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Biomedical subjects

L F Gram

Publications and source records attributed to L F Gram.

At least 37 records · Page 2Linked to original sources
PubMed1998

Polypharmacy and the risk of drug-drug interactions among Danish elderly. A prescription database study.

OBJECTIVE: To analyze the use of all subsidized prescription drugs with special attention to the elderly (> or = 70 years of age), including their use of drug combination generally accepted as carrying a risk of severe interactions. DESIGN: Descriptive prevalence study. SETTING: Odense Pharmacoepidemiological Database, Denmark. The fourth quarter of 1994. SUBJECTS: All inhabitants in the county of Funen, Denmark. MAIN OUTCOME MEASURES: Prevalence of drug use for persons < 70 and > or = 70 years of age including number of drugs used and of drug combinations. Occurrence of 45 drug combinations generally accepted as carrying a risk of severe interactions. RESULTS: Among persons less than 70 years, 67.9% used none, 16.5% used one drug and 15.6% used two or more prescription drugs. The corresponding prevalences for the elderly were 35.7%, 15.9% and 48.4%. The 26,337 elderly patients with at least two drugs used 21,293 different combinations. Of the elderly patients who had purchased > or = two drugs, 4.4% had combinations of drugs carrying a risk of severe interactions. CONCLUSIONS: Most elderly use drugs and usually several drugs concomitantly. The elderly form a heterogeneous group of drug users. Drug combinations carrying a risk of severe interactions are relatively frequent.

Aged↗
PubMed1997

[Antidepressive treatment in general practice--an interview study].

In order to elucidate potential problems concerning the use of antidepressants in general practice, 98 randomly selected antidepressant users from 12 general practices were interviewed. The primary indication for antidepressant treatment was depression (72 patients), partly regular depression (therapeutic/prophylactic treatment) (n = 39), partly depressive tendencies (n = 32) (one patient no information). Median treatment duration was three years; 25% had been in treatment for more than 10 years. The general practitioners judged the treatment problematic/unacceptable in 23 cases, largely because of uncertain indication or because other or no treatment was considered better for the patient. Side effects were modest. The patients often had a relatively high depression score and poor status according to the WONCA-scale. The use of low doses, long duration of treatment, and uncertainty about the relevance of the treatment are important features in the use of antidepressants by general practitioners. The use of antidepressants in general practice differs from the scientifically-based recommendations.

Adult↗
PubMed1997

Changes in the pattern of antidepressant use upon the introduction of the new antidepressants: a prescription database study.

OBJECTIVE: To study whether the newer antidepressants have changed the patterns of antidepressant use, and whether the claimed better adverse effect profile of the lower antidepressants is reflected in their use as monitored by a prescription database. METHOD: By means of a prescription database (OPED), the use of antidepressants from 1991 to 1993 in Odense, Denmark, was analysed. RESULTS: The 1-year prevalence of antidepressant use increased significantly from 1.60% to 2.00%, which still is below the claimed 1-year prevalence of depression of at least 5%. The increase was mainly due to a rapidly increasing use of the newer antidepressants, accompanied by a moderate decline in the use of older antidepressants (mainly tricyclic antidepressants). The patterns of antidepressant use were very polymorphic, with about 5% being on continuous use for all 3 years and groups of each 20-30% being treated with: (1) several series or (2) one series or (3) only by one prescription. The share of patients presenting only one prescription (20%) was the same for older and newer antidepressants. Likewise, the rate of shifts from older to newer antidepressants or vice versa was the same (7% vs 6%). The duration of treatment did not differ much between older and newer antidepressants. Relative to the defined daily dose (DDD), the older antidepressants were given in much lower doses (median 0.63 DDD) than the newer antidepressants (median 1.05 DDD). CONCLUSION: It is concluded that many depressed patients are still not receiving antidepressant treatment and that the claimed better adverse effect profile of the newer antidepressants was not clearly reflected in their use.

Adult↗
PubMed1997

Use of sumatriptan in Denmark in 1994-5: an epidemiological analysis of nationwide prescription data.

AIMS: We describe the use of medication with symptomatic relief of migraine as specific indication by analysing prescription data from the entire Danish population in 1994 and 1995. METHODS: The data for sumatriptan were analysed at the level of the individual user. We used aggregated data for ergotamine drugs. RESULTS: Sumatriptan constituted 46% of the total amount of defined daily doses (DDD) sold and 94% of the total pharmacy retail price expenses in the drug-group studied. In total, 43389 users of sumatriptan were identified who presented 340148 prescriptions, corresponding to 2.2 million DDD of sumatriptan. The quarterly consumption increased by 50% during the study period. Tablets accounted for 92% of consumption. The 1 year period prevalence of use of sumatriptan among persons 16 years and older was 7.8 per 1000 in 1995 with a female to male prevalence ratio of 3.8:1. Use was most common in the age interval 35-54 years. Regional differences in use, which were not large, were positively correlated to the degree of urbanization. The incidence of use of sumatriptan was estimated at 3.6 per 1000 person-years. The intensity of use of sumatriptan varied greatly with 1.1% of patients (n = 507) using 60 DDD or more within 30 days at some time during the observation period. Long-term high use of tablets was common in this group. CONCLUSIONS: We conclude that sumatriptan had a considerable impact on the treatment of migraine with prescription drugs in Denmark. The underlying reasons for high use of the drug in a smaller fraction of the patients deserve further study.

Adolescent↗
PubMed1996

[Serotonin syndrome and malignant neuroleptic syndrome. A review based on the material from the National Board of Adverse Drug Reactions].

The report describes four cases of serotonergic hyperstimulation classified as Serotonin Syndrome (SS) and 13 cases of supposed Neuroleptic Malignant Syndrome (NMS), all reported to the National Board of Adverse Drug Reactions. Diagnostic criteria, pathogenesis and some suspected risk factors are discussed. All patients with a diagnosis of "SS" were treated with more than one psychoactive drug, whereas five out of 13 NMS patients were treated with only one drug which could be suspected to be involved in the pathogenesis of the syndrome. Lithium seemed to be involved in three out of four SS cases and in one out of 13 cases of NMS. The syndrome occurred from less than an hour to several weeks after adding another drug to the patient's treatment. None of the cases of serotonergic hyperstimulation were severe enough to correspond to NMS and all patients recovered without sequelae, whereas at least three NMS patients died.

Adult↗
PubMed1996

Is overuse of sumatriptan a problem? A population-based study.

OBJECTIVE: Sumatriptan is highly efficacious in aborting acute attacks of migraine. Owing to recent reports of misuse of sumatriptan, we performed a study of its use in a Danish population. METHODS: Data were retrieved from a prescription database covering a period of 27 months after release of the drug. Consumption was described by the defined daily dose (DDD) unit and total individual consumption during the period was calculated. Those who received more than one prescription for sumatriptan were classified according to peak use of sumatriptan into high (> or = 60 DDD/31 days) (n = 45), intermediate (30-59 DDD/31 days) (n = 127) and low (< 30 DDD/31 days) (n = 1423) consumption groups. Individual usage of other medication was described. RESULTS: We identified 2,878 users of sumatriptan, of whom 1,283 (45%) only redeemed one prescription. The use of sumatriptan was highly skewed. The 1% heaviest users accounted for 20% of the total consumption. The median total individual consumption of sumatriptan was 500 DDD, 192 DDD, and 24 DDD in the three groups of multiple redeemers, respectively. Pronounced differences in the total amounts of opioids and ergot alkaloids used were also found, with the high peak consumption group being the heaviest consumers of all drug categories, although half of them had only received large doses of sumatriptan. Fifty seven % of high peak users redeemed more than 29 DDD of sumatriptan within one month of initiation of treatment. The 45 high peak users had received the bulk of their medication, largely in tablet formulation, from 31 prescribers. The data points to rebound headache as a plausible underlying mechanism, but incorrect use of sumatriptan for migraine prophylaxis is also a possibility. Overuse of sumatriptan has serious economic consequences and its long-term health effects are not known.

Adult↗
PubMed1996

Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine.

OBJECTIVE: The purpose of this pharmacokinetic study was to investigate the dose-dependent inhibition of model substrates for CYP2D6, CYP2C19 and CYP1A2 by four marketed selective serotonin reuptake inhibitors (SSRIs): citalopram, fluoxetine, fluvoxamine and paroxetine. METHODS: The study was carried out as an in vivo single-dose study including 24 young, healthy men. All volunteers had been identified as sparteine- and mephenytoin-extensive metabolisers. The volunteers received in randomised order, at weekly intervals, increasing single oral doses of one of the four SSRIs, followed 3 h later by sparteine (CYP2D6), mephenytoin (CYP2C19) and caffeine (CYP1A2) tests. Fluoxetine was given at 3-week intervals because of the long half-life of fluoxetine and its metabolite norfluoxetine. Citalopram, fluoxetine and paroxetine were given in doses of 10, 20, 40 and 80 mg and fluvoxamine was given in doses of 25, 50, 100 and 200 mg. RESULTS: With increasing doses, there was a statistically significant increase in the sparteine metabolic ratio (MR) (P < 0.01, Page's test for trend) for all four SSRIs. The increase was modest after intake of citalopram and fluvoxamine, while the increase was more pronounced after fluoxetine intake, although no volunteers changed phenotype from extensive metabolisers to poor metabolisers. Three of the six volunteers changed phenotype from extensive metabolisers to poor metabolisers after intake of 40 or 80 mg paroxetine. There was a statistically significant increase in the mephenytoin S/R ratio (P < 0.01, Page's test for trend) with increasing doses of fluoxetine and fluvoxamine, but not after citalopram and paroxetine. However, no volunteers changed phenotype from extensive to poor metabolisers of S-mephenytoin. After intake of fluvoxamine, the urinary excretion of the metabolites related to N3 demethylation of caffeine were below the limit of quantification, whereas there were no significant changes in the urinary caffeine metabolic ratios after intake of the other three SSRIs. CONCLUSION: This investigation confirms that paroxetine and fluoxetine are potent inhibitors of CYP2D6, that fluvoxamine and fluoxetine are moderate inhibitors of CYP2C19 and that fluvoxamine is a potent inhibitor of CYP1A2 in humans in vivo. The clinical prediction of interaction from single-dose experiments may have to take the degree of accumulation during steady-state after multiple doses into account.

Adult↗
PubMed1996

Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects.

OBJECTIVE: Codeine O-demethylation to morphine is catalysed by the genetic polymorphic sparteine oxygenase (CYP2D6). The objective of the present study was to assess the analgesic effect of codeine on different types of experimental pain in relation to sparteine phenotype. METHODS: Fourteen extensive (EMs) and 14 poor metabolizers (PMs) of sparteine completed a randomized, double-blind, three-way, cross-over study with a single oral dose of codeine (75 or 100 mg) against morphine (20 or 30 mg) and placebo. Pain tests performed before and 1, 2, 3, and 4 h after medication included the cold pressor test and pain thresholds for heat and pressure stimulation. Adverse effects were rated by a structured interview. RESULTS: After morphine, morphine and morphine-6-glucuronide were present in equal amounts in plasma of PMs and EMs. After codeine, neither morphine nor morphine-6-glucuronide could be detected in 13 of the 14 PMs, whereas at least one of the compounds could be detected in all EMs. Peak pain and discomfort rated on a VAS scale during the cold pressor test were significantly reduced by morphine in both EMs and PMs, with a median peak change of 8.5 and 7.0 mm, respectively, for peak pain, and 11.5 and 15.5 mm, respectively, for discomfort. Codeine only reduced these pain measures significantly in EMs, with a median peak change of 5.5 mm for peak pain and 10.5 mm for discomfort. Pain detection and tolerance thresholds to heat and pressure were not consistently altered by either morphine or codeine. In PMs, adverse effects were significantly more pronounced on morphine than on codeine and only showed a slight difference between codeine and placebo. In EMs, there was no difference between codeine and morphine and more pronounced adverse effects on both drugs as compared to placebo. CONCLUSION: This study confirms that codeine O-demethylation depends on CYP2D6; it shows that the 6-glucuronidation of morphine is independent of CYP2D6; it supports the theory that the analgesic effect of codeine depends on its O-demethylation; and it indicates that this is probably also the case for the adverse effects. The results lend no support to the suggestion of a non-opioid analgesic effect of codeine.

Adult↗
PubMed1996

Chloroguanide metabolism in relation to the efficacy in malaria prophylaxis and the S-mephenytoin oxidation in Tanzanians.

S-Mephenytoin and chloroguanide (proguanil) oxidation was studied in 216 tanzanians. The mephenytoin S/R ratio in urine ranged from <0.1 to 1.16. The distribution was skewed to the right, without evidence of a bimodal distribution. Ten subjects (4.6%, 2.2% to 8.3%, 95% CI) with an S/R mephenytoin ratio >0.9, were arbitrarily defined as poor metabolizers of mephenytoin. The chloroguanide/cycloguanil ratio ranged from 0.82 to 249. There was a significant correlation between the mephenytoin S/R ratio and the chloroguanide/cycloguanil ratios (rs = 0.73; p<0.00001). This indicates that cytochrome P4502C19 or CYP2C19 is a major enzyme that catalyzes the bioactivation of chloroguanide to cycloguanil. Chloroguanide is a pro-drug, and hence a low CYP2C19 activity may lead to prophylactic failure caused by inadequate formation of cycloguanil. Fifty-eight women who previously took either 200 mg chloroguanide daily (n = 26) or 200 mg chloroguanide daily plus 300 mg chloroquine weekly (n = 32) in a malaria chemoprophylaxis study showed that there was significant correlation between the number of earlier breakthrough parasitemia episodes and the chloroguanide/cycloguanil ratio (rs = 0.30; p = 0.02). The breakthrough rate did not correlate with the S/R mephenytoin ratio. However, other factors, such as exposure to mosquitoes and sensitivity of the plasmodium to cycloguanil, are probably more important.

Adult↗
PubMed1996

Are young adults with asthma treated sufficiently with inhaled steroids? A population-based study of prescription data from 1991 and 1994.

1. We conducted a descriptive cross-sectional study of asthma therapy among young adults to assess to what extent the current guidelines for asthma therapy have been implemented. In particular, we examined the use of inhaled corticosteroids in heavy users of inhaled beta-adrenoceptor agonists. 2. Data were retrieved from a population-based prescription database. For each of the years 1991 and 1994, all 20 to 44-year-olds who redeemed anti-asthma medication in the Odense area (210,000 inhabitants) were studied. 3. We identified the number of users and total sales volume for specific anti-asthma medications in defined daily doses (DDD) as well as the number of users and median annual doses of common regimens. Combined use of inhaled corticosteroids and inhaled beta-adrenoceptor agonists was also described. 4. The annual sales volume of anti-asthma drugs increased by 23% to 927,636 DDD from 1991 to 1994. Inhaled corticosteroids were mainly responsible for this with a 52% increase in number of users and an 88% increase in DDD. Inhaled beta-adrenoceptor agonists used in monotherapy remained the most popular regimen in 1994 (1685 users = 39%). Inhaled corticosteroids in combination with inhaled beta-adrenoceptor agonist were the second most popular regimen in 1994 (1308 users = 30%), increasing by 64% as compared with 1991. However, among patients with an annual use of inhaled beta-adrenoceptor agonist of 200 DDD (1600 "puffs') or more the percent of patients not receiving inhaled corticosteroids at all only fell from 37 to 33%. Though the number of patients being treated with inhaled corticosteroids has increased, there is still evidence of a substantial underuse.

Administration, Inhalation↗
PubMed1995

Moclobemide, a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6, and CYP1A2: a panel study.

The reversible monoamine oxidase A inhibitor moclobemide was given in single (300 mg) and multiple doses (600 mg/day) to 11 male and four female healthy volunteers (age range, 23 to 27) who were either poor metabolizers of S-mephenytoin (n = 7) or extensive metabolizers of S-mephenytoin (n = 8). All were extensive metabolizers of sparteine. Poor metabolizers of S-mephenytoin had lower moclobemide clearance values (median, single dose: 16.1 versus 43.2 L.hr-1; steady state: 13.4 versus 22.1 L.hr-1) and longer moclobemide half-life values (median, single dose: 4.0 versus 1.8 hours; steady state: 5.1 versus 2.7 hours) than extensive metabolizers of S-mephenytoin. The plasma levels of a metabolite formed by C-hydroxylation (Ro 12-8095) were lower in poor metabolizers of S-mephenytoin than in extensive metabolizers of S-mephenytoin. Moclobemide thus partially undergoes oxidative metabolism by way of the polymorphic CYP2C19. A combined mephenytoin, sparteine, and caffeine test performed before, during, and after multiple dosing of moclobemide showed changes in the metabolic indexes compatible with a reversible inhibition of oxidation by way of the corresponding CYP enzymes--CYP2C19, CYP2D6, and CYP1A2--during moclobemide treatment.

Adult↗
PubMed1995

The hypoalgesic effect of imipramine in different human experimental pain models.

In a randomized, placebo-controlled, double-blind, cross-over study, the hypoalgesic effect of a single oral dose of 100 mg imipramine was investigated in 12 healthy volunteers. Test procedures performed before, 3, 6, and 9 h after medication included determination of (1) pain detection and tolerance thresholds to heat and pressure; (2) the thresholds of quadriceps femoris muscle withdrawal reflex to single and repeated electric stimulation of the sural nerve; (3) amplitude of the reflex evoked by 1.5 times the premedication reflex threshold; and (4) continuous pain rating during the cold pressor test. Imipramine significantly increased pain tolerance thresholds to heat (P = 0.03) and pressure (P = 0.01), and both the psychophysical pain tolerance threshold and the reflex threshold to single electric stimulation (P = 0.02 and P = 0.03, respectively). On the repeated stimuli, which consisted of 4 pulses given at 3 Hz, imipramine induced a significant increase in the threshold at which the pain summated through the stimulation series (P = 0.03), whereas the increase in the threshold at which the reflex summated was not significant (P = 0.09). Pain detection thresholds to heat and pressure, the amplitude of the reflex to single suprathreshold stimulation, and pain ratings during the cold pressor test were unaltered by imipramine. It is concluded that imipramine has a differential hypoalgesic effect on different human experimental pain tests. This provides new possibilities of assessing the differential effect of different tricyclic antidepressants on different pain modalities and intensities.

Adolescent↗
PubMed1995

Nonsteroidal anti-inflammatory drugs and upper gastrointestinal bleeding, identifying high-risk groups by excess risk estimates.

BACKGROUND: The relationship between use of nonsteroidal anti-inflammatory drugs (NSAID) and severe upper gastrointestinal bleeding (UGB) has been established beyond reasonable doubt. The literature on risk factors has almost exclusively focused on comparisons of relative risks in subgroups of patients: men versus women, old versus young and so forth. However, from a pragmatic, clinical viewpoint, only the excess risk provides a meaningful, robust measure of the magnitude of risk factors. The purpose of the study was to determine the excess risks in subgroups of patients and to characterize the utilization pattern of NSAIDs. METHODS: A registry-based cohort study was conducted in a prescription and diagnosis registry in Odense, which covered a population of 207,000 persons for a period of 19 months. RESULTS: In total, 183 (113 men and 70 women) UGB patients were identified, of whom 37 were current users of NSAIDs. The standardized incidence rate of UGB was 46 per 100,000 person-years for nonexposed and 253 per 100,000 person-years for exposed person-time, yielding an excess risk of 207 per 100,000 person-years (confidence interval (CI), 132-319) and a standardized incidence ratio (SIR) of 5.5 (CI, 3.9-7.9). Men had higher excess risk than women (277 versus 150 per 100,000 person-years). The SIR decreased with increasing duration of exposure. The excess risk was particularly high in persons aged 75 years or more (1258 per 100,000 person-years) and in patients with a history of peptic ulcer (879 per 100,000 person-years), being about 10- and 5-fold higher than in the complementary groups. NSAID utilization was remarkably sporadic. We found 31,503 users and a median purchase of 20 defined daily doses. Short-term use was highly prevalent in all age groups. Women, the elderly, and persons with a history of ulcer had a higher prevalence of NSAID use than others. CONCLUSIONS: A history of peptic ulcer is associated with adverse outcome of NSAID therapy and should be regarded as a relative contraindication. A similarly strong effect of high age was shown. Male sex and short-term use are minor risk factors. The incidence of NSAID-related UGB can probably be reduced without affecting the overall utilization of NSAIDs.

Adult↗
PubMed1995

Antidepressant treatment in general practice--an interview study.

OBJECTIVE: To elucidate potential problems concerning the use of antidepressants (AD) in general practice. DESIGN: Cross-sectional, descriptive interview study. SETTING: General practices, Odense, Denmark. SUBJECTS: Random sample consisting of 98 AD users from 12 general practices. MAIN OUTCOME MEASURES: Indication for AD treatment, justification of the treatment, duration of AD treatment, daily dose of AD, side effects, Hamilton depression rating, WONCA score. RESULTS: The primary indication for AD treatment was depression (72 patients), partly regular depression (therapeutic/prophylactic treatment) (n = 39), partly depressive tendencies (n = 32) (1 unknown). Median treatment duration was 3 years; 25% had been in treatment for more than 10 years. The general practitioners judged the treatment problematic/unacceptable in 23 cases, largely because of uncertain indication or because other or no treatment was considered better for the patient. The daily doses of AD were generally low. Side effects were modest. The patients often had a relatively high depression score and poor status according to the WONCA-scale. CONCLUSIONS: The use of low doses, long duration of treatment, and uncertainty about the relevance of the treatment are important features of the use of AD by general practitioners. There seems to be a discrepancy between the use of AD in general practice and the scientifically-based recommendations.

Adult↗