Medication control in hospitals. A practical approach to the problem of drug‐drug interactions.

An important task of pharmacists is medication control by screening the medication of an individual patient. Many computerized drug interaction screening programs are available, but they all have their drawbacks. Screening without a computerized program is possible, but very timeconsuming. In contrast to daily living at home, the patient in a hospital setting is carefully monitored and relevant biochemical parameters are regularly checked. Many potential drug interactions are countered immediately by changing (dosage of) medication. The aim of our study was to determine the number of drugdrug interactions and (pseudo)double medications on the internal, pulmonary and cardiological ward in order to discuss them with the physicians. During this discussion the clinical relevance of interactions was determined. We conclude that the number of clinically relevant interactions and (pseudo)double medication is limited, but that the role of the pharmacist is an important one, especially with regard to medication, that is not regularly used on a ward. Potential drug interactions should be predicted and dealt with by close teamwork of physician and pharmacist at the moment medication is prescribed.     

Buprenorphine signalling is compromised at the N40D polymorphism of the human μ opioid receptor in vitro

Background and Purpose

There is significant variation in individual response to opioid drugs, which may result in inappropriate opioid therapy. Polymorphisms of the μ opioid receptor (MOP receptor) may contribute to individual variation in opioid response by affecting receptor function, and the effect may be ligand-specific. We sought to determine functional differences in MOP receptor signalling at several signalling pathways using a range of structurally distinct opioid ligands in cells expressing wild-type MOP receptors (MOPr-WT) and the commonly occurring MOP receptor variant, N40D.

Experimental Approach

MOPr-WT and MOPr-N40D were stably expressed in CHO cells and in AtT-20 cells. Assays of AC inhibition and ERK1/2 phosphorylation were performed on CHO cells, and assays of K activation were performed on AtT-20 cells. Signalling profiles for each ligand were compared between variants.

Key Results

Buprenorphine efficacy was reduced by over 50% at MOPr-N40D for AC inhibition and ERK1/2 phosphorylation. Buprenorphine potency was reduced threefold at MOPr-N40D for K channel activation. Pentazocine efficacy was reduced by 50% for G-protein-gated inwardly rectifying K channel activation at MOPr-N40D. No other differences were observed for any other ligands tested.

Conclusions and Implications

The N40D variant is present in 10–50% of the population. Buprenorphine is a commonly prescribed opioid analgesic, and many individuals do not respond to buprenorphine therapy. This study demonstrates that buprenorphine signalling to several effectors via the N40D variant of MOP receptors is impaired, and this may have important consequences in a clinical setting for individuals carrying the N40D allele.     

Pro‐cognitive activity in rats of 3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide,a positive allosteric modulator of the α7 nicotinic acetylcholine receptor

Background and Purpose

α7 nicotinic acetylcholine receptors (α7 nAChRs) may represent useful targets for cognitive improvement. The aim of this study is to compare the pro‐cognitive activity of selective α7‐nAChR ligands, including the partial agonists, DMXBA and A‐582941, as well as the positive allosteric modulator, 3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide (PAM‐2).

Experimental Approach

The attentional set‐shifting task (ASST) and the novel object recognition task (NORT) in rats, were used to evaluate the pro‐cognitive activity of each ligand [i.e., PAM‐2 (0.5, 1.0, and 2.0 mg·kg⁻¹), DMXBA and A‐582941 (0.3 and 1.0 mg·kg⁻¹)], in the absence and presence of methyllycaconitine (MLA), a selective competitive antagonist. To determine potential drug interactions, an inactive dose of PAM‐2 (0.5 mg·kg⁻¹) was co‐injected with inactive doses of either agonist ‐ DMXBA: 0.1 (NORT); 0.3 mg·kg⁻¹ (ASST) or A‐582941: 0.1 mg·kg⁻¹.

Key Results

PAM‐2, DMXBA, and A‐582941 improved cognition in a MLA‐dependent manner, indicating that the observed activities are mediated by α7 nAChRs. Interestingly, the co‐injection of inactive doses of PAM‐2 and DMXBA or A‐582941 also improved cognition, suggesting drug interactions. Moreover, PAM‐2 reversed the scopolamine‐induced NORT deficit. The electrophysiological results also support the view that PAM‐2 potentiates the α7 nAChR currents elicited by a fixed concentration (3 μM) of DMXBA with apparent EC₅₀ = 34 ± 3 μM and E_max = 225 ± 5 %.

Conclusions and Implications

Our results support the view that α7 nAChRs are involved in cognition processes and that PAM‐2 is a novel promising candidate for the treatment of cognitive disorders.

Abbreviations

α7 nAChR

nicotinic acetylcholine receptor with α7 subunit

AD

Alzheimer''s disease

apparent EC₅₀

enhancement potency

ASST

attentional set‐shifting task

CD

compound discrimination

DI

discrimination index

E

exploration time

ED

extra‐dimensional

E_max

ligand efficacy

ID

intra‐dimensional

ITI

inter‐trial interval

MLA

methyllycaconitine

NORT

novel object recognition task

n_H

Hill coefficient

PAM

positive allosteric modulator

PAM‐2

3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide

Rev

reversal of discrimination

SD

simple discrimination

T1

familiarisation trial

T2

retention trial

     

Changes to protocol in the regulation of adverse drug reactions – historical and current European view

Adverse drug reactions (ADRs) are an inevitable part of medication use. During clinical trials, limited information was gained on drug safety. After marketing authorization (MA), more safety data is available as more patients use the drug. Major changes in drug regulation came after drug disasters, like with sulphanilamide elixir or thalidomide use. In recent history, withdrawal of rofecoxib has demonstrated the importance of post-marketing safety monitoring. Subsequently, legislation on drug safety changed both in the United States (US) and in the European Union (EU), becoming simplified and more comprehensive. New EU legislation was implemented in 2012 and has broadened ADR definition to medication errors and overdoses. In the EU, the Pharmacovigilance Risk Assessment Committee (PRAC) has been formed within the European Medicines Agency (EMA), regulating all aspects of drug safety. Referral procedures enable a thorough scientific analysis on all issues of medication safety. In both the US and the EU, ADRs can be reported directly by patients. All reports of suspected ADRs are kept on electronic databases and are analyzed regularly using new technologies. New safety signals are subsequently discovered and evaluated. This author expects that the new regulations will effectively safeguard healthcare consumers from major drug risks.     

Cost‐effectiveness analysis of tropisetron vs. chlorpromazine‐dexamethasone in the control of acute emesis induced by highly emetogenic chemotherapy in children

Objective. To perform a costeffectiveness analysis (CEA) between a standard antiemetic regimen chlorpromazine + dexamethasone (CPMDEX) and a 5HT3 receptor antagonist tropisetron (TROP) in the control of acute emesis induced by highly emetogenic chemotherapy in children, considering two analytic perspectives: hospital and patients. Methods. The CEA was performed by constructing a decision tree, for both analytic perspectives, of the possible outcomes of treatment with TROP (single 0.2 mg/kg i.v.) or CPM (515 mg i.v. infusion for 3 doses) plus DEX (2 mg/m2 i.v. bolus i.v. × 2). The patients were stratified by age in two groups (212 and 1317). To estimate the probability of each endpoint at the decision tree we have taken as a base a trial developed in the Department of Pediatrics. Direct medical cost of primary therapy, failure, complications and side effects were included in the cost calculations. Results. From patients' analytic perspective, TROP was more costeffective than CPMDEX for both groups of patients. Discrepancy between both analytic perspectives in 1317 yearold patient's group was resolved in favour of the option chosen from the patients' analytic perspective (TROP). Sensitivity analysis showed the reliability of the results. Conclusions. 1. TROP was more costeffective than CPMDEX. 2. Taking into account the patients' analytic perspective is essential when we compare antiemetics pharmacoeconomically. 3. It seems necessary to increase the effectiveness of TROP in pediatric patients receiving highly emetogenic chemotherapy with strategies such as the addition of a steroid.     

Does the polymorphism of cytochrome P-450 2E1 affect the metabolism of N,N-dimethylformamide?

The aim of this study was to clarify whether phenotypic variation exists when subjects with different genotypes of cytochrome P450 2E1 (CYP2E1) are exposed to N,N-dimethylformamide (DMF). The genotypes of CYP2E1 were confirmed in 123 healthy male volunteer subjects. Of the 123 subjects, the numbers of c1 homozygotes, c2 heterozygotes, and c2 homozygotes were 77, 45, and 1, respectively. Seven of the c1 homozygotes, five of the c2 heterozygotes, and the one c2 homozygote (mean age: 22.7 years, range: 20-27 years) were exposed to DMF vapor twice, once via the skin and once via the lung, for a total of 8 h per subject at a concentration below 10 ppm, the occupational exposure limit recommended by the Japan Society for Occupational Health, the American Conference of Governmental and Industrial Hygienists, and Deutsche Forschungsgemeinschaft, at 27 degrees C and 44% relative humidity. Exposure levels were 6.2+/-1.0 ppm in dermal exposure and 7.1+/-1.0 ppm in inhalation exposure. Urine samples were collected until 72 h after exposure. The half-lives of urinary N-methylformamide (NMF) were obtained as the phenotype. The average urinary NMF half-lives of the c1 homozygotes, the c2 heterozygotes, and the c2 homozygote were 3.86+/-1.90, 4.38+/-1.53, and 4.2 h after dermal exposure, and 1.58+/-0.42, 1.84+/-0.61, and 3.2 h after respiratory exposure. The NMF half-lives of the c1 homozygotes were not significantly different from those of the c2 heterozygotes, and there were no differences between the NMF half-lives on the subjects with and without the c2 allele. Even though the data were obtained from only one c2 homozygote, it is noteworthy that the NMF half-life of this subject was slightly less than that of the c1 homozygotes after respiratory exposure.     

Evidence of carrier‐mediated transport in the penetration of donepezil into the rat brain

The objective of this study was to characterize the mechanism that controls the transport of donepezil into the brain. The apparent brain uptake clearance (CL_app,br) was decreased as a function of the dose of donepezil, suggesting an involvement of a saturable transport process via transporter(s) in the penetration across the blood–brain barrier (BBB). Consistent with in vivo results, the uptake of substrates for organic cation transporters was significantly reduced by donepezil in both MBEC4 cells (i.e., a model for BBB) and HEK 293 cells expressing the transporters found in the brain, indicative of the involvement of organic cation transporters in the transport of the drug. Furthermore, donepezil transport was enhanced (p < 0.01) in HEK 293 cells expressing rOCNT1, rOCTN2, or rCHT1. The CL_app,br was reduced up to 52.8% of the control in rats that had been pretreated with choline, while the CL_app,br was unaffected with pretreatments with organic cations other than choline, suggesting that choline and donepezil share a common transport mechanism in the penetration across the BBB in vivo. Taken together, these observations suggest that the transport of donepezil across the BBB is mediated by organic cation transporters such as choline transport system(s). © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1548–1566, 2010     

Development of patient‐centred performance indicators to guide the delivery of pharmaceutical care in a district general hospital

The aim of this study was to audit clinical pharmacy practice in an acute hospital setting against the individual patient care guidelines set out in the CRAG "Framework for Practice" document, and then to develop practical, patientcentred performance indicators that could be used locally to monitor the delivery of pharmaceutical care. A series of four audits were undertaken to establish key elements in the process of providing pharmaceutical care to patients. Four standard statements describing the performance of the pharmacy service in providing patient care were developed through peer discussion and formulation of ideas based around these data. The four standard statements were then used as performance indicators to evaluate service performance at PRI and tested by means of a further audit cycle. The use of this methodology facilitated operation of a structured service appraisal system and provided a forum that allowed problems with practice to be discussed and resolved.     

An overview of recent studies on the potential of pulp‐mill effluents to alter reproductive parameters in fish

In the early 1990s, many Canadian pulp and paper mills implemented process changes to comply with new regulations that came into effect in 1993. These regulations placed stricter guidelines on a number of parameters in effluent discharges, including limits on acute toxicity, on the discharges of suspended solids, and on biochemical oxygen demand. To meet these new regulations, many of the older Canadian pulp and paper mills had to install secondary treatment systems. The investment by the Canadian pulp and paper industry was in excess of $5 billion, and the implementation of the new regulations and the process changes took several years. The new regulations were an extension of regulations designed in the early 1970s and were not designed specifically to address the reproductive responses recently reported in fish collected downstream of mills in Scandinavia and North America. This report describes a series of projects conducted between 1991 and 1996 to evaluate the effectiveness of the new regulations to address the issue of reproductive responses in fish associated with exposure to pulp‐mill effluents. These studies have shown that the existing short‐term bioassays do not adequately predict the potential of effluents to affect reproduction in wild fish. Laboratory testing using fathead minnows exposed over a full life cycle confirmed depression in sex steroid production, delay in sexual maturity, reduced egg production, and changes in secondary sex characteristics documented at some sites. Our studies demonstrated that both steroid hormone changes and induction of liver detoxification enzymes take place quickly. While short‐term exposures can predict the potential of some effluents to impact steroid hormone production, there is no readily available assay that can be widely applied. In the absence of a usable and transferable laboratory bioassay, field collections were conducted at a number of sites. Generalizations are not possible at this time, but impacts have been seen at a variety of sites, and partial recovery has been documented at five sites in North America following various process and waste treatment changes. Data gaps and critical research areas are identified.     

Noradrenergic mechanism in the regulation of seizures in GEPR.

Genetically epilepsy prone rat (GEPR) is a model of generalized tonic/clonic epilepsy and a useful tool in the understanding of basic mechanisms of human epilepsy. GEPR is susceptible to audiogenic seizure, hyperthermia induced seizure,and has lower threshold for electrical and chemical stimuli. Several strains of GEPR, from GEPR-3 to GEPR-9, are available depending on the degree of the intensity of audiogenic seizure.     

Investigations of the potential for five β-lactam antibiotics to elicit type II hypersensitivity reactions in rats and monkeys

Immunologic reactions are occasionally elicited in patients by various β-lactam antibiotics (e.g., penicillins and cephalosporins). A relatively rare reaction (type II hypersensitivity) may involve antibody-mediated destruction of erythrocytes, leukocytes, and/or platelets. During the safety evaluation of several modified β-lactam compounds (carbapenems), hemolytic anemia and/or neutropenia were observed in rhesus monkeys, and anemia, neutropenia, and thrombocytopenia in rats, after approximately 2 weeks of intravenous administration. Antiglobulin tests and other clinicopathologic findings indicated an immune basis for the cytopenias. A review of summaries of the preclinical data for numerous marketed β-lactam antibiotics revealed that various cytopenias of unknown etiology were commonly seen in animals given high doses of these compounds. To determine whether these hematologic abnormalities were related to those produced by the above carbapenems, we investigated the potential of five widely used β-lactam antibiotics (penicillin G, cephalothin, cefazolin, cefoperazone, and cefamandole) to elicit immune-mediated cytopenias in rhesus monkeys and Sprague-Dawley rats when given intravenously. After approximately 1 month of administration of these compounds at a dose level of 500 mg/kg/day, slight anemia occurred in several drug-treated monkeys; however, direct and indirect antiglobulin tests were negative for all animals, indicating that the anemias were not immune-mediated. In rats, no drug-induced hematologic changes were observed after 1 month of intravenous administration of 500 and 1000 mg/kg/day of each of the β-lactams. In addition, direct antiglobulin tests were negative in rats. Therefore, it appears that the ability of certain carbapenem antibiotics to produce a high incidence of type II hypersensitivity reactions in animals is not typical of β-lactam compounds in general.     

Plasma level of AcMPAG in renal transplant recipients is related to the polymorphism of UGT2B7 211G 〉 T

AIM： To clarify whether Mycophenolic acid（MPA） or its metabolite AcMPAG can cause gastrointestinal disturbances, and to explore the effect of UGT2B7 SNP 211G 〉 T on the pharmacokinetic of AcMPAG. METHODS： Twenty-four renal transplant patients were enrolled in this study. Pharmacokinetic study was performed on day 14 after transplantation and symptoms were recorded on the same day. Multiple blood samples were collected before dosing and 0.5,1,1.5,2,4,6,8, 10 and 12 hours after morning dosing. Plasma concentrations of MPA, MPAG and AcMPAG were detected by HPLC. Genotype of UGT2B7 211G 〉 T was determined using PCR-RFLP method. RESULTS： No significant difference was observed between patients with and without side effects for AUC（0-12） of MPA and MPAG. The values of AUC（0-12）/dose of MPA, MPAG and AcMPAG were （39.7 ± 12.3）,[第一段]     

Use of antibiotics to treat bacteriuria of pregnancy in the Nordic countries. Which antibiotics are appropriate to treat bacteriuria of pregnancy?

Bacteriuria in pregnancy with or without clinical symptoms is frequent and increases the risk of pyelonephritis, preterm labour, and low birth weight infants. Commonly used antibiotics such as ampicillin (pivampicillin), amoxicillin, trimethoprim, and sulphonamide are currently associated with a high degree of resistance of the most common pathogen in the urinary tract, Escherichia coli. During the past few decades a number of new and efficient antibacterial antibiotics have been developed. The presumption that a specific drug is safe for both the pregnant woman and the foetus depends on how widely the drug has been used. A recent survey among general practitioners and obstetricians in Denmark, Finland, Norway, and Sweden confirmed that the beta-lactam antibiotic pivmecillinam and nitrofurantoin are the most commonly used agents in the treatment of bacteriuria in pregnancy in the Nordic countries. However, a surprisingly high number of physicians reported that they prescribe sulphonamides during the first two trimesters in spite of resistance of E. coli and possible adverse effects on the foetus.     

Notification of suspected and unexpected serious adverse reactions according to the Clinical Trials Directive—A descriptive analysis of the legislation and the requirements in a European context

The European Clinical Trials Directive (CTD) came into force on May 1st 2004. The CTD provides the legal basis for monitoring the safety of clinical trials and covers the requirements for notification of SUSAR. Implementation of the CTD into national legislation in each Member State has resulted in various interpretations of CTD requirements. The objective of this paper is to investigate how the European Member States administer the safety reporting requirements of the CTD and to clarify the requirements for SUSAR notification in the different Member States. Data was collected through publicly available sources and questionnaires sent to the Competent Authorities and Ethics Committees in 30 European countries. The results document that Competent Authorities and Ethics Committees in the different Member States administer the legislation very differently. This has resulted in different requirements for notification of SUSARs in the Member States, as well as different requirements between the Competent Authorities and Ethics Committees in the same Member State. These requirements have not previously been described and the present overview of the legislation and the requirements of SUSAR reporting is of immediate practical use to especially non-commercial sponsors when conducting clinical trials in Europe.