Lack of genetic association between OCT1, ABCB1, and UGT2B7 variants and morphine pharmacokinetics.

AIM: A high inter-individual variation in the pharmacokinetics and pharmacodynamics of morphine has been observed. Genetic polymorphisms in genes encoding the organic cation transporter isoform 1 (OCT1), the efflux transporter p-glycoprotein (ABCB1), and the UDP-glucuronosyltransferase-2B7 (UGT2B7) may influence morphine pharmacokinetics and thus, also pharmacodynamics. The aim of this study was to evaluate the association between OCT1, ABCB1, and UGT2B7 variants, and morphine pharmacokinetics and -dynamics in healthy volunteers. METHODS: Pharmacokinetic and pharmacodynamic data were collected from a double-blinded, randomized, crossover trial in 37 healthy subjects. Pharmacokinetic data were analyzed in NONMEM®, and the time-concentration relationship of morphine, morphine-3-glucuronide, and morphine-6-glucuronide was parameterized as the transit compartment rate constant (ktr), clearance (CL), and volume of distribution (VD). The area under the plasma concentration-time curve (AUC0-150min) and the maximum plasma concentration (Cmax) were also calculated. Pharmacodynamic data were measured as pain tolerance thresholds to mechanical stimulation of the rectum and muscle, as well as tonic cold pain stimulation ("the cold pressor test" where hand was immersed in cold water). Six different single nucleotide polymorphisms in three different genes (OCT1 (n=22), ABCB1 (n=37), and UGT2B (n=22)) were examined. RESULTS: Neither AUC0-150min, ktr, CL, nor VD were associated with genetic variants in OCT1, ABCB1, and UGT2B7 (all P>0.05). Similarly, the antinociceptive effects of morphine on rectal, muscle, and cold pressor tests were not associated with these genetic variants (all P>0.05). CONCLUSIONS: In this experimental study in healthy volunteers, we found no association between different genotypes of OCT1, ABCB1, and UGT2B7, and morphine pharmacokinetics and pharmacodynamics. Nonetheless, due to methodological limitations we cannot exclude that associations exist.

Does catastrophic thinking enhance oesophageal pain sensitivity? An experimental investigation.

BACKGROUND: Gastro-oesophageal reflux disease (GORD) is a major health problem that is frequently accompanied by debilitating oesophageal pain symptoms. OBJECTIVES: The first objective of the study was to examine the association between catastrophizing and oesophageal pain sensitivity. The second objective was to examine whether catastrophizing was associated with the magnitude of acid-induced oesophageal sensitization. METHODS: Twenty-five healthy volunteers (median age: 24.0 years; range: 22-31) were recruited and were asked to complete the Pain Catastrophizing Scale (PCS). During two subsequent study visits, mechanical, thermal, and electrical pain sensitivity in the oesophagus was assessed before and after inducing oesophageal sensitization using a 30-min intraluminal oesophageal acid perfusion procedure. RESULTS: Analyses were conducted based on data averaged across the two study visits. At baseline, catastrophizing was significantly associated with mechanical (r = -0.42, p < 0.05) and electrical (r = -0.60, p < 0.01) pain thresholds. After acid perfusion, catastrophizing was also significantly associated with mechanical (r = -0.58, p < 0.01) and electrical (r = -0.50, p < 0.05) pain thresholds. Catastrophizing was not significantly associated with thermal pain thresholds. Subsequent analyses revealed that catastrophizing was not significantly associated with the magnitude of acid-induced oesophageal sensitization. CONCLUSION: Taken together, findings from the present study suggest that catastrophic thinking exerts an influence on oesophageal pain sensitivity, but not necessarily on the magnitude of acid-induced oesophageal sensitization. WHAT DOES THIS STUDY ADD?: Catastrophizing is associated with heightened pain sensitivity in the oesophagus. This was substantiated by assessing responses to noxious stimulation of the oesophagus using an experimental paradigm mimicking features and symptoms experienced by patients with gastro-oesophageal reflux disease (GORD).

Prestorage leukocyte filtration may reduce leukocyte-derived bioactive substance accumulation in patients operated for burn trauma.

Adverse effects of perioperative blood transfusion appear to be storage-time-dependent and may be related to extracellular accumulation of bioactive substances in blood products. In this study the clinical effects of leukofiltered and non-filtered blood products in patients undergoing surgery for burn trauma are investigated. 24 consecutive patients were randomly selected to receive transfusion with non-filtered blood components (group A, n = 12) or similar products, which were prestorage leukofiltered (group B, n = 12). The burn injury was scored using the Bull and Fischer index of age and burn surface area. Histamine, interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), eosinophil cationic protein (ECP) and myeloperoxidase (MPO) were analysed in plasma or serum collected from all patients 30 min before skin incision, at skin incision and 5, 10 and 30 min and thereafter every 30 min after skin incision until the grafts were secured by wrapping. Samples were also taken 8 h after skin incision and in the morning of postoperative days 1-5. The amount of blood products transfused from admission until day 5 postoperatively was recorded. All patients were followed until discharge or death. The Bull and Fischer index was comparable in the two groups. Prestorage leukofiltration reduced the amount of blood products required for transfusion significantly (p < 0.05) compared with non-filtered products. The levels of the various bioactive substances changed during and after the operation. In particular, ECP and MPO levels increased significantly (p < 0.05) in group A patients compared with unchanged (ECP) or decreased (MPO) levels in group B patients. IL-6 analyses showed, that the trauma had more severe impact on group B patients than on group A patients. Nevertheless, 4 patients died in group A and 2 in group B; all with a Bull and Fischer index between 1.0 and 2.0. Prestorage leukocyte filtration may reduce transfusion related accumulation of various bioactive substances and the requirement for blood in burn trauma patients.

[Theophylline treatment of irreversible, chronic obstructive pulmonary disease]. / Teofyllinbehandling ved irreversibel, kronisk obstruktiv lungesygdom.

Even though the clinical efficacy is not well established, theophylline is commonly prescribed as a second or third line drug after inhaled beta 2-agonists and corticosteroids for patients with chronic obstructive pulmonary disease (COPD). The therapeutic index is narrow, and therefore theophylline is often given in a "safe standard dose", e.g. 300 mg b.i.d. We studied the long-term effect of sustained-release theophylline 300 mg b.i.d. over four weeks in 48 patients with severe irreversible COPD (FEV1: 0.99 +/- 0.45 l, FVC: 2.21 +/- 0.68 l) in a randomized, double-blind crossover study. During theophylline treatment there was significant improvements in dyspnoea score (p < 0.001) and morning peak-flow (p < 0.05). In spite of this, there was no significant change in the patients' "sense of well-being" or their daily use of inhaled beta-agonist. Spirometric tests or arterial blood gas values did not change significantly either. It is concluded that addition of theophylline in a "safe standard dose" (i.e. 300 mg b.i.d.) has only limited value in these patients.

[Incidence of drugs and euphoretic agents among motorists on the roads of Denmark. A possible relationship to traffic safety]. / Forekomsten af laegemidler og euforiserende stoffer blandt motortrafikanter i Danmark. En eventuel relation til trafiksikkerheden.

All of the Medicolegal Committee's cases from the period 1981-1985 concerning the influence of drugs on motorized road-users were reviewed. Only cases where a drug was demonstrated in blood and/or urine were included. A total of 442 cases were included in this investigation and 100 different agents, drugs and narcotics were demonstrated. In all of the cases the two drugs most frequently demonstrated were diazepam (46%) and morphine (19%). In the 46 cases where diazepam was demonstrated alone (blood alcohol concentration = 0, a significant correlation could be demonstrated between the sum of the blood concentration of diazepam and demethyldiazepam and the degree of intoxication as estimated by the clinical examination. In 87% of the cases, the road-users were men. Cannabis users had a lower age (21 years) than the road-users who had taken diazepam (28 years) or morphine (26 years) while individuals who had taken methadon had a higher average age (29 years) than those who had taken morphine. The frequencies of accidents in cases with morphine or methadon were lower than in the material as a whole while the frequency of accidents for dextropropoxyphen was higher compared with the other opiods and the material as a whole.

[Obstructive sleep apnoea syndrome. Assessment of the costs of examination and treatment in a department for pulmonary medicine]. / Obstruktivt søvnapnøsyndrom. En vurdering af omkostningerne ved undersøgelse og behandling i lungemedicinsk regi.

Twenty-five patients suspected of having obstructive sleep apnoea syndrome (OSA) were examined in the medical department. Sixteen patients had OSA. The difference between the two groups are described. The socio-economical consequences of the disease are discussed. Five of the patients remitted because of weight loss. Seven patients were successfully treated with nasal airway positive pressure. This treatment is of great benefit for the patients as well as for the society, and is inexpensive.

[Transcutaneous nerve stimulation as palliative treatment of pain]. / Transkutan nervestimulation som smertepalliativum.

The value of transcutaneous nerve stimulation (TNS) for palliative relief of pain is reviewed. The presumed mechanisms of effect are briefly described and a review of recent literature concerning TNS for acute and chronic pain, respectively, is presented. In addition, advice is given for the choice of apparatus and the technique employed is described. It is concluded that TNS may be tried with advantage in the treatment of a number of acute and chronic painful conditions of neurogenic/nocioceptive nature and that TNS has the advantage over e.g. acupuncture that the patient can administer the treatment himself.

Traffic accidents and drivers suspected for drug influence.

All records from the Danish Medicolegal Council concerning drivers suspected for drug influences were examined for the 5 year period 1981-1985. 461 records were included, 62 women and 399 men. In 250 cases drugs from more than one of ten groups had been taken thus making 786 combinations of drug/driving. The major drug group was benzodiazepines, accounting for 65% of all drug intake. Opioids also contributed substantially, found in 38% of the cases. A traffic accident had occurred in 180 (39%) of the records. Drivers who had been taking antidepressives were involved in an accident in 67%, significantly above the mean. For benzodiazepines, the corresponding percentage was 43%, while for opioids it was only 23%, significantly below the mean. This striking difference has been demonstrated in most of the studies concerning drugs in traffic. It may support the hypothesis that opioids do not necessarily make driving dangerous, as do antidepressives, barbiturates and especially benzodiazepines.

[Analgesics, benzodiazepines and traffic]. / Analgetika, benzodiazepiner og trafik.

A number of articles concerned with competence to drive motor vehicles under the influence of psychotropic agents were reviewed with the object of assessing the abilities of patients receiving treatment with pain-killing drugs to drive. The majority of psychotropic agents decreased the capacity to drive considerably, when the person concerned is not used to these drugs and even after habituation where benzodiazepines are concerned. Some investigations suggest that opioids such as metadone are only dangerous in traffic until the person concerned has become adjusted to a regular dosage. The methodological problems in the investigations are discussed with particular attention to the specificity of the method of measurement. Orienting driving tests are recommended compared with epidemiological investigations.

Subclavian vein catheterization for acute and chronic haemodialysis. A safe temporary vascular access.

The technique and use of a percutaneous subclavian vein catheter for haemodialysis in 20 patients are reported. The catheterization procedure carried a very low morbidity, and blood flow rates of 200-250 ml/min were achieved through the catheters. Use of this angioaccess saves future possible sites for permanent vascular access. Infectious complications were not encountered. Subclavian vein catheterization is a favourable alternative to external Silastic Teflon shunt.

Diurnal variations in plasma prolactin, growth hormone, cortisol and blood glucose in labile diabetes mellitus.

In labile diabetes mellitus wihout ketoacidosis we have studied plasma prolactin levels and a possible causal connection between fluctuation in blood glucose concentration and plasma prolactin, growth hormone and cortisol levels. The hormone concentrations in plasma and blood glucose concentration were determined at 20 min intervals for a 24 h period in six male patients with insulin treated diabetes mellitus. Prolactin varied within the normal range but without any significant rise in relation to sleep in five out of the six patients. Growth hormone levels were low with superimposed secretory peaks. Plasma cortisol showed a normal diurnal rhythm. Blood glucose fluctuated as expected, but the variations and especially the falls in blood glucose to non-hypoglycaemic levels were not followed by increases in plasma hormone concentrations. No relationship could be demonstrated between the changes in the plasma concentration of prolactin, growth hormone and cortisol.