical pain has multiple mechanisms, and multimechanistic approaches to postoperative analgesia are recommended and may be associated with improved pain relief, lowered opioid doses, and sometimes a lower rate of opioid-associated side effects. Acetaminophen (paracetamol) is a familiar agent for treating many types of pain, including postsurgical pain. Oral acetaminophen has been shown to be safe and effective in a variety of acute pain models. Combination products using a fixed-dose of acetaminophen and an opioid have also been effective in treating postsurgical pain. Combination products with acetaminophen have demonstrated an opioid-sparing effect, which inconsistently results in a reduced rate of opioid-associated side effects. Intravenous (IV) acetaminophen and an opioid analgesic administered in the perioperative period may be followed by an oral acetaminophen and opioid combination in the postoperative period. Transitioning from an IV acetaminophen and opioid formulation to a similar but oral formulation of the same drugs appears to be a reasonable step in that both analgesic therapies are known to be safe and effective. For postsurgical analgesia with any acetaminophen product, patient education is necessary to be sure that the patient does not concurrently take any over-the-counter products containing acetaminophen and accidentally exceed dose limits.
    No preview · Article · Jun 2011 · Pain Practice

Publication Stats

6k Citations
506.39 Total Impact Points


  • 1975-2015
    • Temple University
      • • Center for Substance Abuse Research (CSAR)
      • • Department of Pharmacology
      • • Department of Medicine
      • • Department of Pharmaceutical Sciences
      Filadelfia, Pennsylvania, United States
  • 1991
    • Treatment Research Institute, Philadelphia PA
      Philadelphia, Pennsylvania, United States