Fibrinolytic treatment in suspected acute myocardial infarction – use and risks in clinical practice

Objectives: To study the adherence to guidelines concerning fibrinolytic treatment of patients with suspected myocardial infarction and to obtain information on severe adverse events in clinical practice. Methods: Prospective reporting of all patients admitted for suspected acute myocardial infarction during 4 months in 1994 from 69 (73.4% of all) Swedish coronary care units. Results: The study covers 10 652 admissions, representing 9726 patients. The mean percentage treated with fibrinolytic drugs of patients with a positive ECG (ST-elevation and/or bundle branch block), a delay <12 h and no contraindications was 56%. The interhospital range was 18.1–94.1%. Fibrinolytic drugs were given with a delay time >24 h in 12.5% of women and 15.7% of men, and 36.1% of patients with verified acute myocardial infarction were given fibrinolytic drugs. Streptokinase was used in 82.7% and alteplase in 15.5% of the patients, respectively (interhospital range 0–53.3%). Conclusions: Fibrinolytic therapy seems to be used in a non-rational way at several hospitals. Local quality systems may be a way to assure better care. Received: 13 August 1996 / Accepted in revised form: 22 November 1996     

Effects and pharmacokinetics of high dose metoprolol on chest pain in patients with suspected or definite acute myocardial infarction

Objective: Pain intensity and the plasma concentrations of metoprolol and its major metabolite α-hydroxymetoprolol as well as noradrenaline (NA), adrenaline (A) and neuropeptide Y (NPY) were determined in patients with pain due to definite or suspected acute myocardial infarction (AMI) after graded metoprolol infusion. Pain intensity and metoprolol kinetics were assessed over 8 h. Methods: Twenty-seven patients of either sex, aged 48–84 years with ongoing chest pain upon arrival to the Coronary Care Unit (CCU) were subdivided into two groups: (1) patients with ECG signs of threatening transmural myocardial damage (n=15); and (2) patients without such ECG signs (n=12). Pain intensity was assessed by a numerical rating scale (NRS) and venous blood was obtained for determination of plasma catecholamine and NPY concentrations. A continuous infusion of metoprolol (3 mg · min⁻¹ i.v) was started and serial blood samples for plasma catecholamines, NPY as well as metoprolol and its major metabolite α-hydroxymetoprolol were obtained from the contralateral arm. Results: Initial pain intensity was 5.9 (arbitrary units) and 5.4 in the groups with and without signs of transmural myocardial damage, respectively. One third of the patients with ST changes reported full pain relief (NRS=0) within 70 min after starting metoprolol infusion (accumulated dose, 15–180 mg). Among the patients without ST changes upon arrival, full pain relief was obtained in 70% (accumulated dose, 30–120 mg). There was a dose-dependent relation between accumulated metoprolol dose and pain relief. The diagnosis of acute myocardial infarction (AMI) was confirmed in all 15 patients with ECG signs on arrival of transmural myocardial damage. The mean metoprolol dose in this group was 91(12) mg. The mean metoprolol dose in the 12 patients without ST changes was 64(8) mg. In all, seven of these patients developed definite AMI. The terminal half-life of unchanged metoprolol ranged from 2.5 to 8.5 h in group 1 and from 2.2 to 5.2 h in group 2. In group 1, metoprolol half-life was 4.5 h and total plasma clearance (CL) 54.1 l · h⁻¹. In group 2, the metoprolol half-life was 3.7 h and total plasma clearance 75.4 l · h⁻¹. There was a significant difference in clearance between the groups. After the intravenous metoprolol infusion, α-hydroxymetoprolol concentrations increased gradually. In groups 1 and 2, maximal concentrations in plasma (C_max) were 143 and 135 nmol · l⁻¹ for α-hydroxymetoprolol and 2830 and 1653 nmol · l⁻¹ for metoprolol, respectively. Plasma NA or NPY did not differ between the groups. In contrast, plasma A was significantly higher during the initial 90 min of observation in patients with ECG signs of transmural myocardial damage. Conclusion: High-dose intravenous metoprolol was well tolerated in patients with suspected AMI. There was a more rapid and almost complete pain relief in patients without signs of transmural ischaemia compared with the patients with ECG signs of transmural AMI at arrival. In the later group of patients, plasma clearance of metoprolol was significantly reduced. Received: 23 August 1996 / Accepted in revised form: 6 March 1997     

Antibiotic utilization at the university hospital after introducing an antibiotic policy

Objective: Antibiotic formulary restrictions are among the most popular methods to control antibiotic utilization in hospitals. The aim of the present survey was to investigate the influence of “reserve antibiotic” on antimicrobial utilization at the University Hospital Center (UHC) Rijeka. Methods: At the UHC Rijeka, reserve antibiotic was implemented in July 1997. The antimicrobial drug consumption was monitored 6 months prior to and 6 months after the introduction of the method. Antimicrobial consumption was measured in defined daily doses (DDDs) among the major clinics. Results: Reserve antibiotic has led to a decrease in total antibiotic consumption at the UHC Rijeka (45.9 DDDs/100 bed days vs 32.9 DDDs/100 bed days). Antibiotic utilization decreased in the second semester at most clinics: at the Clinic for Infectious Diseases 41%, at the Anesthesiology and Intensive Care Unit 30%, at the Clinic for Internal Medicine 18% and at the Surgical Clinic 12%. At the Clinic for Gynecology and Obstetrics, the antibiotic utilization remained the same, while at the Pediatric Clinic an increase of 28% in antibiotic utilization was noted. Conclusion: Our study indicates that restriction of usage of some antibacterial agents is a successful method to decrease antibiotic consumption and a way to bring cost savings and helps prevent emergence of resistant microorganisms in hospitals. To improve antimicrobial prescribing, additional methods such as education are required. Received: 28 October 1999 / Accepted in revised form: 26 January 2000     

Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: efficacy and safety compared to hydrochlorothiazide

Objective: To compare the antihypertensive efficacy of a new angiotensin II antagonist, valsartan, with a reference therapy, hydrochlorothiazide (HCTZ). Methods: In this double-blind study, 167 adult outpatients with mild-to-moderate essential hypertension were randomly allocated in equal number to receive valsartan 80 mg or HCTZ 25 mg for 12 weeks. In patients whose blood pressure (BP) remained uncontrolled after 8 weeks of monotherapy, atenolol 50 mg was added to the initial treatment. Patients were assessed at 4, 8 and 12 weeks. The primary efficacy variable was change from baseline in mean sitting diastolic BP (SDBP) at 8 weeks. Secondary variables included change in sitting systolic BP (SSBP) and responder rates (percentage of patients with SDBP <90 mmHg or drop ≥10 mmHg compared to baseline) at 8 weeks. Results: Valsartan and HCTZ were both effective at lowering diastolic and systolic blood pressure at all time points. Similar falls were seen in both groups with no significant differences between treatments. For the primary variable (decrease in SDBP) there was no significant difference between treatments. For SSBP there was also no significant difference observed. Responder rates at 8 weeks were 74% for valsartan and 62% for HCTZ (P = 0.10). Both treatments were well tolerated, both as monotherapy, and when combined with atenolol 50 mg per day. Conclusion: The data show valsartan 80 mg to be as effective as HCTZ in the treatment of mild-to-moderate hypertension. The results also show valsartan to be well tolerated when taken alone or in combination with atenolol. Received: 7 March 1996 / Accepted in revised form: 29 July 1996     

Inhibition of metoprolol metabolism and potentiation of its effects by paroxetine in routinely treated patients with acute myocardial infarction (AMI)

Objective To investigate the influence of paroxetine on metoprolol concentrations and its effect in patients treated for acute myocardial infarction (AMI) who are routinely given paroxetine as a co-treatment of depression. Methods We recruited 17 depressed AMI patients who received metoprolol as a routine part of their therapy (mean dose 75 ± 39 mg/day). Patients were genotyped for CYP2D6 *3, *4 and gene duplication. Metoprolol and α-hydroxy-metoprolol were analyzed in plasma 0, 2, 6 and 12 h post-dose. Heart rates (HR) at rest were registered after each sampling. Paroxetine 20 mg daily was then administered, and all measurements were repeated on day 8. Results All patients were genotypically extensive metabolizers (EMs) (nine with *1/*1 and eight with *1/*3 or *4). Following the administration of paroxetine, mean metoprolol areas under the concentration–time curve (AUC) increased (1064 ± 1213 to 4476 ± 2821 nM × h/mg per kg, P = 0.0001), while metabolite AUCs decreased (1492 ± 872 to 348 ± 279 n M × h/mg per kg, P < 0.0001), with an increase of metabolic ratios (MR) (0.9 ± 1.3 to 26 ± 29; P < 0.0001). Mean HRs were significantly lower after the study week at each time point. Mean area under the HR versus time curve (AUEC) decreased (835 ± 88 to 728 ± 84 beats × h/min; P = 0.0007). Metoprolol AUCs correlated with patients’ AUECs at the baseline (Spearman r  = −0.64, P < 0.01), but not on the eighth day of the study. A reduction of metoprolol dose was required in two patients due to excessive bradycardia and severe orthostatic hypotension. No other adverse effects of the drugs were identified. Conclusion A pronounced inhibition of metoprolol metabolism by paroxetine was observed in AMI patients, but without serious adverse effects. We suggest, however, that the metoprolol dose is controlled upon initiation and withdrawal of paroxetine.     

Analgesic use and pain in the hospital settings

Aim The aim of this study was to assess the analgesic treatment and the prevalence of pain in patients treated with analgesics in hospitals. Methods Adult patients treated with analgesics were selected from a sample of 1,675 patients in a cross-sectional study carried out in 15 Catalonian hospitals (Spain). Patient characteristics, type of analgesics, treatment schedules, patients’ pain intensity and clinical ward and hospital characteristics were assessed. Adherence to analgesic use guidelines was established according to the principles and recommendations of internationally recognised guidelines for pain management. Pain was determined by asking patients about pain intensity by means of a visual analogue scale (VAS). Results Analgesics were prescribed for 1,173 patients (70%; 95% CI: 67.4–72.6), in whom 57% (95% CI: 54.2–59.8) had pain and in whom 30.5% (95% CI: 27.9–33.1) pain intensity was greater than 30 mm. Adherence to analgesic treatment guidelines was judged appropriate in only 26.9% (95% CI: 24.4–29.4%) of all patients. The administered analgesic dose was in the recommended dose range in 42% (95% CI: 54–58) of all analgesics and in 28% (95% CI: 24–32) of opioid analgesics. A minority of patients was treated with a rescue schedule or patient-controlled analgesia (2%; 95% CI: 1.4–2.6). Pain prevalence was higher in those with analgesic treatment that did not adhere to guidelines (63.6%; 95% CI: 60.4–66.8) than in those considered as having appropriate adherence to guidelines (39.3%; 95% CI: 33.8–44.6) (p < 0.001). Adherence to analgesic treatment guidelines was higher in the large hospitals (21%; 95% CI: 18–24) than in medium and small hospitals (13%; 95% CI: 9–16) (p < 0.001). Conclusions Although analgesic use is high in the hospital settings, adherence to the principles and recommendations of pain guidelines is low, and pain is usually common in patients treated with analgesics. These results once again emphasise the need to improve analgesic use and pain management in hospitals. This work was supported by a grant (056/09/2000) from The Catalan Agency of Research and Medical Technologies.     

Short- and long-term treatments with iloprost in diabetic patients with peripheral vascular disease: effects on the cardiovascular risk factor plasminogen activator inhibitor type-1

Objectives: Iloprost, an analogue of prostacyclin, is often utilised in subjects with diabetes mellitus complicated by macroangiopathy. Methods: The effects of iloprost infusion on plasminogen activator inhibitor type-1 (PAI-1), glucometabolic control and cardiovascular equilibrium in patients with type-2 diabetes mellitus and peripheral arterial occlusive disease were investigated. Thirteen (7 men/6 women) normal-weight, normotensive and non-smoker type-2 diabetic patients (63.8 ± 3.4 years, mean ± SD) with peripheral arterial occlusive disease, stage-II according to Fontaine classification, were enrolled. Eight (four men/four women) patients underwent three study designs, each separated by a 1-week interval: study I, infusion of iloprost (3 ng kg⁻¹ min⁻¹ for 5 h) for 1 day alone (short-term treatment); study II, infusion of saline (for 5 h) for 1 day (control treatment); study III, infusion of iloprost (3 ng kg⁻¹ min⁻¹ for 5 h) over a period of 28 days (long-term treatment). The remaining five (three men/two women) patients underwent study IV only, infusion of saline over a period of 28 days (placebo treatment). Plasma levels of glucose, plasminogen, PAI-1 activity and fibrinogen, blood pressure and heart rate were determined in all studies, while plasma insulin levels, blood HbA_1c, walking distance and Winsor index only in studies III and IV. Results: Both short- and long-term treatments with iloprost significantly reduced PAI-1 activity (baseline vs end: 17.4 ± 1.9 AU/ml vs 15.0 ± 1.6 AU/ml, P < 0.02; 20.5 ± 7.6 AU/ml vs 7.9 ± 2.1 AU/ml, P < 0.002, respectively). Long-term treatment with iloprost significantly increased walking distance (baseline vs end: 325 ± 41 m vs 496 ± 52 m, P < 0.0001), but not Winsor index. Neither glucometabolic control nor cardiovascular equilibrium were affected by short- and long-term treatments with iloprost. Control and placebo treatments did not cause any significant modifications in the parameters evaluated. Conclusion: If confirmed by further investigations, the results of this pilot study suggest that iloprost, infused for both brief and long periods, is able to reduce the cardiovascular risk factor PAI-1, increases free walking capacity and does not affect glucometabolic control and blood pressure in type-2 diabetic patients complicated by macroangiopathy. Received: 25 August 1998 / Accepted in revised form: 8 June 1999     

Incidence of lethal adverse drug reactions in the comprehensive hospital drug monitoring, a 20-year survey, 1974–1993, based on the data of Berne/St. Gallen

Objectives: Realising the limitations of spontaneous drug monitoring systems concerning the epidemiological aspects, a comprehensive program was founded. It was based on previous publications from the US, Canada and Northern Ireland, mainly those of the BCDSP (Boston Collaborative Drug Surveillance Programme). Methods: Drug monitoring was carried out by a group of physicians which included the medical head of each of the divisions of internal medicine, a statistician and an informatician. Only probable or definite drug event relationships were included. A probable event is defined as one in which the drug interaction was more likely to be the cause than any non-drug-related cause. The same criteria were valid for the lethal reactions. Results: In the present evaluation, we found 26 probable lethal adverse drug reactions out of a total of 48,005 patients consecutively admitted to the divisions of internal medicine of three Swiss teaching hospitals during the years 1974–1993, an incidence of 0.054%. The median age of the cohort was 68 years (range 11–103 years), of which 49% were women. The median hospital stay was 14 days and the median number of drugs was eight per patient. Conclusion: The patients with a lethal outcome were presented under the eight pharmacologic–therapeutic classes of drugs and the classification proposed by NS Irey. This is based on long histopathologic experience and helps to identify preventable risks. Received: 30 June 1999 / Accepted in revised form: 10 April 2000     

Oral metamizol (1 g and 2 g) versus ibuprofen and placebo in the treatment of lower third molar surgery pain: randomised double-blind multi-centre study

Objective: To assess the efficacy of metamizol 1 g and 2 g in the relief of pain after surgical extraction of the lower third molar, and to compare the therapeutic effect with that of ibuprofen 600 mg or placebo. Methods: A total of 253 patients aged between 18 years and 60 years who had undergone extraction of the lower third molar (types II–IV) under local anaesthesia, up to a maximum of 108 mg of mepivacaine, were randomly assigned to a single oral dose of a new galenic form (drinkable vials) of metamizol 1 g (n = 75), metamizol 2 g (n = 72), ibuprofen 600 mg (n = 74) or placebo (n = 32). Pain intensity was evaluated by a 100-mm visual analogue scale. To enter the study, a pain level of 50 mm or more was required. The duration of the trial was 1 h. Assessments were carried out at 15, 30 and 60 min after treatment. Results: The analgesic efficacy of metamizol 2 g was significantly better than ibuprofen and placebo with regard to all evaluated parameters. The values of the pain intensity difference at 15 min, the percentage of patients with a decrease of 50% or more on the visual analogue scale at 60 min and the sum of pain intensity differences at 60 min showed metamizol 2 g to be significantly more effective than metamizol 1 g. In general, metamizol 1 g was as effective as ibuprofen 600 mg. The analgesic efficacy of placebo was significantly lower than that of all active treatments. A lower number of patients treated with metamizol 1 g (n = 1) or metamizol 2 g (n = 1) needed rescue medication than those given ibuprofen (n = 7) or placebo (n = 5). No serious adverse effects developed and none of the patients had to leave the study for this reason. Conclusions: The model of the lower third molar, for which the analgesic outcome referred to the first hour after drug administration, demonstrated that the analgesic efficacy of oral metamizol 2 g was significantly higher than that of ibuprofen 600 mg or placebo. Metamizol 1 g and ibuprofen 600 mg showed a similar therapeutic effect. All regimens were as well tolerated as placebo. Received: 6 July 1997 / Accepted in revised form: 6 October 1997     

Comparative trough effects of formoterol and salmeterol on lymphocyte β2-adrenoceptor – regulation and bronchodilatation

Objectives: The primary aim of the present study was to evaluate comparative trough effects of formoterol and salmeterol on β₂-adrenoceptor regulation and bronchodilator response after regular twice-daily treatment, with a secondary aim to evaluate any possible association with β₂-adrenoceptor polymorphism. Methods: Sixteen asthmatic subjects, with mean (SD) age 33(9) years, all taking inhaled corticosteroids and with a forced expiratory volume in 1 s (FEV₁) of 81(12)% predicted were recruited to take part in a randomised single-blind, three-way cross-over study. The subjects received three treatments each for 1 week, with 1-week washout periods in between: (1) formoterol dry powder, 12 μg twice daily, (2) salmeterol dry powder, 50 μg twice daily, or (3) placebo, twice daily. Spirometry and lymphocyte β₂-adrenoceptor parameters were measured before the first dose and 12 h after the last dose of each treatment, as well as domiciliary peak flow during each treatment. Results: There were no differences in β₂-adrenoceptor density (B_max) between the three treatments prior to the first dose; whereas, after the last dose, B_max was lower with both active treatments than with placebo, but was significant for salmeterol only – a 1.2-fold geometric mean fold difference (95% CI 1- to 1.4-fold), P = 0.04. Compared with placebo, there were n = 9 of 16 subjects with salmeterol and n = 6 of 16 with formoterol who had a greater than 15% fall in B_max. Post-hoc trend analysis of polymorphism showed that the propensity for downregulation appeared to be related to the occurrence of an allelic substitution of glycine at codon 16 – 8 of 13 for salmeterol versus 5 of 13 for formoterol with a greater than 15% fall compared with placebo. There were no significant differences between salmeterol and formoterol in terms of mean or individual values for downregulation. There was evidence of persistent bronchodilator activity with both active treatments compared with placebo; this was significant for forced expiratory flow rate between 25% and 75% of vital capacity (FEF_25–75) – the mean difference versus salmeterol was 0.39 l/s (95% CI 0.06–0.70), P = 0.02, and versus formoterol was 0.35 l/s (95% CI 0.16–0.53), P = 0.001. These effects were mirrored by significant improvements in morning peak flow rate compared with placebo – mean difference versus salmeterol was 24 l/min (95% CI 7–42), P = 0.01, and versus formoterol was 36 l/min (95% CI 25–48), P < 0.0001. Conclusion: There were no differences between regular treatment with formoterol and salmeterol in their effects on lymphocyte β₂-adrenoceptor regulation at the end of a 12-h dosing interval, with both drugs exhibiting a residual degree of bronchodilator activity at the same time point. Further studies to evaluate receptor regulation and bronchodilator response are required in susceptible patients who have the homozygous glycine-16 polymorphism. Received: 15 January 1999 / Accepted in revised form: 19 April 1999     

Factors predicting hospital readmissions related to adverse drug reactions

Objective  To analyse the contribution of adverse drug reactions (ADR) to hospital readmissions. Methods  This was a case–control study in which unscheduled admissions of patients who had been admitted to the hospital during the two previous months were assessed during a 21-month period. The patient was considered a case when the main diagnosis of readmission complied with the World Health Organisation’s definition of an ADR. For each case, two controls were selected from those patients that had been admitted for ADR without readmission (n = 177). Information on drugs and other risk factors was obtained from cases by interview and from controls by clinical record review. Results  There were 26,559 unscheduled admissions of which 81 were readmissions associated with ADR (4.5% of the unscheduled readmissions). There were no statistically significant correlations with sex, age or medical history, with the exception of arterial hypertension. The main drug products causing readmission were acenocoumarol (15, 18.5%), antihypertensive-diuretics (14, 17.3%), anticancer drugs (11, 13.6%) and digoxin (seven, 8.6%). In the multivariate logistic analysis, the variables predicting readmission were acenocoumarol [odds ratio (OR) 12.2, 95% confidence interval (CI) 3.8–38.3, P < 0.0001], a record of diabetes mellitus (OR 2.6, 95% CI 1.3–5.5, P < 0.01), the number of drugs taken at the moment of ADR (OR 1.2, 95% CI 1.1–1.4, P < 0.001) and high blood pressure (OR 0.3, 95% CI 0.2–0.6, P < 0.001) even though the latter was a negative predictor, preventing readmission. Of the 81 readmissions associated with ADR, 28 (34.6%) were preventable. Conclusion  A medical record of diabetes mellitus, polypharmacy and acenocoumarol treatment were risk factors predicting hospital readmission related to ADR.     

The influence of hepatic impairment on the pharmacokinetics of the dipeptidyl peptidase IV (DPP-4) inhibitor vildagliptin

Objective Vildagliptin is a potent and selective dipeptidyl peptidase-IV (DPP-4) inhibitor that improves glycemic control in patients with type 2 diabetes mellitus by increasing α- and β-cell responsiveness to glucose. This study investigated the pharmacokinetics of vildagliptin in patients with hepatic impairment compared with healthy subjects. Methods This was an open-label, parallel-group study in patients with mild (n = 6), moderate (n = 6) or severe (n = 4) hepatic impairment and healthy subjects (n = 6). All subjects received a single 100-mg oral dose of vildagliptin, and plasma concentrations of vildagliptin and its main pharmacologically inactive metabolite LAY151 were measured up to 36 h post-dose. Results Exposure to vildagliptin (AUC_0–∞ and C_max) decreased non-significantly by 20 and 30%, respectively, in patients with mild hepatic impairment [geometric mean ratio (90% CI): AUC_0–∞, 0.80 (0.60, 1.06), p = 0.192; C_max, 0.70 (0.46, 1.05), p = 0.149]. Exposure to vildagliptin was also decreased non-significantly in patients with moderate hepatic impairment [−8% for AUC_0–∞, geometric mean ratio (90% CI): 0.92 (0.69, 1.23), p = 0.630; −23% for C_max, geometric mean ratio (90% CI): 0.77 (0.51, 1.17), p = 0.293]. In patients with severe hepatic impairment, C_max was 6% lower than that in healthy subjects [geometric mean ratio (90% CI): 0.94 (0.59, 1.49), p = 0.285], whereas AUC_0–∞ was increased by 22% [geometric mean ratio (90% CI): 1.22 (0.89, 1.68), p = 0.816). Across the hepatic impairment groups, LAY151 AUC_0–∞ and C_max were increased by 29–84% and 24–63%, respectively, compared with healthy subjects. The single 100-mg oral dose of vildagliptin was well tolerated by patients with hepatic impairment. Conclusions There was no significant difference in exposure to vildagliptin in patients with mild, moderate or severe hepatic impairment; therefore, no dose adjustment of vildagliptin is necessary in patients with hepatic impairment.     

Phase II trial of pyrazoloacridine (NSC#366140) in patients with metastatic breast cancer

Purpose: Pyrazoloacridine (PZA) is an investigational nucleic acid binding agent that inhibits the activity of topoisomerases 1 and 2. We conducted a phase II clinical study to determine the efficacy and toxicities of PZA in patients with metastatic breast cancer (MBC). Experimental Design: In this phase II multicenter study, patients who were treated with no more than one prior chemotherapy for MBC were treated with 750 mg/m2 of PZA given as a 3-hour intravenous infusion every 3 weeks. Treatment cycles were continued until disease progression or unacceptable toxicities. The study was designed to distinguish between a response rate of <15% vs >30% (alpha = 0.10, beta = 0.10) using Simons optimal 2-stage design. At least 2 responses were required in the first 12 patients in the 1st stage and 6 of 35 in the 2nd stage to recommend the agent for further study. Results: Two patients in the first stage had a response allowing accrual to second stage. A total of 15 patients (out of 35 planned) were treated on the study prior to premature closure. Three patients had a partial response (20%) lasting 4.5–6 months. Two patients had stable disease for 3 and 5 months. The dose limiting toxicity was granulocytopenia with ten patients requiring dose reduction or dose delay for grade 4 neutropenia. Other grade 3 and 4 toxicities include vomiting (n = 2), nausea (n = 2), neurotoxicity (n = 1), fatigue (n = 1), anemia (n = 1), dyspnea 9n = 1) and renal (n = 1). Conclusions: Pyrazoloacridine demonstrated modest activity in patients with metastatic breast cancer.     

Correlation between steady-state plasma concentrations of mianserin and trazodone in depressed patients

Objective: The correlations between steady-state plasma concentrations of mianserin and its active metabolite desmethylmianserin and those of trazodone and its active metabolite m-chlorophenylpiperazine (m-CPP) were examined in 19 depressed patients. Methods: Ten patients received first mianserin (30 mg per day) and second trazodone (150 mg per day), while 9 patients received these treatments in the opposite sequence, with at least 2-week intervals between the two phases. Blood was sampled at steady state, 1–3 weeks after initiation of each treatment. Plasma concentrations of mianserin, the separate enantiomers S(+)- and R(−)-mianserin, desmethylmianserin, trazodone and m-CPP were measured by means of high-performance liquid chromatography. Results: There was a significant correlation between steady-state plasma concentrations of trazodone and total mianserin (r = 0.59) or S(+)-mianserin (r = 0.57), but not R(−)-mianserin (r = 0.33). Conclusion: The present study thus suggests that the metabolic capacity of mianserin, especially the more active S(+)-enantiomer, and that of trazodone correlate to each other. This finding supports the previous suggestions that cytochrome P4502D6 is involved in the metabolism of mianserin and trazodone. Received: 14 March 1997 / Accepted in revised form: 21 August 1997     

A randomized controlled assessment of the systemic activity of budesonide when given once or twice daily via Turbuhaler

Objective: To compare the effects on the hypothalamo-pituitary-adrenal (HPA) axis of budesonide, delivered via Turbuhaler at doses of 800 μg once daily in the morning or evening or 400 μg twice daily. Methods: Healthy men (n=24) received four treatments in random order: budesonide, 800 μg in the morning and placebo in the evening; budesonide, 800 μg in the evening and placebo in the morning; budesonide, 400 μg in the morning and evening; placebo in the morning and evening. Each treatment was given for 1 week, with a 2-week washout period between treatments. Blood samples for measurement of plasma cortisol were obtained before the evening dose on day 6 of each treatment period and over the following 22 h. Results: All three budesonide regimens produced a statistically significant reduction (mean 16–19%) in the area under the curve of plasma cortisol concentration versus time over 22 h (AUC_0–22h) compared with placebo. There were no statistically significant differences among the three regimens. These reductions in plasma cortisol concentrations were not considered to be clinically significant. Analysis of the fractional AUCs measured 0–10 h and 10–22 h after dosing showed that evening dosing had a greater effect on nocturnal cortisol than morning dosing; daytime cortisol was reduced by all treatments. Conclusion: There was no significant difference between the effects on plasma cortisol of budesonide 400 μg twice daily and 800 μg once daily in the morning or evening. Received: 1 January 2000 / Accepted: 15 March 2000     

Consistency and efficacy of cetirizine (10 mg) versus ebastine (20 mg) at 4 h on skin reactivity

Objective: We compared the consistency and efficacy of the two antihistamines, cetirizine (10 mg) and ebastine (20 mg) on histamine skin reactivity 4 h after treatment. Methods: Twenty-four healthy volunteers participated in a randomised double-blind cross-over study. The areas of wheals and flares induced by increasing (0, 5, 10, 50, 100, 200, 300 mg/ml) histamine concentrations, administered by prick tests, were measured before and 4 h after intake of cetirizine or ebastine. Results: Before treatment, concentration–response curves were similar and threshold concentrations identical (0.57 mg/ml and 0.57 mg/ml for cetirizine and ebastine, respectively). Both treatments exerted a significant effect. However, cetirizine was significantly more efficient than ebastine 20 mg (P < 0.01 both for wheals and flares). After cetirizine, the threshold concentration inducing a 3-mm² wheal was significantly higher (266 mg/ml) than after ebastine (77 mg/ml) (P < 0.01), and total inhibition of the wheal was obtained in 18 of 24 patients for cetirizine and in 4 of 24 for ebastine (P < 0.001). The variation coefficient for the wheal reaction was 31% for cetirizine and 159% for ebastine, indicating a much lower variability after cetirizine. Conclusion: Our study shows clearly that the efficacy of a single therapeutic dosage of cetirizine is greater and consistently better than that of ebastine for suppression of cutaneous reactivity to histamine 4 h after treatment in healthy volunteers. The need for ebastine to metabolise into the active carebastine might explain this difference. Received: 14 June 1999 / Accepted in revised form: 31 July 1999     

Phase I study of pemetrexed and pegylated liposomal doxorubicin in patients with refractory breast,ovarian, primary peritoneal,or fallopian tube cancer

Purpose: Pemetrexed and pegylated liposomal doxorubicin (PLD) are clinically active as single agents and preclinically synergistic. This phase I, open-label trial evaluated the maximum tolerated dose (MTD) and safety of pemetrexed followed by PLD in patients with breast or gynecologic cancers. Patients: Using 3 + 3 dose escalation, cohorts of 3–9 patients received escalating doses of pemetrexed 400–500 mg/m² on days 1 and 15 and PLD 30–45 mg/m² on day 1 of a 28-day cycle. All patients received folic acid and vitamin B₁₂ until 21 days after last pemetrexed dose. Patients continued until dose-limiting toxicity (DLT) or progression (PD). Results: From 11/05 to 2/08, 29 patients entered treatment; median age: 60.6 years (range, 47.5–80.1); ECOG PS 0/1: 27.6%/72.4%; primary disease site: ovarian (55.2%), breast (34.5%), peritoneum (10.3%); prior therapies: chemotherapy (100.0%), surgery (72.4%), hormones/biologics (35%), and radiation (20.7%). Pemetrexed/PLD dose levels: L1 = 400/30 (n = 4), L2 = 400/35 (n = 6), L3 = 500/35 (n = 9), L4 = 500/40 (n = 7), and L5 = 500/45 (n = 3). Treatment-related grade 3-4 toxicities: hematologic—neutropenia (86.2%), leukopenia (58.6%), thrombocytopenia (48.3%), anemia (41.4%); nonhematologic—mucosal inflammation (24.1%), febrile neutropenia (24.1%), hand-foot syndrome (13.8%), hypokalaemia (10.3%). Reasons for discontinuation: PD (48.3%), toxicity (27.6%), patient request (13.8%), and investigator request (10.3%). Efficacy: 5 ovarian patients (20.8%) achieved partial response; median time to progression (TTP) was 6.1 months (range, 1.2–12.5). Conclusion: Pemetrexed plus PLD was reasonably tolerated in this heavily–pretreated population. MTD: pemetrexed 500 mg/m² and PLD 40 mg/m² may be carried forward to phase II studies in specific patient populations. TTP in platinum-refractory ovarian patients was greater than expected.     

The effect of folic acid supplementation on the pharmacokinetics and pharmacodynamics of oral methotrexate during the remission-induction period of treatment for moderate-to-severe plaque psoriasis

Objective We assessed the effect of folic acid (FA) on the pharmacokinetics and pharmacodynamics of low-dose oral methotrexate (MTX) during the remission-induction phase of psoriasis treatment. Methods In a 32-week, open-label, two-way cross-over study, patients (n = 20, seven men, aged 35–70 years) with moderate-to-severe plaque psoriasis were randomly assigned to receive MTX plus FA (20 mg/week) for 16 weeks followed by MTX monotherapy (three doses of MTX separated by 12-h intervals once a week) for an additional 16 weeks (treatment arm A, n = 10) or to receive the opposite sequence of treatments (arm B, n = 10). Dosing of MTX was individualised with the help of pre-study evaluation of plasma MTX pharmacokinetics. The Psoriasis Area and Severity Index (PASI), biochemistry and haematology tests and erythrocyte concentration of MTX polyglutamates (MTXPG) were evaluated throughout the study. Results In arms A and B, the mean (range) concentrations of MTXPG (nmol/L) were comparable [week 16: 96.2 (32.0–157) vs. 111 (73.7–175), P = 0.32; week 32: 103 (55.8–173) vs. 83.6 (27.4–129), P = 0.24]. After 16 weeks, the mean±SEM PASI decreased from 20.1 ± 2.1 to 8.8 ± 1.3 in arm A, while a greater reduction from 27.2 ± 2.1 to 5.1 ± 1.0 occurred in arm B (P < 0.001). Positive correlations were found between the percent improvement in PASI at week 16 and the ratios of the concentration of MTXPG to plasma folate (rho = 0.59, P = 0.008) or RBC folate concentration (rho = 0.56, P = 0.013). Due to an accelerated decline in PASI in arm A and a trend to its worsening in arm B after crossing over of treatments, the mean absolute PASI scores in both arms were comparable at week 32. Conclusion The antipsoriatic effect of MTX during the remission-induction phase of treatment is influenced by folate status and may be significantly less if combined treatment with FA is used, irrespective of pre-treatment folate levels. The individual tailoring of MTX dosing needs further attention because the mean percent PASI improvement from baseline was 83% and the inter-patient variability in response was low after 16 weeks of monotherapy with MTX.