O-demethylation of codeine to morphine inhibited by low-dose levomepromazine.

PURPOSE: Codeine/paracetamol (C/P) and levomepromazine (L) are frequently co-administered for the treatment of acute back pain, but the efficacy/effectiveness of this combination drug therapy has not been evaluated. The demethylation of codeine to morphine is catalyzed by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6), of which levomepromazine (methotrimeprazine) is a known inhibitor. The aim of this study was to investigate whether low-dose levomepromazine inhibits the formation of morphine from codeine in a patient population of homozygous extensive (EM) and heterozygous extensive (HEM) metabolizers of CYP2D6. METHODS: Our patient cohort consisted of 29 patients hospitalized for acute back pain who were randomized to a 24-h treatment with either C/P (60 mg codeine + 1000 mg paracetamol) four times daily or to L+C/P (levomepromazine 5 + 5 + 5 + 10 mg + C/P) four times daily. After zero-urine sampling (baseline), the treatment was started and urine collected for 24 h. Blood samples were later genotyped for the CYP2D6*3, *4, and *6 polymorphisms by the PCR (LightCycler system) and for the *5 polymorphism using long PCR, to identify EM and HEM and to eliminate CYP2D6 poor metabolizers. Urine samples were analyzed using the CEDIA immunoassay and gas chromatography-mass spectrometry after enzymatic hydrolysis of glucuronide conjugates. O-demethylation ratios of codeine were calculated as hydrolyzed (total) concentrations of morphine/morphine + codeine. RESULTS: Twenty-two of the patients fulfilled the inclusion criteria, of whom ten were EM (five C/P and five L+C/P) and twelve were HEM (six C/P and six L+C/P) for functional CYP2D6 alleles. In the EM group, the median O-demethylation ratio was significantly higher (P = 0.016, Mann-Whitney test) after the C/P treatment (0.092, range 0.041-0.096) than after the L+C/P treatment (0.031, range 0.009-0.042). However, there was no significant difference between these two treatments in either the HEM group [n = 12; 0.024 (range 0.011-0.042) vs. 0.026 (range 0.009-0.041), respectively; P = 1.00] or in the combined EM/HEM group [11 C/P + 11 L+C/P; 0.041 (range 0.011-0.096) vs. 0.030 (range 0.009-0.042), respectively; P = 0.122]. CONCLUSIONS: Our study revealed significant inhibition in the O-demethylation of codeine to morphine in homozygous EM of CYP2D6 treated with low-dose levomepromazine and codeine/paracetamol, compared to treatment with codeine/paracetamol only. No significant difference could be detected in HEM or in the mixed and heterogenous group of EM/HEM. In patients prescribed this drug combination, the amount of morphine generated by the O-demethylation of codeine may be insufficient for effective pain relief. The therapeutic effect of codeine in the treatment of acute back pain should be assessed with and without levomepromazine.

Clinical assessment compared to laboratory screening in acutely poisoned patients.

Acute poisonings may require identification of the toxic agents. It is impossible for routine laboratories to provide a full spectrum of toxicological analyses, and clinicians should know the reliability of the clinical diagnoses of toxic agents. We performed a 1-year study of hospitalized acute poisonings to determine the agreement between the clinical assessment on admission and serum laboratory tests for eight common toxic agents. Blood samples were drawn in 665 (70%) of the 947 admissions. The total number of laboratory found agents (967) exceeded the clinically suspected (871) by 11%. The agreement between the clinical assessment and laboratory analyses was good for ethanol and paracetamol (kappa = 0.70 for both), whereas only moderate or fair for other agents (kappa 0.22-0.51). Sensitivities of the clinical assessments compared to the laboratory results were better for common than rare agents, and better for higher than lower serum concentrations. The four most common agents (ethanol, benzodiazepines, paracetamol, and opiates) had overall sensitivity of 82% for higher-than-median serum concentrations, whereas the other agents had sensitivities ranging from 14% to 71% for higher-than-median concentrations. The reliability of the clinical diagnoses varied to such an extent that agents, which are important to recognize for specific treatment, should be tested for.

Evidence that nitroprusside stimulates glucose uptake in isolated rat cardiomyocytes via mitogen-activated protein kinase.

Sodium nitroprusside (SNP), a nitric oxide (NO.) donor, stimulates glucose uptake in skeletal muscle. We investigated the stimulatory effect of SNP on glucose uptake in cardiomyocytes and the possible role of soluble guanylate cyclase, phosphatidylinositol-3-kinase (PI-3-kinase) and the mitogen-activated protein kinases (MAPKs). Cardiomyocytes were isolated from adult male Wistar rats by trypsin/collagenase perfusion and glucose uptake determined from the accumulation of 3H-2-deoxyglucose. SNP caused a dose-dependent increase in glucose uptake with 200-300% increase at 30 mM. Cytochalasin B completely prevented the SNP-induced increase in glucose uptake. 8-Br-cGMP (100 microM) and the NO. donor spermineNONOate (100 microM) were without effect on basal glucose uptake. SNP-stimulated glucose uptake was not inhibited by the guanylate cyclase inhibitor ODQ (10 microM). Sodium ferrocyanide (Na4Fe(CN)6), a compound structurally related to SNP, but without any NO. group, also stimulated glucose uptake in cardiomyocytes suggesting that the effect of SNP could be unrelated to liberation of NO. Wortmannin, an inhibitor of PI-3-kinase, inhibited insulin-stimulated glucose uptake completely but did not affect SNP-stimulated glucose uptake. SNP-stimulated glucose uptake was inhibited by 50 microM PD 098059 (inhibitor of the MAPK-kinases that activate external regulated kinase [ERK1/2]) and by 50 microM SB203580 (inhibitor of p38MAPK). In conclusion, high SNP concentrations dose-dependently stimulate glucose uptake in cardiomyocytes and our data suggest a role for MAPK signalling, but not PI-3-kinase and soluble guanylate cyclase, in stimulation of glucose uptake.

A placebo-controlled study of high dose buprenorphine in opiate dependents waiting for medication-assisted rehabilitation in Oslo, Norway.

AIMS: To evaluate whether buprenorphine. even without additional control and psychosocial treatment and support, alleviates the problems faced by patients waiting for medication assisted rehabilitation (MAR). DESIGN: A randomized, double-blind, 12-week study of Subutex versus placebo without additional support as an interim therapy. PARTICIPANTS: One hundred and six patients, 70 males and 36 females, waiting for MAR in Oslo. The average age was 38 years with an average history of heroin use of 20 years. Fifty-five patients were assigned to buprenorphine and 51 to a placebo. INTERVENTION: Subutex or placebo sublingual tablets were given under supervision in a daily dose of 16 mg with the exception of a double dose on Saturday and no dose on Sunday. MEASUREMENT: Retention, compliance, self-reported drug-abuse, wellbeing and mental health. FINDINGS: The average number of days of participation was significantly higher in the buprenorphine group, 42 (median: 29) compared to 14 (median: 11) for the placebo group (P < 0.001). The retention of patients after 12 weeks was 16 patients in the buprenorphine group and one patient in the placebo group. The buprenorphine group had a larger decrease in reported opioid use (p < 0.001) and in reported use of other drugs, tablets and alcohol abuse (p < 0.01). The group also showed a stronger increase in wellbeing (p < 0.01) and life satisfaction (p < 0.05). None of the participants died. CONCLUSION: The patients waiting for MAR benefited significantly from the buprenorphine as an interim therapy according to retention, self-reported use of drugs and wellbeing. However, the patients had difficulties in remaining in treatment over time without psychosocial support.

Adverse drug events in children during hospitalization and after discharge in a Norwegian university hospital.

UNLABELLED: The frequency and characteristics of adverse drug events (ADEs) in children hospitalized in the paediatric department of Ullevaal University Hospital, Norway, were determined using intensive monitoring. Of 579 children treated with drugs, 28% experienced ADEs; 7% at the time of admission, 18% during hospitalization and 9% after discharge. All children treated for cancer, 19% treated with anti-infective drugs, 15% treated with antiasthmatics and 10% treated with drugs affecting the nervous system experienced ADEs. The most frequent events were gastrointestinal, CNS- and skin reactions and 19% were considered as serious. ADEs caused 6% of the admissions and 44% required interventions. Most ADEs were found by screening patient records, where physicians mostly described adverse drug events requiring interventions and nurses described less serious events. Parents reported 14% of the events, of which a majority were CNS reactions. CNS reactions may be more common than expected and observations by parents are important when investigating such reactions in children. CONCLUSIONS: ADEs, mainly gastrointestinal, CNS and skin reactions related to drugs affecting the nervous system, anti-infectives and antiasthmatics, were seen in 28% of the patients. The reporting of events by parents was a useful supplement to the screening of patient records.

Drug-related deaths in a department of internal medicine.

BACKGROUND: Drug therapy is associated with adverse effects, and fatal adverse drug events (ADEs) have become major hospital problems. Our study assesses the incidence of fatal ADEs in a major medical department and identifies possible patient characteristics signifying fatal ADE risk. METHODS: During a 2-year period, a multidisciplinary study group examined all 732 patients who died--5.2% of the 13992 patients admitted to the Department of Internal Medicine, Central Hospital of Akershus, Nordbyhagen, Norway. Decisions about the presence or absence of fatal ADEs were based on aggregated clinical records, autopsy results, and findings from premortem and postmortem drug analyses. RESULTS: In 18.2% of the patients (133/732) (95% confidence interval, 15.4%-21.0%), deaths were classified as being directly (64 [48.1%] of 133) or indirectly (69 [51.9%] of 133) associated with 1 or more drugs (this equals 9.5 deaths per 1000 hospitalized patients). Those with fatal ADEs (cases) were older, had more diseases, and used more drugs than those without fatal ADEs (noncases). In 75 of the 133 patients with fatal ADEs, autopsy findings and/or drug analysis data were decisive for recognizing the ADEs; in 62 of the remaining 595 patients, similar data proved necessary to exclude the suspicion of a fatal ADE. Major culprit drugs were cardiovascular, antithrombotic, and sympathomimetic agents. CONCLUSIONS: Fatal ADEs represent a major hospital problem, especially in elderly patients with multiple diseases. A higher number of drugs administered was associated with a higher frequency of fatal ADEs, but whether a high number of drugs is an independent risk factor for fatal ADEs is unsettled. Autopsy results and the findings of premortem and postmortem drug analyses were important for recognizing and excluding suspected fatal ADEs.

Increased [Mg2+]o reduces Ca2+ influx and disruption of mitochondrial membrane potential during reoxygenation.

Increase in extracellular Mg2+ concentration ([Mg2+]o) reduces Ca2+ accumulation during reoxygenation of hypoxic cardiomyocytes and exerts protective effects. The aims of the present study were to investigate the effect of increased [Mg(2+)](o) on Ca2+ influx and efflux, free cytosolic Ca2+ ([Ca2+]i) and Mg2+ concentrations ([Mg2+]i), Ca2+ accumulation in the presence of inhibitors of mitochondrial or sarcoplasmatic reticulum Ca2+ transport, and finally mitochondrial membrane potential (Delta(psi)m). Isolated adult rat cardiomyocytes were exposed to 1 h of hypoxia and subsequent reoxygenation. Cell Ca2+ was determined by 45Ca2+ uptake, and the levels of [Mg2+]i and [Ca2+]i were determined by flow cytometry as the fluorescence of magnesium green and fluo 3, respectively. Ca2+ influx rate was significantly reduced by approximately 40%, whereas Ca2+ efflux was not affected by increased [Mg2+]o (5 mM) during reoxygenation. [Ca2+]i and [Mg2+]i were increased at the end of hypoxia, fell after reoxygenation, and were unaffected by increased [Mg2+]o. Clonazepam, a selective mitochondrial Na+/Ca2+ exchange inhibitor (100 microM), significantly reduced Ca2+ accumulation by 70% and in combination with increased [Mg2+]o by 90%. Increased [Mg2+]o, clonazepam, and the combination of both attenuated the hypoxia-reoxygenation-induced reduction in Delta(psi)m, determined with the cationic dye JC-1 by flow cytometry. A significant inverse correlation was observed between Delta(psi)m and cell Ca2+ in reoxygenated cells treated with increased [Mg2+]o and clonazepam. In conclusion, increased [Mg2+]o (5 mM) inhibits Ca2+ accumulation by reducing Ca2+ influx and preserves Delta(psi)m without affecting [Ca2+]i and [Mg2+]i during reoxygenation. Preservation of mitochondria may be an important effect whereby increased [Mg2+]o protects the postischemic heart.

Fatal adverse drug events: the paradox of drug treatment.

OBJECTIVE: Study patient characteristics, morbidity patterns and drug regimens associated with fatal adverse drug events (FADEs) amongst medical department inpatients. DESIGN: An observational, descriptive study using aggregated medical records, autopsies and pre and postmortem drug analyses. SETTING: A department of internal medicine at a Norwegian county hospital. SUBJECTS: All patients dying in the department over a 2-year period. RESULTS: The incidence of FADEs were 18.2% (133/732). Compared with non-FADE cases, FADE cases were older, used more drugs both on admission and at death, and had higher comorbidity (P < 0.001). Drugs suspected to cause or contribute to fatal outcome were mainly those used for treating chronic pulmonary diseases (terbutaline, theophylline), antithrombotic drugs (aspirin, warfarin, heparines) and drugs for treating coronary heart disease and heart failure (e.g. diuretics, nitrates, angiotensin converting enzymes (ACE) inhibitors, calcium channel blockers). Bronchodilatory drugs, antithrombotic drugs and cardiovascular drugs account for 26, 31 and 30 FADE cases, respectively. Patients dying from gastrointestinal diseases had the highest relative FADE occurrence (42%), cancer patients the lowest occurrence (4%). Serious drug-drug and drug-disease interactions were frequently suspected. Various degrees of inappropriateness in choice of drug, dosage or administration route were seen in 50% of FADE cases. CONCLUSIONS: This study shows a high incidence of FADEs associated with high age, high comorbidity and polypharmacy, and partly to inappropriate drug prescribing or use. Treatments frequently associated with FADEs were bronchodilatory treatment of patients with both chronic obstructive lung disease and coronary heart disease, vasodilatory treatment in patient with endstage heart failure and the combination of several antithrombotic drugs. A systematic strategy is needed to avoid unnecessary adverse drug events (ADEs).

Effect of extracellular Mg(2+) on ROS and Ca(2+) accumulation during reoxygenation of rat cardiomyocytes.

The effects of Mg(2+) on reactive oxygen species (ROS) and cell Ca(2+) during reoxygenation of hypoxic rat cardiomyocytes were studied. Oxidation of 2',7'-dichlorodihydrofluorescein (DCDHF) to dichlorofluorescein (DCF) and of dihydroethidium (DHE) to ethidium (ETH) within cells were used as markers for intracellular ROS levels and were determined by flow cytometry. DCDHF/DCF is sensitive to H(2)O(2) and nitric oxide (NO), and DHE/ETH is sensitive to the superoxide anion (O(2)(-).), respectively. Rapidly exchangeable cell Ca(2+) was determined by (45)Ca(2+) uptake. Cells were exposed to hypoxia for 1 h and reoxygenation for 2 h. ROS levels, determined as DCF fluorescence, were increased 100-130% during reoxygenation alone and further increased 60% by increasing extracellular Mg(2+) concentration to 5 mM at reoxygenation. ROS levels, measured as ETH fluorescence, were increased 16-24% during reoxygenation but were not affected by Mg(2+). Cell Ca(2+) increased three- to fourfold during reoxygenation. This increase was reduced 40% by 5 mM Mg(2+), 57% by 10 microM 3,4-dichlorobenzamil (DCB) (inhibitor of Na(+)/Ca(2+) exchange), and 75% by combining Mg(2+) and DCB. H(2)O(2) (25 and 500 microM) reduced Ca(2+) accumulation by 38 and 43%, respectively, whereas the NO donor S-nitroso-N-acetyl-penicillamine (1 mM) had no effect. Mg(2+) reduced hypoxia/reoxygenation-induced lactate dehydrogenase (LDH) release by 90%. In conclusion, elevation of extracellular Mg(2+) to 5 mM increased the fluorescence of the H(2)O(2)/NO-sensitive probe DCF without increasing that of the O(2)(-).-sensitive probe ETH, reduced Ca(2+) accumulation, and decreased LDH release during reoxygenation of hypoxic cardiomyocytes. The reduction in LDH release, reflecting the protective effect of Mg(2+), may be linked to the effect of Mg(2+) on Ca(2+) accumulation and/or ROS levels.