Development of a computerised alert system, ADEAS, to identify patients at risk for an adverse drug event.

INTRODUCTION: Adverse drug events (ADEs) are frequent and pose an important risk for patients treated with drugs. Fortunately, a substantial part of ADEs is preventable, and computerised physician order entry with a sophisticated clinical decision support system may be used to reach this goal. OBJECTIVE: To develop a new automated system that could improve the quality of medication surveillance. The system should focus on detecting patients at risk for an ADE by combining data from the hospital information system and computerised physician order entry (drug prescription data, drug-drug interaction alerts, clinical chemical laboratory parameters, demographic features), using clinical rules. METHODS: The clinical rules were formulated in a multidisciplinary team, based on seven risk categories. The new system was composed in a guideline-based decision support framework consisting of both a guideline development module and a decision support module. A total of 121 clinical rules were built into the system. Validation of the system and a proof of principle test were performed. RESULTS: The adverse drug event alerting system (ADEAS) was developed and validated successfully. The proof of principle test showed that ADEAS has potential clinical usefulness. ADEAS generated alerts and detected additional potential risk situations, which were not generated by the conventional medication surveillance. CONCLUSION: We developed a pharmacy decision support system ADEAS that focuses on the detection of situations prone to lead to an ADE and might help clinicians to take timely corrective interventions and thereby can prevent patient harm.

The tolerability and efficacy of low-dose simvastatin in statin-intolerant patients.

BACKGROUND/AIM: Statin intolerance is increasingly recognized as a therapy limiting factor in the primary and secondary prevention of cardiovascular disease. Since vulnerability to dose related adverse events differ between subjects treated with statins we hypothesized low-dose simvastatin would be tolerated and effective in statin-intolerant patients. METHOD: A single center open label prospective observational study was performed assessing tolerability and efficacy of low-dose simvastatin treatment in 35 statin-intolerant patients. Statin intolerance was defined as not being able to tolerate a registered dose statin due to myalgia-myopathy, myositis, or elevation of serum liver enzyme levels. These statin-intolerant patients were treated with simvastatin with an initial dose of 2.5mg every other day. The dose was titrated upwards if possible. Tolerability was defined as remaining on treatment. Efficacy was defined as change of LDL-cholesterol compared to baseline. RESULTS: The reached simvastatin dose ranged from 0.825 to 8.75mg/day with a mean dose of 4mg/day. Fifty-seven percent of the patients tolerated low-dose therapy and remained on treatment. Of these patients, 30% noted recurrent myalgia. Low-dose simvastatin significantly decreased mean(SD) LDL-cholesterol levels with 25.9(12.1)% (p<0.001). Eleven percent of the patients reached LDL-cholesterol target levels (<2.6mmol/l) in an intention to treat analysis and in 20% of patients that tolerated low-dose simvastatin. CONCLUSION: Low-dose simvastatin therapy is tolerated in a considerable proportion of statin-intolerant patients with significant lipid lowering efficacy. Low-dose statin therapy can be considered in multidrug regimens in statin-intolerant patients.

Intrathecal baclofen for dystonia of complex regional pain syndrome.

Dystonia in complex regional pain syndrome (CRPS) responds poorly to treatment. Intrathecal baclofen (ITB) may improve this type of dystonia, but information on its efficacy and safety is limited. A single-blind, placebo-run-in, dose-escalation study was carried out in 42 CRPS patients to evaluate whether dystonia responds to ITB. Thirty-six of the 38 patients, who met the responder criteria received a pump for continuous ITB administration, and were followed up for 12 months to assess long-term efficacy and safety (open-label study). Primary outcome measures were global dystonia severity (both studies) and dystonia-related functional limitations (open-label study). The dose-escalation study showed a dose-effect of baclofen on dystonia severity in 31 patients in doses up to 450 microg/day. One patient did not respond to treatment in the dose-escalation study and three patients dropped out. Thirty-six patients entered the open-label study. Intention-to-treat analysis revealed a substantial improvement in patient and assessor-rated dystonia scores, pain, disability and quality-of-life (Qol) at 12 months. The response in the dose-escalation study did not predict the response to ITB in the open-label study. Eighty-nine adverse events occurred in 26 patients and were related to baclofen (n=19), pump/catheter system defects (n=52), or could not be specified (n=18). The pump was explanted in six patients during the follow-up phase. Dystonia, pain, disability and Qol all improved on ITB and remained efficacious over a period of one year. However, ITB is associated with a high complication rate in this patient group, and methods to improve patient selection and catheter-pump integrity are warranted.

Intravenous busulfan in children prior to stem cell transplantation: study of pharmacokinetics in association with early clinical outcome and toxicity.

We studied the pharmacokinetics of intravenous busulfan (Bu) in children in order to further optimize intravenous Bu dosing in relation to toxicity and survival. A total of 31 children undergoing Bu-based conditioning for allogeneic SCT were enrolled in a study. The starting dose was 1.0 mg/kg (age < 4 years) and 0.8 mg/kg (age > or =4 years), four doses per day during 4 days. Dose adjustment was allowed up to a maximum dose of 1.0 mg/kg per dose if the target area under the serum concentration-time curve (AUC) was not reached. Pharmacokinetic studies were performed after the first dose. Donor engraftment was established in 28 out of 31 patients. The average AUC after the first dose was the same in children < 4 years as in children > or =4 years. Mean clearance was higher in children < 4 years than in children > or =4 years. In 35% of all patients, total AUC was within the target AUC. The other children's AUCs were below the target range. No relationships were found between systemic exposure to Bu and toxicity or clinical outcome. We concluded that, in accordance with previous data, within the observed AUCs no clear relationship was observed between Bu AUC and outcome with respect to toxicity, engraftment and relapse.

The sugar absorption test in the evaluation of the gastrointestinal intolerance to bisphosphonates: studies with oral pamidronate.

UNLABELLED: RATIONALE AND AIMS Some bisphosphonates induce gastrointestinal side effects, but the localization in the gastrointestinal tract and the underlying mechanism are unknown. The feasibility of the sugar absorption test was investigated to assess the gastrointestinal effects of oral enteric-coated pamidronate. The sugar absorption test measures the urinary excretion of lactulose, mannitol, and sucrose after oral intake. Increases in the lactulose/mannitol ratio and sucrose excretion indicate increased small intestinal permeability and gastroduodenal disease, respectively. SUBJECTS AND METHODS: Twelve volunteers (5 women and 7 men) participated in a randomized, double-blind, 4-way crossover study. The sugar absorption test was performed 2 hours after the final drug intake following a 3-day course of enteric-coated pamidronate (300 mg daily), placebo, or acetylsalicylic acid (3 g daily). The lactulose/mannitol ratio and sucrose excretion were measured in urine collected for 5 hours after ingestion of the solution. The fourth treatment consisted of intravenous administration of pamidronate. Treatment comparison was with paired t tests after log-transformation. RESULTS: The lactulose/mannitol ratio after pamidronate and acetylsalicylic acid administration was 54% and 118% higher than that after placebo (95% confidence intervals [CI], +8%, +119%, and +69%, +182%). The lactulose/mannitol ratio after pamidronate administration was 29% lower (95% CI, -54%, +3%) than that after acetylsalicylic acid. Compared with placebo the sucrose excretion was 290% higher after acetylsalicylic acid (95% CI, +46%, +518%) but only 8% higher after pamidronate (95% CI, -41%, +97%). The absorption of pamidronate was below 1%, and there was no relationship with the increased lactulose/mannitol ratio. CONCLUSION: Oral enteric-coated pamidronate increases intestinal but not gastroduodenal permeability. There was no relationship between intestinal permeability and absorption of pamidronate. It appears that the sugar absorption test is an appropriate, noninvasive method for evaluation of gastrointestinal effects of bisphosphonates in humans.

Effect of oral L-arginine on airway hyperresponsiveness to histamine in asthma.

BACKGROUND: Nitric oxide (NO) may exert protective properties within the airways of asthmatic patients. It was postulated that airways obstruction in asthma may be associated with endogenous NO deficiency caused by limited availability of NO synthase substrate. METHODS: In a double blind, crossover study 14 asthmatic patients received pretreatment with oral L-arginine (50 mg/kg body weight) or placebo prior to histamine challenge. Histamine challenge was performed until a 50% fall in forced expiratory volume in one second (FEV(1)) occurred and the response was expressed as the provocative concentration causing a 20% fall in FEV(1) (PC(20)) and as the dose-response slope (maximal % fall in FEV(1)/cumulative dose (micromol)). RESULTS: Pretreatment with L-arginine did not affect PC(20) histamine (mean change in doubling dose 0.18 (95% confidence interval (CI) -0.36 to 0.71), p = 0.5) but the dose-response slope to histamine was slightly reduced (mean change: 0.7 (95% CI 0.6 to 0. 9), p = 0.016). CONCLUSIONS: Oral L-arginine does not influence airway hyperresponsiveness to histamine as reflected by PC(20), although the dose-response slope is slightly reduced in patients with asthma. This indicates only marginal, clinically unimportant limitation of NO synthase substrate in asthma.

The effects of nitrogen-containing bisphosphonates on human epithelial (Caco-2) cells, an in vitro model for intestinal epithelium.

Nitrogen-containing bisphosphonates (N-PCP) are bisphosphonates with an increased antiresorptive potency. Aminobisphosphonates, N-PCPs with an amino group, can cause nonspecific gastrointestinal complaints. It is not known whether these side effects are specific for these bisphosphonates or for the whole class of N-PCPs. In this study, we investigated the effects of two aminobisphosphonates (pamidronate and alendronate) and a structurally similar N-PCP (olpadronate) and their three respective calcium complexes on the viability and the intracellular calcium concentration ([Ca2+]i) of cultured Caco-2 cells a model for intestinal epithelium. These cells were also examined for apoptosis or necrosis. In the presence of calcium, pamidronate and alendronate were toxic to the cells, with pamidronate being more toxic than alendronate. Olpadronate induced toxicity only at concentrations more than ten times higher than the toxic concentrations of pamidronate. In the absence of calcium definite signs of toxicity were observed only with pamidronate at clinically relevant concentrations. The complexes of pamidronate and alendronate with calcium were considerably less soluble than the olpadronate calcium complex. There were no signs of apoptosis. [Ca2+]i was transiently raised after treatment with the N-PCPs. Doses at which responses were seen were, respectively, 0.02 mM (pamidronate), 0.3 mM (alendronate), and 2 mM (olpadronate). The peak of response was slightly greater after pamidronate treatment than after alendronate or olpadronate, respectively. In conclusion pamidronate, either as an ion or as a calcium complex, is the most toxic of the bisphosphonates tested for Caco-2 cells. Alendronate was less toxic while olpadronate was the least toxic in presence of calcium. The solubility of the bisphosphonate complexes with calcium may account for these differences in toxicity.

Bisphosphonates in bone diseases.

Bisphosphonates are a class of drugs which are strongly attracted to the bone where they influence the calcium metabolism, mainly by inhibition of the osteoclast-mediated bone resorption. This property makes these compounds suited for the treatment of several diseases of the bone. In Paget's disease, several bisphosphonates can reduce bone pain and decrease the bone turnover 60-70%. Cyclical oral etidronate and daily oral alendronate both proved to reduce the vertebral fracture rate for postmenopausal osteoporotic woman, while most investigated bisphosphonates can increase spinal bone mass in osteoporosis. Bisphosphonates can help lowering serum calcium and reverse skeletal complications in malignancy mediated bone diseases. Oral and intravenous administration of therapeutic doses is relatively safe. In general, gastrointestinal disturbances are described most often and the oldest, least potent, bisphosphonate etidronate can induce osteomalacia. The various characteristics of bisphosphonates: physicochemical, biological, therapeutic and toxicological, vary greatly depending on the structure of the individual bisphosphonate. Even small changes in the structure can lead to enormous differences in potency. Overall, this class of drugs offers several prospects for the future.

Exhaled nitric oxide (NO) is reduced shortly after bronchoconstriction to direct and indirect stimuli in asthma.

Exhaled NO is increased in patients with asthma and may reflect disease severity. We examined whether the level of exhaled NO is related to the degree of airway obstruction induced by direct and indirect stimuli in asthma. Therefore, we measured exhaled NO levels before and during recovery from histamine and hypertonic saline (HS) challenge (Protocol 1) or histamine, adenosine 5'-monophosphate (AMP), and isotonic saline (IS) challenge (Protocol 2) in 11 and in nine patients with mild to moderate asthma, respectively. The challenges were randomized with a 2-d interval. Exhaled NO and FEV1 were measured before and at 4, 10, 20, and 30 min after each challenge. NO was measured during a slow VC maneuver with a constant expiratory flow of (0.05 x FVC)/s against a resistance of 1 to 2 cm H2O. Baseline exhaled NO levels were not significantly different between study days in Protocol 1 (mean +/- SD: 4.8 +/- 1.8 ppb [histamine] versus 5.4 +/- 2.1 ppb [HS], p = 0.4) or in Protocol 2 (7.9 +/- 4.7 ppb [histamine], 8.3 +/- 5.2 ppb [AMP], and 7.2 +/- 3.7 ppb [IS], p = 0.7). A significant reduction in exhaled NO was observed directly after HS (mean +/- SEM: 39.2 +/- 3.9 %fall) and AMP challenge (32.3 +/- 7.3 %fall) (MANOVA, p < 0.001), respectively, whereas exhaled NO levels tended to decrease after histamine challenge. Isotonic saline challenge did not induce changes in exhaled NO (p = 0.7). There was a positive correlation between %fall in FEV1 and the %fall in exhaled NO after histamine, HS, and AMP challenge as indicated by the mean slope of the within-subject regression lines (p <= 0.04). We conclude that acute bronchoconstriction, as induced by direct and indirect stimuli, is associated with a reduction in exhaled NO levels in asthmatic subjects. This suggests that airway caliber should be taken into account when monitoring exhaled NO in asthma.

Cytotoxic effects of pamidronate on monolayers of human intestinal epithelial (Caco-2) cells and its epithelial transport.

Pamidronate (APD) is a new drug in the treatment of osteolytic bone diseases. Caco-2 cells were used to study the cytotoxic effects of APD on intestinal epithelium and also the transport (mechanism) of APD across the intestinal epithelium. We investigated the cytotoxic effect of APD by combining two spectrophotometric assays [neutral red (NR) uptake and lactate dehydrogenase (LDH) release] with a morphological assay (electron microscopy). The amount of APD transported across the Caco-2 monolayer was measured by HPLC. The permeability of the monolayer was studied by determining the transepithelial electrical resistance (TEER). The results show that after exposing the Caco-2 cells to increasing concentrations of APD [dose range calculated on the basis of relevance to the oral dose administered to patients] the NR uptake decreased while LDH loss increased, which is indicative of a cytotoxic effect of APD. Ultrastructural alterations, including a widening in intercellular spaces and, at higher doses, complete cell death, were observed. The transport percentage of nontoxic doses of APD was low, while the TEER decreased with increasing doses of APD. In conclusion, APD is cytotoxic for Caco-2 cells. As the transport percentage of nontoxic doses of APD is low and APD reduces the TEER, it is hypothesized that APD is transported paracellularly.

Cytotoxic effects of topical antimicrobial and antiseptic agents on human keratinocytes in vitro.

The cytotoxicity of commonly used antimicrobial and antiseptic agents to cultured human keratinocytes was investigated, combining a morphologic assay with a quantitative neutral red (NR) spectrophotometric assay. Main outcome criteria of response were the initial cytotoxicity (NR 90) and midpoint cytotoxicity (NR 50) and the highest tolerated dose (HTD), a concentration causing the first observed morphologic alterations. These values were compared with commonly administered clinical doses or calculated doses. Thirty-five agents were evaluated; five agents were also subjected to an assay for cell morphologic alterations, and HTD and percentage of cells taking up trypan blue and annihilation dose were assessed. These studies show that in clinical concentrations many, but not all, agents exert profound cytotoxic effects. The results suggest that under certain conditions cultured epithelial grafts may be exposed to clinical concentrations of neomycin, clindamycin, framycetin, erythromycin, gentamicin, and 0.1% solutions of povidone-iodine. Tetrachlorodecaoxygen anion complex (TCDO) should be further evaluated as a likely effective cleansing agent before culture grafting.

Role of microtubuli in secretion of very-low-density lipoprotein in isolated rat hepatocytes: early effects of thiol reagents.

The secretion of very-low-density lipoprotein from hepatocytes proceeds through the microtubules. In this study, the role of glutathione in the maintenance of intact microtubules and the secretion of very-low-density lipoprotein has been investigated. When rat hepatocytes were incubated with reagents that deplete glutathione (e.g., diethylmaleate, alpha-bromoisovalerylurea or allyl alcohol) or reacted directly with protein thiols (disulfiram), the secretion of very-low-density lipoprotein by the cells was inhibited and the microtubules were severely damaged as visualized by immunofluorescence staining. Both events occurred within 30 min; long before, an effect on the energy status of the cells became evident. The observed inhibition of the secretion therefore seems due to an effect of the toxicants on the microtubules. For alpha-bromoisovalerylurea, diethylmaleic acid and allyl alcohol, it may be related to glutathione depletion; preincubation of the hepatocytes with N-acetyl-L-cysteine reduced the decrease of glutathione by alpha-bromoisovalerylurea and allyl alcohol (but not of diethylmaleic acid) and almost completely prevented the inhibition of very-low-density lipoprotein secretion and microtubule damage. Depletion of glutathione may result in modification of a small group of essential free protein thiols. Disulfiram did not deplete glutathione, and N-acetyl-L-cysteine could not prevent the effects of disulfiram on microtubules. The binding to protein thiols of radiolabeled disulfiram, which binds to microtubules in vitro, was determined. At 0.2 mmol/L disulfiram, only 3% of total cellular protein thiols were conjugated, but secretion of very-low-density lipoprotein was already inhibited by 25%, and microtubules were severely affected. We propose that modification of a small fraction of cellular protein thiols results in the loss of microtubular ultrastructure and thereby leads to inhibition of very-low-density lipoprotein secretion.