Reassessment of inappropriate prescriptions of proton pump inhibitors in elderly in-patients: It's time to take action.

OBJECTIVES: To determine the impact of awareness sessions, proposed by the pharmaceutical team to the hospital physicians, on the reassessment of off-label non-hospital proton pump inhibitor prescriptions dedicated to hospitalized patients in the internal medicine department of a university hospital. METHODS: We conducted a retrospective and comparative cohort study of in-patients aged 65 years old and older with a prescription including a proton pump inhibitor. Patients who were admitted before the implementation of the awareness sessions were enrolled in the control group; others were enrolled in the awareness experimental group. The awareness sessions relating to the appropriate use of proton pump inhibitors involved a presentation about the national consensus guidelines, their side effects, the possible drug interactions with this therapeutic class, and recommendations about proton pump inhibitor discontinuation. Discussions took place around clinical cases during this multidisciplinary meeting. RESULTS: In total, 105 patients were included in the control group, and 52 in the awareness experimental group. In total, 10.8% of the non-hospital prescriptions were in accordance with the guidelines. The spontaneous reassessment of non-hospital proton pump inhibitors prescriptions was significantly higher in the experimental group (55.6%) compared to the control group (35.8%) (P=0.02). At discharge, 66.7% of the off-label non-hospital proton pump inhibitor prescriptions were reassessed in the experimental group versus 28.4% in the control group P<0.01). CONCLUSIONS: This multidisciplinary team meetings on the appropriate use of proton pump inhibitors were proved effective to improve prescription conformity to guidelines in older patients.

Implementation study of patient-ready syringes containing 25 mg/mL methotrexate solution for use in treating ectopic pregnancy.

BACKGROUND: Ectopic pregnancy (EP) is a significant cause of morbidity and mortality during the first trimester of pregnancy. Small unruptured tubal pregnancies can be treated medically with a single dose of methotrexate (MTX). OBJECTIVE: The aim of this study was to evaluate the stability of a 25 mg/mL solution of MTX to devise a secure delivery circuit for the preparation and use of this medication in the management of EP. METHOD: MTX solutions were packaged in polypropylene syringes, stored over an 84-day period, and protected from light either at +2 to +8°C or at 23°C. We assessed the physical and chemical stability of the solutions at various time points over the storage period. A pharmaceutical delivery circuit was implemented that involved the batch preparation of MTX syringes. RESULTS: We show that 25 mg/mL MTX solutions remain stable over an 84-day period under the storage conditions tested. Standard doses were prepared, ranging from 50 mg to 100 mg. The results of this study suggest that MTX syringes can be prepared in advance by the pharmacy, ready to be dispensed at any time that a diagnosis of EP is made. CONCLUSION: The high stability of a 25 mg/mL MTX solution in polypropylene syringes makes it possible to implement a flexible and cost-effective delivery circuit for ready-to-use preparations of this drug, providing 24-hour access and preventing treatment delays.

The specific PKR inhibitor C16 prevents apoptosis and IL-1ß production in an acute excitotoxic rat model with a neuroinflammatory component.

The double-stranded RNA-dependent protein kinase (PKR), an apoptotic inducer, regulates much pro-inflammatory cytokine production. The purpose of this study was to evaluate in vivo the effects of the specific PKR inhibitor C16 in the striatum in an acute excitotoxic rat model with an important neuroinflammatory component. Inflammation was induced by unilateral striatal injection of quinolinic acid (QA) in 10-week-old normotensive rats. Animals were separated into groups receiving either vehicle or C16 for both sham and QA rats. The effects were assessed in ipsi- and contralateral striata by immunoblotting for PKR activation, by Luminex assay for cytokine levels and by immunofluorescent staining for cleaved caspase-3 to detect neuronal apoptosis. The highest dose of C16 (600µg/kg; C16-2) in QA rats reduced expression of the active catalytic domain of the PKR vs. that in vehicle-injected QA rats. A robust increase of IL-1ß levels on the contralateral side of QA rats was prevented by C16-2 (97% inhibition). Macroscopic and microscopic observation of cerebral tissue (Hematoxylin & Eosin staining) revealed that tissue integrity was more preserved with C16-2 treatment than its vehicle in QA rats. Furthermore, C16-2 treatment decreased by 47% the neuronal loss and by 37% the number of positive cleaved caspase-3 neurons induced by QA injection. In conclusion, C16 prevented not only the PKR-induced neuronal loss but also the inflammatory response in this acute excitotoxic in vivo model, highlighting its promising neuroprotective properties to rescue acute brain lesions.

A stability-indicating, ion-pairing, reversed-phase liquid chromatography method for studies of daunorubicin degradation in i.v. infusion fluids.

A new stability-indicating method based on high-performance liquid chromatography coupled to ultraviolet and evaporative light scattering detection (HPLC-UV-ELSD) was developed for the quantification of daunorubicin. This is an ion-pairing, reversed-phase method. The column was a Synergi MAX-RP C12 4 µm (150 mm × 4.6 mm). The mobile phase was 6.2mM nonafluoropentanoic acid in aqueous solution and acetonitrile under isocratic elution mode. The drug was subjected to oxidation, basic and acid hydrolysis to apply stress conditions. Good resolution was achieved between daunorubicin, related products and all degradation products in an overall analytical run time of approximately 16 min with the parent compound daunorubicin eluting at approximately 8 min. The method was fully validated according to ICH guidelines and SFSTP protocols in terms of accuracy, precision, specificity and linearity. For daunorubicin, the decision criteria selected consisted of the acceptability limits (±3%) and the proportion of results within the calculated tolerance intervals (95%). In conclusion, the proposed analytical procedures were validated over the selected validation domains daunorubicin (0.25-0.45 mg/mL) and shown to provide a very effective method. Physical and chemical stability study was carried out on daunorubicin preparation in our hospital centralized pharmacy unit.

Stability of amoxicillin in portable pumps is drug concentration dependent.

Continuous amoxicillin infusion for deep infection's intravenous treatment is performed using elastomeric portable pumps carried under clothing and requires high doses of antibiotic. Therefore, we evaluated the stability of amoxicillin in those medical devices, with particular focus on both drug concentration and storage temperature. Stability of 20, 40, and 60g/L amoxicillin solutions in 300 mL portable pumps stored at 20 or 35 degrees C was studied by visual examination and drug concentration measurements at T0; T0 + 12 h; T0 + 24 h and; T0 + 48 h. Twenty and 40 g/L amoxicillin solutions were stable over 48 h, with a degradation rate that never exceeded 12% at T0 + 24 h, and 18% at T 0 + 48 h. However, the 60 g/L amoxicillin solution degradation rate was significant (p < 0.05, versus C1 and C2) at T0 + 24 h: 24.5 and 26.9% at 20 and 35 degrees C, respectively. This degradation process was amplified at T0 + 48 h, with degradation rates of 37 and 42% at 20 and 35 degrees C, respectively. Stability of amoxicillin in pump is guarantied over 48 h up to concentrations of 40 g/L. At 60 g/L major degradation of the antibiotic was observed.

Heart rate variability in rats with chronic hypoxic pulmonary hypertension.

The precise role of pulmonary hypertension as a possible factor inducing a decrease in heart rate variability is poorly known. Spectral analysis of heart rate variability (HRV) was carried out in 21 Wistar rats before and after exposure to normoxia (N = 10) or to 3 weeks of hypobaric hypoxia inducing chronic pulmonary hypertension and right ventricular hypertrophy (N= 11). Continuous ECG was recorded in conscious animal at rest. Compared to the control group, rats exposed to hypoxia had a similar heart rate but a lower overall HRV (total power, 27.9 +/- 15.2 vs. 57.6 +/- 24.7 ms2, P < 0.01). Low frequency power (0.25-0.8 Hz) and high frequency power (0.8-3 Hz) were similar in both groups suggesting that HRV was decreased in the very low frequency power (0-0.25 Hz). The effects of atropine and propranolol on heart rate and HRV were similar in rats exposed or not to hypoxia. HRV is decreased in rats with hypoxic induced pulmonary hypertension, mainly in the very low frequency band, suggesting an increase in sympathetic activity. However, this decrease is moderate and the modulation of HRV with pharmacologic autonomic blockade remains similar to that of normal rats.

[Identification and analysis of errors in prescription, preparation and administration of drugs in intensive care, medicine and surgery at the University Hospital Center of Tours]. / Identification et analyse des erreurs de prescription, de préparation et d'administration des médicaments en réanimation, médecine et chirurgie au CHU de Tours.

OBJECTIVE: Within the framework of a project to establish "the safety of drug use and the prevention of iatrogenic risks", the pharmaceutical team conducted a review on the errors in drug prescription in order to implicate the medical professionals in its development. In collaboration with the medical teams, the pharmacy organised a series of therapeutic surveys aimed at quantifying and qualifying the errors related to the prescription, preparation and administration of medicinal products. METHODS: A prospective survey was conducted in three types of care units (Medicine, surgical intensive care and paediatric vascular surgery) over a 30-day period in each unit. A resident pharmacist studied the preparations and administration of drugs and compared them to the prescriptions and recommendations of in the literature. The investigator also conducted the pharmaceutical analysis of the prescriptions (dose, drug interactions, administration timetable...). The clinical impact of the errors on the patient were scored 0 (none) to 3 (lethal) by a duo composed of an external physician and the resident physician in charge of the study on site. RESULTS: Among the 3,023 drugs prescribed, the error rate was of 0.04 [0.033; 0.047], 44% of which scored 2. The errors in preparation or administration were of 0.134 [0.117; 0.151] among the 1,632 drug administrations observed, 19% of which scored 2. Regarding errors in prescription and administration, no significant difference was revealed between the three units [p > 0.09]. DISCUSSION: This study enhanced the awareness of the nursing and medical staff and the hospital management with regards to the reality of medical errors. Our data were comparable to the results of other studies published elsewhere.

[Generalized tonic-clonic status epilepticus: therapeutic strategy]. / L'état de mal épileptique généralisé tonico-clonique: stratégie thérapeutique.

BASIC STRATEGY: Generalized tonic-clonic status epilepticus is a medical emergency requiring very rapid administration of anti-epilepsy drugs to avoid or prevent neurological damage. First intention treatment is based on rapid-action intravenous benzodiazepine (BZD) associated with another long-action anti-epilepsy drug. General anesthesia with respiratory assistance may be needed if the seizures are refractory. We considered the pharmacodynamic, pharmacokinetic and pharmacoeconomic properties of drugs proposed for the treatment of status epilepticus. TREATMENT EFFICACY: An analysis of the literature and clinical practice show that, used alone, BZDs have a rapid effect and are effective in 54 to 84% of the cases. When hydantoins are combined with BZD, cessation of seizures can be achieved in 94% of the patients compared with 82% when phenobarbital is used alone. However, the administration of hydantoins requires 15 to 30 min whereas phenobarbital is effective in 5 minutes. Irrespective of the type of BZD combined with hydantoins, no difference has been observed concerning clinical efficacy. Midazolam appears to be as effective as barbiturics. Cardiac function must be monitored when hydantoins are used although admission in an intensive care unit may not be required, unlike the situation with phenobarbital that may lead to intubation. IN CLINICAL PRACTICE: Considering non-refractory status epilepticus, a comparison of the efficacy of the proposed drugs, their side effects and their cost demonstrates a good cost/benefit ratio for phenobarbital and good tolerance for fosphenytoin. If cessation of the seizures cannot be achieved, other therapeutic strategies may have be to used: induction of barbituric coma with thiopental, general anesthesia using propofol, or midazolam or lidocaine.

Idazoxan does not prevent but worsens focal hypoxic-ischemic brain damage in neonatal Wistar rats.

We examined the neuroprotective efficacy of a post-treatment with idazoxan (Idaz): an alpha2-adrenoceptor antagonist with activity at the I1- and I2-subtypes of the imidazoline receptor (I-receptor), in an experimental model of perinatal hypoxic-ischemic (HI) brain damage. Seventy-two, 7-day-old Wistar rats were subjected to permanent unilateral ligation of the common carotid artery and transient (2 hr) hypoxia (8% O(2)). The surviving animals were sub-divided into 3 groups: one "control" group received intraperitoneal (i.p.) injection of saline (Sigma; n = 21) and two "treated" groups received, 10 min post-HI, i.p. treatments with Idaz (I3: 3 mg/kg; n = 19) or (I8: 8 mg/kg; n = 20). Idaz effects were assessed by TTC-staining 72 hr post-HI for Sigma (n = 13), I3 (n = 11), and I8 (n = 12) groups and by MRI-examination 5 weeks post-HI for Sigma (n = 8), I3 (n = 8), and I8 (n = 6) groups. Total ratio of brain infarct areas were significantly (P < 0.01) different between Sigma and Idaz-treated rats: 20.9 +/- 4.0%, 35.6 +/- 5.9 % and 36.8 +/- 5.8% for Sigma, I3 and I8, respectively, when determined with TTC-staining and; 23.3 +/- 3.7%, 39.8 +/- 4.2%, and 43.2 +/- 10.1%, for Sigma, I3, and I8, respectively, when assessed by MRI. Our results suggest that Idaz, given as a post-HI treatment, does not exert neuroprotective effects but enhances the brain injury induced by focal neonatal cerebral HI. The deleterious mechanism may result from an overactivity of sympathetic tone and/or the immaturity of central I-receptors in newborn rats.

Effects of neonatal focal cerebral hypoxia-ischemia on sleep-waking pattern, ECoG power spectra and locomotor activity in the adult rat.

The aim of this study was to determine the influence of neonatal focal cerebral hypoxia-ischemia (HI) on sleep-waking pattern, electrocorticogram (ECoG) power spectra and locomotor activity (LA) in adult Wistar rats. Seven-day old pups were subjected to permanent unilateral ligation of the common carotid artery and transient hypoxia (8% O2). At 10 weeks of age, the extent of brain damages was evaluated by magnetic resonance imaging (MRI) and homogenous injured animals were selected before chronic implantation of radiotelemetry device. Using a single ECoG recording channel method, waking (W), paradoxical sleep (PS) and slow wave sleep (SWS) were continuously recorded for 72 h and they were semi-automatically analyzed off-line. We observed that neonatal HI triggers a cascade of events leading, in adult rats, to brain dysfunction characterized by an increase in SWS (55.0 vs. 40.2% in sham-operated rats, p<0.05) and a marked decrease in W phases duration (43.4 vs. 51.5%, p<0.05) while PS was almost suppressed in HI rats (1.6 vs. 8.3%, p<0.05). In addition, power spectral analysis of ECoG revealed significant (p<0.05) alteration in PS power density with a shift of the dominant frequency peak (5.0 to 7.5 Hz for HI and sham-operated rats, respectively). During the light period, we found that HI induced a pronounced reduction of LA (-30%, p<0.05). These results indicate that Wistar rats exposed to a neonatal unilateral cerebral HI present significant ECoG activity, sleep-waking pattern and behavioral disturbances when adults. However, it remains to establish whether such alterations can be prevented by neuroprotective agents.

Influence of neonatal focal cerebral hypoxia-ischemia on cardiovascular and neurobehavioral functions in adult Wistar rats.

No experimental studies looked at the disturbances appearing after a neonatal focal cerebral hypoxia-ischemia (HI) when animals become adults. Using radiotelemetry, we examined the effects of neonatal focal cerebral HI on blood pressure (BP), heart rate (HR), locomotor activity (LA), body temperature (BT) levels and circadian rhythm parameters of unrestrained adult Wistar rats. At 15 weeks of age, we continuously recorded the cardiovascular and neurobehavioral parameters of HI (n = 6) and sham-operated (n = 6) rats. In adult rats, HI induced persistent hypertensive effects associated with alteration in BP circadian rhythms and pronounced decreases in mesor and percent rhythm of LA. HR and BT parameters were not significantly modified. Therefore, our results suggest that the rat cardiovascular and behavioural circadian control systems may involve several structures which present selective vulnerability to early cerebral HI.

Venom phospholipase A2-induced impairment of glutamate uptake: an indirect and nonselective effect related to phospholipid hydrolysis.

In a nominally calcium-free medium, a toxic phospholipase A2, paradoxin, PDX (1-200nM) was able to significantly decrease glutamate uptake by rat hippocampal mini-slices. Under the same experimental conditions, PDX could also inhibit the reuptake of choline and dopamine, suggesting a nonselective action. Furthermore, we found no evidence of competition between PDX and [3H]L-Aspartate described as a marker of glutamate carrier proteins. A direct blockage of glutamate uptake by binding to the glutamate transporters is thus unlikely to occur. Implication of the free fatty acids (FFAs), or their metabolites, was clearly shown by the total suppression of PDX effect on reuptake in a medium inhibiting its catalytic activity (EGTA/Sr2+ buffer). Moreover, analysis of the FFAs liberated showed a significant increase in polyunsaturated fatty acid (PUFA) levels. Arachidonic acid (AA) concentration reached in the water phase, though in the low micromolar range, may be especially relevant in explaining this effect. Much higher concentrations are found in the membranes and may also participate in the action on reuptake. Evidence for the involvement of FFAs was also provided by the antagonistic, although partial, action of bovine serum albumine (BSA, 1%). Finally, free radicals or eicosanoids did not seem to play a significant role given the persistence of inhibition in the presence of NDGA (1 microM) or indomethacin (10 microM), inhibitors of the two major AA metabolic pathways. Altogether, PDX-induced uptake impairment may thus be related to the direct action of AA and other PUFAs on the glutamate transporter, as well as through less selective actions.