Impact of pharmaceutical validation on prescribing errors in a neonatal intensive care unit. Randomised and controlled study.

Purpose: To compare the frequency of electronic prescription errors when the prescription was validated by the clinical pharmacist vs. when it was not. Methods: This prospective randomised controlled study was conducted in three phases. A randomised phase, in which patients were divided into control and intervention groups, and a pre- and post-intervention phase were consecutively performed to analyse the impact of pharmaceutical validation of prescriptions in a neonatal intensive care unit (NICU). This study was performed at a highly complex NICU at a tertiary hospital. All patients born during the study period who were admitted to the NICU, with a stay lasting ≥24 h, and received active pharmacological treatment were included in the study. Pharmaceutical validation was performed according to the paediatric pharmaceutical care model. A high level of validation was selected for this study. In the intervention group, discrepancies found during the review process were communicated to the medical team responsible for the patients and resolved on the same day. Results: In total, 240 patients were included in this study. Sixty-two patients were allocated to the pre-intervention (n = 38) or post-intervention (n = 24) groups, and 178 patients were randomly sorted into two groups, control (n = 82 newborns) and intervention (n = 96 newborns). During the randomisation phase, the number of prescription errors detected was significantly lower in the intervention group than that in the control group (129 vs. 270; p < 0.001). Similarly, prescription errors reaching the patient were significantly reduced from 40% (n = 108) in the control group to 1.6% (n = 2) in the intervention group. In the pre- and post-intervention periods, the prescription lines containing prescription errors decreased from 3.4% to 1.5% (p = 0.005). Conclusions: This study showed that the pharmaceutical validation process decreased both the number of errors in the electronic prescribing tools and the number of prescription errors reaching the patient.

Primary care pharmacist-led medication review in older adult patients in coordination with general practitioners: an observational retrospective cohorts study.

Background: Polypharmacy and risk of potentially inappropriate prescribing (PIP) in older adult are being continuously increased. Including a primary care pharmacist (PCP) in the healthcare team is associated with lower rates of medication-related problems (MRPs). Objectives: To determine the impact (in terms of variation of PIP, MRPs and polymedication) of treatment reviews (TR) carried out by the PCP by comparing two cohorts: standard TR vs coordinated TR with prescribing General Practitioners (GP). To assess possible health outcomes in both groups 6 months post-TR. Methods: This is an observational study of two retrospective cohorts (2018 to 2020). All patients who met the inclusion/exclusion criteria were analyzed. Patients ≥65 years, who underwent complete TR by the PCP were included. Patients in a situation of exitus at the time of TR and those who underwent a partial TR were excluded. Control group cohort consisted of patients who underwent standard TR, and intervention group cohort consisted of those who underwent TR coordinated with GP. Sociodemographic, clinical and pharmacological variables were analyzed. Results: 181 patients were enrolled. Mean age 84.4 ± 7.2 years, 78.5% women. Variables (GP-coordinated vs standard TRs) pre-post: decrease in drugs/patient 1.9 (95%CI: 1.4-2.4) vs 0.6 (95%CI: 0.2-1.3), p < 0.05; decrease in MRPs/patient 3.1 (95%CI: 2.8-3.4) vs 1.0 (95%CI: 0.6-1.4), p < 0.05; decrease in PIP/patient 2.0 (95% CI: 1.6-2.2) vs 0.6 (95% CI: 0.2-0.9), p < 0.05. Health outcomes: there was significant difference in average primary-care visits/patient 1.3 ± 0.5 vs 2.2 ± 1.8, p < 0.05. Conclusions: Multidisciplinary interventions between PCP and GP, together with a systematic approach to TR can improve the quality of pharmacotherapy in the elderly. Prospective large follow-up studies are needed to demonstrate a positive trend in health outcomes.

Medication errors in the care transition of trauma patients.

RATIONALE, AIMS, AND OBJECTIVE: Traumatological patients are vulnerable to medication error given multiple handoffs throughout the hospital since they often require rapid diagnosis and management of multiple concurrent complex conditions. The purpose of this study was to analyze the medication errors (MEs) occurring in the care transition of the traumatological patient. The secondary objectives were to classify the MEs and the level of risk of the pharmacological groups involved. In addition, the causes and contributing factors of those MEs were analyzed. METHODS: An observational, descriptive, and prospective study, spanning 4 months, was performed in a tertiary hospital. All patients admitted to the traumatology service were selected for the study. Data were collected in different locations of the hospital stay: Emergency Service, Resuscitation and Post-Anaesthesia Unit, and Traumatology Hospitalization Unit. In each location, data from the different processes (reconciliation, prescription, validation, dispensing, and administration of medicines) were collected. The medication error (ME) was established as a dependent variable. RESULTS: A total of 31.3% (132) of the patients analyzed showed some ME. The Traumatology Unit was the location where most errors were detected, followed by the Emergency Service. Having analyzed all the locations, it was observed that 64.2% (172) of the MEs were detected in the reconciliation process, 29.5% (79) in the prescription, 3.7% (10) in the dispensing, 1.5% (4) in the administration, and 1.1% (3) in the validation. In terms of risk weighting, the drugs involved in the MEs detected were 53.8% of medium risk, 20.7% of high risk, and 20.3% of low risk. CONCLUSIONS: There is a high prevalence of MEs in the reconciliation process of medication in traumatological patients (64.2%) from our hospital setting. Interestingly, most MEs occurred in this process regardless of the location in the healthcare chain.

Reversal of cytosine arabinoside (ara-C) resistance by the synergistic combination of 6-thioguanine plus ara-C plus PEG-asparaginase (TGAP) in human leukemia lines lacking or expressing p53 protein.

BACKGROUND: Sequence-specific combinations of purine analogs, such as fludarabine or 6-mercaptopurine (6-MP), administered prior to cytosine arabinoside (ara-C) have been shown to abrogate ara-C resistance in human leukemia cells in vitro and in patients with relapsed acute myeloid or lymphoblastic leukemias. The two-drug combination of 6-MP plus ara-C results in greater cytotoxicity than that achieved with either ara-C or 6-MP alone. Further preclinical investigations have shown that the addition of PEG-asparaginase (PEG-ASNase) to the combination of 6-MP plus ara-C (6-MP + ara-C + PEG-ASNase) results in 15.6-fold synergism over that achieved with the two-drug regimen. This is due to increased DNA damage leading to apoptotic cell death. PURPOSE: Since the intravenous preparation of 6-MP is no longer available and since oral 6-thioguanine (6-TG) provides higher levels of intracellular thioguanine nucleotides than an isotoxic dose of oral 6-MP, we investigated the potential drug synergism of 6-TG plus ara-C plus PEG-ASNase (TGAP) in myeloid (HL60/S, HL60/SN3, U937) and lymphoblastic (CEM/0, CEM/ ara-C/B, CEM/ara-C/I, MOLT-4) leukemia cell lines. The CEM clones, MOLT-4 and HL60/SN3 cell lines expressed functional or measurable p53 protein, while the other cell lines did not. METHODS: The MTT and trypan blue dye exclusion assays were used to determine drug cytotoxicity. In addition, cellular apoptosis and cellular p53, p21/waf-1 and bcl-2 protein concentrations were determined by FACS analysis and ELISA assays. RESULTS: Sequential exposure to 6-TG (24 h) plus ara-C (24 h) plus PEG-ASNase (24 h) produced 1.3- to 18.3-fold drug synergism over the two-drug combination of 6-TG plus ara-C. The molecular mechanism of synergism was due to the fact that the three-drug combination was capable of downregulating bcl-2 oncoprotein levels in these cell lines even when p53 was absent. CONCLUSION: These studies strongly demonstrate that the TGAP regimen is highly synergistic in p53-null and p53-expressing leukemia cell lines. We conclude that this combination regimen is collaterally sensitive with ara-C and further evaluation in an investigational phase I trial in relapsed leukemia patients is warranted.

Pharmacological modification of endogenous antioxidant enzymes by ursolic acid on tetrachloride-induced liver damage in rats and primary cultures of rat hepatocytes.

The purpose of this study was to investigate possible protective effects of ursolic acid against CCl4-induced alterations of antioxidant defence enzymes in vivo as well as its effects against CCl4-intoxication in vitro. Pre-treatment of rats with ursolic acid significantly reduced serum levels of glutamate-oxalate-transaminase and glutamate-pyruvate-transaminase previously increased by administration of CCl4. Treatment with ursolic acid also significantly reversed the decreased superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase activities and glutathione levels in the liver, as the concentration of reduced glutathione was increased and the content of oxidized glutathione decreased in ursolic acid treated groups. Levels of lipid peroxidation were higher in the CCl4 group but the increase was also reduced after drug treatment (p < 0.01 for 1, 2.5 and 5 mmol/kg). In vitro results indicated that addition to the culture medium of ursolic acid (p < 0.01 for 500 microM) resulted in a reduction of glutamate-oxalate-transaminase, lactate dehydrogenase activities and in a good survival rate for the CCl4-intoxicated hepatocytes. Ursolic acid also ameliorated lipid peroxidation in primary cultured rat hepatocytes exposed to CCl4, as demonstrated by a reduction in malondialdehyde production. Moreover, ursolic acid (50-500 microM) showed radical scavenging properties in terms of hydroxyl formation. The results obtained suggest that ursolic acid treatment can normalize the disturbed antioxidant status of rats intoxicated with CCl4 by maintaining the levels of glutathione and by inhibiting the production of malondialdehyde due to its radical scavenging properties.

Development of a double-drug-resistant human leukemia model to cytosine arabinoside and L-asparaginase: evaluation of cross-resistance to other treatment modalities.

We have developed an in vitro model of 38 T-lymphoblastic leukemia lines resistant to cytosine arabinoside (ara-C) and L-asparaginase (ASNase). Of these, 26 cell lines resistant to both drugs, 6 resistant to ara-C, and 6 resistant to ASNase were isolated. In 18 of these cell lines, all randomly selected, resistance to ara-C, ASNase and gamma radiation was documented by the MTT and trypan blue assays, as well as flow cytometry with Annexin V and propidium iodide (PI) staining. In these lines, p53, p21WAF1, and bcl-2 levels were measured by ELISA. Results show that P21WAF1 upregulation following p53 induction did not occur, suggesting that p53 function may be lost. Moreover, the data imply that upregulation of bcl-2 is critical in the development of resistance to ara-C and ASNase in these leukemic lines. In the CEM/0 parent line, p53 maintained its ability to interact with its DNA binding site as documented by the electrophoretic mobility shift assay (EMSA). But in one single- and one double-resistant leukemic cell line examined, p53 was not shown to maintain this ability. We conclude that double-resistant clones to ara-C and ASNase are refractory to both drugs, providing an excellent leukemic model to investigate the multiple-drug resistance.

Cytosine arabinoside (ara-C) resistance confers cross-resistance or collateral sensitivity to other classes of anti-leukemic drugs.

The major limitation of treatment with antimetabolite drugs is that they produce resistant clones both in vitro and in patients who either do not respond to treatment or relapse soon after response has been documented. To better understand the phenomenon of cross-resistance, we developed seven CEM/ara-C-resistant leukemic clones from the CEM/0 (wt) cell line. These clones ranged from 4- to 3.5 x 10(8)-fold more resistant to ara-C than the wt CEM/0 cell line. Using this model, we determined IC50 concentrations to several chemotherapeutic agents and gamma radiation, and we also studied pro- (p53) and anti-apoptotic (bcl-2) proteins, as well as P-glycoprotein (P-gp) and multidrug resistance related protein (MRP). The cell viability assays showed that these clones were cross-resistant to 6-thioguanine (6-TG) or 6-mercaptoguanosine (6-TGuo) from 1.1- to 8.8-fold with ara-C; cross-resistance to vincristine (VCR) was from 200- to 1 x 10(4)-fold with ara-C. Taxotere (TXR) showed cross-resistance with ara-C from 1.39- to 3.03 x 10(3)-fold; dexamethasone (DEX) also showed a significant degree of cross-resistance from 27.4- to 3.87 x 10(7)-fold. Gamma radiation treatments from 0.77 Gy to 12.3 Gy showed a radiation dose-dependent cross-resistance with ara-C from 1.43- to 2.93-fold. Idarubicin was collaterally sensitive with ara-C from 4.6- to 1 x 10(9)-fold in these cell lines. The CEM/ara-C/G resistant cell line was 3-fold more sensitive to 6-TG or VCR than CEM/0 (wt), and 5-fold more sensitive to 6-TGuo. This cell clone expressed p53 and did not overexpress bcl-2 protein. All of the cell lines studied, CEM/0 (wt) and the ara-C resistant clones, showed functional p53 protein. The cell treatment with 0.1, 1 and 10 microM ara-C for 48 hours showed increased p53 protein expression in most of these lines. No increase in bcl-2 protein expression was seen in the wt cell line after ara-C treatment for 48 hours. Three cell lines resistant to ara-C (CEM/ara-C/B, CEM/ara-C/D and CEM/ara-C/I) showed an important increased expression of bcl-2 protein after treatment with 1 microM ara-C, but not after 10 microM. This alteration may lead to resistance to apoptosis and enhanced cell survival. The ratio of bcl-2 to p53 was increased significantly in these three clones, thus favoring an anti-apoptotic drive. All of the cell lines examined were negative for MRP expression and only two, CEM/ara-C/B and CEM/ara-C/J, were positive for MRP functional activity. However, three ara-C resistant cell clones, CEM/ara-C/7A, CEM/ara-C/B and CEM/ara-C/G, were positive for P-gp expression and functional activity. It is apparent that selection for ara-C resistance confers cross-resistance to many other classes of drugs and gamma radiation, probably due to bcl-2 protein overexpression or P-gp and MRP expression, as independent mechanisms.

Effects of the antioxidant (6,7-dihydroxycoumarin) esculetin on the glutathione system and lipid peroxidation in mice.

The attempt to retard senescence by environmental manipulation includes the use of nutrients or drugs that decrease the oxidative damage to tissues associated with aging. The effects of esculetin treatment (25 mg/kg, orally for 30 days), a phenolic antioxidant compound, on the glutathione system and lipid peroxidation were examined in liver supernatants from male C57BL/6J mice. The effects of esculetin were compared to treatment with 3,5-di-terc-butyl-4-hydroxytoluene (BHT), a well-known synthetic phenolic antioxidant. Reduced glutathione (GSH) concentration in liver supernatants was only increased significantly in esculetin-treated mice compared to control animals, whereas the concentration of oxidized glutathione (GSSG) was significantly decreased by BHT treatment compared to the control group. The GSSG/GSH ratio was significantly lower in esculetin and BHT groups than in the control group. The decrease in this ratio was greater in BHT-treated mice than in esculetin-treated mice. Increases in glutathione reductase (GR) activity were observed with both treatments, although BHT resulted in a superior induction of this activity compared to esculetin. The extent of decline in the GSSG/GSH ratio was correlated with the increase in GR activity. The formation of thiobarbituric acid-reactive substances (TBARs), an index of stress, was lower following treatment with esculetin and BHT compared to control mice (although not significant). This index was very similar for both treatments. Based on the level of TBARs obtained in this study, the accumulation of lipid peroxides declines when the GSH levels are enhanced or GSSG levels are decreased. Finally, we found similar antioxidant effects in vivo with esculetin and BHT treatments and a decrease in the oxidative damage evaluated. The enhancement of glutathione status following esculetin treatment could be a possible defense strategy for the organism under 'stress conditions' and may be related to the delay of age-dependent degenerative disorders.

Determination of malonaldehyde in Alzheimer's disease: a comparative study of high-performance liquid chromatography and thiobarbituric acid test.

The concentration of malonaldehyde (MDA) was measured in human erythrocytes obtained from subjects suffering from senile dementia of the Alzheimer type (SDAT), non-demented elderly subjects, and from young controls by two methods: high-performance liquid chromatography (HPLC) and the thiobarbituric acid (TBA) test. The MDA concentration measured by HPLC showed significant differences between SDAT and young control groups (p < 0.01) and between SDAT and non-demented elderly groups (p < 0.01), respectively. Nevertheless, significant differences were not exhibited between young control and non-demented elderly. Moreover, the rate of accumulation of TBA-reactive substances was not significantly different among the three groups. Our results indicate that the HPLC method is highly specific and accurate and distinguishes between true MDA and other aldehydes that may react with TBA. Significant increases in the concentration of MDA of SDAT subjects were found in comparison with the two other groups, indicating that the measurement of MDA in erythrocytes could be used as a marker of oxidative damage in Alzheimer's disease.

Effects of fraxetin on glutathione redox status.

We have evaluated the effects of an oral treatment of mice with fraxetin (25 mg/kg for 30 days) on the glutathione system (GSH, GSSG, and GSSG/GSH ratio as stress index), glutathione reductase (GR) and glutathione peroxidase (GPx) in liver supernatants from male C57BL/6J mice (18-month old). A significant antioxidant effect in vivo was found under this treatment by a decrease in the GSSG/GSH ratio and an increased activity of GR compared with the control mice. GSSG rate and GSSG/GSH ratio were correlated with the decline of GPx++ activity. Our results of increased GR activity could be considered as a supercompensation in glutathione redox status that involves a decrease in the accumulation of GSSG, as well as, in GSSG/GSH ratio. Finally, we suggest that this possible mechanism of supercompensation could lead to an enhancement in the average life span.

Modifications on antioxidant capacity and lipid peroxidation in mice under fraxetin treatment.

Fraxetin belongs to an extensive group of natural phenolic antioxidants. We have investigated the modifications in endogenous antioxidant capacity; superoxide dismutase (SOD), catalase (CAT), total and selenium-dependent glutathione peroxidases (GPx) and glutathione reductase (GR) and stress index; glutathione disulphide (GSSG)/reduced glutathione (GSH) ratio and thiobarbituric acid-reactive substances (TBARs) in liver and brain supernatants of C57BL/6J male 12-month-old mice under fraxetin treatment for 30 days. Liver SOD and GPx (total and Se-dependent) activities were not significantly affected by fraxetin, whereas they were increased in the brain compared with control animals. GR activity increased significantly only in the liver of treated mice. Fraxetin treatment-related decreases were shown for GSSG/GSH ratio and rate of accumulation of TBARs (not significant in TBARs) in both tissues. We concluded that the net effect of fraxetin treatment on endogenous antioxidant capacity suggests that this compound might provide an important resistance to, or protection against, free-radical-mediated events which contribute to degenerative diseases of ageing.