The incidence of psychoactive substances and alcohol among impaired drivers in Denmark in 2015-2019.

This study examines the presence of psychoactive drugs and alcohol in blood from apprehended drivers driving under the influence of drugs (DUID) and alcohol in Denmark in a five-year period from 2015 to 2019. Data were analysed with respect to gender, age, substances with concentrations above the Danish legal limit, arresting time of day and repeat arrest. By request of the police, the blood samples were subjected to analysis for alcohol and/or tetrahydrocannabinol (THC) alone, for "other drugs" (covering all drugs including new psychoactive substances (NPS), except THC, listed in the Danish list of narcotic drugs) or for both THC and other drugs. About the same number of alcohol traffic cases (37,960) and drug traffic cases (37,818) were submitted for analysis for the five-year period. The number of drug traffic cases per year increased from 5660 cases in 2015 to 9505 cases in 2019, while the number of alcohol traffic cases per year (average, 7600) was unchanged. Ethanol (89.2%) was the overall most frequent single substance, followed by THC (68.2%). CNS stimulants (46.8%) were the second most prevalent group of non-alcoholic drugs. Cocaine (23.8%) and amphetamine (22.9%) were the most frequent CNS stimulants. The proportion of CNS-stimulant positive drivers more than doubled in ten years. Benzodiazepines/z-hypnotics (12.7%) were the third most prevalent drug group detected, with clonazepam (8%) as the most frequent drug. Opioids were above the legal limit in 9.8% of the cases. NPS was above the legal limit in 128 cases (0.6%). Poly-drug use occurred in 40% of the DUID cases in the requested groups: other drug or other drug/THC. Young males dominated the DUID cases (median age 26). Drink-drivers (median age 39) were also mainly men, but the age distribution was equally spread over the age groups. Re-arrest occurred more often in DUID drivers (18-29%) than in drinking drivers (6-12%). DUID was evenly spread over the week, while drink-driving was most frequent on weekends. This study is an important supplement to the knowledge of drug use in Denmark. It was the well-known psychoactive substances that were detected. Only a few NPS occurred. However, the abuse pattern has changed, and CNS stimulants now account for a much higher proportion than earlier. Our results indicate a drug use problem among DUID drivers. This gives rise to concern because of a risk of traffic accidents. Treating the underlying abuse problem is therefore recommended, rather than focusing solely on prosecuting.

Postmortem analysis of three methoxyacetylfentanyl-related deaths in Denmark and in vitro metabolite profiling in pooled human hepatocytes.

Methoxyacetylfentanyl belongs to the group of fentanyl analogues and has been associated with several deaths in recent years. We present three case reports of deceased individuals that tested positive for methoxyacetylfentanyl consumption, as well as in vitro and in vivo metabolite profiles. Methoxyacetylfentanyl was quantified by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) in femoral blood, as well as in urine and brain tissue when these were available. Metabolite profiling was performed by incubating methoxyacetylfentanyl with pooled human hepatocytes (pHH) in Leibovitz's L-15 medium supplemented with fetal bovine serum. Metabolites were identified in vivo and in vitro using UHPLC-high resolution (HR)-MS/MS. The measured methoxyacetylfentanyl concentration was 0.022-0.056mg/kg (N=3) in femoral blood, 0.12mg/kg (N=1) in urine, and 0.074mg/kg (N=1) in brain tissue homogenate. A total of 10 metabolites were identified. The observed metabolic pathways were: hydroxylation(s), N-dealkylation, O-demethylation, deamination, glucuronidation, and combinations thereof. Major analytical targets in vitro and across measured biological samples in vivo were methoxyacetylfentanyl, the O-demethyl- metabolite, and the deamide-metabolite. Intoxication with methoxyacetylfentanyl was judged as the cause of death or a major contributing factor in all three presented cases.

General practitioners' and nurses' views on medication reviews and potentially inappropriate medicines in elderly patients - a qualitative study of reports by educating pharmacists.

OBJECTIVE: The aim with this study was to understand more about how general practitioners (GPs) and nurses in primary care experience their work with medication reviews in elderly patients. DESIGN: This qualitative study was nested within a cluster randomised trial and analysed narrative and unstructured diaries written by two pharmacists who performed academic detailing, i.e. educational outreach visits in primary care. The educational sessions dealt with potentially inappropriate medicines, and stimulated interprofessional dialogue in relation to medication reviews. The purpose of the diaries was to document and structure the pedagogical process of academic detailing and contained quotes from 194 GP and 113 nurse participants in the sessions, and the pharmacists' reflections. The data was explored using thematic analysis. SETTING: Thirty-three primary care practices in Stockholm, Sweden. SUBJECTS: GPs and nurses working in primary care. MAIN OUTCOME MEASURES: Thematic descriptions of academic detailing by pharmacists. RESULTS: Five themes were identified: 1) Complexity in 3 'P': patients, pharmacotherapy, and primary care; 2) What, when, who? Clash between GPs' and nurses' experiences and guidelines; 3) Real-world problems and less-than-ideal solutions; 4) Eureka? Experiences with different steps during a medication review; and 5) Threats to GP autonomy. CONCLUSION: GPs and nurses should participate in the construction and release of guidelines in order to increase their usability in clinical practice. Future research should analyse if alternative strategies such as condensed medical reviews and feedback on prescribing are easier to implement in primary care. Key points Complex medication reviews have been introduced on a large scale in Swedish primary care, but knowledge on GPs' and nurses' views on such reviews is lacking. In the context of primary care alternative strategies such as condensed medication reviews and feedback on prescribing may be more applicable than medication reviews according to guidelines. GPs and nurses should make contributions to the development of guidelines on medication reviews in order to increase their usability in clinical practice.

Educational intervention on medication reviews aiming to reduce acute healthcare consumption in elderly patients with potentially inappropriate medicines-A pragmatic open-label cluster-randomized controlled trial in primary care.

PURPOSE: Potentially inappropriate medicines (PIMs) may cause 10% of unplanned admissions in elderly people. We performed an educational intervention in primary care to reduce acute health care consumption and PIMs through the promotion of medication reviews (MRs) in elderly patients. METHODS: This cluster-randomized controlled trial was conducted in the context of an official campaign promoting rational drug use in elderly people. Sixty-nine primary health care practices with 119,910 patients aged older than or equal to 65 were randomized, with 1 dropout in the intervention group. The intervention consisted of educational outreach visits with feedback on prescribing and the development of a working procedure on MRs. Follow-up was 9 months. Outcomes were assessed in an administrative health care database. The combined primary outcome was unplanned hospital admission and/or emergency department visit. Secondary outcomes were among other PIMs and rates of MRs. The risk differences in outcomes between intervention and control group were estimated by using regression models. RESULTS: During follow-up, 22.8% of patients in the intervention and 22.0% in the control group were admitted unplanned to hospital and/or experienced at least 1 emergency department (nonsignificant risk difference 0.8%, 95% CI -0.7% to 2.4%). There were no significant differences regarding secondary outcomes such as PIMs or MRs. CONCLUSIONS: No changes were seen in acute health care consumption, PIMs, and MRs in elderly patients after an educational intervention in primary care. The reasons for the lack of effect could be a suboptimal intervention, limitations in outcome measures, and the use of administrative data to monitor outcomes.

The use of a Swedish telephone medical advice service by the elderly - a population-based study.

OBJECTIVE: The present study aimed to describe contact made by the elderly to Sweden's nationwide medical helpline, Healthcare Guide 1177 by Phone (HGP). Other objectives were to study potential gender differences and the association between different HGP referral levels and acute visits to hospital-based emergency departments and acute visits to primary care centres. DESIGN: De-identified data from recorded calls to HGP was extracted for analysis (n = 7477 for the oldest age group). Information about acute visits to emergency departments and to primary care reception was extracted from the patient administration system. SETTING: Västerbotten County, Sweden. SUBJECTS: Patients over 80 years. MAIN OUTCOME MEASURES: Calling and visiting frequencies for different age groups as well as reasons for contact and individual recommendations. RESULTS: The utilisation rate of the telephone advice service for the oldest age group was high, with an incidence rate of 533 per 1000 person-years. Women had a 1.17 times higher incidence rate compared with men. The most common reason for contact was drug-related questions (17% of all contacts). Calls that were recommended to care by a medical specialist correlated with total emergency department visits (r = 0.30, p < 0.05) and calls that were given advice correlated with acute primary healthcare visits (r = 0.38, p = 0.005). CONCLUSION: The high utilisation of the telephone advice service by the elderly gives the telephone advice service a unique ability to function as a gatekeeper to further healthcare. Our data suggest that with the telephone advice service's present guidelines, a significant proportion of all calls are being directed to further medical help. The high frequency of drug-related questions raises concerns about the elderly's medication regimens. Key points Patients over 80 years of age had a high utilisation of the telephone medical advice service compared with other age groups. Drug-related questions were the most common reason for contact. A significant proportion of all calls made resulted in further heatlhcare contacts.

Nurse-led empowerment strategies for patients with hypertension: a questionnaire survey.

BACKGROUND: Hypertension is common and may lead to cerebrovascular and cardiovascular events and mortality. District nurses frequently encounter patients requiring blood pressure monitoring, lifestyle counsel and support. Empowerment as a method enables patients to both increase their control over their health and improve it. AIM: This study aims to describe the effects of the counsel and support from district nurses to patients with hypertension. METHODS: A randomized controlled intervention trial. Questionnaires were answered by patients with hypertension before and after the intervention comprising district nurses' counsel and support based upon empowerment. A specially developed card for blood pressure monitoring was also used. RESULTS: Blood pressure decreased in intervention and the control groups. The intervention group experienced significantly improved health, with better emotional and physical health, and reduced stress. Living habits did not change significantly in either group. Satisfaction with knowledge of hypertension increased significantly in both groups. The intervention group reported that their care was based upon their health needs. LIMITATIONS: Conducting large multi-centre studies with long follow-ups is complicated and results sometimes have a tendency to decline with time. A shorter follow-up might have shown a greater difference between the groups. CONCLUSION: Nursing interventions through district nurses' counsel and support with empowerment improved patients' health. More research is needed to evaluate nursing interventions' effect on hypertension. IMPLICATIONS FOR NURSING AND HEALTH POLICY: This study highlighted that district nurses' counsel and support increased patients' health and decreased stress by focusing on empowerment.

The suprasacral parallel shift vs lumbar plexus blockade with ultrasound guidance in healthy volunteers--a randomised controlled trial.

Surgical anaesthesia with haemodynamic stability and opioid-free analgesia in fragile patients can theoretically be provided with lumbosacral plexus blockade. We compared a novel ultrasound-guided suprasacral technique for blockade of the lumbar plexus and the lumbosacral trunk with ultrasound-guided blockade of the lumbar plexus. The objective was to investigate whether the suprasacral technique is equally effective for anaesthesia of the terminal lumbar plexus nerves compared with a lumbar plexus block, and more effective for anaesthesia of the lumbosacral trunk. Twenty volunteers were included in a randomised crossover trial comparing the new suprasacral with a lumbar plexus block. The primary outcome was sensory dermatome anaesthesia of L2-S1. Secondary outcomes were peri-neural analgesic spread estimated with magnetic resonance imaging, sensory blockade of dermatomes L2-S3, motor blockade, volunteer discomfort, arterial blood pressure change, block performance time, lidocaine pharmacokinetics and complications. Only one volunteer in the suprasacral group had sensory blockade of all dermatomes L2-S1. Epidural spread was verified by magnetic resonance imaging in seven of the 34 trials (two suprasacral and five lumbar plexus blocks). Success rates of the sensory and motor blockade were 88-100% for the major lumbar plexus nerves with the suprasacral technique, and 59-88% with the lumbar plexus block (p > 0.05). Success rate of motor blockade was 50% for the lumbosacral trunk with the suprasacral technique and zero with the lumbar plexus block (p < 0.05). Both techniques are effective for blockade of the terminal nerves of the lumbar plexus. The suprasacral parallel shift technique is 50% effective for blockade of the lumbosacral trunk.

Antihypertensive treatment and control in a large primary care population of 21 167 patients.

The efficacy of antihypertensive drug therapy is undisputed, but observational studies show that few patients reach a target blood pressure <140/90 mm Hg. However, there is limited data on the drug prescribing patterns and their effectiveness in real practice. This retrospective observational survey of electronic patient records extracted data from 24 Swedish primary health-care centres, with a combined registered population of 330 000 subjects. We included all patients > 30 years with a recorded diagnosis of hypertension who consulted the centres in 2005 or 2006 (n=21 167). Main outcome measures were systolic and diastolic blood pressures, and prescribed antihypertensive drug classes. Only 27% had a blood pressure <140/90 mm Hg. The number of prescribed drugs increased with age, except among the oldest (> 90 years). Only 29% of patients given monotherapy had a blood pressure <140/90 mm Hg. Women more often received diuretics (52 vs 42%), and less often angiotensin-converting enzyme inhibitors (22 vs 33%) and calcium channel blockers (26 vs 31%) than men. ß-Blockers and diuretics were the most common drug classes prescribed, independent of comorbidity. In conclusion, one out of four primary care patients with hypertension reach target blood pressure. More frequent use of drug combinations may improve blood pressure control.

Potential savings without compromising the quality of care.

AIMS: This study was designed to analyse the association between adherence to guidelines for rational drug use and surrogate outcome markers for hypertension, diabetes and hypercholesterolaemia. METHODS: The study used a cross-sectional ecological design. Data from dispensed prescriptions and medical records were analysed from 24 primary healthcare centres with a combined registered population of 330,000 patients in 2006. Guideline adherence was determined calculating the proportion of the prescribed volume of antidiabetic agents, antihypertensives and lipid-lowering agents representing the 14 different drugs included in the guidelines for these three areas. Patient outcome was assessed using surrogate marker data on HbA1C, blood pressure (BP) and s-cholesterol. The association between the guidelines adherence and outcomes measures was analysed by logistic regression. RESULTS: The proportion of guideline antidiabetic drugs in relation to all antidiabetic drugs prescribed varied between 80% and 97% among the practices, the ratio of angiotensin converting enzyme (ACE)-inhibitors to all renin-angiotensin drugs 40-77% and the ratio of simvastatin to all statins 58-90%. The proportion of patients reaching targets for HbA1C, BP and s-cholesterol varied between 34% and 66%, 36% and 57% and 46% and 71% respectively. No significant associations were found between adherence to the guidelines and outcome. The expenditures for antihypertensives and lipid-lowering drugs could potentially be reduced by 10% and 50% respectively if all practices adhered to the guidelines as the top performing practices. CONCLUSION: A substantial amount of money can be saved in primary care without compromising the quality of care by using recommended first-line drugs for the treatment diabetes, hypertension and hypercholesterolaemia.

Fully automated on-line quantification of quetiapine in human serum by solid phase extraction and liquid chromatography.

A quantitative method for determination of quetiapine (QTP) in human serum is presented. The method is fully automated and based on high performance liquid chromatography (HPLC) with on-line solid phase extraction (SPE). The extraction procedure is based on a C2 cartridge, which is eluted with methanol. The eluate is injected onto a silica column with a mobile phase consisting of methanol:20 mM NH(4)CH(3)COO, pH 5.0 (99:1). Quetiapine is quantified by ultra-violet (UV) absorbance at 257 nM with trifluoperazine as the internal standard (I.S.). The extraction recoveries for quetiapine and trifluoperazine were 69 and 57%, respectively. The total inter day coefficient of variation was 11.1, 3.8 and 3.1% at 20, 500 and 1000 nM, respectively. The detection limit was 10.3 nM quetiapine. The method has been used in our therapeutic drug monitoring (TDM) laboratory where co-administered drugs often are observed. In an investigation of analytical interference from co-administered drugs, demethyl-mianserine was the only drug which interfered with the internal standard. There was no interference with quetiapine itself. The method showed good agreement with mass spectrometric quantification of quetiapine.

Pharmacokinetics and non-analgesic effects of S- and R-ketamines in healthy volunteers with normal and reduced metabolic capacity.

OBJECTIVE: There is a growing interest in low-dose ketamine as an analgesic agent in different intractable pain conditions. Due to its narrow therapeutic window, well-defined pharmacokinetic parameters are essential for its successful use in these situations. Arterial data for ketamine or its enantiomers have not been reported before. The metabolic pathways involved in the metabolism of S- and R-ketamines are not known. METHODS: Ten healthy male volunteers received 7 mg infusions of R- and S-ketamine-hydrochloride in a randomised order over 30 min on 2 separate days. Six were extensive metabolisers, two were poor metabolisers of debrisoquine (CYP2D6) and two were poor metabolisers of mephenytoin (CYP2C19). Arterial and venous concentrations and non-analgesic side effects were measured. RESULTS: Subjective side effects were mild but more pronounced for S- than for R-ketamine. There were no salient differences between the subjects with reduced and normal metabolic capacity in pharmacokinetic parameters or in side effects. Volumes of distribution and mean residence times were 40% smaller for arterial than for venous data. The mean clearance of R-ketamine, 0.020 l min(-1) kg(-1), was slightly but significantly lower than of S-ketamine, 0.024 l min(-1) kg(-1). CONCLUSIONS: There are large differences between arterial and venous data in the pharmacokinetic parameters that are heavily dependent on distribution processes. Parameters mainly reflecting elimination, such as clearance and area under the concentration time curve, are unchanged. The choice of sampling site could be important when computer-controlled infusions are used.

Auger resonant Raman scattering in itinerant electron systems: continuum excitation in Cu.

The role of electron localization for resonant photoemission and Auger resonant Raman scattering to occur in an extended system was studied by polarization dependent resonant photoemission at the Cu L edges. Auger resonant Raman scattering was observed for continuum excitation into van Hove singularities at the L(1) and X(1) points, 4.2 and 7.7 eV above threshold. These findings show that resonant photoemission and Auger resonant Raman scattering are general features of photoemission independent of the degree of electron localization.

How carbon monoxide adsorbs in different sites.

The interplay between the electronic and the geometric structure of adsorbates is of fundamental importance for the understanding of many surface phenomena. Using x-ray emission spectroscopy and ab initio cluster calculations, this issue has been investigated in unprecedented detail for CO adsorption in different adsorption sites. The investigation establishes pi bonding and sigma repulsion, both increasing with the number of coordinated metal atoms. The two contributions partly compensate each other, leading to only small differences in adsorption energies for the different adsorption sites despite very large variations in the electronic structure.

Supercritical fluid chromatography as a method of analysis for the determination of 4-hydroxybenzylglucosinolate degradation products.

In the present study analytical and preparative supercritical fluid chromatography (SFC) were used for investigation of myrosinase catalysed degradation of 4-hydroxybenzylglucosinolate (sinalbin). Sinalbin occurs as a major glucosinolate in seeds of Sinapis alba L., in various mustards and other food products. The degradation products were identified and quantified by analysis based on a developed SFC method using a bare silica column. Determinations comprised transformation products of sinalbin, produced both during degradation of isolated sinalbin, and during autolysis of meal from S. alba seeds. The conditions in the developed SFC method were used as basis for the preparative SFC procedure applied for isolation of the components prior to their identification by nuclear magnetic resonance (NMR) spectroscopy. Myrosinase catalysed sinalbin hydrolysis resulted in the reactive 4-hydroxybenzyl isothiocyanate as an initial product at pH values from 3.5 to 7.5 whereas 4-hydroxybenzyl cyanide was one of the major products at low pH values. 4-Hydroxybenzyl isothiocyanate was found to disappear from the aqueous reaction mixtures in a few hours, as it reacted easily with available nucleophilic reagents. 4-Hydroxybenzyl alcohol was found as the product from reaction with water, and with ascorbic acid, 4-hydroxybenzylascorbigen was produced.

Effect of codeine on oro-cecal transit time in Chinese healthy volunteers in comparison with Caucasian subjects.

OBJECTIVES: To evaluate the effect of codeine on oro-cecal transit time (OCTT) in Chinese subjects. METHODS: OCTT was measured with the hydrogen breath test in 12 Chinese healthy volunteers on two occasions: after placebo and after a single oral dose of codeine 50 mg. Codeine and its metabolites in urine were measured by HPLC. The Results of this study were compared with those previously obtained from Caucasian subjects. RESULTS AND CONCLUSION: The mean OCTT increased significantly after a single oral dose of codeine 50 mg [2.6 (1.2) h] compared with placebo [1.9 (0.6) h] in the Chinese subjects (P = 0.05). The increase in OCTT after codeine was similar in the Caucasian [0.9 (0.8) h] and in the Chinese subjects [0.7 (0.9) h]. However, the Chinese subjects had a significantly longer OCTT after placebo [1.9 (0.6) h] compared with the Caucasian subjects [1.3 (0.6) h, P < 0.05], possibly due to different environmental factors.

The analgesic effect of racemic ketamine in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans.

BACKGROUND: Ketamine in sub-dissociative doses has been shown to have analgesic effects in various pain conditions, including neuropathic and phantom-limb pain, where conventional treatment has often failed. Chronic ischemic pain due to lower extremity arteriosclerosis obliterans often responds poorly to analgesics, and the pain-generating mechanisms are not well understood. METHODS: Eight patients with rest pain in the lower extremity due to arteriosclerosis obliterans were given sub-dissociative doses of 0.15, 0.30, or 0.45 mg/kg racemic ketamine and morphine 10 mg as a 5-min infusion on four separate days in a cross-over, double-blind, randomised protocol. Plasma levels of (S)- and (R)-ketamine and their nor-metabolites were analysed with an enantioselective high-performance liquid chromatography (HPLC) method. Pain levels were evaluated with a visual analogue scale (VAS). RESULTS: Individual pain levels were highly variable during and after all the infusions but the pooled pain levels showed a dose-dependent analgesic effect of ketamine with a transient but complete pain relief in all the patients at the highest dose (0.45 mg/kg). Side-effects, mainly disturbed cognition and perception, were pronounced and dose-dependent. Morphine 10 mg had an analgesic peak at 20 min and 5/8 patients had complete pain relief. These 3 patients also had high baseline pain scores, indicating a higher analgesic potency for the 0.30 and 0.45 mg/kg ketamine doses than for morphine 10 mg. CONCLUSION: We have demonstrated a potent dose-dependent analgesic effect of racemic ketamine in clinical ischemic pain. Due to a narrow therapeutic window, this analgesic effect is probably best utilised in combination with other analgesics.

The effect of codeine on gastrointestinal transit in extensive and poor metabolisers of debrisoquine.

METHODS: Codeine (50 mg) was administered to 12 extensive metabolisers (EM) and 12 poor metabolisers (PM) of debrisoquine. The oro-caecal transit time was estimated by the hydrogen breath test. The urinary excretion of codeine and metabolites during a 6-h interval was estimated after simultaneous analysis of codeine, morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), morphine (M), normorphine (NM), norcodeine, norcodeine glucuronide and codeine-6-glucuronide using HPLC. RESULTS: The mean transit times after placebo were 1.3 h in the EM and 1.4 h in the PM. The corresponding figures after ingestion of codeine were 2.2 h and 2.1 h. The differences between the groups were statistically and clinically insignificant. The effect of codeine compared with placebo was significantly different in both groups. As expected, the metabolites of the O-demethylation pathway, M, M6G, M3G and NM were significantly lower in the PM. Interestingly, the recovery of the dose in the form of codeine (> 1.7 times) and norcodeine (> 2.5 times) was significantly higher in the PM, indicating compensatory metabolism via N-demethylation. CONCLUSION: In contrast to the analgesic effect, the prolongation of gastrointestinal transit caused by the drug does not depend on the formation of O-demethylated active metabolites M, M6G or NM.

Asthma education for Swedish primary care physicians--a study on the effects of "academic detailing" on practice and patient knowledge.

OBJECTIVE: To assess the effect of an intervention on general practitioners' (GPs) knowledge about the diagnosis and treatment of asthma, including the prescribing of anti-asthmatic drugs, and asthmatic patients' knowledge about their disease. METHODS: The study took place in the south-west region of Stockholm County. In the area where the intervention took place (area 1), 44 GPs at 21 health centres were visited by a clinical pharmacologist and a pharmacist presenting oral and written information. The basic messages were: (1) the central role of inhaled glucocorticoids; (2) the use of peak expiratory flow (PEF) meters; and (3) the use of reversibility tests. In the control area (area 2), there were 19 GPs at nine health centres. The GPs knowledge about the intervention message was evaluated by a questionnaire pre- and post-intervention. The ratios of prescribed inhaled be beta-adrenoceptor agonists to inhaled glucocorticoids were determined. At the 26 local pharmacies, all asthmatic patients who presented a prescription for anti-asthmatic drugs, issued at the 30 health centres, were given a questionnaire before and after the intervention regarding their knowledge of asthma and its treatment. RESULTS: GPs in area 1 showed significantly more knowledge about item numbers 2 and 3 in the above-described intervention message than did the GPs in the control area 2. The data on prescriptions showed lower ratios of beta-adrenoceptor agonists to glucocorticoids in area 1 than in area 2. The difference, however, between area 1 and area 2 was not significant. After the GP intervention, the patients' knowledge about asthma had increased in area 1, as assessed by the questionnaire filled in by the patients. However, there was no significant difference from that in area 2. CONCLUSIONS: The study shows differences between the intervention and control areas regarding the knowledge and practice of GPs after the intervention. We found changes in knowledge, attitudes and actual practice, the latter being measured by the prescriptions.

Disposition and analgesic effects of systemic morphine, morphine-6-glucuronide and normorphine in rat.

Morphine, morphine-6-glucuronide and normorphine were administered to male Sprague-Dawley-rats. Analgesic effect was estimated with the hot plate and spinal nociceptive reflex depression. After intraperitoneal administration the molar potency ratio of morphine-6-glucuronide/morphine was 1.7 estimated by the paw lick latency on the hot plate utilizing a linked pharmacokinetic-pharmacodynamic model. The potency ratio of morphine-6-glucuronide/morphine utilizing the spinal nociceptive reflex depression after intravenous administration was estimated to be within the earlier reported range of 1-4 after systemic administration of the drugs. In contrast to what is seen in man virtually no morphine-6-glucuronide was formed in Sprague-Dawley rats after administration of morphine, much lower levels of morphine-3-glucuronide were also seen. The molar AUC ratio of morphine-3-glucuronide/morphine was 1.8 +/- 0.5 and the corresponding ratio for normorphine/morphine was 0.2 +/- 0.06. After intraperitoneal administration of morphine, morphine-6-glucuronide and normorphine mean systemic clearance values of 413 +/- 95, 50 +/- 11 and 187 +/- 54 ml.min.kg-1 respectively were observed. Varea was 9.0 +/- 2.1, 0.8 +/- 0.2 and 4.9 +/- 1.4 L.kg-1 respectively. The slow absorption of morphine-6-glucuronide was illustrated by the mean Tmax-value of the 16 min. as compared with 9 min. for morphine and 10 min. for normorphine. It was possible to fit pharmacokinetic and pharmacodynamic data of behavioural analgesic effect of both morphine and morphine-6-glucuronide to a parametric model linking the sigmoid Emax model to standard pharmacokinetic equations.