Morphine glucuronide-to-morphine plasma ratios are unaffected by the UGT2B7 H268Y and UGT1A1*28 polymorphisms in cancer patients on chronic morphine therapy

OBJECTIVE: UDP-glucuronosyltransferase (UGT) 2B7 is the major UGT isoform responsible for the 3- and 6-glucuronidation of morphine in humans. Studies in rats have indicated that UGT1A1 may also contribute to the formation of morphine 3-glucuronide (M3G). Our objective was to investigate whether the UGT2B7 H268Y and UGT1A1*28 polymorphisms contribute to the variability in morphine glucuronide-to-morphine plasma ratios among cancer patients undergoing analgesic therapy with morphine. METHODS: Seventy patients with normal hepatic and renal function using slow-release morphine to relieve cancer pain were included. UGT2B7 genotyping was performed using restriction enzyme analysis of polymerase chain reaction (PCR)-amplified DNA fragments. Wild-type and variant alleles of the UGT1A1 gene were identified using sizing of PCR-amplified fragments. Morphine 6-glucuronide (M6G)/morphine, M3G/morphine, and M3G/M6G plasma ratios were compared between genotypes. RESULTS: The M3G/morphine, M6G/morphine, and M3G/M6G plasma ratios varied 16-, 42-, and sevenfold, respectively, among individuals. No statistically significant differences in plasma ratios were found between individuals possessing UGT2B7 H/H ( n=20), H/Y ( n=30), or Y/Y ( n=20) genotypes. Five patients were homozygous for the UGT1A1 TA(7) allele, which is associated with reduced UGT1A1 gene expression. However, the mean M3G/M6G and M3G/morphine plasma ratios in TA(7) homozygous subjects did not differ significantly from those of heterozygous or homozygous wild-type (TA(6)) individuals. CONCLUSION: The UGT2B7 H268Y polymorphism cannot account for the considerable variation in glucuronide-to-morphine ratios in cancer patients. Moreover, the contribution of UGT1A1 to the formation of M3G appears to be of minor biological significance, at least in a UGT2B7 background.     

Stimulant and relaxant drugs combined with stimulant and relaxant information: a study of active placebo

Rationale The active placebo hypothesis states that placebo effects are potentiated when an active drug is administered.Objective This hypothesis was tested in an experiment where information about the effect of a drug was combined with administration of an active drug or placebo.Methods Information that a drug acted as a relaxant, a stimulant, or as a placebo was crossed with oral administration of a relaxant drug (700 mg carisoprodol), a stimulant drug (400 mg caffeine) or placebo (lactose) in healthy volunteers (n=94). Dependent variables were subjective and physiological measures of arousal, as well as serum carisoprodol and caffeine levels. Data were collected from 15 to 280 min after administration of drug or placebo.Results Caffeine increased alertness, systolic and diastolic blood pressure, startle blink reflexes, and skin conductance responses. Subjects were calmer after carisoprodol, and heart rate was increased. There was a positive correlation between increased arousal and carisoprodol levels when stimulant information had been provided. However, this was only seen when carisoprodol levels were very low. There was no evidence that caffeine modulated the placebo response.Conclusions Active placebo responses were seen only transiently when carisoprodol levels were low, and only in the subjective arousal data. Caffeine did not support active placebo responses. The overall findings did not favour the active placebo hypothesis.     

Subthreshold depression in patients with Parkinson's disease and dementia--clinical and demographic correlates

BACKGROUND: About 40% of the patients with Parkinson's disease (PD) have depressive symptoms, either major depression (MD) or subthreshold depression. Depression was found to be associated with age and age at onset of PD, female gender, more severe parkinsonism, in particular with left-sided and akinetic-rigid symptoms, more functional impairment and cognitive impairment.However, the findings are inconsistent and partly contradictory and most of the studies focused on major depression in PD without dementia.The aim of this study was to examine the relationship between subthreshold depression and other clinical features in 538 PD patients with dementia but without MD drawn from a randomized, placebo-controlled multicentre trial of rivastigmine in PD. RESULTS: One hundred and sixteen patients (21%) had subthreshold depression. Depression was associated with a younger age and age at onset and female gender, but not with severity of parkinsonism, cognition or activities of daily living or laterality of motor symptoms. However, in male patients, an association between depression and left-sided parkinsonism was found. CONCLUSION: In contrast to previous findings in PD patients with major depression but without dementia, we found no relationship between subthreshold depression and other clinical symptoms in patients with PDD.     

Erysipelothrix rhusiopathiae serotype 5‐associated metritis in a Norwegian Red heifer

This report summarized the findings of a case of Erysipelothrix rhusiopathiae infection in a farmed Norwegian Red heifer located in the south‐east of Norway. The 2.5‐year‐old pregnant heifer was found dead after a short episode of inappetence. On gross exam, the heifer was severely dehydrated with uterine torsion. Microscopically, necrosis of the endometrium was present throughout the uterus along with presence of intralesional Gram‐positive bacteria, interstitial nephritis, and pyelonephritis. E. rhusiopathiae was isolated from the uterus and placenta and was also demonstrated by immunohistochemistry (IHC) in the uterus, placenta, and kidney. The E. rhusiopathiae isolate was further characterized as serotype 5. To the authors’ knowledge, this is the first report of bacterial metritis associated with E. rhusiopathiae serotype 5 infection. The etiology of the infection is unknown but the E. rhusiopathiae could have been a primary or opportunistic pathogen. Serotype 5 of E. rhusiopathiae has been identified in several mammalian species in recent years and could be emerging.     

Placental passage of metformin in women with polycystic ovary syndrome

Metformin passes the placenta. Fetal serum levels are comparable with maternal values.     

Frequency of left ventricular thrombus in patients with anterior wall acute myocardial infarction treated with percutaneous coronary intervention and dual antiplatelet therapy

The aim of the present study was to investigate the prevalence of left ventricular (LV) thrombus formation and important determinants in patients with acute ST elevation myocardial infarction localized to the anterior wall treated with percutaneous coronary intervention (PCI) and dual-antiplatelet therapy. One hundred selected patients with ST elevation myocardial infarctions revascularized with PCI in the left anterior descending coronary artery were included. The patients participated in the Autologous Stem Cell Transplantation in Acute Myocardial Infarction (ASTAMI) trial. All were treated with aspirin 75 mg/day and clopidogrel 75 mg/day and underwent serial echocardiography and magnetic resonance imaging during the first 3 months after PCI. After 4 to 5 days, the ejection fraction and infarct size in percentage of the left anterior descending coronary artery area were assessed using single photon-emission computed tomography in addition to the ejection fraction by echocardiography. LV thrombi were detected in 15 patients during the first 3 months, 2/3 of them within the first week. No differences in baseline characteristics between the groups with and without LV thrombi were shown. However, in the thrombus group, significantly higher peak creatine kinase levels (6,128 vs 2,197 U/L, p <0.01), larger infarct sizes (82.5% vs 63.8%, p <0.01), and lower ejection fractions on single photon-emission computed tomography (35.5% vs 40.0%, p = 0.03) and on echocardiography (43.0% vs 46.0%, p = 0.03) were found compared to patients without LV thrombi. In conclusion, LV thrombus formation is a frequent finding in patients with anterior wall ST elevation myocardial infarction treated acutely with PCI and dual-antiplatelet therapy and should be assessed by echocardiography within the first week.