Oral diacetylmorphine (heroin) yields greater morphine bioavailability than oral morphine: bioavailability related to dosage and prior opioid exposure

AIMS: In the Swiss heroin substitution trials, patients are treated with self-administered diacetylmorphine (heroin). Intravenous administration is not possible in patients that have venosclerosis. Earlier studies have demonstrated that oral diacetylmorphine may be used, although it is completely converted to morphine presystemically. Morphine bioavailability after high-dose oral diacetylmorphine is considerably higher than would be predicted from low-dose trials. The aim was to investigate whether the unexpectedly high bioavailability is due to a difference in the drug examined, and whether it depends on previous exposure or on dose. METHODS: Opioid-naive healthy volunteers and dependent patients from the Swiss heroin trials (n = 8 per group) received low doses of intravenous and oral deuterium-labelled morphine and diacetylmorphine, respectively. Patients also received a high oral diacetylmorphine dose. RESULTS: The maximum plasma concentration (C(max)) of morphine was twofold higher after oral diacetylmorphine than after morphine administration in both groups. However, morphine bioavailability was considerably higher in chronic users [diacetylmorphine 45.6% (95% confidence interval 40.0, 51.3), morphine 37.2% (30.1, 44.3)] than in naive subjects [diacetylmorphine 22.9% (16.4, 29.4), morphine 23.9% (16.5, 31.2)] after low oral doses (48.5 micromol) of either diacetylmorphine or morphine. Morphine clearance was similar in both groups. Moreover, oral absorption of morphine from diacetylmorphine was found to be dose dependent, with bioavailability reaching 64.2% (55.3, 73.1) for high diacetylmorphine doses (1601 micromol). CONCLUSIONS: Oral absorption of opioids is substance-, dose- and patient collective-dependent, suggesting that there may be a saturation of first-pass processes, the exact mechanism of which is not yet understood.

Oral heroin in opioid-dependent patients: pharmacokinetic comparison of immediate and extended release tablets

In diacetylmorphine prescription programs for heavily dependent addicts, diacetylmorphine is usually administered intravenously, but this may not be possible due to venosclerosis or when heroin abuse had occurred via non-intravenous routes. Since up to 25% of patients administer diacetylmorphine orally, we characterised morphine absorption after single oral doses of immediate and extended release diacetylmorphine in 8 opioid addicts. Plasma concentrations were determined by liquid chromatography-mass spectrometry. Non-compartmental methods and deconvolution were applied for data analysis. Mean (+/-S.D.) immediate and extended release doses were 719+/-297 and 956+/-404 mg, with high absolute morphine bioavailabilities of 56-61%, respectively. Immediate release diacetylmorphine caused rapid morphine absorption, peaking at 10-15 min. Morphine absorption was considerably slower and more sustained for extended release diacetylmorphine, with only approximately 30% of maximal immediate release absorption being reached after 10 min and maintained for 3-4h, with no relevant food interaction. The relative extended to immediate release bioavailability was calculated to be 86% by non-compartmental analysis and 93% by deconvolution analysis. Thus, immediate and extended release diacetylmorphine produce the intended morphine exposures. Both are suitable for substitution treatments. Similar doses can be applied if used in combination or sequentially.

Prevalence of halitosis in the population of the city of Bern, Switzerland: a study comparing self-reported and clinical data

Epidemiological data on halitosis are rare. In this study we evaluated the prevalence of halitosis in the population of the city of Bern, Switzerland, using a standardized questionnaire and clinical examination. First of all, a standardized questionnaire was filled out by all 419 participants. In the clinical examination, 'objective' values for halitosis were gathered through two different organoleptic assessments and by the measurement of volatile sulfur compounds (VSC). Additionally, tongue coating and the modified periodontal screening index (PSI) were evaluated for each participant. The questionnaire revealed that 32% of all subjects sometimes or often experienced halitosis. The organoleptic evaluation (grade 0-5) identified 48 persons with grade 3 and higher. Measurement of VSC identified 117 subjects (28%) with readings of >or= 75 parts per billion (ppb). Tongue coating, modified PSI, and smoking were significantly associated with higher organoleptic scores, and tongue coating and smoking were associated with higher VSC values. For about one-third of the Bernese city population, halitosis seems to pose an oral health problem. Only a weak correlation between self-reported halitosis and either organoleptic or VSC measurements could be detected.

Is a change in patient-reported dysphagia after induction chemotherapy in locally advanced esophageal cancer a predictive factor for pathological response to neoadjuvant chemoradiation?

GOALS OF WORK: In patients with locally advanced esophageal cancer, only those responding to the treatment ultimately benefit from preoperative chemoradiation. We investigated whether changes in subjective dysphagia or eating restrictions after two cycles of induction chemotherapy can predict histopathological tumor response observed after chemoradiation. In addition, we examined general long-term quality of life (QoL) and, in particular, eating restrictions after esophagectomy. MATERIALS AND METHODS: Patients with resectable, locally advanced squamous cell- or adenocarcinoma of the esophagus were treated with two cycles of chemotherapy followed by chemoradiation and surgery. They were asked to complete the EORTC oesophageal-specific QoL module (EORTC QLQ-OES24), and linear analogue self-assessment QoL indicators, before and during neoadjuvant therapy and quarterly until 1 year postoperatively. A median change of at least eight points was considered as clinically meaningful. MAIN RESULTS: Clinically meaningful improvements in the median scores for dysphagia and eating restrictions were found during induction chemotherapy. These improvements were not associated with a histopathological response observed after chemoradiation, but enhanced treatment compliance. Postoperatively, dysphagia scores remained low at 1 year, while eating restrictions persisted more frequently in patients with extended transthoracic resection compared to those with limited transhiatal resection. CONCLUSIONS: The improvement of dysphagia and eating restrictions after induction chemotherapy did not predict tumor response observed after chemoradiation. One year after esophagectomy, dysphagia was a minor problem, and global QoL was rather good. Eating restrictions persisted depending on the surgical technique used.

Postmortem multislice computed tomography and magnetic resonance imaging of odontoid fractures, atlantoaxial distractions and ascending medullary edema

Non-invasive imaging methods are increasingly entering the field of forensic medicine. Facing the intricacies of classical neck dissection techniques, postmortem imaging might provide new diagnostic possibilities which could also improve forensic reconstruction. The aim of this study was to determine the value of postmortem neck imaging in comparison to forensic autopsy regarding the evaluation of the cause of death and the analysis of biomechanical aspects of neck trauma. For this purpose, 5 deceased persons (1 female and 4 male, mean age 49.8 years, range 20-80 years) who had suffered odontoid fractures or atlantoaxial distractions with or without medullary injuries, were studied using multislice computed tomography (MSCT), magnetic resonance imaging (MRI) and subsequent forensic autopsy. Evaluation of the findings was performed by radiologists, forensic pathologists and neuropathologists. The cause of death could be established radiologically in three of the five cases. MRI data were insufficient due to metal artefacts in one case, and in another, ascending medullary edema as the cause of delayed death was only detected by histological analysis. Regarding forensic reconstruction, the imaging methods were superior to autopsy neck exploration in all cases due to the post-processing possibilities of viewing the imaging data. In living patients who suffer medullary injury, follow-up MRI should be considered to exclude ascending medullary edema.

Virtopsy: forensic traumatology of the subcutaneous fatty tissue; multislice computed tomography (MSCT) and magnetic resonance imaging (MRI) as diagnostic tools

Traumatic lesions of the subcutaneous fatty tissue provide important clues for forensic reconstruction. The interpretation of these patterns requires a precise description and recording of the position and extent of each lesion. During conventional autopsy, this evaluation is performed by dissecting the skin and subcutaneous tissues in successive layers. In this way, depending on the force and type of impact (right angle or tangent), several morphologically distinct stages of fatty tissue damage can be differentiated: perilobular hemorrhage (I), contusion (II), or disintegration (III) of the fat lobuli, and disintegration with development of a subcutaneous cavity (IV). In examples of virtopsy cases showing blunt trauma to the skin and fatty tissue, we analyzed whether these lesions can also be recorded and classified using multislice computed tomography (MSCT) and magnetic resonance imaging (MRI). MSCT has proven to be a valuable screening method to detect the lesions, but MRI is necessary in order to properly differentiate and classify the grade of damage. These noninvasive radiological diagnostic tools can be further developed to play an important role in forensic examinations, in particular when it comes to evaluating living trauma victims.

Constitutive interaction of the P2Y2 receptor with the hematopoietic cell-specific G protein G(alpha16) and evidence for receptor oligomers

Hematopoietic cells uniquely express G(alpha16), a G protein alpha-subunit of the G(q)-type. G(alpha16) is obligatory for P2Y2 receptor-dependent Ca2+-mobilization in human erythroleukemia cells and induces hematopoietic cell differentiation. We tested whether P2Y2 receptors physically interact with G(alpha16). Receptor and G protein were fused to cyan (CFP) and yellow (YFP) variants of the green fluorescent protein (GFP), respectively. When expressed in K562 leukemia cells, the fusion proteins were capable of triggering a Ca2+-signal upon receptor stimulation, demonstrating their functional integrity. In fluorescence resonance energy transfer (FRET) measurements using confocal microscopy, a strong FRET signal from the plasma membrane region of fixed, resting cells was detected when the receptor was co-expressed with the G protein as the FRET acceptor, as well as when the CFP-tagged receptor was co-expressed with receptor fused to YFP. We conclude that, under resting conditions, G(alpha16) and P2Y2 receptors form constitutive complexes, and that the P2Y2 receptor is present as an oligomer.

A standardized protocol for the prevention of clinically relevant venous air embolism during neurosurgical interventions in the semisitting position

OBJECTIVE: We report the results and complications associated with standardized intraoperative management designed for the prevention of hemodynamically relevant venous air embolism during surgery performed in the semisitting position. METHODS: A protocol for preoperative evaluation and intraoperative monitoring was developed and applied in 187 consecutive patients who underwent surgery in the semisitting position between 1999 and 2004. The protocol included preoperative transesophageal echocardiography examination (TEE), intraoperative TEE monitoring, catheterization of the right atrium and a combination of fluid input, positive end expiratory pressure, and standardized positioning aiming at a positive pressure in the transverse and sigmoid sinuses. Data were collected retrospectively from the charts and intraoperative anesthesiological protocols of the patients for the incidence of clinically relevant air embolism (i.e., TEE-diagnosed air embolism plus a decrease in end tidal CO2 or hemodynamic changes) and other complications related to the semisitting position. RESULTS: Three cases (1.6%) of relevant venous air embolism occurred in 187 patients. Only 1 case (0.5%) was hemodynamically relevant, with temporary arterial blood pressure decrease and heart rate increase. Pneumatocephalus leading to lethargy was a frequent postoperative finding, which resolved spontaneously in all except 1 patient with epileptic seizure and oculomotor nerve palsy attributable to space-occupying subdurally trapped air, which had to be treated surgically. There was no permanent morbidity or mortality related to the semisitting position. CONCLUSION: Fear of massive venous air embolism is one reason for dramatic decline in the use of the semisitting position in neurosurgical practice. We found that strict adherence to a standardized protocol using TEE monitoring before and during surgery; exclusion of patients with patent foramen ovale; and a combination of positive end expiratory pressure, fluid input, and a standardized position aiming a positive pressure in the transverse and sigmoid sinuses helped to greatly minimize this complication to a rate of 0.5% for hemodynamically relevant events.

MR angiography of infrapopliteal arteries in patients with peripheral arterial occlusive disease by using Gadofosveset at 3.0 T: diagnostic accuracy compared with selective DSA

To prospectively compare the diagnostic accuracy of steady-state, high-spatial-resolution magnetic resonance (MR) angiography of the lower leg, performed with a blood pool contrast agent, with selective digital subtraction angiography (DSA) as the reference standard in patients with symptomatic peripheral arterial disease.