Risk of depression in diabetes is highest for young persons using oral anti-diabetic agents.

AIMS: Previous studies report an increased risk of depression in patients with diabetes, but there is little knowledge about if or how the risk varies according to sex, groups of age and different type of treatments for the diabetes. We therefore aimed to investigate the risk of depression in different types of treatment for diabetes and in subgroups of age and sex. METHODS: Data on the Norwegian population from 20 years of age being prescribed antidepressants (n = 253 668) and anti-diabetic agents (n = 121 392) in 2006 was obtained from the National Register of Prescriptions and analysed in a cross-sectional design. RESULTS: Individuals using insulin in monotherapy (n = 29 611) had an age- and sex-adjusted odds ratio of 1.47 (95% CI 1.42-1.53) for receiving antidepressants. Corresponding odds ratios for individuals receiving oral anti-diabetic agents in monotherapy (n = 76 387) and for those who received both insulin and oral anti-diabetic agents (n = 15 394) were 1.44 (95% CI 1.41-1.47) and 1.82 (95% CI 1.80-1.97), respectively. No major differences in risk according to age were found for persons receiving insulin in monotherapy, while a marked and inverse association between age and risk of receiving antidepressants was found for those receiving oral anti-diabetic agents. Highest risk of antidepressant treatment [odds ratio 4.15 (95% CI 3.12-5.52)] was found for patients receiving both oral anti-diabetic agents and insulin at 30-39 years. The risk was equally increased among men and women. CONCLUSIONS: The risk of depression among patients with diabetes varies strongly according to age and type of treatment for diabetes.

[What do health professionals ask RELIS Vest service and how satisfied are they with the answers?]. / Hva spør helsepersonell RELIS Vest om og hvor fornøyde er de med svarene?

RELIS Vest provides drug information by answering questions from mainly physicians and pharmacists. In the present paper we evaluated this service. All questions to RELIS Vest during the 1995-98 period were systematically categorized and analysed. The quality of the service was assessed by evaluation forms. Of a total of 875 queries, 393 came from physicians and 370 from pharmacists. 42% were about psychoactive drugs; the most frequent types of queries concerned documentation and adverse effects. Analysis of 180 evaluation forms showed that 79% of the physicians and 56% of the pharmacists found the answers fast enough, relevant, adequately comprehensive and with valuable references while 16% of the physicians and 29% of the pharmacists found that the answers satisfied three of these four criteria. We conclude that problem-oriented drug information based on actual cases of prescribing is highly appreciated.

Absorption of bismuth from two bismuth compounds before and after healing of peptic ulcers.

BACKGROUND/AIMS: Previous reports state that there is absorption of bismuth through active peptic ulcers. It was therefore of interest to investigate the extent of absorption in patients at the ulcer and post-ulcer stages. METHODOLOGY: Twenty H. pylori-positive patients with gastroscopically verified gastric or duodenal ulcers were randomly allocated to ingest 3000 mg bismuth subnitrate (BSN) (10 patients) or 480 mg colloidal bismuth subcitrate (CBS) (10 patients). Bismuth serum concentration in 12 samples drawn during the first 4 hours after drug intake was analyzed and the area under the curve (Bi-AUC) was calculated. Anti-H. pylori therapy with amoxicillin and lanzoprazole eradicated H. pylori in 10 patients and healed the ulcers in all patients 4 weeks after therapy ended, then the bismuth absorption test was repeated. RESULTS: There was no significant difference between ulcer- and post-ulcer Bi-AUC for patients receiving BSN or for patients receiving CBS. On a molar basis, CBS gave a 17.4-fold greater absorption of bismuth compared to BSN. CONCLUSIONS: The presence of an active ulcer does not significantly influence the absorption of bismuth from CBS or BSN.

Bismuth-based combination therapy for Helicobacter pylori-associated peptic ulcer disease (metronidazole for eradication, ranitidine for pain).

OBJECTIVES: 180 Helicobacter pylori-positive patients with peptic ulcer disease were randomly allocated to double-blind placebo-controlled treatment with one of four anti-H. pylori regimens consisting of bismuth subnitrate suspension (B), oxytetracycline (OT), metronidazole (M)/metronidazole placebo, or ranitidine (R)/ranitidine placebo. METHODS: Regimen 1: B 150 mg q.i.d., OT 500 mg q.i.d., M 400 mg t.i.d. for 10 days and R 300 mg b.i.d. for 4 wk. Regimen 2: same as regimen 1 except ranitidine. Regimen 3: same as regimen 1 except metronidazole. Regimen 4: same as regimen 1 except metronidazole and ranitidine. Gastroscopy and 14C-urea breath test were performed 4 wk after cessation of therapy, and breath test six months after cessation. RESULTS: According to intention-to-treat analysis, H. pylori eradication rates were 96%, 91%, 20%, and 9% with regimens 1, 2, 3, and 4, respectively. Comparing regimens 1+2 and 3+4, the eradication rates with and without metronidazole were 93% and 14%, respectively (p < 0.0001). Metronidazole increased the occurrence of diarrhea and abdominal pain. Comparing regimens 1+3 with 2+4 ranitidine did not influence H. pylori eradication (58% with and 50% without ranitidine; p = 0.37) or ulcer healing (93% with and 90% without ranitidine; p = 0.72) significantly, but reduced the occurrence of pain (p < 0.01). Six months after treatment, three patients who were H. pylori negative at 4 wk had become positive. These three had all received metronidazole placebo. H. pylori status remained negative in the other 85 patients. CONCLUSIONS: H. pylori eradication with this triple therapy is critically dependent on metronidazole. Adding ranitidine reduces the occurrence of abdominal pain during such therapy.

Bismuth therapy for Helicobacter pylori infection. A review of five years experience at a university hospital in Norway.

BACKGROUND: Eradication of H. pylori cures peptic ulcer disease. Bismuth and antibiotics in various combinations were tested at a single university hospital. METHODS: The standard treatment was bismuth subnitrate, metronidazole and oxytetracycline. A positive biopsy urease test was the main inclusion criterium, whereas a negative 14C-urea breath test performed at least four weeks after cessation of therapy was the main indicator of cured infection, and performed later for reinfection. In separate studies we tested the absorption of bismuth subnitrate compared to other bismuth preparations, what aspects of bismuth-based triple therapy are most important to obtain maximum eradication, what can be done to decrease side effects, and the reliability of diagnostic methods. RESULTS: The absorption of bismuth from bismuth subnitrate was very low. More than 90% cure rates were usually obtained. Including metronidazole in the regimen increased side effects but was crucial for effectiveness. Spiramycine could replaced oxytetracycline without substantial loss of effectiveness. Effectiveness was decreased if the patients had recently used metronidazole. Aluminium containing antacids and chlorhexidine were not very useful. Side effects were frequent, up to 60%, but usually mild and very few patients withdrew from treatment. Adding ranitidine to the regimen reduced abdominal pain. 14C-urea breath test was the "gold standard" and the specificity of the biopsy urease test in diagnosing H. pylori infection was high. CONCLUSIONS: Bismuth combination therapy combines high effectiveness with acceptable side effects and low cost. Biopsy urease test and urea breath test are reliable indicators of H. pylori infection.

[10 days of triple treatment of Helicobacter pylori infection and peptic ulcer. Status after treatment of 4 weeks and of one year]. / Ti dagers trippelkur for Helicobacter pylori-infeksjon og magesår. Status fir uker og ett år etter.

We treated 143 Helicobacter pylori positive ulcer patients (duodenal ulcer 81, gastric ulcer 24, pyloric ulcer nine, previous duodenal ulcer 27, others two) with a ten days regimen of bismuth subnitrate, oxytetracycline and metronidazole. Four weeks after cessation of treatment the 14C-urea breath test showed that the infection was eradicated in 133 out of 140 patients (95%). The ulcer had healed in 129 (97%) of the H. pylori negative patients. Status at one year after treatment showed that 121 (98.4%) of 123 patients who had become H. pylori negative had remained negative. None of the H. pylori negative patients experienced ulcer relapse. The results show that the treatment is effective and that the rate of recurrence of H. pylori during the first year is very low.

Helicobacter pylori eradication with bismuth subnitrate, oxytetracycline and metronidazole in patients with peptic ulcer disease.

A total of 152 patients with recurrent peptic ulcer disease were treated with bismuth subnitrate, oxytetracycline and metronidazole. The 51 patients in Group 1 were included following a study of the effect of cognitive psychotherapy on the recurrence rate after curative treatment for duodenal ulcer (DU). Group 2 comprised 101 consecutive patients referred to us with recurrent peptic ulcer. Their Helicobacter pylori (Hp) status was assessed before, and 4 weeks after, discontinuation of treatment, using the 14C-urea breath test. The primary aim of the study was to determine the effect of the triple treatment regimen on Hp eradication. All but two patients were Hp-positive prior to treatment. Four weeks after termination of treatment, Hp was found to have been eradicated in 50 out of 51 patients (98%) in Group 1, and in 86 out of 97 patients (89%) in Group 2. The respective ulcer healing rates for the two groups were 100% and 95%. Fifty percent of the patients noted moderate to severe adverse effects, mainly nausea and diarrhea, but only 5 patients discontinued treatment prematurely. The results indicate that virtually all patients with recurrent peptic ulcer disease have gastric Hp infection, and that the present triple treatment is highly effective in terms of both Hp eradication and ulcer healing.

Free plasma concentrations of piroxicam in patients with osteoarthritis: relation to age, sex and efficacy.

Steady state piroxicam plasma samples from 85 patients suffering from osteoarthritis of the hip and/or the knee, and treated with piroxicam 20 mg daily for at least four weeks, were obtained. Twenty-seven of these patients had a newly diagnosed osteoarthritis and had not been treated with a nonsteroidal antiinflammatory drug (NSAID) previously. The plasma samples were subjected to equilibrium dialysis, analyzed by HPLC and total and free drug concentrations measured and unbound fractions were calculated. In the 27 newly diagnosed patients with free piroxicam concentrations ranging from 0.004 to 0.117 micrograms/ml, there was no correlation between free concentration and change in any of the clinical response variables from pretrial to week 4. In the total patient population free concentrations were 0.057 +/- 0.038 micrograms/ml (mean +/- standard deviation). Females had a 79% higher free concentration than males (p < 0.0002) and there was a statistically significant (p < 0.01) increase of free concentration with increasing age in females. The unbound fraction was 0.87% +/- 0.36% (mean +/- SD). There was no difference in unbound fraction between the sexes, nor could we detect any change with increasing age.

Total and free plasma and total synovial fluid piroxicam concentrations: relationship to antiinflammatory effect in patients with reactive arthritis and other arthritides.

Twenty-five patients (14 males, 11 females), sixteen with reactive arthritis and 9 with other arthritides were treated with piroxicam, 40 mg at day 1 and 20 mg daily the following 9 days. Both local knee joint and general disease activity were assessed at day 0 and day 10. At day 10, plasma and synovial fluid were drawn. Total and free (determined after equilibrium dialysis) plasma concentrations and total synovial fluid concentrations were measured by HPLC. Total plasma piroxicam concentrations (micrograms/ml) were 4.1 (0.5-8.3) [median (range)], free piroxicam plasma concentrations were 0.051 (0.012-0.118), total synovial fluid concentrations were 2.2 (0.3-4.6) and ratios total synovial to total plasma concentration were 0.51 (0.39-0.90). The effect of piroxicam treatment varied among the patients. We found no relationship between drug concentration and change in any of the disease activity parameters nor any correlation between the ratio of synovial fluid to plasma piroxicam concentration and the local knee joint disease activity parameters.

[Treatment of stomach ulcer with bismuth subnitrate, oxytetracycline and metronidazole]. / Behandling av magesår med vismutsubnitrat, oksytetracyklin og metronidazol.

60 patients with recurrent duodenal ulcers were treated with bismuth subnitrate, oxytetracycline and metronidazole. Helicobacter pylori status was assessed before and after treatment by means of the 14C-urea breath test. All patients were helicobacter positive before treatment. Four weeks after cessation of therapy H pylori had been eradicated in 57 out of 60 patients (95%). The ulcer healing rate was 100% after six weeks. 43% of the patients complained of moderate to severe side effects, mainly nausea and diarrhoea, but no patients discontinued the treatment prematurely. The study indicates that nearly all patients with recurrent duodenal ulcer are infected with H pylori, and that the present triple treatment regimen is very effective both in eradicating H pylori and in healing the ulcer.

Naproxen free plasma concentrations and unbound fractions in patients with osteoarthritis: relation to age, sex, efficacy, and adverse events.

Plasma samples from 237 patients with osteoarthritis treated with 750 mg naproxen daily were obtained after four weeks of active therapy. The samples were subjected to equilibrium dialysis, analyzed by high-performance liquid chromatography, and free concentrations and unbound fractions were determined. Within the free plasma concentration range in this large patient group, we could detect no association between free naproxen concentration and efficacy score or between free concentrations and adverse events. Free concentrations were 0.295 +/- 0.260 microgram/ml (mean +/- SD) and unbound fractions were 0.33 +/- 0.24%. Females had 65% higher free concentration compared to males (p less than 0.001). For females, but not for males, there was a statistically significant correlation (p less than 0.005) between age and free concentration. The free concentration was estimated to be 88% higher in an 80-year-old female compared to a 50-year-old. Females had a 41% higher unbound fraction than males (p less than 0.005). For females, but not for males, a statistically significant relationship between age and unbound fraction was found. The unbound fraction was estimated to be 62% higher in an 80-year-old female than in a 50-year-old.

Determination of free concentration of piroxicam and naproxen in plasma. The influence of experimental conditions in equilibrium dialysis.

An equilibrium dialysis method was established in order to investigate possible relationships between free drug concentrations of piroxicam and naproxen and clinical events. Therefore the influence of variations in pH, phosphate concentration and sodium azide concentration of the dialysis buffer on the free concentrations of piroxicam and naproxen was investigated. Piroxicam was found to have a pH-dependent protein binding. Therefore a good control of pH during the dialysis process is necessary. This has been achieved by increasing the buffer capacity of the dialysis buffer, by adding an antibacterial agent to the dialysis buffer and by cleansing the dialysis cells with 70% ethanol before use to prevent bacterial growth. Addition of 0.03% sodium azide as an antibacterial agent and the use of a 0.09 mol/l phosphate buffer gave good pH control. A method to correct for deviations of pH in measurements of free concentrations of piroxicam by a simple mathematical correction has been found. As naproxen was found to have a protein binding independent of pH, a pH-correction is not necessary for this drug. Standardized conditions in determination of protein binding of drugs by equilibrium dialysis are important, as composition of the dialysis buffer and pH of plasma compartment at equilibrium may influence the free concentration measurements. Comparisons of data from experiments using different methods are therefore difficult; the importance of pH-control is stressed. With the methods used in the present investigation, equilibrium dialysis in connection with HPLC, the coefficients of variation for piroxicam and naproxen free concentrations are 5.5% and 7.4%, respectively.

Acute effects of paracetamol on prostaglandin synthesis and renal function in normal man and in patients with renal failure.

The effects of oral dosing with paracetamol (40 mg/kg/day for 3 days) on serum thromboxane B2 (TXB2), glomerular filtration rate (GFR), sodium homeostasis, urinary excretion of prostaglandin E2 (PGE2) and on some other renal function parameters were investigated in 10 healthy young controls aged 23-26 years, 9 healthy elderly persons with normal renal function aged 66-78 years and 9 patients with chronic stable impaired renal function. Plasma paracetamol concentration was unaffected by age and GFR, whereas the sulphate and glucuronide metabolites of paracetamol accumulated substantially in patients with renal failure, and to a lesser degree in elderly controls. Serum TXB2 was significantly reduced 1 and 4 hours after oral ingestion of a single dose of paracetamol (18 mg/kg), but the values were normalized after 12 hours. Urinary sodium excretion was reduced by 23.4% on the first treatment day in elderly controls, but unchanged in young controls and in patients with renal failure. Urinary excretion of PGE2 was unchanged in young controls, but reduced by 35.9% on the first day on paracetamol treatment in elderly controls and from 22-29% on the 3 days on paracetamol in patients with impaired renal function. Paracetamol was without effect on potassium homeostasis or on the excretion of glandular kallikrein or proteins in urine. Our study indicates that oral treatment with paracetamol in therapeutic doses reversibly reduces serum TXB2 for at least 4 hours after ingestion both in healthy controls and in patients with impaired renal function. Our data also suggest that paracetamol effects renal PGE2 excretion, especially in patients with impaired renal function. Renal glomerular and tubular function parameters were unchanged by paracetamol.

Piroxicam and naproxen plasma concentrations in patients with osteoarthritis: relation to age, sex, efficacy and adverse events.

Piroxicam and naproxen plasma concentrations were obtained after 4 weeks active therapy between 3 and 12 hours post-dose in 640 and 629 patients, respectively. These patients are a subset of 2,035 patients with osteoarthritis on whom we have reported previously (11) in a double-blind multicentre safety and efficacy trial comparing piroxicam 20 mg/day and naproxen 750 mg/day. The purpose of the present study was to look for an association of plasma drug concentration with the variables of: age, sex, adverse events and efficacy. There was a statistically significant increase in plasma concentrations of both drugs with increasing age and females had higher concentrations than males. The increase in plasma concentration seen with increasing age was of a magnitude of 25% for piroxicam and 20% for naproxen when comparing a 50 year old to an 80 year old. However, less than 15% of the variability in plasma concentrations seen between patients is accounted for by age and sex. Within the plasma concentrations achieved with these doses, no association with adverse events, non-serious or serious, and efficacy was noted.