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PubMed2005

Reduction in anticoagulation-related adverse drug events using a trigger-based methodology.

BACKGROUND: An initiative was undertaken by Novant Health System to address warfarin-related adverse drug events (ADEs) using lab-based patient-specific International Normalized Ratio (INR) triggers and pharmacy-based patient-specific Vitamin K triggers. The goal was to reduce ADEs related to the use of warfarin in both the inpatient and outpatient settings. Process improvements and medication management protocols were developed for patients managed with warfarin anticoagulation. METHODS: During each month's seven-day sampling period, the hospital information system generated the lab and pharmacy triggers, and the clinical pharmacists used these patient-specific triggers to identify the patient charts for review. All triggered charts were reviewed. Preliminary harm classification based on the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) index was assigned by the clinical pharmacists and recorded for each patient. RESULTS: The system achieved reductions in ADEs related to warfarin administration on an inpatient management (45%) and outpatient management (52%) basis. DISCUSSION: Although based on inpatient facility-generated triggers, the initiative also served as a reasonable outpatient model, with improvements seen in the outpatient physician intervention groups.

Adverse Drug Reaction Reporting Systems↗

PubMed2003

Free-energy calculations of protein-ligand cation-pi and amino-pi interactions: from vacuum to proteinlike environments.

To probe the role of cation-pi and amino-pi interactions in the context of protein-ligand interactions, the stability of 55 X-ray cation/amino-pi motifs involving the Ade moieties of cofactor molecules and Arg, Lys, Asn, or Gln side chains of their host protein was evaluated using quantum chemistry calculations. The conjunction of vacuum interaction energies, vibrational entropy, and solvation contributions led to identify Arg-Ade as the most favorable cation/amino-pi complex in the solvents considered, followed by Asn/Gln-Ade and Lys-Ade: their minimum interaction free energies are approximately equal to -7, -4, and -2 kcal/mol, respectively, in the solvents of dielectric constant similar to that estimated for proteins (i.e., acetone, THF, and CCl(4)). Remarkably, these free-energy values of cation/amino-pi interactions correlate well with their frequency of occurrences in protein-ligand structures, which corroborates our approach in the absence of experimental data.

Amino Acids↗

PubMed2003

DNA adduct formation from acrylamide via conversion to glycidamide in adult and neonatal mice.

Acrylamide (AA) is a high production volume chemical with many industrial uses; however, recent findings of ppm levels in starchy foods cooked at high temperature have refocused worldwide attention on the neurotoxicity, germ cell mutagenicity, and carcinogenicity of AA. Oxidative metabolism of AA to its epoxide metabolite, glycidamide (GA), has been observed in experimental animals and humans and may be associated with many of the toxic effects of AA exposure, including formation of N7-(2-carbamoyl-2-hydroxyethyl)guanine (N7-GA-Gua) in vivo. This paper describes the characterization of two new GA-derived DNA adducts formed in vitro, N3-(2-carbamoyl-2-hydroxyethyl)adenine (N3-GA-Ade) and N1-(2-carboxy-2-hydroxyethyl)-2'-deoxyadenosine. A sensitive method for quantification of N7-GA-Gua and N3-GA-Ade, based on LC with tandem mass spectrometry and isotope dilution, was developed and validated for use in measuring DNA adduct formation in selected tissues of adult and whole body DNA of 3 day old neonatal mice treated with AA and GA. In adult mice, DNA adduct formation was observed in liver, lung, and kidney with levels of N7-GA-Gua around 2000 adducts/10(8) nucleotides and N3-GA-Ade around 20 adducts/10(8) nucleotides. Adduct levels were modestly higher in adult mice dosed with GA as opposed to AA; however, treatment of neonatal mice with GA produced 5-7-fold higher whole body DNA adduct levels than with AA, presumably reflective of lower oxidative enzyme activity in newborn mice. DNA adduct formation from AA treatment in adult mice showed a supralinear dose-response relationship, consistent with saturation of oxidative metabolism at higher doses. These results increase our understanding of the mutagenic potential of GA and provide further evidence for a genotoxic mechanism in AA carcinogenesis.

Acrylamide↗

PubMed2005

The structure of DNA dictates purine atom site selectivity in alkylation by primary diazonium ions.

The 1-propanediazonium ion, generated from N'-nitro-N-nitroso-N-propylguanidine in aqueous solutions, was reacted with the purine nucleosides dGuo and dAdo or single-stranded or double-stranded DNA. After nucleobase liberation by acid hydrolysis, the percent yields of products were determined by LC/MS using either isotopically distinct internal standards in the case of the nucleoside reactions or an internal standard and the ratios of response factors of all other products that were separately determined in the case of the reactions with DNA. In the reactions of nucleosides, products of both n-propylation and iso-propylation at all of the heroatoms were observed. For these reactions, the yields of the three most abundant n-propyl adducts of Gua are in the order O6 > N7 > N2, in the ratio of 9.0/6.4/1, while for Ade, the order of the yields of N-propyl products is N1 > N7 > N3 > N6 in the ratio 2.5/1.8/1.1/1. The ratios of n-propylated to iso-propylated products at each site, P(n)/P(i), generally a measure of enhancement of S(N)2 displacement on the diazonium ion, vary with each heteroatom but by no more than a factor of 6 for Gua and a factor of 3 for Ade. In the reactions with duplex DNA, products of reactions at all sites could not be detected. In addition, much larger selectivities are observed, similar to what has been observed by others in the reactions with ethanediazonium ion. Thus, P(n)/P(i) = 30, 21, and 0.9 for N7, O6, and N2 of Gua. Similarly, the values of P(n)/P(i) are 11 and 8 for N3 and N7 of Ade. Reactions with single-stranded DNA give values of P(n)/P(i) that are intermediate between the nucleoside reactions and the reactions of duplex DNA in most cases. The factors responsible for the relatively small atom site selectivities intrinsic to the nucleosides are analyzed, and reasons for enhanced S(N)2 nucleophilicity in duplex DNA are discussed.

Alkylation↗

PubMed1997

Synthesis of depurinating DNA adducts formed by one-electron oxidation of 7H-dibenzo[c,g]carbazole and identification of these adducts after activation with rat liver microsomes.

It is hypothesized that 7H-dibenzo[c,g]carbazole (DBC) is metabolically activated by one-electron oxidation in accordance with its propensity to be easily oxidized to its radical cation. Iodine oxidation of DBC produces a radical cation that subsequently binds to nucleophilic groups of dG or Ade. Oxidation of DBC in the presence of dG products three adducts: DBC-5-N7Gua, DBC-6-N7Gua, and DBC-6-C8Gua, whereas in the presence of Ade, four adducts are obtained: DBC-5-N7Ade, DBC-5-N3Ade, DBC-5-N1Ade, and DBC-6-N3Ade. Formation of these adducts demonstrates that the DBC radical cation reacts at C-5 or C-6 with the reactive nucleophiles N-7 and C-8 of dG and N-7, N-3, and N-1 of Ade. Formation DNA adducts by DBC was studied by using horesradish peroxidase or 3-methylcholanthrene-induced rat liver microsomes for activation. Identification of the biologically-formed depurinating adducts was achieved by comparison of their retention times on HPLC in two different solvent systems and by matrix-assisted laser desorption ionization (MALDI) mass spectrometry. Quantitation of the adducts formed by rat liver microsomes shows that 96% are depurinating adducts, DBC-5-N7Gua (11%), DBC-6-N7Gua (32%), and DBC-5-N7Ade (53%), and 4% are unidentified stable adducts. Activation of DBC by horseradish peroxidase affords 32% stable unidentified adducts and 68% depurinating adducts: 19% DBC-5-N7Gua, 13% DBC-6-N7Gua, 27% DBC-5-N7Ade, and 9% DBC-5-N3Ade. Thus, activation of DBC by cytochrome P450 predominantly forms depurinating adducts by one-electron oxidation.

Animals↗

PubMed1999

A novel method for the isolation and identification of stable DNA adducts formed by Dibenzo[a,l]pyrene and Dibenzo[a,l]pyrene 11, 12-dihydrodiol 13,14-epoxides in vitro.

Our laboratory previously reported the identification and quantification of depurinating DNA adducts of dibenzo[a,l]pyrene (DB[a,l]P) in vitro, which comprise about 84% of all the DNA adducts that are formed [Li, K.-M., et al. (1995) Biochemistry 34, 8043-8049]. To determine a complete adduct profile and identify both stable and depurinating DNA adducts, we have developed a relatively simple, nonradioactive method for the identification of stable DNA adducts by combining enzymatic digestion, HPLC, and fluorescence line-narrowing spectroscopy (FLNS) techniques. Calf thymus DNA, bound to either (+/-)-anti- or (+/-)-syn-DB[a,l]PDE or rat liver microsome-activated DB[a,l]P, was first digested to 3'-mononucleotides with micrococcal nuclease and spleen phosphodiesterase. The adducts were then separated by HPLC with an ion-pair column and identified by FLNS by using the spectra of standards for comparison. In reactions with (+/-)-anti-DB[a,l]PDE, three adducts, an anti-cis-DB[a,l]PDE-dGMP, an anti-trans-DB[a, l]PDE-dAMP, and an anti-cis-DB[a,l]PDE-dAMP, were identified by HPLC and FLNS. In reactions with (+/-)-syn-DB[a,l]PDE, a pair of syn-trans-DB[a,l]PDE-dGMP adducts as well as a syn-cis-DB[a, l]PDE-dGMP, a syn-cis-DB[a,l]PDE-dAMP, and a pair of syn-trans-DB[a, l]PDE-dAMP adducts were identified. From the digest of microsome-activated DB[a,l]P-bound DNA, a syn-trans-DB[a,l]PDE-dGMP, an anti-cis-DB[a,l]PDE-dGMP, a syn-trans-DB[a,l]PDE-dAMP, and a syn-cis-DB[a,l]PDE-dAMP adduct were identified. An anti-cis-DB[a, l]PDE-dAMP adduct was identified only by (32)P-postlabeling. A total of five of the stable adducts formed by DB[a,l]P and nine of the stable adducts formed by DB[a,l]PDE in vitro have been identified. These adducts were also correlated to adduct spots in the (32)P-postlabeling method by cochromatography with standards. Approximately 93% of the stable adducts formed in reactions with (+/-)-anti-DB[a,l]PDE, 90% of adducts with (+/-)-syn-DB[a,l]PDE, and 85% of adducts formed with microsome-activated DB[a,l]P have been identified as Gua or Ade adducts. Equal amounts of stable Gua and Ade adducts were observed in the microsome-catalyzed binding of DB[a, l]P to calf thymus DNA, while 1.4 times more Gua adducts than Ade adducts were obtained in reactions with (+/-)-anti- or (+/-)-syn-DB[a,l]PDE.

Animals↗

PubMed1981

Monoclonal anti-Fc receptor IgG blocks antibody enhancement of viral replication in macrophages.

Flaviviruses, when complexed with antibody at subneutralizing concentrations, show enhanced replication in human and simian peripheral blood leukocytes (ref. 1, and J.S.M.P. and J.S.P., unpublished observations) and in P388 D1 and other macrophage cell lines. A comparable phenomenon has been demonstrated with alphaviruses and Bunyaviruses in P388 D1 cells, (J.S.M.P. and J.S.P., unpublished observations) but cells lacking macrophage characteristics fail to show antibody-dependent enhancement (ADE) of viral replication. It has been suggested that the macrophage Fc receptor (FcR) provides an efficient route of entry of virus through the attachment of non-neutralized virus-antibody complexes and that for those viruses that escape destruction by the phagocyte, antibody results in a paradoxical increase in virus replication. West Nile virus (WNV) replication in the P388 D1 macrophage cell line provides a reproducible model system for studying ADE of viral replication. Mouse macrophages have two FcRs-FcRI, which is trypsin-sensitive and binds IgG2a, and FcRII, which is trypsin-resistant and binds IgG2b and IgG1 complexes. The FcR has been purified using rat anti-mouse FcR monoclonal antibody which blocks FcRII. We show here that anti-FcRIgG and its Fab fragment block ADE of virus replication by anti-WNV monoclonal antibodies.

Animals↗

PubMed2005

Genetic aspects of immune-mediated adverse drug effects.

Adverse drug effects (ADEs) are of great importance in medicine and account for up to 5% of all hospital admissions. ADEs can arise from several mechanisms and a wide range of drugs can cause immune-mediated ADEs (IMADEs). For a drug to elicit an IMADE, it must be both immunogenic (that is, able to sensitize the immune system) and antigenic (that is, able to evoke a response from a sensitized immune system). Unlike protein therapeutics, small-molecule drugs (or xenobiotics) are usually neither immunogenic nor antigenic. IMADEs are therefore the result of complex interactions between drug-metabolizing enzymes, immune sensitization and immune effectors. The genetic aspects of this interplay are discussed in this review.

Adverse Drug Reaction Reporting Systems↗

PubMed2006

Time-resolved photoelectron and photoion fragmentation spectroscopy study of 9-methyladenine and its hydrates: a contribution to the understanding of the ultrafast radiationless decay of excited DNA bases.

The excited state dynamics of the purine base 9-methyladenine (9Me-Ade) has been investigated by time- and energy-resolved photoelectron imaging spectroscopy and mass-selected ion spectroscopy, in both vacuum and water-cluster environments. The specific probe processes used, namely a careful monitoring of time-resolved photoelectron energy distributions and of photoion fragmentation, together with the excellent temporal resolution achieved, enable us to derive additional information on the nature of the excited states (pipi*, npi*, pisigma*, triplet) involved in the electronic relaxation of adenine. The two-step pathway we propose to account for the double exponential decay observed agrees well with recent theoretical calculations. The near-UV photophysics of 9Me-Ade is dominated by the direct excitation of the pipi* ((1)L(b)) state (lifetime of 100 fs), followed by internal conversion to the npi* state (lifetime in the ps range) via conical intersection. No evidence for the involvement of a pisigma* or a triplet state was found. 9Me-Ade-(H(2)O)(n) clusters have been studied, focusing on the fragmentation of these species after the probe process. A careful analysis of the fragments allowed us to provide evidence for a double exponential decay profile for the hydrates. The very weak second component observed, however, led us to conclude that the photophysics were very different compared with the isolated base, assigned to a competition between (i) a direct one-step decay of the initially excited state (pipi* L(a) and/or L(b), stabilised by hydration) to the ground state and (ii) a modified two-step decay scheme, qualitatively comparable to that occurring in the isolated molecule.

Adenine↗

PubMed2006

COMP-angiopoietin-1 promotes wound healing through enhanced angiogenesis, lymphangiogenesis, and blood flow in a diabetic mouse model.

Microvascular dysfunction is a major cause of impaired wound healing seen in diabetic patients. Therefore, reestablishment of structural and functional microvasculature could be beneficial to promote wound healing in these patients. Angiopoietin-1 (Ang1) is a specific growth factor functioning to generate a stable and functional vasculature through the Tie2 and Tie1 receptors. Here we determined the effectiveness of cartilage oligomeric matrix protein (COMP)-Ang1, a soluble, stable, and potent form of Ang1, on promotion of healing in cutaneous wounds of diabetic mice. An excisional full-thickness wound was made in the dorsal side of the tail of diabetic (db/db) mice, and mice were then treated systemically with adenovirus (Ade) encoding COMP-Ang1 or with control virus encoding beta-gal (Ade-beta-gal) or treated topically with recombinant COMP-Ang1 protein or BSA. Time course observations revealed that mice treated with Ade-COMP-Ang1 or COMP-Ang1 protein showed accelerated wound closure and epidermal and dermal regeneration, enhanced angiogenesis and lymphangiogenesis, and higher blood flow in the wound region compared with mice treated with control virus or BSA. COMP-Ang1 promotion of wound closure and angiogenesis was not dependent on endothelial nitric oxide synthase or inducible nitric oxide synthase alone. Taken together, these findings indicate that COMP-Ang1 can promote wound healing in diabetes through enhanced angiogenesis, lymphangiogenesis, and blood flow.

Angiopoietin-1↗

PubMed1997

Isozyme-dependent sensitivity of adenylyl cyclases to P-site-mediated inhibition by adenine nucleosides and nucleoside 3'-polyphosphates.

Recombinant adenylyl cyclase isozyme Types I, II, VI, VII, and three splice variants of Type VIII were compared for their sensitivity to P-site-mediated inhibition by several adenine nucleoside derivatives and by the family of recently synthesized adenine nucleoside 3'-polyphosphates (Désaubry, L., Shoshani, I., and Johnson, R. A. (1996) J. Biol. Chem. 271, 14028-14034). Inhibitory potencies were dependent on isozyme type, the mode of activation of the respective isozymes, and on P-site ligand. For the nucleoside derivatives potency typically followed the order 2',5'-dideoxyadenosine (2',5'-ddAdo) > beta-adenosine > 9-(cyclopentyl)-adenine (9-CP-Ade) >/= 9-(tetrahydrofuryl)-adenine (9-THF-Ade; SQ 22,536), with the exception of Type II adenylyl cyclase, which was essentially insensitive to inhibition by 9-CP-Ade. For the adenine nucleoside 3'-polyphosphates inhibitory potency followed the order Ado < 2'-dAdo < 2',5'-ddAdo and 3'-mono- < 3'-di- < 3'-triphosphate. Differences in potency of these ligands were noted between isozymes. The most potent ligand was 2',5'-dd-3'-ATP with IC50 values of 40-300 nM. The data demonstrate isozyme selectivity for some ligands, suggesting the possibility of isozyme-selective inhibitors to take advantage of differences in P-site domains among adenylyl cyclase isozymes. Differential expression of adenylyl cyclase isozymes may dictate the physiological sensitivity and hence importance of this regulatory mechanism in different cells or tissues.

Adenosine↗

PubMed1998

A novel mechanism-based inhibitor (6'-bromo-5', 6'-didehydro-6'-deoxy-6'-fluorohomoadenosine) that covalently modifies human placental S-adenosylhomocysteine hydrolase.

Most inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase function as substrates for the "3'-oxidative activity" of the enzyme and convert the enzyme from its active form (NAD+) to its inactive form (NADH) (Liu, S., Wolfe, M. S., and Borchardt, R. T. (1992) Antivir. Res. 19, 247-265). In this study, we describe the effects of a mechanism-based inhibitor, 6'-bromo-5', 6'-didehydro-6'-deoxy-6'-fluorohomoadenosine (BDDFHA), which functions as a substrate for the "6'-hydrolytic activity" of the enzyme with subsequent formation of a covalent linkage with the enzyme. Incubation of human placental AdoHcy hydrolase with BDDFHA results in a maximum inactivation of 83% with the remaining enzyme activity exhibiting one-third of the kcat value of the native enzyme. This partial inactivation is concomitant with the release of both Br- and F- ions and the formation of adenine (Ade). The enzyme can be covalently labeled with [8-3H]BDDFHA, resulting in a stoichiometry of 2 mol of BDDFHA/mol of the tetrameric enzyme. The 3H-labeled enzyme retains its original NAD+/NADH content. Tryptic digestion and subsequent protein sequencing of the [8-3H]BDDFHA-labeled enzyme revealed that Arg196 is the residue that is associated with the radiolabeled inhibitor. The partition ratio of the Ade formation (nonlethal event) to covalent acylation (lethal event) is approximately 1:1. From these experimental results, a possible mechanism by which BDDFHA inactivates AdoHcy hdyrolase is proposed: enzyme-mediated water addition at the C-6' position of BDDFHA followed by elimination of Br- ion results in the formation of homoAdo 6'-carboxyl fluoride (HACF). HACF then partitions in two ways: (a) attack by a proximal nucleophile (Arg196) to form an amide bond after expulsion of F- ion (lethal event) or (b) depurination to form Ade and hexose-derived 6-carboxyl fluoride (HDCF), which is further hydrolyzed to hexose-derived 6-carboxylic acid (HDCA) and F- ion (nonlethal event).

Adenosylhomocysteinase↗

PubMed2005

Combined broncho-oesophagoscopy for diagnosis of HIV-associated disorders.

The aim of the study was to characterize the value of combined endoscopy of tracheobronchial tree and oesophagus within 1 session for diagnosis of HIV-associated disorders. Hospitalized HIV-positive patients who underwent combined flexible broncho-oesophagoscopies between 1999 and 2002 in 2 units for infectious diseases were studied retrospectively. 54 HIV patients were analysed; 89% were at stage CDC C, 79% were male, mean age was 40 y. Bronchoscopy led to a diagnosis in 57.4% (95% CI 43.2-70.8). In 40.7%, these were AIDS-defining events (ADE) and 16.7% were general disorders (GD). Oesophagoscopy was diagnostic in 46.3% (95% CI 32.6-60.4). In 35.2% these were ADE, and 11.1% were GD. Patients with pathological oesophagoscopy had a significantly lower CD4 cell count and a higher viral load. There was no association of pathological bronchoscopy with pathological oesophagoscopy regarding ADE. No severe complication was recorded. It is concluded that combined flexible broncho-oesophagoscopy is a valuable and safe method for the diagnosis of HIV-associated disorders. The diagnostic output is highest in patients with advanced disease. A pathological finding in oesophagoscopy cannot be predicted by the presence of bronchoscopic abnormalities. Prospective studies are necessary to confirm these results.

AIDS-Related Opportunistic Infections↗

PubMed2000

ASHP national survey of pharmacy practice in acute care settings: monitoring, patient education, and wellness--2000.

Results of the 2000 ASHP national survey of pharmacy practice in acute care settings that pertain to patient medication monitoring, education, and wellness are presented. Pharmacy directors at 1063 general and children's medical-surgical hospitals in the United States were surveyed by mail. The response rate was 50.2%. Although the respondents indicated that most pharmacists spent less than 20% of their time on medication-monitoring activities, the amount of time devoted to such activities was increasing. Pharmacists were selective about which patients they chose to monitor for medication-related problems. Patients were frequently chosen on the basis of service or medication. Pharmacists used a number of mechanisms to monitor patients for adverse drug events (ADEs). Although internal ADE reporting had generally increased within the preceding three years, 81% of the Institutions had implemented strategies to improve reporting. When ADEs were reported externally (59% of the respondents), FDA was most commonly alerted. About 92% of the respondents indicated that nursing had primary responsibility for counseling patients about medications. Pharmacists were infrequently involved in medication education during the hospital stay; however, 48% of the institutions used some method to identify patients needing counseling by pharmacists. Slightly more than half of the respondents reported having wellness programs. Pharmacists were most commonly involved in disease-based wellness programs. Pharmacists in acute care settings appear to be well positioned to improve the patient-monitoring, education, and wellness components of the medication-use process.

Adverse Drug Reaction Reporting Systems↗

PubMed2003

Impact of emerging technologies on medication errors and adverse drug events.

Published evidence on the effects of computerized physician order entry (CPOE), automated dispensing machines (ADMs), bar coding, and computerized medication administration records (CMARs) on medication errors and adverse drug events (ADEs) were reviewed. Emerging technologies have been recommended as potential mechanisms for reducing medication errors. Critical evaluations of the impact of these new technologies on medication errors and other adverse outcomes are lacking. PubMed was searched to identify all peer-reviewed publications linking four technologies (CPOE, ADMs, bar coding, and CMARs) with reductions in medication errors and ADEs and secondary endpoints. All controlled studies that assessed the impact of the technologies were evaluated. The appropriateness of the use of these technologies was also examined. Few studies were identified that evaluated the technologies' impact on these endpoints. Of the evaluated technologies, CPOE was the most studied; however, investigations were limited to selected medical centers. The appropriateness of use of the technologies was evaluated even more infrequently. A literature review revealed a paucity of controlled, generalizable studies confirming the benefits of technologies intended to reduce medication errors and ADEs. Very little evidence on the appropriateness of the use of these technologies was found.

Drug Therapy, Computer-Assisted↗

PubMed1983

Identification of receptor mechanism mediating epinephrine-induced arrhythmias during halothane anesthesia in the dog.

The adrenergic receptor mechanism by which halothane sensitizes the myocardium to the ventricular arrhythmogenic properties of catecholamines is unknown. The new generation of selective adrenergic receptor antagonists have been used to determine which receptor blockade causes the greater increase in the dose of epinephrine needed to achieve a threshold for ventricular arrhythmias. Dogs anesthetized with 1.2 MAC halothane had an arrhythmogenic dose of epinephrine (ADE) of 2.2 micrograms X kg X min-1 that significantly increased (P less than 0.01) to 27 micrograms X kg-1 X min-1 after alpha 1 blockade with prazosin. beta 1 blockade with metoprolol also significantly increased the ADE to 12 micrograms X kg-1 X min-1 (P less than 0.05) but was less than the effect noted after prazosin treatment (P less than 0.05). The dramatic increase in the threshold for arrhythmias noted after prazosin could not be ascribed solely to its hemodynamic properties because treatment with sodium nitroprusside did not change the ADE (2.7 micrograms X kg-1 X min-1) significantly; yet nitroprusside treatment resulted in a similar drop in mean arterial pressure (59 mmHg) to that of prazosin treatment (51 mmHg) when compared with the control group. Thus postsynaptic myocardial alpha 1 adrenergic receptors mediate most of the sensitization by halothane to the ventricular arrhythmogenic effects of catecholamines, while a lesser contribution is conferred by the beta 1 adrenoceptors. These results have implications for the treatment and identification of patients particularly at risk from halothane-epinephrine interactions.

Adrenergic alpha-Antagonists↗

PubMed1985

Halothane concentration does not alter the threshold for epinephrine-induced arrhythmias in dogs.

Halothane lessens the dose of epinephrine necessary to induce ventricular arrhythmias. However, results of a previous study in dogs anesthetized at two halothane concentrations suggested, but did not confirm, that at the higher concentration (1.7%) myocardial sensitization to epinephrine was less pronounced. This study was designed to determine the myocardial sensitizing effect of halothane at four concentrations: 0.5, 1.0, 1.5, and 2%. To define the appropriate time interval between repeated epinephrine infusions, plasma epinephrine decay curves were assessed. These data indicated that at 7 min the contribution of the residual epinephrine level to the peak level was negligible. Therefore, 7 min was selected as the interval between epinephrine infusions. The arrhythmogenic dose of epinephrine (ADE) was measured at four concentrations of halothane, 0.5, 1.0, 1.5, and 2.0%. To determine the ADE at the subanesthetic concentration of halothane (0.5%), anesthesia was supplemented with etomidate. In a preliminary study, the authors confirmed that this intravenous hypnotic agent did not affect the halothane-epinephrine arrhythmogenic interaction. By analysis of variance, halothane concentration was shown to have no significant influence on the ADE (P greater than 0.05). The authors' data indicate that, over a clinically appropriate range, halothane concentration does not alter the threshold for the development of epinephrine-induced ventricular arrhythmias.

Animals↗

PubMed1985

Alpha 1-adrenergic blockade raises epinephrine-arrhythmia threshold in halothane-anesthetized dogs in a dose-dependent fashion.

The authors determined whether increasing alpha 1-adrenergic blockade resulted in progressively less arrhythmic activity in the canine halothane-epinephrine arrhythmia model. Dogs (n = 7) were anesthetized with halothane (1.5%) in oxygen. Stepwise increases in steady-state plasma levels of either of two alpha 1-adrenoceptor antagonists (droperidol, doxazosin) were produced by applying Wagnerian principles to the known pharmacokinetic parameters of these drugs. At each steady state plasma level of these antagonists, the extent of the alpha 1-adrenergic blockade produced was assessed by defining a phenylephrine (PE) dose pressor response curve. The degree of alpha 1-blockade produced was quantitated as the dose of PE that caused a 25-mmHg increase in mean arterial pressure (ED25) as derived by polynomial regression analysis. By analysis of variance (ANOVA) the ED25 increased significantly for each targeted steady state plasma level of either droperidol (P less than 0.001) or doxazosin (P less than 0.001). For an assessment of the antiarrhythmic activity of these alpha 1-antagonists, the arrhythmogenic dose of epinephrine (ADE) was determined at each of the states of alpha 1-adrenergic blockade previously defined. By ANOVA there was a significant increase in the ADE over the range of alpha blockade produced for either droperidol (P less than 0.001) or doxazosin (P less than 0.001). A close correlation (r2) existed between the ED25 and the ADE for the target steady state levels that were achieved for either droperidol (0.99) or doxazosin (0.74).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗