OBJECTIVEPharmacokinetics of 4-methyl-amino-antipyrine (MAA), the active metabolite of the nonsteroidal anti-inflammatory agent dipyrone, whose time course correlates to the therapeutic effect of the drug, are studied.STUDY DESIGN AND SETTING153 patients hospitalized in the Department of Medicine at the Hadassah University Hospital, Jerusalem, Israel.INTERVENTIONPatients receiving dipyrone for the treatment of fever or pain were asked to participate in the study. Pharmacokinetics and statistical analysis: Using the population approach based on a formerly developed experimental model, the relationships between pharmacokinetic parameters and demographic and physiological covariates are explored.RESULTSThe results of the analysis show considerable variability in pharmacokinetics across the study population, and a significant decrease in clearance with age.CONCLUSIONA population pharmacokinetic analysis of MAA, the active product of dipyrone, reveals that age is a significant predictor of MAA disposition. Covariates that measure hepatic and renal function do not appear to be good predictors of the rate of MAA disposition.

AIM:To investigate the effectiveness of a computer monitoring system that detects adverse drug reactions (ADRs) by laboratory signals in gastroenterology.METHODS:A prospective, 6-month, pharmaco-epidemiological survey was carried out on a gastroenterological ward at the University Hospital Erlangen-Nuremberg. Two methods were used to identify ADRs. (i) All charts were reviewed daily by physicians and clinical pharmacists. (ii) A computer monitoring system generated a daily list of automatic laboratory signals and alerts of ADRs, including patient data and dates of events.RESULTS:One hundred and nine ADRs were detected in 474 admissions (377 patients). The computer monitoring system generated 4454 automatic laboratory signals from 39 819 laboratory parameters tested, and issued 2328 alerts, 914 (39%) of which were associated with ADRs; 574 (25%) were associated with ADR-positive admissions. Of all the alerts generated, signals of hepatotoxicity (1255), followed by coagulation disorders (407) and haematological toxicity (207), were prevalent. Correspondingly, the prevailing ADRs were concerned with the metabolic and hepato-gastrointestinal system (61). The sensitivity was 91%: 69 of 76 ADR-positive patients were indicated by an alert. The specificity of alerts was increased from 23% to 76% after implementation of an automatic laboratory signal trend monitoring algorithm.CONCLUSION:This study shows that a computer monitoring system is a useful tool for the systematic and automated detection of ADRs in gastroenterological patients.

Background. Recent studies show that nearly half of the hospitalized patients are readmitted within 6 months from discharge. No data exist about the relationship between adverse drug reactions (ADRs) and readmittance to a department of internal medicine.Objectives. The primary aims of the study were to determine if ADRs could be used as predictors for recurrent hospitalizations in internal medicine and to evaluate the economic impact of ADRs on hospitalization costs.Design and setting. A cohort-based, prospective, 18-month pharmacoepidemiological survey was conducted in the Department I of Internal Medicine at the University Hospital of Erlangen. All patients were intensively monitored for ADRs by a pharmacoepidemiological team. ADRs were evaluated for their offending drugs, probability, severity, preventability and classified by WHO-ART. During a 6-month period ADR-positive patients were matched to non-ADR patients applying diagnosis-related group categorization in order to measure the impact of ADRs on the duration and frequency of hospitalization.Results. Of 1000 admissions 424 patients had single admissions and 206 patients had recurrent readmissions (min 1, max 9). The prevalence of readmissions was 37% (n = 370). In 145 (23%) of 630 patients, 305 ADRs were observed. The ADR incidence was similar in first admissions and readmissions. ADRs were not found to predict further readmissions and lack of ADRs did not preclude readmissions. ADRs caused hospitalizations in 6.2% of first admissions and in 4.2% of readmissions. According to the Schumock algorithm 135 (44.3%) ADRs were found to be preventable. The occurrence and numbers of ADRs per admission were found to prolong hospitalization period significantly (r = 0.48 and 0.51, P < 0.001, n = 135). Of 9107 treatment days 20% were caused by in-house (1130 days) and community-acquired ADRs (669 days). In admissions and readmissions 11% (>973 days) of all treatment days were judged to be preventable.Conclusions. Intensified drug monitoring supported by information technology in internal medicine is essential for early detecting and prevention of ADRs and saving hospital resources.

AIMS:To estimate the frequency of adverse drug reactions (ADRs) identified through the use of automatic signals generated from laboratory data (ALS) in hospitalised patients. To determine the frequency of spontaneous recognition of these ADRs by the attending physicians and to assess the potential value of ALS for detection of ADRs.METHODS:Laboratory results of patients hospitalised in a nine bed medical ward were automatically recorded over a period of 17 months. Values exceeding defined boundaries were used as ALS. Charts of every third patient were analysed retrospectively with regard to adverse drug related reactions and causality was evaluated as well as whether the ADR had been recognised during the period of hospitalisation.RESULTS:The charts and ALS of 98 patients were analysed. In 18 cases a drug-related adverse reaction was probable. Awareness to the reaction by the treating physicians was evident in 6 out of these 18 ADRs. Approximately 80% of the ADRs were considered predictable. Three ADRs were regarded as serious.CONCLUSIONS:Adverse drug reactions are common and often preventable. Only one third of ADRs which could have been detected through ALS were recognised by the attending physicians. An increased doctor's awareness of the frequency of drug related abnormal laboratory results by means of ALS is likely to increase the recognition rate of ADRs and might help to prevent them.

OBJECTIVE:To implement and measure the effects of automatic computerized laboratory signals (ALS) as a detection support tool of adverse drug reactions (ADRs) in hospital.METHODS:This was a prospective observational study of a total of 192 patients (199 sequential medical admissions) during a 2-month period in a 34-bed medical ward at the Hadassah University Hospital, Jerusalem, Israel. The study involved the routine (daily) distribution to staff physicians of lists of automatic signals generated from computerized laboratory data as potential indicators of ADRs. Patient charts were reviewed by the clinical pharmacology team for ADRs and to see whether these were recognized by the staff physicians.RESULTS:Seventy-one ADRs were detected in 64 of the 199 (32%) admissions. Twenty-seven per cent of the ADRs were serious, 9% of the admissions were due to ADRs. Two hundred and ninety-five ALS were generated involving 69% of the admissions. Sixty-one per cent of the ADRs were identified by ALS. ALS were present in 58% of the ADR negative admissions. Eighty-five per cent of the ADRs were recognized as such and 19% of the ALS-positive ADRs were not recognized by the staff physicians.CONCLUSIONS:The routine implementation of ALS doubled the number of ADRs recognized by the physicians while patients were hospitalized in the medical ward. The use of the system appeared valid, simple and potentially cost-effective.

BACKGROUND:A large number of drugs have been shown to affect the metabolism of cyclosporin A (CSA) and, since cyclosporin is characterized by a narrow therapeutic range, the consequences of such drug interactions may often be of clinical importance.OBJECTIVE:To evaluate the effect of short-term administration of dipyrone on steady state CSA pharmacokinetics.METHODS:Six kidney- and two heart-transplanted patients on chronic CSA therapy participated in this study, which consisted of two 4-day study periods separated by 3-week washout periods. The patients received, in addition to their usual drugs, dipyrone 500 mg or placebo t.i.d., as identical-looking tablets, and the order of administration was randomized. CSA concentrations were measured in whole blood by means of radio-immunoassay (CYCLO-Trac SP) daily during the study periods and periodically over 24 h on the fourth study day.RESULTS:CSA concentrations over time were reduced after dipyrone (ANOVA, P < 0.01), but statistical significance was noted only at 2, 4, 5 and 10 h after drug intake (P < 0.05). Peak CSA concentration was not altered by dipyrone, but the time required to reach maximal concentration was longer with dipyrone treatment than with the placebo (3.8 +/- 2.6 h vs 2.1 +/- 0.6 h, P < 0.05). No consistent changes were noted for CSA trough level, elimination half-life and area under the concentration-time curve from 0 h to 12 h. Separate analysis of the kidney transplanted patients yielded similar results.CONCLUSIONS:Short-term administration of dipyrone is associated with a mild decrease in CSA blood concentration, which is most prominent in the first few hours after drug intake. In practice, no dose adjustment of CSA seems to be indicated during a short course of dipyrone treatment.

Familial Mediterranean fever (FMF; recurrent polyserositis, periodic disease) is an autosomal recessive hereditary disease which primarily affects populations surrounding the Mediterranean basin. It is characterised by recurrent attacks of fever and peritonitis, pleuritis, arthritis, or erysipelas-like skin disease.

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Objective: The object of this study was to evaluate the time course of thromboxane B-2 and prostaglandin E-2 concentrations in cerebrospinal fluid after oral administration of dipyrone (INN, metamizole),Methods: A single 1.0 gn oral dose of dipyrone was given to consenting patients undergoing elective diagnostic lumbar puncture 0,5, 1, 1.5, 2, 4, 6, 8, or 12 hours before the tap.Results: For thromboxane B-2 a time decrease in cerebrospinal fluid concentration was apparent. In contrast, for prostaglandin E-2 cerebrospinal fluid levels no consistent trend was observed.Conclusions: A time-related decrease in cerebrospinal fluid thromboxane B-2 level was noted in patients receiving dipyrone, Thirty minutes after dipyrone intake cerebrospinal fluid thromboxane B-2 levels already tended to be lower than those seen in patients with neurologic diseases who were not receiving dipyrone, These results are consistent with the hypothesis that dipyrone acts in the central nervous system by inhibition of particular prostanoids.

OBJECTIVE:Dipyrone is a veteran analgesic and antipyretic drug. After oral administration it is rapidly converted by hydrolysis to 4-methylaminoantipyrine (MAA), which is further metabolized to 4-formylaminoantipyrine (FAA), 4-aminoantipyrine (AA) and 4-acetylaminoantipyrine (AAA). It is still debated whether the site of dipyrone action is in the central nervous system or in the periphery. The purpose of this study was to assess whether dipyrone metabolites cross the blood-brain barrier (BBB) when administered systemically.METHODS:Twenty-eight patients undergoing diagnostic lumbar puncture (LP) were randomly assigned to receive two 0.5-g dipyrone tablets either 30 min, 1, 1.5, 2, 4, 6, 8 h or 12 h before the lumbar tap. A 5-ml blood sample was drawn concomitantly.RESULTS:All four metabolites were found in the cerebrospinal fluid (CSF). Their appearance in the CSF lagged but followed that found in the plasma. Mean CSF/plasma ratios were 0.40 (for samples taken between 0.5-2 h) and 0.83 (for samples taken between 4-12 h) for MAA, 0.62 for AA, 0.55 for FAA and 0.40 for AAA (for all samples). Significant correlation was found between plasma and CSF concentrations for MAA, AA, FAA and AAA.CONCLUSION:The concentration-time course of dipyrone metabolite CSF concentrations are in agreement with that of their plasma concentrations and the analgesic effect of dipyrone.

Colchicine is an alkaloid drug commonly used in familial Mediterranean fever (FMF), gout, Behcet's syndrome, psoriasis and Sweet's syndrome. The exact mechanism of its action in these diseases is not entirely known. However, it has been shown that colchicine may inhibit neutrophil chemotaxis, thereby decreasing the inflammatory process. Recently, it was shown that colchicine accumulates in neutrophils in higher concentrations than in lymphomonocytes. Studies dealing with the multiple drug resistance (MDR) issue disclosed that neutrophils lack the P-glycoprotein (P-gly) membranal pump (encoded by the MDR1 gene). We propose that the preferential accumulation of colchicine in neutrophils compared with lymphomonocytes is due to the absence of the P-gly efflux pump in the former. This may explain the effectiveness of colchicine in diseases where increased chemotaxis is evident. The hypothesis may also provide an explanation for FMF patients who do not respond to the drug.

OBJECTIVE To clarify whether colchicine is excreted in breast milk, and to compare its concentrations in the serum and breast milk of lactating women who have familial Mediterranean fever (FMF). METHODS Using a specific radioimmunoassay, we determined colchicine concentrations in the serum and breast milk of 4 patients at various time points, following oral administration of the drug. The study evaluated 4 patients with FMF who had been taking colchicine on a long-term basis. RESULTS Colchicine was found to be excreted in breast milk. Its levels ranged between 1.9 and 8.6 ng/ml, which were similar to those found in the serum (parallel concentration time curves). However, there appeared to be a considerable variation in colchicine milk concentration among the different patients, which might be related to individual breast milk composition and, possibly, to other nutritional or metabolic factors. CONCLUSION The extensive peripheral tissue binding and relatively low concentration of colchicine in breast milk suggests that the amount ingested by the infant is small. Furthermore, based on our clinical experience, nursing appears to be safe for lactating women with FMF who continue to take colchicine.

Following an overnight fast and 2 days of abstention from caffeine, a single 1.0-g oral dose of antipyrine was administered to 20 obese but otherwise healthy subjects (group A) and 11 healthy volunteers (group B). Weight, Body Mass Index (BMI) and % of Ideal Body Weight (IBW) were significantly greater in the obese than in the lean group. (Mean 110.4 vs 62.7 kg; 38.5 vs 22.3 kg · m−2 and 181vs 106 % respectively). In a subgroup of 6 obese subjects (group C) antipyrine was given again 11.3 months later after a 29.8 kg mean weight loss.

OBJECTIVE:To compare carbamazepine pharmacokinetic parameters between obese and lean subjects following the administration of a single 200-mg tablet.DESIGN:Single-dose intervention, open study.SETTING:Teaching university hospital.SUBJECTS:Eighteen obese (group A) otherwise healthy subjects, referred to the metabolic outpatient clinic, and 13 healthy lean (group B) volunteers. Inclusion criterion for the obese subjects was a body mass index (BMI = weight/height2) of more than 30 kg/m2. In the obese group, mean +/- SD total body weight (TBW), BMI, and percent of ideal body weight (IBW) were 111.4 +/- 19.9 kg, 38.8 +/- 6.0 kg/m2, and 182.7% +/- 30.7%, respectively. These values were significantly greater than the respective values of 63.2 +/- 8.3 kg, 22.4 +/- 1.6 kg/m2, and 105.8% +/- 5.8% obtained in the lean group (p < 0.001).INTERVENTION:Single-dose oral administration of carbamazepine 200-mg tablet (Teril, Taro, Israel).OUTCOMES:Carbamazepine elimination half-life (t1/2), apparent volume of distribution (Varea/F), and its oral clearance (Clpo/F) were derived from the drug concentration-time curves.RESULTS:Carbamazepine Varea/F and t1/2 were significantly greater in group A than in group B (98.4 +/- 26.9 vs. 60.7 +/- 8.5 L, respectively, p < 0.001; and 59.4 +/- 14.7 vs. 31.0 +/- 5.0 h, respectively, p < 0.001), but its Clpo/F was reduced only slightly in obese as compared with lean subjects (19.8 +/- 5.2 vs. 23.0 +/- 4.6 mL/min, respectively, p = 0.07). Correction for IBW yielded similar results for Varea/F and t1/2, but Clpo/F per kg of IBW was significantly smaller in the obese than in the lean subjects (0.32 +/- 0.07 vs. 0.39 +/- 0.06 mL/min/kg of IBW, respectively, p < 0.02). Linear correlations were observed between Varea/F and TBW for both group A (r = 0.92, p < 0.001) and group B (r = 0.77, p < 0.002).CONCLUSIONS:In comparison with lean subjects, carbamazepine Varea/F is significantly greater in obese subjects and its t1/2 is markedly prolonged. The minor nonsignificant effect of obesity on carbamazepine Clpo/F suggests that in obese subjects the carbamazepine daily dose should be based on IBW, not on TBW.

OBJECTIVES To compare caffeine pharmacokinetics (200 mg single oral dose) between obese and lean subjects and in obese subjects prior to and following weight reduction. In the obese group antipyrine (1000 mg single oral dose) pharmacokinetics were also evaluated one week before caffeine administration. SETTING Teaching university hospital. DESIGN Single dose, open study. SUBJECTS Twenty obese subjects (Group A) (BMI exceeding 30 kg/m2), referred from the outpatient metabolic clinic and 14 lean (Group B) subjects participated in the study. Weight (mean +/- s.d.) and BMI were significantly greater in the obese than the lean subjects (110.4 +/- 19.2 vs 66.9 +/- 13.3 kg respectively, and 38.5 +/- 5.8 vs 22.6 +/- 1.7 kg/m2 respectively, P < 0.001). INTERVENTIONS Single dose oral administration of caffeine (200 mg) and antipyrine (1000 mg) in Group A and only caffeine in Group B. Twice single dose oral administrations of caffeine (200 mg) in six subjects (Group C), prior to and following weight loss. MAIN OUTCOME MEASURES Caffeine and antipyrine pharmacokinetics were derived from the plasma concentrations-time curves. RESULTS Caffeine elimination half-life (T1/2) and clearance (CLo) were similar in obese and lean subjects (6.54 +/- 2.85 vs 6.08 +/- 2.23 h respectively and 100.7 +/- 49.5 vs 82.6 +/- 34.0 ml/min respectively, P > 0.05). Caffeine Varea was greater in group A than in Group B (48.3 +/- 11.4 vs 40.1 +/- 13.0 L respectively, P = 0.06) but when corrected for body weight significantly reduced values were obtained in the obese group (0.44 +/- 0.06 vs 0.59 +/- 0.10 L/kg respectively, P < 0.001). In group A subjects caffeine and antipyrine Varea were similar (48.3 +/- 11.4 vs 49.9 +/- 9.3 L respectively, P > 0.3). Caffeine T1/2 and CLo were not significantly altered by the 30.2 +/- 12.3 kg weight loss obtained in Group C subjects, but caffeine Varea was significantly reduced (55.6 +/- 9.3 L before, 47.8 +/- 9.5 L after, P < 0.04) and Varea corrected for body weight was significantly increased (0.46 +/- 0.03 L/kg before, 0.52 +/- 0.05 L/kg after, P < 0.05). CONCLUSIONS Caffeine pharmacokinetics are only minimally altered by obesity. The use of caffeine containing drugs in obese subjects does not necessitate significant dosage modification.

Plasma and saliva pharmacokinetics of dipyrone (CAS 5907-38-0) metabolites, 4-methylaminoantipyrine (MAA), 4-aminoantipyrine (AA), 4-formylaminoantipyrine (FAA) and 4-acetylaminoantipyrine (AAA), has been studied in 10 healthy volunteers, after oral administration of 1.0 g dipyrone, MAA, AA, FAA and AAA saliva concentrations correlated significantly with the respective plasma concentrations (r = 0.81, r = 0.62, r = 0.83 and r = 0.91, p < 0.001). MAA and AA concentrations in saliva were lower than in plasma while the FAA and AAA saliva concentrations were similar to the respective plasma concentrations. The saliva/plasma concentration ratios were highly dependent on sampling time. The elimination half-life of the final metabolites FAA and AAA can be equally evaluated from plasma and saliva data. For MAA, plasma and saliva t1/2 values were significantly correlated despite a substantial intra-subject difference. No correlation was found for AA plasma and saliva derived pharmacokinetic parameters. Similar to the plasma AAA/AA ratio, the saliva AAA/AA ratio in spot sample 6 h following oral dose might be proven to be a reliable discriminatory index for acetylation phenotyping.

The general objective of this study was to evaluate the risks of agranulocytosis and aplastic anemia in relation to drug use. Other potential risk factors, including history of infectious mononucleosis, were also evaluated. In an international populationbased case-control study, cases of agranulocytosis and aplastic anemia and controls, who were patients with selected diagnoses, were identified from the same hospitals. Information on drug use was obtained in a structured interview. Limited information on environmental exposures and on selected items of medical history, including infectious mononucleosis, was also recorded. The possible effects of these factors on the risk of the two blood dyscrasias were evaluated. Relative risks were estimated by stratified analysis and by multiple logistic regression. Among 319 cases of arganulocytosis, 12 patients (4%) gave a history of infectious mononucleosis at least 1 year previously; among 2180 controls the corresponding number was 11 (0.5%) (multivariate relative risk estimate, 6.2; 95% confidence interval, 2.3–17). A nonsignificant elevation in the relative risk was observed for aplastic anemia. The data suggest that infectious mononucleosis may confer a long-term increase in the risk of agranulocytosis. However, the association was an unexpected one, identified in the course of multiple comparisons, and it must be independently confirmed.