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Biomedical subjects

O Dale

Publications and source records attributed to O Dale.

At least 19 recordsLinked to original sources
PubMed2005

Genetic variability and clinical efficacy of morphine.

The individual variability of opioid pharmacology suggests that the patients' genetic disposition influences the response to opioids. Given the complexity of morphine pharmacology, variability may be caused by several genes. We review data which shows that variability in genes coding the enzyme metabolizing morphine (UGT2B7 gene), mu-opioid receptors (OPRM gene) and blood-brain barrier (BBB) transport of morphine by multidrug resistance transporters (MDR1 gene) influences the clinical efficacy of morphine. Furthermore, variability in an enzyme degrading catecholamines (COMT gene) alters the efficacy of morphine demonstrating that genetic variability in non-opioid systems may indirectly influence the clinical efficacy from morphine. Thus, results obtained so far strongly argue that opioid efficacy is partly related to inborn properties caused by genetic variability.

Catechol O-Methyltransferase↗
PubMed2005

Effects of autotransfusion of mediastinal shed blood on biochemical markers of myocardial damage in coronary surgery.

BACKGROUND: Previous studies have shown conflicting results regarding the effect of autotransfusion of mediastinal shed blood after coronary artery bypass grafting (CABG) on the serum levels of myocardial band (MB) isoenzymes of creatine kinase (CK-MB) and cardiac troponins. The effect of autotransfusion on serum levels of human heart fatty acid binding protein (H-FABP), another marker of myocardial necrosis, has not been studied. The aim of the present study was to investigate the effects of autotransfusion of mediastinal shed blood on the serum levels of CK-MB, cardiac troponin T (cTnT), and H-FABP after uncomplicated primary CABG. METHODS: Fifty patients were randomized to post-operative autotransfusion of mediastinal shed blood or no autotransfusion. Blood samples for the analysis of the biochemical markers of myocardial damage were drawn pre-operatively and 1, 4, 12, 24, 48, and 72 h after the termination of cardiopulmonary bypass. Samples from the mediastinal shed blood were collected after 1 and 4 h. RESULTS: The levels of the biochemical markers of myocardial injury were all markedly elevated in mediastinal shed blood. Autotransfusion did not significantly affect the serum levels of cTnT or H-FABP. However, during the early post-operative hours, there was a trend towards a higher level of cTnT and H-FABP in the autotransfusion group. During the first 24 h after surgery, the autotransfusion group had a significantly higher serum level of CK-MB. CONCLUSION: Post-operative autotransfusion of mediastinal shed blood may contribute to elevated serum levels of biochemical markers of myocardial injury.

Aged↗
PubMed2004

Supplemental remifentanil during coronary artery bypass grafting is followed by a transient postoperative cardiac depression.

BACKGROUND: The pharmacokinetic properties of the short-acting micro opioid receptor-agonist remifentanil makes it possible to give cardiac surgical patients a deep intraoperative anesthesia without experiencing postoperative respiratory depression and a prolonged stay in the intensive care unit (ICU). However, previous investigations have shown that patients who received remifentanil required additional analgesia during the early postoperative period as compared to patients who received fentanyl. The aim of the present study therefore was to investigate the effects of supplementing remifentanil to a standard fentanyl-based anesthesia in coronary artery bypass grafting (CABG). METHODS: The study was prospective, randomized, double-blind, and placebo-controlled. Twenty male patients aged 55-70 years were included. All patients received a standard fentanyl and isoflurane-based anesthesia. In addition, the patients were randomized to receive either remifentanil 0.5 micro g kg(-1) min(-1) or placebo during surgery. Hemodynamic recordings and measurements of blood glucose and plasma adrenaline and noradrenaline were performed intra- and postoperatively. RESULTS: Remifentanil reduced the hemodynamic and metabolic response to surgical stress compared to the standard fentanyl-based anesthetic regimen. However, the patients in the remifentanil group had a lower cardiac output (CO), left ventricular stroke work index (LVSWI), and mixed venous oxygen saturation (SvO(2)), and a higher central venous pressure (CVP) than the patients in the placebo group during the early postoperative phase, indicating a postoperative cardiac depression in the remifentanil group. CONCLUSION: In CABG, remifentanil reduces the hemodynamic and metabolic responses during surgery but seems to give a cardiac depression in the early postoperative phase.

Aged↗
PubMed2004

The 118 A > G polymorphism in the human mu-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease.

BACKGROUND: Dispositions for genes encoding opioid receptors may explain some variability in morphine efficacy. Experimental studies show that morphine and morphine-6-glucuronide are less effective in individuals carrying variant alleles caused by the 118 A > G polymorphism in the mu-opioid receptor gene (OPRM1). The purpose of the study was to investigate whether this and other genetic polymorphisms in OPRM1 influence the efficacy of morphine in cancer pain patients. METHODS: We screened 207 cancer pain patients on oral morphine treatment for four frequent OPRM1 gene polymorphisms. The polymorphisms were the -172 G > T polymorphism in the 5'untranslated region of exon 1, the 118 A > G polymorphism in exon 1, and the IVS2 + 31 G > A and IVS2 + 691 G > C polymorphisms, both in intron 2. Ninety-nine patients with adequately controlled pain were included in an analysis comparing morphine doses and serum concentrations of morphine and morphine metabolites in the different genotypes for the OPRM1 polymorphisms. RESULTS: No differences related to the -172 G > T, the IVS2 + 31 G > A and the IVS2 + 691 G > C polymorphisms were observed. Patients homozygous for the variant G allele of the 118 A > G polymorphism (n = 4) needed more morphine to achieve pain control, compared to heterozygous (n = 17) and homozygous wild-type (n = 78) individuals. This difference was not explained by other factors such as duration of morphine treatment, performance status, time since diagnosis, time until death, or adverse symptoms. CONCLUSION: Patients homozygous for the 118 G allele of the mu-opioid receptor need higher morphine doses to achieve pain control. Thus, genetic variation at the gene encoding the mu-opioid receptor contributes to variability in patients' responses to morphine.

Aged↗
PubMed2003

Gender differences in drug effects: implications for anesthesiologists.

BACKGROUND: The gender aspect in pharmacokinetics and pharmacodynamics of anesthetics has attracted little attention. Knowledge of previous work is required to decide if gender-based differences in clinical practice is justified, and to determine the need for research. METHODS: Basis for this paper was obtained by Medline searches using the key words 'human' and 'gender' or 'sex,' combined with individual drug names. The reference lists of these papers were further checked for other relevant studies. RESULTS: Females have 20-30% greater sensitivity to the muscle relaxant effects of vecuronium, pancuronium and rocuronium. When rapid onset of or short duration of action is very important, gender-modified dosing may be considered. Males are more sensitive than females to propofol. It may therefore be necessary to decrease the propofol dose by 30-40% in males compared with females in order to achieve similar recovery times. Females are more sensitive than males to opioid receptor agonists, as shown for morphine as well as for a number of kappa (OP2) receptor agonists. On this basis, males will be expected to require 30-40% higher doses of opioid analgesics than females to achieve similar pain relief. On the other hand, females may experience respiratory depression and other adverse effects more easily if they are given the same doses as males. CONCLUSION: These examples illustrate that gender should be taken into account as a factor that may be predictive for the dosage of several anesthetic drugs. Moreover, there is an obvious need for more research in this area in order to further optimize drug treatment in anesthesia.

Adrenergic Agents↗
PubMed2003

Randomized, double-blind, placebo-controlled study of the effect of rectal paracetamol on morphine consumption after abdominal hysterectomy.

BACKGROUND: Paracetamol is widely used for postoperative analgesia. The effect is well documented in minor and moderate extensive surgery, but the effect of paracetamol as an adjunct to opioids in major abdominal surgery is less examined. METHODS: Seventy-eight patients scheduled for elective, benign, and abdominal hysterectomy were included in a prospective, randomized, double-blind, parallel group, placebo-controlled study to evaluate the effect of rectal paracetamol in conjunction with intravenous patient-controlled analgesia (PCA) morphine. Paracetamol 1000 mg or placebo suppositories were given four times daily during the 60-h study period. I.V. morphine was administered via a PCA pump, limited to maximum of 12 mg h-1. Morphine consumption, pain and morphine-related adverse effects were recorded. A single-point analysis was comprised of serum concentrations of paracetamol and morphine. RESULTS: Sixty patients were evaluated: 30 in each group. A 16.6% reduction in overall-accumulated morphine consumption in the treatment group (99.6 vs. 83.3 mg) was observed (NS, P = 0.06). Mean paracetamol serum concentration was 0.03 mmol l-1 (range: 0.01-0.06 mmol l-1). None of the patients had a paracetamol concentration within the therapeutic range for antipyretic efficacy. Patients with a higher paracetamol concentration had a lower concomitant morphine (P = 0.025) and morphine-6-glucuronide (P = 0.014) concentration 2 h after paracetamol administration. CONCLUSION: A dosage of rectal paracetamol 1000 mg four times daily is too low, as all displayed a suboptimal serum paracetamol concentration. To study the effect of rectal paracetamol after major surgery we have to increase the dose, as higher serum concentrations of paracetamol may cause lower serum concentrations of morphine.

Acetaminophen↗
PubMed2003

Influences on serum concentrations of morphine, M6G and M3G during routine clinical drug monitoring: a prospective survey in 300 adult cancer patients.

BACKGROUND: In order to make treatment decisions physicians should have knowledge about the relations between patient characteristics and drug disposition. Dose, route of administration, gender, age and renal function are reported to influence the serum concentrations of morphine, morphine-6-glucurnide (M6G) and morphine-3-glucuronide (M3G) during chronic treatment of cancer pain. These factors, however, are not evaluated in studies with a sample size sufficient to explore predictive factors. METHODS: Three hundred consecutive morphine users admitted because of a malignant disease were recruited. The relations of serum concentrations of morphine, M6G and M3G to patient characteristics (gender, age, weight, renal function, liver function, dose, route of administration) were explored, and regression analysis performed to investigate whether these characteristics predicted serum concentrations obtained during routine clinical drug monitoring. RESULTS: Morphine dose was associated with serum concentrations of morphine (r = 0.69), M6G (r = 0.76) and M3G (r = 0.76). Oral morphine resulted in higher dose-adjusted M6G and M3G serum concentrations compared with s.c. morphine. Creatinine serum concentrations correlated with serum concentrations of M6G and M3G. Dose and route of administration predicted morphine serum concentrations, while dose and renal function predicted M6G and M3G serum concentrations. Age was an additional factor predicting M3G concentrations. Dose was the only factor that explained a clinically significant part of the observed variability. CONCLUSION: Patient characteristics predict only minor parts of the variability of morphine, M3G and M6G serum concentrations observed during routine clinical drug-monitoring in cancer patients.

Adult↗
PubMed2002

Nasal administration of opioids for pain management in adults.

BACKGROUND: Nasal administration of opioids may be an alternative route to intravenous, subcutaneous, oral transmucosal, oral or rectal administration in some patients. Key features may be self-administration, combined with rapid onset of action. The aim of this paper is to evaluate the present base of knowledge on this topic. METHODS: The review is based on human studies found in Medline or in the reference list of these papers. The physiology of the nasal mucosa and some pharmaceutical aspects of nasal administration are described. The design of each study is described, but not systematically evaluated. RESULTS: Pharmacokinetic studies in volunteers are reported for fentanyl, alfentanil, sufentanil, butorphanol, oxycodone and buprenorphine. Mean times for achieving maximum serum concentrations vary from 5 to 50 min, while mean figures for bioavailability vary from 46 to 71%. Fentanyl, pethidine and butorphanol have been studied for postoperative pain. Mean onset times vary from 12 to 22 min and times to peak effect from 24 to 60 min. There is considerable interindividual variation in pharmacokinetics and clinical outcome. This may partly be due to lack of optimization of nasal formulations. Patient-controlled nasal analgesia is an effective alternative to intravenous PCA. Adverse effects are mainly those related to the opioids themselves, rather than to nasal administration. Some experience with nasal opioids in outpatients and for chronic pain has also been reported. CONCLUSION: Nasal administration of opioids has promising features, but is still in its infancy. Adequately designed clinical studies are needed. Improvements of nasal sprayer devices and opioid formulations may improve clinical outcome.

Administration, Intranasal↗
PubMed1999

Decreased glutamate metabolism in cultured astrocytes in the presence of thiopental.

The effect of thiopental on glutamate metabolism was studied by 13C magnetic resonance spectroscopy. Cerebral cortical astrocytes were incubated with 0.5 mM [U-13C]glutamate for 2 hr in the presence of 0.5 or 1 mM thiopental. Labeled glutamate, glutamine, aspartate, and glutathione were observed in cell extracts, and glutamine, aspartate, and lactate in the medium. Not only present in the medium was uniformly labeled glutamate, but also glutamate derived from the tricarboxylic acid (TCA) cycle, and thus glutamate release could be detected. The amounts of [U-13C]glutamate and unlabeled glucose taken up by astrocytes were unchanged in the presence of 0.5 mM thiopental and decreased to about 50% and 80%, respectively when the concentration was increased to 1 mM. The amounts of most metabolites synthesized from [U-13C]glutamate were unchanged in the presence of 0.5 mM thiopental, but decreased [U-13C]glutamine, [U-13C]aspartate, and [U-13C]lactate were observed in the 1 mM group. Surprisingly, the amounts of [1,2,3-13C]glutamate, [2,3-13C]aspartate, and [3,4-13C]aspartate (2nd turn via the TCA cycle) were unchanged. However, this was not the case for [1,2-13C]lactate and [2,3-13C]lactate. Such variations indicate cellular compartmentation, possibly caused by a heterogeneous glutamate concentration within the cells affecting TCA cycle turnover rates differently.

Anesthetics, Intravenous↗
PubMed1999

Focus on mobilisation after lower abdominal surgery. A double-blind randomised comparison of epidural bupivacaine with morphine vs. lidocaine with morphine for postoperative analgesia.

BACKGROUND: Epidural infusion of morphine, usually with bupivacaine, for postoperative pain relief has proved to be safe and effective. Lidocaine with its short duration of action and low toxicity may be an alternative to bupivacaine. The clinical importance of the choice of local anaesthetic drug on mobilisation after lower abdominal surgery has not been studied previously. METHODS: A total of 52 patients was randomised to epidural infusion of morphine (1.6-4.4 micrograms.kg-1.h-1) with either lidocaine (0.44-0.98 mg.kg-1.h-1) or bupivacaine (0.10-0.28 mg.kg-1.h-1) in a double-blind fashion. The time to mobilisation, degree of pain relief, blood pressure, respiration and motor function were recorded at regular intervals postoperatively for 40 h. Serum concentrations of lidocaine, its main metabolite monoethylglycinexylidide (MEGX) and bupivacaine were measured at 3, 15 and 40 h. RESULTS: There were no significant differences in the clinical characteristics between the two patient groups. There were no significant differences in the time from the end of surgery to the time the patients were able to stand without support (bupivacaine: median 24 h (interquartile range (IQR): 22-31), lidocaine: median 28 h (IQR 23-40), P = 0.15) or were able to walk without support (bupivacaine: median 46 h (IQR 28-62), lidocaine: median 48 h (IQR 35-54), P = 0.78). No significant differences between the groups were recorded with respect to pain relief, blood pressure, respiration, sedation score and motor function. The plasma concentration of lidocaine and bupivacaine increased significantly during the treatment period (P < 0.01 for both drugs), but not the concentration of MEGX. The highest venous lidocaine concentration was 17.5 mumol/l and the highest bupivacaine concentration was 18.8 mumol/l. There was a significant correlation between the concentration of both lidocaine and bupivacaine and the concentration of alpha 1-acid glycoprotein (AAG) (lidocaine: r = 0.77, P < 0.001, bupivacaine: r = 0.60, P < 0.001), suggesting that the free fraction of the drugs did not increase. No patients showed serious signs of toxicity. The epidural infusion rates remained stable in both groups during the study period. CONCLUSION: There were no clinically or statistically significant differences in the postoperative course after lower abdominal surgery in patients who received an epidural infusion of morphine combined with bupivacaine as compared to patients who received morphine with lidocaine. Further clinical studies to establish the place of lidocaine in postoperative epidural analgesia should be performed.

Abdomen↗
PubMed1999

Pharmacokinetics of eltanolone in male and female patients following intravenous bolus injection.

BACKGROUND: The pharmacokinetics of the steroid anesthetic eltanolone have been studied in male volunteers. However, steroids may exhibit gender-related differences in pharmacokinetics and surgery may alter drug disposition. METHODS: Male (n = 12) and female (n = 9) ASA 1-2 patients (age 26-45 yrs) undergoing discectomy with microsurgical technique were included. Anesthesia was induced with eltanolone 0.75 mg/kg and maintained with nitrous oxide, fentanyl and atracurium. Venous blood was sampled for up to 12 h and analyzed for eltanolone and its major metabolites. RESULTS: Induction was smooth and anesthesia uneventful, except that five cases developed a mild transient erythema. Loss of verbal contact occurred within 20-60 s. Pharmacokinetics in one person deviated significantly from the rest of the subjects. No difference between groups with respect to the primary outcome variable noncompartmental clearance (Cl, 1/min) 1.7 vs 1.6, was found. However, the volume of distribution at steady state (Vss, 1/kg) was larger in women (3.1) compared to men (1.3). The pharmacokinetics followed a three-compartment model. The half-lives (min) of the alpha, beta and gamma phases (men vs women, medians) were 1.5 vs 2.2, 42 vs 40 and 222 vs 360, respectively. Area under the curve (AUC, min microgram/l) was 39,810 vs 34,905. Context-sensitive modelling indicated that it may take 10 min more for women than men to recover from an eltanolone infusion of 2 h duration. CONCLUSION: The gender-related differences in the pharmacokinetics of eltanolone were small, and of little clinical significance for induction of anesthesia with eltanolone.

Adult↗
PubMed1999

Gender aspects of liver slice incubations with N,N,N-triethylene-thiophosphamide (Thio-TEPA) in rats and mice.

This study was conducted to investigate if biotransformation of N,N,N-triethylene-thiophosphoramide (thio-TEPA) by liver slice incubations reflects the established gender pattern for rat and mouse. Liver slices from rat and mice of both genders were incubated with start concentrations of thio-TEPA of 5.2, 26, 52 and 104 microM for up to 240 min. Male rat liver slices eliminated thio-TEPA faster and formed more TEPA than female liver slices at any concentration. No gender difference was found for the elimination of thio-TEPA in mice, however, the female liver slices formed less TEPA than the male ones. Apparently female rat liver slices formed less TEPA than female mice liver slices. It is concluded that the liver slice incubation system in a robust manner reflects gender differences in rat drug biotransformation with special reference to thio-TEPA. It is also confirmed that these aspects of gender are less pronounced in the examined mouse species than in rats.

Animals↗
PubMed1995

[Oral contraceptives and elective surgery. Strategies in Norwegian hospitals, thromboembolic complications and perioperative conception].

It is widely accepted that treatment with combined oral contraceptives may increase the risk of venous thromboembolism perioperatively. Serious adverse effects such as allergic reactions or bleeding may result from thromboprophylaxis, while stopping the pill may lead to unwanted pregnancy. The objectives of this study were to examine how women on oral contraceptives were treated in Norwegian hospitals in relation to elective surgery, the number of spontaneously reported adverse drug reactions related to thromboprophylaxis, the number of diagnoses of venous thrombo-embolism combined with elective surgery in Norwegian hospitals, and the pregnancy rate in the perioperative pill-free period in this group of women. The study showed that Norwegian hospitals treated women on oral contraceptives in accordance with widely accepted guidelines. No serious adverse drug reactions related to thromboprophylaxis were found, and the frequency of venous thromboembolism in relation to elective surgery seemed to be remarkably small. The pregnancy rate in a perioperative pill-free period appeared to be low, since the women resumed contraception relatively soon after their first postoperative menstrual cycle. It is concluded that the procedures applied in Norwegian hospitals in 1989-90 were safe for this group of patients.

Adolescent↗