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PubMed1993

Interaction between alcohol deprivation and morphine withdrawal in mice.

Hybrid mice having had 12 weeks free access to flavored alcohol were deprived of it for 3 days. The increase in alcohol intake rate during first 1.5 h of renewal access as compared with its intake rate during the remaining 22.5 h (alcohol-deprivation effect, ADE) was used to select individuals having (HD) or lacking (LD) the ADE. The mice received morphine or placebo pellet implantation for 4 days followed by removal of alcohol and pellets. Cross-maze, acoustic startle response, and tail flick tests were conducted 1 day after morphine withdrawal and after 2 days of alcohol deprivation. Next day, during a second ADE test, placebo-treated HDs again showed ADE and LDs showed no ADE; the HDs during morphine withdrawal also still showed an ADE similar to those in placebo HDs, but LDs after morphine removal differed in showing an ADE. Significantly more hyperalgesia in HD than LD mice was observed during morphine withdrawal. Placebo HDs differed from placebo LDs in showing stereotyped behavior and kindling-like rise in acoustic startle response. Morphine withdrawal caused body weight loss, and converted the startle response curve in both LD and HD mice to a bell-shape curve. In HD mice the alcohol deprivation behavioral pattern was substituted by the corresponding morphine withdrawal pattern. The existence of distinct neural circuits responsible for the development of alcohol and morphine dependence is proposed.

Alcoholism↗

PubMed2004

Adverse drug events in two emergency departments in Naples, Italy: an observational study.

The aims of this study, conducted in the emergency departments of two hospitals of Naples (Italy), which differ in type of catchment area and in the number of daily visits, were to determine: (1) the percent of emergency department visits due to adverse drug events (ADEs); (2) the percent of visits requiring hospitalisation due to acute ADEs; (3) the drugs implicated in ADEs; and (4) the types of ADEs and their frequency. We studied all emergency department visits at the A. Cardarelli and Incurabili hospitals between 8.00 a.m. and 8.00 p.m. (prospectively), and between 8.00 p.m. and 8.00 a.m. (retrospectively) for two 10-day periods. When possible, a form was completed for each subject. Patients were asked if they had taken a drug (name, dosage and reason for its use) in the previous 2 weeks. Of the 2442 emergency visits considered, 34 (1.3%) were drug related. Of the 480 patients who were subsequently hospitalised 17 (3.6%) had an ADE. The number increased to 34 (8.9%) in the 379 patients who took drugs in the 2 previous weeks. Non-steroidal anti-inflammatory drugs accounted for 26.5% of cases, antibiotics 23.6%, and antihypertensive agents 17.7%. The most frequent ADEs were gastrointestinal diseases (diarrhea, vomiting and haemorrhagic gastritis) and cutaneous rash (erythema, dermatitis). This study shows that ADEs account for a large percent of hospital admissions and confirms that drug-induced disorders is a notable public health problem.

Adolescent↗

PubMed1998

Metabolism and metabolic actions of 6-methylpurine and 2-fluoroadenine in human cells.

Activation of purine nucleoside analogs by Escherichia coli purine nucleoside phosphorylase (PNP) is being evaluated as a suicide gene therapy strategy for the treatment of cancer. Because the mechanisms of action of two toxic purine bases, 6-methylpurine (MeP) and 2-fluoroadenine (F-Ade), that are generated by this approach are poorly understood, mechanistic studies were initiated to learn how these compounds differ from agents that are being used currently. The concentration of F-Ade, MeP, or 5-fluorouracil required to inhibit CEM cell growth by 50% after a 4-hr incubation was 0.15, 9, or 120 microM, respectively. F-Ade and MeP were also toxic to quiescent MRC-5, CEM, and Balb 3T3 cells. Treatment of CEM, MRC-5, or Balb 3T3 cells with either F-Ade or MeP resulted in the inhibition of protein, RNA, and DNA syntheses. CEM cells converted F-Ade and MeP to F-ATP and MeP-ribonucleoside triphosphate (MeP-R-TP), respectively. The half-life for disappearance of HeP-ribonucleoside triphosphate from CEM cells was approximately 48 hr, whereas the half-lives of F-ATP and ATP were approximately 5 hr. Both MeP and F-Ade were incorporated into the RNA and DNA of CEM cells. These studies indicated that the mechanisms of action of F-Ade and MeP were quite different from those of other anticancer agents, and suggested that the generation of these agents in tumor cells by E. coli PNP could result in significant advantages over those generated by either herpes simplex virus thymidine kinase or E. coli cytosine deaminase. These advantages include a novel mechanism of action resulting in toxicity to nonproliferating and proliferating tumor cells and the high potency of these agents during short-term treatment.

3T3 Cells↗

PubMed2001

Suspected iron dextran-related adverse drug events in hemodialysis patients.

Despite the use of recombinant erythropoietin, anemia remains a significant problem for patients with end-stage renal disease, in part related to chronic dialysis-related blood loss and resultant iron deficiency. Because oral iron preparations have been relatively ineffective and poorly tolerated in this population, intravenous (IV) iron dextran has been widely prescribed, despite a finite risk for adverse effects associated with its use. We analyzed data from Fresenius Medical Care North America (FMCNA) clinical variance reports to determine the incidence of suspected iron dextran-related adverse drug events (ADEs) and associated patient characteristics, dialysis practice patterns, and outcomes. We used a case-cohort study design, comparing individuals who experienced suspected ADEs with the overall FMCNA population. Among 841,252 IV iron dextran administrations from October 1998 through March 1999, there were 165 reported suspected ADEs, corresponding to an overall rate of 0.000196%, or approximately 20 per 100,000 doses. Forty-three patients (26%) required an independent emergency department evaluation, 18 patients (11%) required hospitalization, and 1 patient (0.6%) died. Dyspnea (43%), hypotension (23%), and neurological symptoms (23%) were the most common major ADEs; nausea (34%), vomiting (23%), flushing (27%), and pruritus (25%) were the most common other ADEs. ADEs were 8.1-fold more common among patients administered Dexferrum (American Regent Laboratories, Inc, Shirley, NY) compared with those administered InFed (Watson Pharmaceuticals, Phoenix, AZ). In summary, serious adverse reactions to IV iron dextran are rare in clinical practice. The risk appears to depend on the specific formulation of IV iron dextran. Otherwise, iron dextran-related ADEs are difficult to predict.

Humans↗

PubMed2005

Computational study of IAG-nucleoside hydrolase: determination of the preferred ground state conformation and the role of active site residues.

The mechanism of action of inosine-adenosine-guanosine nucleoside hydrolase (IAG-NH) has been investigated by long-term molecular dynamics (MD) simulation in TIP3P water using stochastic boundary conditions. Special attention has been given to the role of leaving group pocket residues and conformation of the bound substrate at the active site of IAG-NH. We also describe the positioning of the residues of an important flexible loop at the active site, which was previously unobservable by X-ray crystallography due to high B-factors. Five MD simulations have been performed with the Enzyme x Substrate complexes: Enzyme x anti-Adenosine with Asp40-COOH [E(40H) x Ade(a)], Enzyme x anti-Adenosine with Asp40-COO- [E(40) x Ade(a)], Enzyme x syn-Adenosine with Asp40-COOH [E(40H) x Ade(s)], Enzyme x syn-Adenosine with Asp40-COO- [E(40) x Ade(s)], and Enzyme x anti-Inosine with Asp40-COO- [E(40) x Ino(a)]. Overall, the structures generated from the MD simulation of E(40H) x Ade(s) preserve the catalytically important hydrogen bonds as well as electrostatic and hydrophobic interactions to provide a plausible catalytic structure. When deprotonated Asp40 (Asp4-COO-) is present, the active site is open to water solvent which interferes with the base stacking between Trp83 and nucleobase. A calculation using Poisson-Boltzmann equation module supports that Asp40 indeed has an elevated pK(app). Solvent accessible surface area (SASA) calculations on all the five MD structures shows that systems with protonated Asp40, namely, E(40H) x Ade(a) and E(40H) x Ade(s), have zero SASA. It is found that a water molecule is hydrogen-bonded to the N7 of the nucleobase and is probably the essential general acid to protonate the departing nucleobase anion. The N7-bonded water is in turn hydrogen-bonded to waters in a channel, held in place by the residues of the flexible loop, Tyr257, His247, and Cys245. Using normal-mode analysis with elastic network model, we find that the flexible loop explores a conformational space much larger than in the MD trajectory, leading to a "gating"-like motion with respect to the active site.

Adenosine↗

PubMed1999

Academic detailing improves identification and reporting of adverse drug events.

In a prospective, crossover study, we assessed the impact of a clinical pharmacist on identification and reporting of adverse drug events (ADEs) in hospitalized patients. The study was conducted on four units of a medical ward of a university hospital, with two units serving as test, the other two as control units. After 12 months, test and control units were switched. In the test units, a pharmacist participated in daily ward rounds, solicited additional information from physicians and nurses, and reviewed the charts of all patients. In control units, information on ADEs was based solely on voluntary reports from physicians and nurses. A total of 1,959 patients (941 in test, 1,018 in control units) were hospitalized during the study period. In 137 test units patients, 224 ADEs (14.6%; 95%-CI: 12.3%-16.9%) were detected (8 severe, 60 moderate, 156 mild), while 25 ADEs (1 severe, 11 moderate, 13 mild) occurring in 21 patients (2.1%; 95%-CI: 1.2%-3.0%) were reported from the control units (p < 0.0001). Of the ADEs in the test units, 51% were reported spontaneously, 39% were identified on rounds, and 10% by chart review. After changing the status of test and control units, the number of identified ADEs returned to preintervention levels. Clinical pharmacists as part of the medical care team can improve the identification of ADEs which may ultimately translate into improved quality of care.

Adverse Drug Reaction Reporting Systems↗

PubMed2001

Physicians' attitudes towards voluntary reporting of adverse drug events.

At the time a new drug is placed on the market, information on its therapeutic effect and toxicity is limited. Because of its simplicity and widespread use, the voluntary reporting by clinical physicians is the main method for detecting rare or unexpected adverse drug events (ADEs). However, the usefulness of this method may be compromised if the reporting rate is low. We present the results of a questionnaire-based case-control study carried out among 692 physicians from Galicia (north-west region of Spain), in which we assessed their attitudes and opinions towards ADEs. In general, the Galician physicians think it is difficult to link a given ADE with a drug (P < 0.05) and have very heterogeneous opinions on the fact that very severe ADEs are known before the drug is commercialized. They globally disagree with the proposal that ADE reporting should be renumerated and the fact that ADE reporting can be risky for the physician. Some of the beliefs concerning ADEs are incorrect. It is crucial to improve the training of the physicians through active educational strategies based on personal contact.

Adult↗

PubMed2004

Magnesium deficiency alters the threshold for epinephrine-induced arrhythmias during halothane or sevoflurane anesthesia in the rat.

OBJECTIVE: To determine the effect of chronic magnesium (Mg2+) deficiency on the relative arrhythmogenicity of halothane and sevoflurane in the rat. DESIGN: Prospective, randomized, nonblinded study. SETTING: University laboratory. PARTICIPANTS: Male Sprague-Dawley rats (n = 48). INTERVENTIONS: Rats were maintained on a Mg2+-deficient or control diet for 14 days, at which time they were anesthetized with halothane or sevoflurane, a tracheostomy was performed, and the lungs were ventilated to maintain normocapnia. Catheters were inserted into a femoral vein and carotid artery. Lead II of the electrocardiogram was monitored to determine the threshold for epinephrine-induced arrhythmias. MEASUREMENTS AND MAIN RESULTS: Chronic Mg2+ deficiency significantly decreased the dose of epinephrine required for arrhythmias (ADE). The reduction in the ADE was approximately one third during halothane anesthesia (p < 0.05) and one fifth during sevoflurane anesthesia (p < 0.001). Infusion of magnesium sulphate completely reversed the reduction in ADE. In normomagnesemic rats, the halothane ADE was significantly less than the sevoflurane ADE (mean difference = 6.0 microg/kg, 95% confidence interval of the difference = 3.6 to 8.4 microg/kg) (p < 0.005). Mg2+ deficiency significantly attenuated the difference between the halothane ADE and the sevoflurane ADE (mean difference in the Mg2+-deficient group = 0.6 microg/kg, 95% confidence interval of the difference = -0.2 to 1.5 microg/kg). CONCLUSION: Chronic Mg2+ deficiency decreased the threshold for epinephrine-induced arrhythmias and attenuated differences between the arrhythmogenic potential of halothane and sevoflurane, suggesting that arrhythmias are as likely to develop with sevoflurane as with halothane in the presence of coexisting magnesium deficiency and elevated catecholamines.

Anesthesia, Inhalation↗

PubMed2005

Dynamic effects of antibody-dependent enhancement on the fitness of viruses.

Antibody-dependent enhancement (ADE), a phenomenon in which viral replication is increased rather than decreased by immune sera, has been observed in vitro for a large number of viruses of public health importance, including flaviviruses, coronaviruses, and retroviruses. The most striking in vivo example of ADE in humans is dengue hemorrhagic fever, a disease in which ADE is thought to increase the severity of clinical manifestations of dengue virus infection by increasing virus replication. We examine the epidemiological impact of ADE on the prevalence and persistence of viral serotypes. Using a dynamical system model of n cocirculating dengue serotypes, we find that ADE may provide a competitive advantage to those serotypes that undergo enhancement compared with those that do not, and that this advantage increases with increasing numbers of cocirculating serotypes. Paradoxically, there are limits to the selective advantage provided by increasing levels of ADE, because greater levels of enhancement induce large amplitude oscillations in incidence of all dengue virus infections, threatening the persistence of both the enhanced and nonenhanced serotypes. Although the models presented here are specifically designed for dengue, our results are applicable to any epidemiological system in which partial immunity increases pathogen replication rates. Our results suggest that enhancement is most advantageous in settings where multiple serotypes circulate and where a large host population is available to support pathogen persistence during the deep troughs of ADE-induced large amplitude oscillations of virus replication.

Animals↗

PubMed1986

Biosynthesis of zeatin from N-(Delta-isopentenyl)adenine in Actinidia: Sites and seasonal changes in activity.

In Actinidia arguta (hardy kiwifruit) plants, the potential to accumulate the cytokinin zeatin (io(6)Ade) during feeding with a precursor, N(6)-(Delta(2)-isopentenyl)adenine (i(6)Ade), varies depending on the tissue. This can be demonstrated by incubating explants for 24 hr on a basal nutrient medium supplemented with 30 muM i(6)Ade and then extracting the tissues and analyzing cytokinin contents using HPLC methodology. Under these conditions, the potential for io(6)Ade accumulation in tissue slices from growing roots was 93 nmol/g at the root tip, >200 nmol/g immediately behind the tip (1.0-mm diameter), approximately 100 nmol/g in 2-mm diameter root, and progressively lower in older tissues. A similar gradient of io(6)Ade accumulation was detected in growing stems, with relatively low activity (40 nmol/g) in the terminal 0.5 cm, approximately 170 nmol/g in the 5- to 15-cm interval, and about 25 nmol/g in stem tissues taken 15-100 cm from the tip. Growing leaves accumulated little io(6)Ade (7-26 nmol/g) during feeding, as did fruits (0-8 nmol/g) at various stages of development and maturation. Seasonally, root activity was detected as early as March 1, whereas stem activity did not appear until March 15. Thus, the activation of i(6)Ade metabolism in both of these organs preceded sap flow (March 29) and bud break (April 16) by several weeks. The results suggest that root and stem tissues may be sites of cytokinin biosynthesis in growing Actinidia plants and that cytokinin production may not be the critical factor controlling the beginning of shoot growth in the spring.

Journal Article↗

PubMed2003

Antibody-dependent enhancement of virus infection and disease.

In general, virus-specific antibodies are considered antiviral and play an important role in the control of virus infections in a number of ways. However, in some instances, the presence of specific antibodies can be beneficial to the virus. This activity is known as antibody-dependent enhancement (ADE) of virus infection. The ADE of virus infection is a phenomenon in which virus-specific antibodies enhance the entry of virus, and in some cases the replication of virus, into monocytes/macrophages and granulocytic cells through interaction with Fc and/or complement receptors. This phenomenon has been reported in vitro and in vivo for viruses representing numerous families and genera of public health and veterinary importance. These viruses share some common features such as preferential replication in macrophages, ability to establish persistence, and antigenic diversity. For some viruses, ADE of infection has become a great concern to disease control by vaccination. Consequently, numerous approaches have been made to the development of vaccines with minimum or no risk for ADE. Identification of viral epitopes associated with ADE or neutralization is important for this purpose. In addition, clear understanding of the cellular events after virus entry through ADE has become crucial for developing efficient intervention. However, the mechanisms of ADE still remain to be better understood.

Animals↗

PubMed2003

Adverse drug events and medication errors in Australia.

PURPOSE: To review information about adverse drug events (ADEs) and medication errors in Australia. DATA SOURCES: Systematic literature reviews and reports from data collections of the Australian Bureau of Statistics, Institute of Health and Welfare, Council for Health Care Standards and Patient Safety Foundation. RESULTS: (medical record reviews): We have shown that 2-4% of all hospital admissions, and up to 30% for patients > 75 years of age, are medication-related; up to three-quarters are potentially preventable. RESULTS (routine data collections): Routine death certificate and hospital discharge data coded using the International Classification of Diseases capture less than half as many ADEs as medical record reviews. Of coded adverse events that contributed to death, 27% involved an ADE, as did 20% of adverse events identified at discharge and 43% at general practice encounters. There is a strong correlation between increases in medication use and rates of adverse drug reactions (ADRs) associated with hospitalization. RESULTS (drugs implicated): These were similar in all the above studies: anticoagulants, anti-inflammatory drugs, opioids, anti-neoplastics, antihypertensives, antibiotics, cardiac glycosides, diuretics, hypoglycaemic agents, steroids, hypnotics, anticonvulsants, and antipsychotics. RESULTS (clinical indicators): An ADE is reported in 1% of hospital admissions, while some hospitals do not report ADRs to the national collection. Only three-quarters of patients with acute myocardial infarction receive thrombolytics within 1 hour of presentation. Five per cent of patients on warfarin record an international normalized ratio > 5, and 1%, 0.05%, and 0.2% -suffer abnormal bleeding, cerebral haemorrhage, or death, respectively. RESULTS (the Australian Incident Monitoring System): Twenty-six per cent of 27 000 hospital-related incidents were medication-related, as were 36% of 2000 anaesthesia-related incidents, and 50% of 2500 general practice incidents. RESULTS (errors): Errors occur in 15-20% of drug administrations when ward stock systems are used and 5-8% when individual patient systems are used. Previous allergic reactions to drugs may not be recorded more than 75% of the time. CONCLUSION: ADEs are common in the Australian health system. Anticoagulant, anti-inflammatory, and cardiovascular drugs feature prominently as preventable, high impact problems, and collectively make up over one-half of all ADEs. Methods for monitoring and preventing ADEs should be progressively improved.

Australia↗

PubMed1997

Substitution and deletion mutations induced by 2-hydroxyadenine in Escherichia coli: effects of sequence contexts in leading and lagging strands.

To evaluate the mutation frequency and the mutation spectrum of 2-hydroxyadenine (2-OH-Ade), an oxidative DNA lesion, the modified base was site-specifically incorporated into a unique restriction enzyme site (SalI, GTCGA*C or AflII, CTTA*AG where A* represents 2-OH-Ade) in single- and double-stranded vectors. The 2-OH-Ade residues were introduced into (+)- and (-)-strands of the double-stranded vectors and into the (+)-strand of single-stranded vectors. When the vectors were transfected intoEscherichia coli, the modified base showed little to no cytotoxicity. The mutation frequencies of 2-OH-Ade in the SalI and AflII sites were approximately 0.8 and 0.07%, respectively, with double-stranded (+)-vectors. An increase in the mutation frequencies was not observed with single-stranded vectors. When incorporated into the (-)-strand, the mutation frequencies of 2-OH-Ade in the SalI and AflII sites were approximately 0.3 and 0.1%, respectively. The mutations observed most frequently were -1 deletions at both positions, in the case of the (+)-strand. On the other hand, we observed that 2-OH-Ade in the (-)-strand induced A-->G and A-->T substitutions. These results indicate that 2-OH-Ade residues in DNA induce substitution and deletion mutations without blocking replication inE.coli.

DNA↗

PubMed1986

Epinephrine arrhythmogenicity is enhanced by acute, but not chronic, aminophylline administration during halothane anesthesia in dogs.

The authors determined the effect of acute and chronic aminophylline treatment on the arrhythmogenicity of epinephrine during halothane anesthesia. The dose of epinephrine required to achieve an arrhythmia threshold (ADE) was determined in nine unpremedicated dogs anesthetized with halothane (1.5% v/v) in oxygen (A0). Aminophylline was then infused to achieve and sustain a therapeutic theophylline level (mean +/- SD) of 17 +/- 2 micrograms X ml-1 (A1), at which time the ADE was reassessed. The aminophylline infusion regimen was then adjusted to provide a supratherapeutic level of theophylline of 34 micrograms X ml-1 (A2) and the ADE was reassessed. In an additional seven dogs the ADE was assessed before and after 6 weeks of oral aminophylline treatment that yielded a plasma theophylline level of 18 +/- 3 micrograms X ml-1. The ADE was significantly (P less than 0.01) reduced from a basal value (mean +/- SD) of 2.63 +/- 0.97 micrograms X kg X -1 X min-1 to 1.39 +/- 0.47 in the A1 state. There was no further decrement in the ADE at the A2 state (1.17 +/- 0.36). The plasma epinephrine level at the arrhythmia threshold decreased commensurately from 50.7 +/- 40.2 ng X ml-1 (A0) to 20.0 +/- 7.9 and 19.2 +/- 7.6 in the A1 and A2 states, respectively (P less than 0.01). In contrast to these acute treatment experiments, neither the ADE (2.65 +/- 0.95 vs. 2.97 +/- 1.49 micrograms X kg-1 X min-1) nor the plasma epinephrine levels at the arrhythmia threshold (47.2 +/- 13.7 vs. 51.1 +/- 22.0 ng X ml-1) were different after chronic aminophylline treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminophylline↗

PubMed1991

Comparison of logdose and bracket protocols for determination of epinephrine arrhythmia thresholds in dogs anesthetized with thiopental-halothane.

Previous studies in dogs of anesthetic-epinephrine arrhythmias have used logdose or bracketed epinephrine infusion protocols to determine the arrhythmic dose of epinephrine (ADE) or plasma level of epinephrine at arrhythmias (PCE). Reported logdose ADE values for halothane preceded by thiopental induction (thiopental-halothane) are twice those with the bracket protocol. There are no reported PCE data for the bracket protocol, and neither protocol has been directly compared in the same dogs. Therefore, direct comparisons were made of thiopental-halothane ADE and PCE in seven dogs (group 1). Dogs were induced with thiopental (20 mg/kg), followed by halothane inhalation at end-tidal concentrations equivalent to MAC 1.25. Epinephrine infusion protocols were compared on two weekly test occasions, with the sequence and order of protocol testing randomized. Logdose ADE for four or more ventricular beats within 15 s was 3.92 +/- 0.60 micrograms/kg (mean +/- standard error), higher than the bracket ADE (2.54 +/- 0.34 micrograms/ml) (P less than 0.05). PCE at ADE were similar for both protocols, but six separate infusions of epinephrine were required to establish ADE with the logdose compared to four with the bracket protocol (P less than 0.05). These findings suggested enhanced epinephrine clearance with the logdose protocol. Therefore, five additional but similarly anesthetized dogs (group 2) were tested to determine if physiologic or hemodynamic conditions prior to epinephrine infusions ("initial conditions") were equivalent for both protocols. Protocols were modified to avoid provocation of ventricular arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Adverse events related to drugs and drug withdrawal in nursing home residents.

OBJECTIVE: To (1) develop and standardize explicit criteria to link clinical adverse events to drug withdrawal, (2) determine the incidence and severity of Adverse Drug Events (ADEs) and Adverse Drug Withdrawal Events (ADWEs) in a nursing home population, and (3) establish the contribution of demographic, clinical, and functional characteristics to ADEs and ADWEs. DESIGN: Retrospective record review of an admission cohort. SETTING AND SUBJECTS: Consecutive admissions of residents of an academic Veterans Affairs nursing home with available records and lengths of stay > 30 days (n = 175). Subjects were 96% men, aged 70 +/- 12 years, and took 7.0 +/- 3.4 medications. METHODS: We applied standardized algorithms to determine incidence, probability, and severity of ADEs and ADWEs. Multiple regression techniques were used to identify factors associated with frequency and risk of events. RESULTS: Ninety five residents experienced 201 ADEs. Twelve required hospitalization or prolonged hospitalization, and one resident died. Sixty two persons had 94 ADWEs. None were associated with death and one with hospitalization. The four most commonly prescribed drug classes accounted for 72% of ADEs and 80% of ADWEs. Results of multivariate analyses showed common risk factors for both ADEs and ADWEs: number of diagnoses, number of medications, and hospitalization during the nursing home stay. CONCLUSIONS: ADEs and ADWEs were common in nursing home residents in this Veteran's Affairs setting. Explicit criteria developed and applied in this study should be applied prospectively in other settings, both to further define risk of drug discontinuation and to assist in development of specific drug discontinuation guidelines.

Aged↗

PubMed2002

Adenine nucleotide-induced activation of adenosine A(2B) receptors expressed in Xenopus laevis oocytes: involvement of a rapid and localized adenosine formation by ectonucleotidases.

We recently demonstrated that extracellular ATP effectively activates adenosine (Ade) A(2B) receptors indirectly through a localized rapid conversion to Ade by ectonucleotidases on the membrane surface of C6Bu-1 rat glioma cells. These responses were observed even in the presence of adenosine deaminase (ADA). Here, we demonstrate that such responses indeed occur in A(2B) receptor-expressing Xenopus laevis oocytes, which possess endogenous ectonucleotidase activity. In oocytes coexpressing the A(2B) receptor and cystic fibrosis transmembrane conductance regulator (CFTR), Ade induced a concentration-dependent increase in a cyclic AMP-activated CFTR current, a response that was inhibited by the P1 antagonist xanthine-amine congener (XAC). A brief application of ATP and beta,gamma-methylene ATP (beta,gamma-MeATP) also induced the CFTR current in a manner similar to that seen with Ade. Among several nucleotide agonists, ADP, AMP, and adenosine-5'-O-(3-thio)triphosphate induced the CFTR current. Although adenine nucleotide-induced CFTR currents were inhibited by XAC, they were highly resistant to ADA treatment; 5 U/ml ADA was required for inhibition of adenine nucleotide-induced CFTR current, whereas 1 U/ml ADA was sufficient to abolish the Ade-induced response. In addition, the ecto-5'-nucleotidase inhibitor alpha,beta-methylene ADP markedly inhibited the beta,gamma-MeATP-induced response but not the Ade-induced one. These results support our hypothesis that adenine nucleotides are rapidly and locally converted into Ade on the membrane surface, resulting in the activation of A(2B) receptors.

Adenosine↗

PubMed2000

Specific ablation of antiviral gene expression in macrophages by antibody-dependent enhancement of Ross River virus infection.

Ross River virus (RRV) is an indigenous Australian arthropod-borne alphavirus responsible for epidemic polyarthritis (EPA), myalgia, and lethargy in humans. Macrophages and monocytes have been associated with human RRV disease, and previous studies have shown that RRV is capable of infecting macrophages via both a natural virus receptor and by Fc receptor-mediated antibody-dependent enhancement (ADE). Similar to other viruses, such as human immunodeficiency virus and dengue virus, ADE infection results in dramatic RRV growth increases for in vitro macrophage cultures. This study demonstrates that RRV could resist lipopolysaccharide (LPS)-induced antiviral activity in macrophage cultures when infection was via the ADE pathway. Investigation of this infection pathway found that RRV was able to suppress the transcription and translation of key antiviral genes (tumor necrosis factor and inducible nitric oxide synthase) in LPS-stimulated macrophages by disrupting the transcription into mRNA of the genes coding for the associated transcription factors IRF-1 and NF-kappaB. The transcription of non-antiviral control genes was not perturbed by RRV-ADE infection, and de novo protein synthesis also was not significantly affected in RRV-ADE infected cells. The ADE pathway of infection allowed RRV to specifically target antiviral genes in macrophages, resulting in unrestricted virus replication. As ADE has been observed for several virus families and associated with disease and adverse vaccination outcomes, these findings may have broad relevance to viral disease formation and antiviral vaccination strategies.

Alphavirus Infections↗