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PubMed2004

On the relative safety of parenteral iron formulations.

BACKGROUND: Intravenous iron is usually required to optimize the correction of anaemia in persons with advanced chronic kidney disease and end-stage renal disease. Randomized clinical trials may have insufficient power to detect differences in the safety profiles of specific formulations. METHODS: We obtained data from the US Food and Drug Administration on reported adverse drug events (ADEs) related to the provision of three formulations of intravenous iron during 1998-2000. We estimated the relative risks [odds ratios (OR)] of ADEs associated with the use of higher molecular weight iron dextran and sodium ferric gluconate complex compared with lower molecular weight iron dextran using 2 x 2 tables. RESULTS: The total number of reported parenteral iron-related ADEs was 1981 among approximately 21,060,000 doses administered, yielding a rate of 9.4 x 10(-5), or approximately 94 per million. Total major ADEs were significantly increased among recipients of higher molecular weight iron dextran (OR 5.5, 95% CI 4.9-6.0) and sodium ferric gluconate complex (OR 6.2, 95% CI 5.4-7.2) compared with recipients of lower molecular weight iron dextran. We observed significantly higher rates of life-threatening ADEs, including death, anaphylactoid reaction, cardiac arrest and respiratory depression among users of higher molecular weight compared with lower molecular weight iron dextran. There was insufficient power to detect differences in life-threatening ADEs when comparing lower molecular weight iron dextran with sodium ferric gluconate complex. CONCLUSIONS: Parenteral iron-related ADEs are rare. Using observational data, overall and most specific ADE rates were significantly higher among recipients of higher molecular weight iron dextran and sodium ferric gluconate complex than among recipients of lower molecular weight iron dextran. These data may help to guide clinical practice, as head-to-head clinical trials comparing different formulations of intravenous iron have not been conducted.

Ferric Compounds↗

PubMed1999

Strong correlation between the complement-mediated antibody-dependent enhancement of HIV-1 infection and plasma viral load.

OBJECTIVE: We have previously demonstrated that complement-mediated antibody-dependent enhancement (C-ADE) of HIV-1 infection correlates with accelerated immunosuppression and disease progression in HIV-1-infected individuals. In the present work the relationship between C-ADE and plasma HIV-1 RNA concentrations was studied to determine the effect of C-ADE on viral replication. METHODS: Three studies were performed: (a) C-ADE and HIV-1 RNA concentrations were determined in the serum and plasma aliquots taken at the same time from 98 HIV patients, mostly in the advanced stage of the disease; (b) the above two parameters as well as HIV enzyme-linked immunosorbent assay (ELISA)-reactive antibodies (Abbott HIV 1/2 test), and p24 antigen levels (Abbott antigen test; Abbott, Delkenheim, Germany) were determined in four seroconversion panels purchased from the Boston Biomedica firm; (c) changes of HIV-1 RNA concentration and C-ADE during a 17 month follow-up period were determined in 18 HIV-infected patients. C-ADE was measured by the method previously established in our laboratories. The results were expressed by an enhancement/neutralization index (E/NI). HIV-1 RNA levels were determined with the Amplicor monitor kit (Roche, Basel, Switzerland), and in some experiments with the nucleic acid sequence based amplification (Organon Teknika, Turnhout, Belgium) kits. RESULTS: (a) We found a highly significant (P<0.0001) positive correlation between E/NI values reflecting the extent of HIV-1 infection enhancement and plasma HIV-1 RNA levels. Both E/NI and HIV-1 RNA levels negatively correlated to the CD4 cell counts. (b) C-ADE was first detected just before, or concomitantly with, seroconversion in 4/4 seroconversion panels. (c) Both E/NI values and HIV-1 RNA levels significantly (P<0.001) increased during a 17 month observation period in 18 HIV-infected patients. CONCLUSION: We found strong association between the extent of the complement-mediated antibody-dependent enhancement of HIV-1 infection and the plasma viral load in HIV patients. On the basis of these findings, C-ADE correlates with HIV replication in vivo, and potentially contributes to the progression of HIV disease.

Adolescent↗

PubMed1999

Influence of physicians' attitudes on reporting adverse drug events: a case-control study.

BACKGROUND: Voluntary physician reporting of adverse drug events (ADEs) in among their patients remains the single most important source of information on serious and rare ADEs. Yet, substantial under-reporting exists and the factors producing its causes are unclear. OBJECTIVES: The objectives of the study are to: (1) identify the practitioner's demographic and professional characteristics associated with ADE reporting; and (2) identify knowledge, attitudes, and opinions associated with ADE reporting. DESIGN: Case-control study. SUBJECTS: Physicians within the National Health Service in Galicia (Northwestern Spain). The 194 case doctors are those who reported at least one ADE to the regional drug surveillance center between 1991 and their enrollment in the study. The 498 controls were randomly selected among the remaining physicians. All were interviewed using a mail questionnaire. MAIN OUTCOME MEASURES: We used logistic regression to determine the ADE reporting odds ratio. RESULTS: The response rate was 63.7%. The probability of reporting ADEs increases with increasing volume of prescriptions and decreases with increasing patient load. The following attitudes are associated with a smaller probability of reporting: (1) belief that really serious adverse drug events are well documented by the time a drug is marketed; (2) belief that it is nearly impossible to determine if a drug is responsible for a particular adverse event; (3) only reporting an adverse drug reaction if one is sure that it is related to the use of a particular drug; and (4) belief that the one case an individual physician might see cannot contribute to medical knowledge. CONCLUSIONS: Some physician attitudes regarding ADEs are associated with underreporting.

Adult↗

PubMed1993

Neuraminidase augments Fc gamma receptor II-mediated antibody-dependent enhancement of dengue virus infection.

Antibody-dependent enhancement (ADE) of dengue virus infection occurs when neutralizing antibodies at sub-neutralizing concentrations or non-neutralizing antibodies form complexes with the virus. These virus-antibody complexes can then attach to a Fc gamma receptor-bearing cell, via the Fc portion of the immunoglobulin, resulting in an increased number of infected cells. ADE may be responsible in part for the most severe clinical manifestations of dengue virus infection which include haemorrhage and shock. Three classes of human Fc gamma receptors exist, Fc gamma RI, Fc gamma RII and Fc gamma RIII. In this study, we examined the effects of neuraminidase on ADE of dengue virus infection mediated by the low-affinity Fc gamma RII. K562 cells, which express only Fc gamma RII, treated with neuraminidase resulted in augmentation of ADE of dengue virus infection by human anti-dengue antibodies. This augmented ADE of infection could be blocked by anti-Fc gamma RII monoclonal antibody IV.3. Incubation of neuraminidase-treated K562 cells with IgG-coated human red blood cells resulted in an increase in the percentage of rosette formations compared with the untreated K562 cells. A bispecific antibody directed against Fc gamma RII and dengue virus (IV.3 x 2H2) enhanced virus infection. Neuraminidase also augmented ADE mediated by this antibody, but to a much lesser degree (by 50%) compared with that seen using conventional human anti-dengue antibody (by 200 to 300%). Fluorescence-activated cell sorting analysis of neuraminidase-treated K562 cells showed that the number of Fc gamma RII-specific antibodies that bind to Fc gamma RII increases by 15 to 20% after treatment with neuraminidase. These results indicate that neuraminidase augments ADE of dengue virus infection and that the augmented ADE is mediated through Fc gamma RII.

Antibodies, Monoclonal↗

PubMed2003

Differential in vivo cytokine mRNA expression in lesional skin of intrinsic vs. extrinsic atopic dermatitis patients using semiquantitative RT-PCR.

BACKGROUND: A small subgroup of atopic dermatitis (AD) patients with normal serum IgE levels and without specific IgE sensitization has been termed 'intrinsic type of AD' (ADi) as a counterpart to the term 'extrinsic type of AD' (ADe). However, there are neither molecular markers nor clinically diagnostic tools for distinguishing between ADi and ADe. OBJECTIVE: The present studies were undertaken to clarify the pathogenesis and in vivo cytokine micromilieu of ADi patients in comparison with ADe patients. METHODS: We used semiquantitative RT-PCR to investigate the expression of various cytokines and assessed the tissue eosinophil counts in skin biopsies from both types of AD patients. RESULTS: Although there was no significant difference of cellular infiltrates in the lesional skin between ADe and ADi patients, ADe had significantly increased tissue eosinophilia than ADi. Based on our RT-PCR, the expression patterns of cytokines could be categorized into four groups. The first group includes IL-5, IL-13, and IL-1beta, whose levels of mRNA expression were higher in both types of AD patients than non-atopic (NA) subjects, while ADe patients had even higher levels than ADi patients. The second group includes interferon-gamma (IFN-gamma), IL-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-4, and IL-10, whose levels of mRNA expression were elevated in both types of AD patients without differences between ADe and ADi patients. The third group includes tumour necrosis factor-alpha (TNF-alpha), whose mRNA expression was more decreased in both types of AD patients than NA, and the fourth group includes IL-6 and transforming growth factor-beta (TGF-beta), which did not show any differences among the three groups. CONCLUSION: These current data demonstrate that the expressions of cytokines IL-5, IL-13, and IL-1beta mRNA and the number of dermal infiltrating eosinophils are increased in ADe patients compared with ADi patients.

Adult↗

PubMed2005

Adverse drug events occurring following hospital discharge.

OBJECTIVE: To describe the incidence of adverse drug events (ADEs), preventable ADEs, and ameliorable ADEs occurring after hospital discharge and their associated risk factors. DESIGN: Prospective cohort study. SETTING: Urban academic health sciences center. PATIENTS: Consecutive patients discharged home from the general medical service. INTERVENTIONS: We determined posthospital outcomes approximately 24 days following discharge by performing a chart review and telephone interview. Using the telephone interview, we identified new or worsening symptoms, the patient's health system use, and recollection of processes of care. Posthospital outcomes were judged by 2 internists independently. RESULTS: Four hundred of 581 potentially eligible patients were evaluated. Of the 400 patients, 45 developed an ADE (incidence, 11%; 95% confidence interval [CI], 8% to 14%). Of these, 27% were preventable and 33% were ameliorable. Injuries were significant in 32 patients, serious in 6, and life threatening in 7. Patients were less likely to experience an ADE if they recalled having side effects of prescribed medications explained (OR, 0.4; 95% CI, 0.2 to 0.8). The risk of ADE per prescription was highest for corticosteroids, anticoagulants, antibiotics, analgesics, and cardiovascular medications. Risk increased with prescription number. Failure to monitor was an especially common cause of preventable and ameliorable ADEs. CONCLUSION: Following discharge, ADEs were common and many were preventable or ameliorable. Medication side effects should be discussed, and interventions should include better monitoring and target patients receiving specific drug classes or multiple medications.

Boston↗

PubMed2006

[Preventable adverse drug events in hospitalized patients].

BACKGROUND AND OBJECTIVE: To determine the incidence of adverse drug events (ADE) in hospitalized patients, identify those that were potentially preventable, and asses the drug classes involved, the clinical symptoms and the type of medication errors that led to the preventable ADE. PATIENTS AND METHOD: An observational study of ADE prevalence in hospitalized patients in internal medicine, pneumology, gastroenterology, nephrology and neurology wards, over a six-month period, at a tertiary university hospital. ADE were prospectively detected through physician and nurses reporting fostered by daily visits of a clinical research and retrospectively through review of medical records using event codes as defined by the IDC-9-CM system. RESULTS: In a total of 2,643 hospitalized patients, 191 (7.2%) ADE were detected. Of these, 38 cases (19.9%) were classified as preventable, of which 21.1% were mild; 60.5% moderate and 18.4% serious or life-threatening. Preventable ADE were frequently associated with anti-infective drugs (22.9%), diuretics (18.8%) and digoxin (16.7%). Inadequate therapy monitoring (28.3%), excessive dosage (21.7%), selection of an inappropriate drug according to patient characteristics and/or to diagnosis (15.0%), lack of prescription of a necessary drug (15.0%) and drug-drug interactions (11.7%) were the most common identified type of errors leading to preventable ADE. CONCLUSIONS: 1.4% of hospitalized patients in medical wards experienced potentially preventable ADE. Healthcare professionals and administrators must be made aware of the scope of this problem so that they will implement effective safety practices directed to reduce the incidence of medication errors, particularly prescription and monitoring errors.

Drug-Related Side Effects and Adverse Reactions↗

PubMed1997

[Effects of adenosine and adenine on cold acclimation in mice].

The effects of adenosine (ADO) and adenine (ADE) on cold acclimation were studied in mice of the ddY strain. At 5 weeks of age, mice were maintained at 4 degrees C for 4 weeks. Test groups of mice were supplied with a 0.05% (w/v) solution of ADO or ADE as drinking water in addition to water. We measured changes in body weight, intake of water and food, rectal temperature upon acute exposure to -20 degrees C, weight of interscapular brown adipose tissue (BAT) and the levels of glucose, nonesterified fatty acids (NEFA) and 3H-butyrate in the blood prior to and after exposure to the lower temperature of -20 degrees C. Chronic exposure to cold (4 degrees C) reduced body-weight gain for the first two weeks but weight gain recovered within the next two weeks. ADO partially but selectively inhibited the gain in body weight. This effect was marked in mice maintained at room temperature. Such an inhibitory effect was the case of ADE in the room temperature. Exposure to cold stimulated the daily consumption of food. ADO further and selectively enhanced food intake, but ADE enhanced that in room temperature. Cold increased in daily intake of water. Both ADO and ADE accelerated the intake of water. This effect was marked in mice maintained at 4 degrees C and the effect of ADE was considerable. Mice chose to drink the water that contained ADO, while the choice of water that contained ADE was apparent only during exposure to cold. Exposure to cold rendered mice resistant to severe cold (-20 degrees C). ADO and ADE partially reduced this resistance. Exposure to cold increased the weight of BAT but ADO selectively prevented this increase. Cold did not change the levels of the various compounds measured in the blood. In mice exposed to 4 degrees C for 4 weeks, acute exposure to severe cold decreased the glucose level and increased the levels of NEFA and 3H-butyrate. ADO selectively prevented the changes in the levels of NEFA and 3H-butyrate. It remains to be confirmed whether the growth of brown adipocytes is always necessary when mice acclimate to cold.

Acclimatization↗

PubMed2006

Adverse drug events in general practice patients in Australia.

OBJECTIVE: To investigate the frequency, cause, and severity of adverse drug events (ADEs) among general practice patients. DESIGN: Between May 2003 and February 2004, a subsample of 282 general practitioners in the BEACH (Bettering the Evaluation And Care of Health) data collection program recorded patient responses to questions about ADEs. MAIN OUTCOME MEASURES: Frequency, cause, and severity of ADEs; and frequency of hospitalisation and proportion of events that were preventable. RESULTS: From 8215 encounters, GPs reported that 852 patients (10.4%) had experienced an ADE in the previous 6 months. Patients aged over 45 years (versus under 45 years), children aged 1-4 years (versus older children), and female patients (versus male patients) were significantly more likely to have experienced an ADE. Most patients (83.5%) had experienced only one ADE, with 10.7% and 5.8% experiencing two and three or more events, respectively. For 71.9% of patients, one reason for the most recent event was a recognised side effect, followed by drug sensitivity (12.4%) and allergy (11.0%). Over half of patients were rated as having a "mild" event, with 35.8% rated as "moderate", and 10.0% as "severe". GPs classified 23.2% of events as preventable, and 7.6% of events resulted in hospitalisation. CONCLUSION: Our study reveals the high frequency of ADEs in patients attending general practice. This level of morbidity makes ADEs one of the most significant causes of morbidity in the Australian community.

Adolescent↗

PubMed2006

Medication dispensing errors and potential adverse drug events before and after implementing bar code technology in the pharmacy.

BACKGROUND: Many dispensing errors made in hospital pharmacies can harm patients. Some hospitals are investing in bar code technology to reduce these errors, but data about its efficacy are limited. OBJECTIVE: To evaluate whether implementation of bar code technology reduced dispensing errors and potential adverse drug events (ADEs). DESIGN: Before-and-after study using direct observations. SETTING: Hospital pharmacy at a 735-bed tertiary care academic medical center. INTERVENTION: A bar code-assisted dispensing system was implemented in 3 configurations. In 2 configurations, all doses were scanned once during the dispensing process. In the third configuration, only 1 dose was scanned if several doses of the same medication were being dispensed. MEASUREMENTS: Target dispensing errors, defined as dispensing errors that bar code technology was designed to address, and target potential ADEs, defined as target dispensing errors that can harm patients. RESULTS: In the pre- and post-bar code implementation periods, the authors observed 115,164 and 253,984 dispensed medication doses, respectively. Overall, the rates of target potential ADEs and all potential ADEs decreased by 74% and 63%, respectively. Of the 3 configurations of bar code technology studied, the 2 configurations that required staff to scan all doses had a 93% to 96% relative reduction in the incidence of target dispensing errors (P < 0.001) and 86% to 97% relative reduction in the incidence of potential ADEs (P < 0.001). However, the configuration that did not require scanning of every dose had only a 60% relative reduction in the incidence of target dispensing errors (P < 0.001) and an increased (by 2.4-fold) incidence of target potential ADEs (P = 0.014). There were several potentially life-threatening ADEs involving intravenous dopamine and intravenous heparin in that configuration. LIMITATIONS: The authors used surrogate outcomes; did not mask assessors to the purpose of study; and excluded the controlled substance fill process (a process with low error rates at baseline) from the study, which may bias the combined decrease in error rates toward a larger magnitude. CONCLUSIONS: The overall rates of dispensing errors and potential ADEs substantially decreased after implementing bar code technology. However, the technology should be configured to scan every dose during the dispensing process.

Drug Labeling↗

PubMed1991

Development of a computerized adverse drug event monitor.

Adverse events during drug therapy are receiving renewed attention. Some adverse drug events (ADEs) are identified only after the widespread clinical use of a drug. The Food and Drug Administration advocates post-marketing surveillance systems to provide early warnings of previously undetected ADEs. The identification of ADEs by U.S. hospitals is now required by the Joint Commission on Accreditation of Healthcare Organizations. We developed a series of computer programs and data files on the HELP System to help identify ADEs. The HELP System monitors laboratory test results, drug orders, and data entered through a computerized ADE reporting program. A nurse or pharmacist verifies computer alerts of possible ADEs. The computerized system identified 401 ADEs during the first year of use compared to 9 by voluntary reporting methods during the previous year (p less than 0.001). This paper describes the development and early use of the computerized ADE surveillance system.

Adverse Drug Reaction Reporting Systems↗

PubMed1976

[Intravital survival and deformability of weakly amidinated rat erythrocytes].

Rat erythrocytes previously labelled with 51Cr were treated with 0.1 mM and 0.5 mM dimethyladipic imidate (ADE) pH 9.5, respectively, or with borate buffer pH 9.5 for 15 minutes each. After reinjection into rats of amidinated or nonamidinated erythrocytes their elimination form the streaming blood was followed for 50 days (0.1 mM ADE) or 38 days (0.5 mM ADE). During the 1st day about 10% of amidinated erythrocytes were sequestered. There was no increased initial elimination rate of borate incubated red blood cells detectable. During the following period the elimination rate of erythrocytes amidinated with 0.5 mM ADE was slightly greater than in the case of erythrocytes treated with 0.1 mM ADE. The mean life span of 0.5 mM ADE-erythrocytes was shorter compared with the controls and with 0.1 mM ADE-erythrocytes. Red blood cells previously treated with 0.5 mM ADE are significantly less deformable. Presumably, the stiffness of amidinated erythrocytes causes their increased elimination rate.

Adipates↗

PubMed1994

[Suppressive effects of adenosine on nonspecific and humoral immunities in mice].

Adenosine (Ade) 1.3, 13, 130 mg.kg-1 ip inhibited the ability of peripheral leukocytes and peritoneal macrophages in phagocytosing the Staphylococcus albus with [3H]TdR incorporation in mice, declined the hemolytic ability of plaque-forming cells and the production of antibody in mice immunized by sheep erythrocytes. Ade 13, 130 mg.kg-1 ip decreased the mouse serum muramidase (lysozyme) concentration. Dipyridamole (Dip) 10 mg.kg-1 ip attenuated the effects of Ade 130 mg.kg-1 on humoral immunity reaction, but the nonspecific immunity was not attenuated. These results showed that the uptake of Ade may play an important role in the effects of Ade on humoral immunity reaction. Aminophylline (Ami) 100 mg.kg-1 ip attenuated the effects of Ade 130 mg.kg-1 on hemolytic ability of plaque-forming cells and the ability of peripheral leukocytes in phagocytosing Staphylococcus albus. These results suggested that the effects of Ade on murine humoral and nonspecific immunity reaction were mediated by Ade A2 receptor (A2DR).

Adenosine↗

PubMed2001

Risk factors for adverse drug events among nursing home residents.

BACKGROUND: In a prospective study of nursing home residents, we found adverse drug events (ADEs) to be common, serious, and often preventable. To direct prevention efforts at high-risk residents, information is needed on resident-level risk factors. METHODS: Case-control study nested within a prospective study of ADEs among residents in 18 nursing homes. For each ADE, we randomly selected a control from the same home. Data were abstracted from medical records on functional status, medical conditions, and medication use. RESULTS: Adverse drug events were identified in 410 nursing home residents. Independent risk factors included being a new resident (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.5-5.2) and taking anti-infective medications (OR, 4.0; CI, 2.5-6.2), antipsychotics (OR, 3.2; CI, 2.1-4.9), or antidepressants (OR, 1.5; CI, 1.1-2.3). The number of regularly scheduled medications was associated with increased risk of ADEs; the OR associated with taking 5 to 6 medications was 2.0 (CI, 1.2-3.2); 7 to 8 medications, 2.8 (CI, 1.7-4.7); and 9 or more, 3.3 (CI, 1.9-5.6). Taking supplements or nutrients was associated with lower risk (OR, 0.42; CI, 0.27-0.63). Preventable ADEs occurred in 226 residents. Independent risk factors included taking opioid medications (OR, 6.6; CI, 2.3-19.3), antipsychotics (OR, 4.0; CI, 2.2-7.3), anti-infectives (OR, 3.0; CI, 1.6-5.8), antiepileptics (OR, 2.2; CI, 1.1-4.5), or antidepressants (OR, 2.0; CI, 1.1-3.5). Scores of 5 or higher on the Charlson Comorbidity Index were associated with increased risk of ADEs (OR, 2.6; CI, 1.1-6.0). The number of regularly scheduled medications was also a risk factor: the OR for 7 to 8 medications was 3.2 (CI, 1.4-6.9) and for 9 or more, 2.9 (CI, 1.3-6.8). Residents taking nutrients or supplements were at lower risk (OR, 0.27; CI, 0.14-0.50). CONCLUSIONS: It is possible to identify nursing home residents at high risk of having an ADE. Particular attention should be directed at new residents, those with multiple medical conditions, those taking multiple medications, and those taking psychoactive medications, opioids, or anti-infective drugs.

Aged↗

PubMed1977

Biochemical genetics of Chinese hamster cell mutants with deviant purine metabolism: characterization of Chinese hamster cell mutants defective in phosphoribosylpyrophosphate amidotransferase and phosphoribosylglycinamide synthetase and an examination of alternatives to the first step of purine biosynthesis.

Activities of the first three enzymes in the de novo purine biosynthetic pathway have been measured in cell-free extracts of the Chinese hamster ovary cell (CHO-K1) and two purine-requiring auxotrophs of this cell. Ade-A has been found to be defective in phosphoribosylpryophosphate (PRPP) amidotransferase while Ade-C has been found to be defective in glycinamide ribonucleotide (GAR) synthetase. Neither enzyme deficiency is due to the presence of an excess of diffusible inhibitor, and mixed extracts of Ade-A and Ade-C are capable of performing both enzymatic steps in a coupled assay. Assays of GAR formyltransferase show that it is present in Ade-A and Ade-C, indicating that these cell types are defective in only one enzyme each of the early purine biosynthetic enzymes. Using the Ade-A mutant, analysis of alternatives to PRPP plus glutamine as substrates for the first step in the purine biosynthetic pathway showed that a common genetic unit must direct the synthesis for both PRPP plus glutamine and PRPP plus ammonia activities. Although ribose-5-phosphate plus ammonia can be used in cell-free extracts to perform the first step in purine biosynthesis, it is shown that this activity is apparently not used by intact CHO-K1 cells.

Amidophosphoribosyltransferase↗

PubMed1999

Effects of opiate antagonist treatment on the alcohol deprivation effect in long-term ethanol-experienced rats.

RATIONALE: Opiate antagonists are promising pharmacotherapeutic agents for the treatment of alcohol dependence, reducing craving and relapse rates in weaned alcoholics. However, preclinical findings indicate that they can also increase ethanol consumption and preference in animals with a strong liking for ethanol, depending on the dose and treatment regimen. OBJECTIVE: The present study examined the effects of chronic, intermittent and acute opiate antagonist treatment on the alcohol deprivation effect (ADE) in long-term ethanol- experienced rats, which is an animal model of craving and relapse. METHODS: Long-term ethanol-experienced rats were either implanted with mini-osmotic pumps delivering 0, 0.5 or 1 mg/kg per hour naloxone (chronic treatment) or received intermittent naltrexone injections (2x5 mg/kg per day SC). Effects of chronic and intermittent treatment on the ADE were studied in a four-bottle home cage drinking paradigm. In a second experiment, long-term ethanol-experienced rats trained in an operant ethanol self-administration paradigm received acute naltrexone treatment (0, 0.1, 1 or 10 mg/kg SC) before a 23-h session either during basal drinking or during the ADE. RESULTS: Chronic naloxone treatment increased ethanol preference during the ADE. Intermittent naltrexone treatment at a dose comparable to the lower dose of chronic treatment moderately attenuated the ADE. Acute naltrexone treatment selectively reduced lever pressing for ethanol both during the ADE and during basal drinking only at the lowest dose, whereas higher doses also suppressed water intake. The ethanol-specific suppressant effect on the ADE was long lasting. Concerning basal drinking, however, naltrexone had a long lasting reductive effect only on lever pressing for water. CONCLUSIONS: A low dose of naltrexone and an intermittent treatment regimen seem to be necessary to maintain a specific reduction in ethanol intake in individuals with a high motivation to consume ethanol. These findings are consistent with the notion that, at low doses, opiate antagonists reduce the reward value of reinforcers.

Alcoholism↗

PubMed1998

Skin and plasma levels of acetylsalicylic acid: a comparison between topical aspirin/diethyl ether mixture and oral aspirin in acute herpes zoster and postherpetic neuralgia.

OBJECTIVE: The aim of this investigation was to elucidate whether the analgesic effect was due to the local aspirin or to the systemic drug. This was done by comparing skin and plasma levels of acetylsalicylic acid (ASA) and salicylic acid (SA) after topically administered ASA/diethyl ether (ADE) mixture in acute herpetic neuralgia (AHN) and postherpetic neuralgia (PHN). The analgesia and the plasma and skin levels of ASA were also determined after oral administration of aspirin. METHODS: Nineteen patients, 11 (57.9%) with AHN and 8 (42.1 %) with PHN were given, on different days, a single 500-mg oral dose of ASA or a topical dose (750 mg) of (ADE) daubed onto the painful skin. The analgesic effect was assessed by means of a visual analogue scale (VAS). Overall pain relief was graded as: excellent, good, fair, or poor. AHN as well as PHN patients had severe pain at baseline (6.83 and 5.93). Levels of ASA and SA in plasma and in the stratum corneum after adhesive tape stripping of the treated area were determined by HPLC. RESULTS: After ADE application, the analgesic effect was very rapid and VAS scores were lower than at baseline. Pain significantly decreased by 82.6% after topical and 15.4% after oral ASA. After ADE, 95% of the patients had excellent or good pain relief, but after oral administration 79% of the patients had a poor response. Pain relief was similar in the two subgroups after ADE. Skin concentrations of ASA, but not of SA, after ADE were about 80- to 100-fold those after oral administration. Levels of ASA and SA in plasma after oral administration were similar to those previously found, but after ADE were undetectable or very low. Patients with excellent pain relief showed a trend towards higher ASA skin concentrations. CONCLUSIONS: The analgesic effect can be obtained only after topical administration, because by this route the skin levels of ASA are much higher than after oral administration. The mechanism is exclusively local; there are no active drugs in plasma after topical administration.

Acute Disease↗

PubMed1999

Suspected adverse drug events requiring emergency department visits or hospital admissions.

OBJECTIVE: To analyse the contribution of adverse drug events (ADEs) to the overall number of referrals or visits at an emergency department, to determine the proportion of more severe episodes requiring hospital admission and to characterize the different causes of drug-related visits or admissions. METHODS: A 1-year prospective collection of data on visits performed at an emergency department. All visits, observed during 1 week every month, were analyzed in order to identify suspected ADEs. The effects of age and sex on the frequency of ADE-related visits and admissions were evaluated. All patients hospitalized because of an ADE were followed up in order to collect information about progress and outcome of the events, which were also assessed in terms of avoidability. RESULTS: Among the 5497 patients who visited the Emergency Department over 1 year, 235 (4.3%) experienced an ADE, 45 of these (19.1%) were subsequently hospitalized, among whom there were five deaths. Dose-related therapeutic failures were the main causes of drug-related admissions (55.6%), whereas adverse drug reactions caused the most frequent drug-related visits to the Emergency Department (63.8%). Although the frequency of drug-drug interactions leading to a visit to the Emergency Department was small (3.8%), this type of event was more severe, because most of these patients were hospitalized. No age/sex effect was observed in the proportion of ADE-related hospital admissions. Twenty-five (1.4% of the total admissions) of the 45 ADE-related admissions were evaluated as preventable, contributing by more than 61% of the overall length of hospital stay. CONCLUSION: The high proportion of drug therapeutic failures leading to an admission highlights the need for public education, particularly to prevent non-compliance.

Adult↗