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The main objective of this study was to analyse the minimum direct cost to the Public Health System (PHS) of diagnosing and treating those patients attended to in the emergency ward (EW) for suspected adverse drug reaction (ADR). The cases were collected during March 1995 in the emergency ward of a 900-bed tertiary teaching hospital that covers 900,000 inhabitants. ADR was considered according to the WHO definition. The following EW costs were used: EW physician visit 78.5 ecus (1 ecu=156 pesetas), thorax or abdomen radiograph 21.5 ecus, computerized tomography 112.7 ecus, endoscopy 48 ecus, specialist physician visit 62 ecus. Three types of laboratory costs were considered: block of biochemical tests 16 ecus, biochemical tests with blood count 22.5 ecus, and biochemical tests with blood count and coagulation study 41.6 ecus. Pharmacotherapy of the ADR and changes in patient's usual drug therapy due to ADR were estimated. For patients admitted in the hospital, a per day cost of 391 ecus was considered. A mean ADR cost per organ or system affected (cutaneous, metabolic, gastrointestinal, nervous) was computed. The main conclusion of this study is that ADR, apart from inflicting damage on the patients, also incur PHS costs. The quantity of 42,732 ecus during the month of March, in a single hospital, can seem small when compared with the cost of some diseases such as AIDS or ischemic heart disease. But remembering that about 40% of all ADR attended to in hospitals is avoidable, a decrease of 40% could produce an annual saving of 205,216 ecus to the hospital, which is twice the annual budget of the Pharmacovigilance Centre of the Basque Country. Pharmacovigilance centres should include cost analysis of ADR among their objectives, to provide health systems managers with enough information to implement those measures that will result in a better utilization of the scarce resources of the Public Health System., (Copyright 1999 John Wiley & Sons, Ltd.)

The effect of omeprazole (2 mg kg-1 i.v.) on respiratory depression induced in rats by acute oral methadone administration (5 mg kg-1) was examined and compared with control animals that only received methadone. Quantitative assessments of arterial Pco2,Po2, pH, and respiratory rate were employed as criteria for evaluation. Intragastric pH was measured in each rat immediately before and 2 h after methadone. Plasma concentration of methadone was measured for 3 h. The relationship between drug effect and the systemic bioavailability of methadone, measured as the area under the plasma concentration-time curve (AUC0-180), was also evaluated. The intensity of the methadone-induced respiratory depression was significantly greater in the omeprazole group than in control rats. A significant variation (p < 0.01) in all respiratory parameters was detected from 30 to 120 min after methadone. Omeprazole caused a significant increase in methadone levels (Cmax = 156 +/- 6.5 ng mL-1 against 51 +/- 5.8 ng mL-1 in control; p < 0.05). AUC0-180 was higher (p < 0.05) after omeprazole treatment (18.6 +/- 1.4 micrograms mL-1 min) than in control (6.8 +/- 0.6 microgram mL-1 min). Two hours after treatment with omeprazole, intragastric pH values were significantly elevated (4.7 +/- 0.1 against 2.2 +/- 0.04) and continued increasing, being 6.4 +/- 0.1 at the end of the experiment. Correlation was observed between intragastric pH and the area under the effect- (respiratory depression-) time curve (r = 0.74; p < 0.001). A relationship between plasma methadone levels at 120 min and gastric pH (r = 0.92; p < 0.001) was detected. A significant correlation between the area under the effect-time curve (0-120 min) and AUC0-180 has been also observed (r = 0.90; p < 0.01). These pharmacokinetic and pharmacodynamic changes could be gastric pH dependent because they were mimicked when gastric pH was experimentally modified by bicarbonate whereas opposite results were obtained with acidic pH2 solution.

The protein binding of felodipine in concentrations ranging from 3 to 65 nmol L-1 has been characterized in pooled serum, and in isolated human plasma proteins: albumin (HSA) and a1-acid glycoprotein (AAG). Protein binding was determined by an ultrafiltration technique using an Amicon Micropartition System. Serum protein binding of felodipine (16 nmol L-1) was measured in five groups of individuals: I: healthy subjects (n = 16). II: patients with chronic renal disease before and after dialysis (n = 10). III: patients with liver disease (n = 9). IV: diabetics Type I (n = 10) and Type II (n = 12) and V: cancer patients (n = 12). Concentrations of HSA, AAG, lipoproteins and non esterified fatty acids (NEFA) were also measured. The drug was extensively bound in pooled serum and the protein binding was essentially unchanged over the concentrations of felodipine studied (99.60 +/- 0.31% at 3 nmol L-1; 99.70 +/- 0.15% at 65 nmol L-1). In albumin solution (40 g L-1) felodipine was also highly bound. The mean of percentage bound was not significantly different from that in serum and was also independent of the felodipine concentrations (98.57 +/- 0.35 at 3 nmol L-1; 98.31 +/- 0.90 at 65 nmol L-1). The extent of binding to AAG was significantly lower than in serum (p < 0.01) and HSA (p < 0.01) and was independent of felodipine concentrations (85.64 +/- 2.25 at 3 nmol L-1; 85.68 +/- 2.3 at 65 nmol L-1). The percentage of bound felodipine in group II (before dialysis) was significantly lower than in group I (p < 0.001). The variability in the percentage of bound felodipine was greater in group II, before dialysis, than in the rest of the groups. After dialysis, protein binding was similar to that in group I. HSA did not change and AAG was increased. NEFA was significantly higher after dialysis when compared with group I (p < 0.01). In vitro carbamylation of serum did not change felodipine protein binding. HSA was decreased significantly in group III patients (p < 0.05). However, protein binding did not change. Binding of felodipine in the rest of the groups was not significantly different from that in group I. Linear regression analysis of the data for all individuals indicated that the binding of felodipine was related to serum lipoproteins and that age, HSA, AAG, and NEFA were not significant determinants of binding.

The pharmacokinetic and pharmacodynamic profiles of penbutolol were examined in healthy volunteers and in cancer patients using a pharmacokinetic/pharmacodynamic (pk/pd) model. After receiving a 40 mg single oral dose of penbutolol, the absorption rate constant, apparent volume of distribution and serum clearance of penbutolol were found to be reduced in the cancer group. Changes in the disposition of the conjugate metabolite were also observed in the cancer patients. Penbutolol unbound fraction in serum was statistically decreased (p < 0.005) in the cancer group, according to the increase in the serum levels of alpha 1-acid glycoprotein seen in that group (p < 0.05). The pharmacodynamic effect of penbutolol was measured as the reduction in heart rate (HR); in healthy volunteers, a linear relationship (p < 0.01) between effect and penbutolol serum concentrations (total or unbound) was found. In contrast, in cancer patients, values of HR did not vary statistically in respect to baseline values. These results show that in cancer patients, a change in the pharmacokinetics of penbutolol occurs (associated with changes in drug protein binding), together with an alteration in the pharmacodynamics.

The influence of altered protein binding on the neuromuscular effect of atracurium has been studied in rats with experimental inflammation induced by subcutaneous injection of turpentine oil. Doses of atracurium ranging from 0.45 to 1.5 mg.kg-1 were administered to control (n = 30) and to experimental inflammation induced rats (n = 30). Neuromuscular transmission was monitored by recording the twitch tension of the tibialis-anterior muscle elicited by stimulation of the sciatic nerve. Three effect parameters were recorded: (i) intensity of the effect, measured as percentage depression of baseline twitch tension, (ii) duration of drug action (min) and (iii) recovery time (min). The dose-intensity of the effect relationship was modelled using a sigmoid Emax model. The ED50 (effective dose eliciting 50% of the maximum effect) was significantly increased (P < 0.01) in the inflammation group as compared to the control group (0.94 vs. 0.68 mg.kg-1). This change was reflected in a shift of the dose-response curve to the right in the pretreated rats. For equipotent doses ED95 (defined as the effective dose eliciting 95% of maximum effect), no differences were found in recovery time and duration of action between the two groups of rats. Mucoproteins levels (index of alpha 1-acid glycoprotein (AAG) and protein binding were significantly increased in rats with experimental inflammation as compared to control rats. Based on these results, altered serum protein binding of atracurium appears to be responsible, at least in part, for the resistance to atracurium.

In a group of mice bearing experimentally induced tumors, the protein binding of mianserin in vitro was measured and compared with a control group. The analgesic effect and the brain uptake of drug was also compared with a control group after an intraperitoneal dose of mianserin. The unbound percentage of mianserin in the plasma of mice with experimental cancer decreased with respect to control animals (5.20 +/- 0.12 vs 6.06 +/- 0.26; p<0.05) and alpha1-acid glycoprotein (AAG) levels, measured as plasma mucoprotein concentrations, were significantly increased (p<0.05). The brain/plasma drug concentration ratio of mianserin decreased in mice with experimental cancer when compared with control mice (1.11 +/- 0.03 vs 1.42 +/- 0.10; p<0.02). In both groups of mice, the mianserin analgesic effect was evaluated by the hot plate test after intraperitoneal drug administration. When the analgesia response-dose curve (0-60 mg/kg) was studied, a significant decrease in the response in mice with experimental cancer versus control mice was observed. These results suggest that resistance to the mianserin analgesic response may occur in animals with cancer disease. This resistance may be associated, in part, with an altered plasma protein binding, but other mechanisms could be involved.

The effect of ascorbic acid on the availability of propranolol has been examined. After oral administration of propranolol 80 mg with or without ascorbic acid pretreatment (2 g), the plasma concentrations and urinary excretion of propranolol and its metabolites, 4-hydroxy-propranolol and propranolol-conjugated, were determined by HPLC. Compared to controls, vitamin C decreased the maximum concentration of propranolol from 463 to 334 nmol.l-1, and the area under the propranolol concentration-time curve (from 0 to 24 hours) from 3.13 to 1.96 mumol.l-1.h. The time to reach maximum propranolol concentration was increased from 1.9 to 2.7. The total amount of drug recovered in urine has also significantly diminished (from 12.6 to 4.29 mg). No change in elimination rate was observed, indicating that ascorbic acid had affected both the absorption process and the first pass metabolism. The heart-rate decreased less when propranolol was administered with ascorbic acid in comparison to control subjects, although this interaction has little biological importance.

The interaction between nimodipine, a calcium channel blocker, used for the treatment of subarachnoid haemorrhage, and atracurium, was studied in rabbits. An intravenous dose of 0.1 mg.kg-1 of nimodipine given over 3 min caused a potentiation of the neuromuscular blocking action of atracurium (administered at an infusion rate of 7.5 micrograms.kg-1.min-1), measured on the indirectly stimulated tibialis-anterior muscle of the animal. (ED50)inf and (ED95)inf were significantly reduced (30.7% and 23.3%) in nimodipine-treated animals (P less than 0.05 and P less than 0.02, respectively). No changes were observed in recovery rate.

The in vitro effect of the halothane metabolite, trifluoroacetic acid, on the protein binding of three different benzodiazepines (diazepam, lorazepam and midazolam) has been investigated. Furthermore, protein binding of these drugs was studied in serum from patients under the effect of halothane anesthesia (1-2.5%; 2.5 h). Trifluoroacetic acid, 4 mmol/l, displaced diazepam and midazolam from serum and produced a marked increase in the free percentage, but did not influence lorazepam binding. Moreover, 48 h after the end of halothane anesthesia, there were changes in protein binding of diazepam (3.9 +/- 0.3% at 48 h vs. 3.3 +/- 0.3% before halothane anesthesia; p less than 0.05). It can be concluded that halothane anesthesia (1-2.5%; 2.5 h) may temporarily potentiate the pharmacological effect of diazepam in the postoperative period following anesthetic procedures.

Penbutolol is a beta-adrenoceptor antagonist that is extensively bound to alpha 1-acid glycoprotein (alpha 1-AGP), a protein that increases in inflammatory diseases thereby binding more drug in such conditions. Changes in serum binding can lead to modifications in the pharmacokinetics and pharmacodynamics of a drug, therefore, the central effect (as the anticonvulsant response) and brain uptake of penbutolol given intravenously to mice with experimental inflammation have been measured. A significant decrease of the central effect of penbutolol and its brain uptake was seen in diseased when compared with control animals (P less than 0.01). A parallel decrease in free fraction of penbutolol in diseased vs normal animals was detected. These results suggest that there is an increase in serum binding of basic drugs related to increments in alpha 1-AGP concentration, which reduces their central pharmacological effect.

Information contained in the package inserts of drugs chosen as potential causes of blood dyscrasia, renal toxicity, hepatotoxicity, and cardiac toxicity has been studied. Chloramphenicol and pyrazolones were chosen as representatives of drugs that could produce blood dyscrasia, aminoglycosides and cephaloridine as potential nephrotoxic agents, isoniazid and monoamine oxidase inhibitors as possible hepatotoxic drugs, and tricyclic antidepressants and digitalis as drugs of recognized cardiac toxicity. Adverse effects were clearly described in only 27.8% of the package inserts, whereas 40.3% did not mention them, and 15.7% specifically stated that the product was devoid of adverse effects. Information about the type of toxicity that led to the selection of drugs included in this study was uncommon in most cases.

Serum protein binding of penbutolol, a non-cardioselective beta-blocker agent of basic nature, has been studied in healthy subjects and in patients with hepatic cirrhosis. The percentage of free penbutolol in serum containing 200 ng/ml was markedly increased in patients with hepatic cirrhosis, when compared with the group of healthy volunteers (8.17 +/- 1.13% in patients vs 3.41 +/- 0.19 in control). No significant differences in the levels of serum alpha-acid-glycoprotein (the major protein implicated in the serum binding of penbutolol) were detected. Differences in the overall affinity constant for the binding were apparent between both groups (nKa = 5.28 X 10(5) M-1 in patients vs 12.03 X 10(5) M-1 in healthy volunteers). These results suggest a qualitative change in alpha-acid-glycoprotein molecule, from hepatic patients, but further studies are needed to clarify this point.

Non-esterified fatty acids have been shown to displace diazepam from its plasma binding sites both in vitro and in vivo. However, the binding of other benzodiazepines such as lorazepam is not affected in similar situations. Flunitrazepam exhibits a substantial degree of binding to plasma proteins, therefore it was deemed interesting to investigate the role of free fatty acids on flunitrazepam binding to human plasma proteins. Incubation of plasma with sodium oleate (1.5 and 3.0 microEq per ml) produced a decrease in the binding of flunitrazepam. The free fraction increased from 4.20 +/- 0.34 to 6.30 +/- 0.53 and to 22.18 +/- 1.28% respectively). Sodium heparin administration (10IU/kg, intravenously) increased free fatty acids levels and produced similar changes in the binding of flunitrazepam. After ten minutes of heparin administration free fatty acids increased from 0.16 +/- 0.03 mEq/l to 0.34 +/- 0.01 mEq/l and the free fraction of flunitrazepam in plasma increased from 3.70 +/- 0.22% to 6.20 +/- 1.24%. These binding data further support a relationship between increases in the concentrations of free fatty acids and decreases in the fraction of flunitrazepam bound to plasma proteins.

The displacement of midazolam, a new water-soluble, short acting benzodiazepine, from its plasma binding sites by sodium valproate, has been studied in man. An increase of its free fraction (ranging from 2.71 to 5.35%) in plasma from epileptic patients receiving sodium valproate was observed. A similar situation was created in rabbits by pretreatment with sodium valproate (600 mg kg-1 day-1) and posterior hypnosis with midazolam. Due to the interaction, sodium valproate-pretreated rabbits showed an increase in midazolam brain levels (130.91 micrograms g-1 in cortex vs 84.55 micrograms g-1 in control animals). Therefore, it seems likely that displacement of midazolam by sodium valproate in epileptic patients could lead to an increase of the midazolam response.