Prompt impact of first prospective statin mega-trials on postoperative lipid management of CABG patients: a 20-year follow-up in a single hospital.

BACKGROUND: The long-term success of coronary artery bypass grafting (CABG) depends on secondary prevention. Vast evidence provided by the results of cholesterol mega-trials over two decades has shown that effective reduction of LDL cholesterol improves the prognosis of patients with coronary heart disease. However, the implementation of these results into the clinical practice has turned out to be challenging. We analysed how the information derived from clinical statin trials and international recommendations affected the local treatment practices of dyslipidaemia of CABG patients during a 20-year time period. METHODS: The cohort includes all CABG patients (n = 953) treated in Kanta-Häme Central Hospital during the time period 1990-2009. At the postoperative visits in the cardiology outpatient clinic, each patient's statin prescription was recorded, and blood lipids were determined. RESULTS: During 1990-1994, 12.0 % of patients were on statins and during the following 5-year time periods the proportion was 57.2, 82.2 and 96.8 %, respectively. During the 20-year observation period (1990-2009), the effective statin dose increased progressively during these 5-year periods up to 36-fold, while the mean concentration of LDL cholesterol decreased from 3.7 to 2.1 mmol/l and that of apolipoprotein B from 1.3 to 0.8 g/l. In the very last year of follow-up, the mean concentrations of LDL-C and apoB were 1.83 mmol/l and 0.78 g/l, respectively. The most prominent increase in statin use and dosage took place during 1994-1996 and 2003-2005, respectively. CONCLUSIONS: Among CABG patients the lipid-lowering efficacy of statin therapy improved dramatically since 1994. This progress was accompanied by significant and favourable changes of lipid and apolipoprotein-B values. This study shows that it is possible to effectively improve lipid treatment policy once the results of relevant trials are available, and that this may happen even before international or national guidelines have been updated.

Enhanced oxidizability of ubiquinol and alpha-tocopherol during lovastatin treatment.

A double-blinded, placebo-controlled cross-over trial was carried out with 27 hypercholesterolemic men with coronary heart disease. During the 6-week treatment period lovastatin (60 mg/day) decreased fasting serum LDL cholesterol by 45%, LDL phosphorus by 38% and apoB by 33%. Ubiquinol content diminished by 13% as measured per LDL phosphorus. When LDL was oxidized ex vivo with AMVN both LDL ubiquinol and alpha-tocopherol were exhausted faster after lovastatin treatment compared to placebo, by 24% (P < 0.005) and 36% (P < 0.0001), respectively. Lag time in copper-induced oxidation of LDL decreased by 7% (P < 0.01). This suggests diminished antioxidant-dependent resistance of LDL to the early phase of oxidative stress.

Celiprolol augments the effect of physical exercise on insulin sensitivity and serum lipid levels in chronic heart failure.

PURPOSE: Impaired insulin sensitivity has been linked with chronic heart failure (CHF). Exercise has a beneficial effect on insulin sensitivity in healthy subjects. It is used also as an adjunctive therapy in patients with CHF. We studied the effect of randomized treatment with celiprolol, a vasodilating beta(1)-adrenoceptor antagonist, 200 mg once daily (n=20) or placebo (n=11) on serum lipid levels and insulin sensitivity in patients with CHF. In addition, all subjects participated in a 6-month exercise training protocol. Thirteen subjects in the celiprolol and eight subjects in the control group were on additional beta(1)-adrenoceptor antagonist as part of their tailored CHF therapy. Insulin sensitivity was determined using the hyperinsulinemic euglycemic clamp test (diabetic subjects excluded, n=11 for the celiprolol group and n=8 for the placebo group). RESULTS: Insulin sensitivity index (ISI) increased by 33% (P<0.05) in the celiprolol group and by 17% (NS) in the control group. The mean increase in the whole group was 20% [from 68.2+/-11.5 to 81.7+/-10.7 ml/min/kg (mU/l), P<0.05]. No change was found in the total cholesterol level. HDL cholesterol levels increased by 12% (from 0.98+/-0.05 to 1.10+/-0.05 mmol/l, P<0. 005), and HDL/total cholesterol and HDL/LDL cholesterol ratios by 15% and 16%, respectively (P<0.005). The increase in serum fasting HDL cholesterol level was greater in the celiprolol-treated group (P<0.05). At baseline ISI correlated with maximal oxygen uptake (r=0. 65, P<0.0001) and body mass index (r=-0.55, P<0.001). The change in ISI correlated weakly with the improvement in muscle exercise capacity (r=0.53, P<0.05). CONCLUSIONS: Insulin sensitivity and serum lipid levels may be favorably affected by exercise training in subjects with mild-to-moderate CHF. Celiprolol, a vasodilating beta1- selective adrenoceptor antagonist, potentiates this effect.

Evaluation of Sysmex UF-100 urine flow cytometer vs chamber counting of supravitally stained specimens and conventional bacterial cultures.

We evaluated the Sysmex UF-100 urine flow cytometer (TOA Medical Electronics, Kobe, Japan) with 269 uncentrifuged urine specimens by comparing it with Sternheimer staining and particle counting in 1-microL disposable chambers with both brightfield and phase-contrast microscopy (the reference method). Results of routine test strip analysis, sediment microscopy (182 specimens), and bacterial culture (204 specimens) were also available. Detection of urinary WBCs and RBCs was highly reliable with the UF-100 compared with manual chamber counting (r = .98 and .88, respectively). Identification of bacteria was equal to that with visual microscopy of uncentrifuged specimens; sensitivity was 55%, and specificity 90%, compared with bacterial cultures at a cutoff of > 10(3) colony-forming units per milliliter. Renal damage was difficult to evaluate even with manual methods because of the low counts of renal tubular cells and casts; with standard manual Sternheimer-stained sediment analysis, sensitivity was 65% to 69% and specificity 66% to 91%, compared with the uncentrifuged chamber method at a cutoff of 3 and 10 particles per microliter, respectively. Renal damage was demonstrated with the UF-100 with a sensitivity of 26% to 69% and specificity 92% to 94%, compared with chamber counts. Automated urinalysis with the UF-100 urine flow cytometer offers considerable savings in time and labor. When high sensitivity is needed, visual microscopic review should be performed to detect renal disease.

Comparison of LDL trap assay to other tests of antioxidant capacity; effect of vitamin E and lovastatin treatment.

Oxidized low density lipoprotein (LDL) has a major impact in the development of atherosclerosis. Risk for oxidative modification of LDL is usually determined indirectly by measuring the capability of LDL to resist radical insult. We compared three different methods quantifying the antioxidative capacity of LDL ex vivo in dyslipidemic patients with coronary heart disease. Plasma samples were obtained from two double-blinded cross-over trials. The duration of all interventions (placebo, lovastatin 60 mg/day, RRR-alpha-tocopherol 300 mg/day and lovastatin + RRR-alpha-tocopherol combined) was 6 weeks. The total radical capturing capacity of LDL (TRAP) in plasma was determined using 2,2-azo-bis(2,4-dimethyl-valeronitrile) (AMVN) -induced oxidation, and measuring the extinction time of chemiluminescence. TRAP was compared to the variables characterizing formation of conjugated dienes in copper-induced oxidation. Also the initial concentrations and consumption times of reduced alpha-tocopherol (alpha-TOH) and ubiquinol in AMVN-induced oxidation were determined. Repeatability of TRAP was comparable to that of the lag time in conjugated diene formation. Coefficient of variation within TRAP assay was 4.4% and between TRAP assays 5.9%. Tocopherol supplementation produced statistically significant changes in all antioxidant variables except those related to LDL ubiquinol. TRAP increased by 57%, the lag time in conjugated diene formation by 34% and consumption time of alpha-TOH by 88%. When data of all interventions were included in the analyses, TRAP correlated with the lag time (r = 0.75, p < 10(-6)), with LDL alpha-TOH (r = 0.50, p < 0.001) and with the consumption time of alpha-TOH (r = 0.58, p < 0.0001). In the baseline data, the associations between different antioxidant variables were weaker. TRAP correlated with the lag time (r = 0.55, p < 0.001) and alpha-TOH consumption time (r = 0.48, p < 0.05), and inversely with apolipoprotein Al (r = -0.51, p < 0.05). Lag time at the baseline did not correlate with ubiquinol or tocopherol parameters, or with any plasma lipid or lipoprotein levels analyzed. Lovastatin treatment did not significantly affect the antioxidant capacity of LDL. In conclusion, TRAP reflects slightly different properties of LDL compared to the lag time. Thus, LDL TRAP assay may complement the other methods used to quantify the antioxidant capacity of LDL. However, TRAP and the lag time react similarly to vitamin E supplementation.

Effects of chronic celiprolol treatment on brown fat, feeding, and drinking in fa/fa Zucker rats.

Celiprolol is a novel beta-adrenoceptor blocking drug that displays clinically favorable effects on glucose and lipid metabolism. Because some other atypical beta-adrenoceptor blocking drugs have been described to act as agonists on beta(3)-adrenoceptors, we aimed to investigate the effects of celiprolol on brown fat and beta(3)-adrenoceptors. Chronic treatment of obese fa/fa Zucker rats with celiprolol (50 mg/kg/day orally for 20 days) increased GDP binding to brown fat mitochondria by 1.5-fold, whereas beta(3)-adrenoceptor agonist ZD7114 ((S)-4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]-N-(2-methoxyet hyl )phenoxyacetamide, 3 mg/kg/day) increased the binding by 3.3-fold. Weight gain was reduced by 19% due to decreased water and food intakes in celiprolol-treated rats. Celiprolol did not activate lipolysis in rat adipocytes in vitro or stimulate human beta(3)-adrenoceptors expressed in Chinese hamster ovary cells as measured with Cytosensor microphysiometer. Therefore, celiprolol does not seem to activate brown fat via beta(3)-adrenoceptors.

Effects of celiprolol on insulin sensitivity and glucose tolerance in dyslipidemic hypertension.

The effects of celiprolol on insulin sensitivity, glucose tolerance and serum lipids were compared to those of other antihypertensive drugs (beta- or Ca-blocker or ACE-inhibitor) in 23 dyslipidemic non-diabetic patients with controlled hypertension. Hyperinsulinemic euglycemic clamp and independent oral glucose tolerance tests (OGTT) were performed before and 6 months after the study treatment. Six patients out of 23 were randomized to the control group where antihypertensive monotherapy was kept unchanged. Mean glucose disposal rate (M, mean +/- SEM) determined in the clamp test increased in the celiprolol group from 24.4 +/- 2.3 to 34.9 +/- 2.4 mumol/kg/min (p < 0.001). Insulin sensitivity improved during celiprolol treatment independent of the previous treatment. In the control group, M remained practically unchanged (21.6 +/- 3.7 mumol/kg/min). During 2 h OGTT, incremental glucose and insulin AUC decreased in the celiprolol group from 4.5 +/- 0.7 to 2.0 +/- 0.6 mM*h (p < 0.002) and from 113 +/- 16 to 72 +/- 10 mU/l*h (p < 0.005), respectively. There was also a small beneficial change in serum lipids in the celiprolol group: a reduction in serum total cholesterol (-4%), triglycerides (-11%) and LDL-cholesterol (-9%), and an increase in HDL-cholesterol (+6%) and HDL/LDL ratio (+15%). No significant change occurred in the control group. Fasting serum glucose and insulin did not change significantly in either group. In this study with a limited control group, celiprolol improved insulin sensitivity, glucose tolerance and serum lipid profiles of dyslipidemic hypertensive patients.

Effects of short-term lamotrigine treatment on pharmacokinetics of carbamazepine.

AIM AND METHOD: The effects of short-term treatment with lamotrigine (LTG) (100 mg twice daily for one week) on single dose pharmacokinetics of carbamazepine (CBZ, 200 mg) were investigated in a randomized, double-blinded, placebo-controlled cross-over study with 10 healthy volunteers. RESULTS: Pharmacokinetic parameters for CBZ or for CBZ-10,11-epoxide, the main metabolite of CBZ, were not significantly affected by LTG pretreatment. The mean (+/- SEM) elimination half-life of CBZ was 33.0+/-1.8 h after pretreatment with placebo and 30.1+/-2.0 h after a one-week-pretreatment with LTG (NS). The area under the serum concentration curve to infinity (AUC) of CBZ was 638+/-45 micromol/l after placebo and 624+/-53 micromol/l after LTG (NS). Changes in the peak serum concentration, from 9.0+/-0.3 micromol/l to 9.2+/-0.4 micromol/l (LTG), and in the time to peak serum concentration, from 9.3+/-1.1 h to 9.1+/-1.2 h (LTG), were also not significant. CONCLUSION: These data support the earlier findings that LTG does not significantly affect the rate or extent of absorption, or elimination of CBZ.

Nifedipine is not feasible for biliary pain in patients with gallbladder stones.

OBJECTIVE: Biliary pain is generally treated with NSAIDs and spasmolytics, but some patients do not tolerate them. Nifedipine has been suggested to have some analgesic effect and it has been used successfully in many painful smooth muscle disorders. Our aim was to evaluate the effect of nifedipine for biliary colics and gallbladder volume. PATIENTS AND METHODS: Twenty-seven patients suffering from uncomplicated symptomatic gallbladder stones were prospectively randomized to receive either oral nifedipine (10 mg 3 times daily) or placebo in a double-blind manner. Liver chemistry and ultrasonography were examined before and after the 8-week study period. The patients completed each day a diary of their pain, headache, palpitation, burning feeling in skin, dizziness, and their use of painkillers. RESULTS: Biliary pain seemed to be less intensive and shorter in duration, but without statistical significance, whereas headache tended to be more common (p = 0.077) in nifedipine group than that in placebo group. This difference would have reached statistical significance with over 155 patients randomized. Overall additional drug use was similar in both groups, and was increased in nifedipine group for headache (p = 0.05). The fasting gallbladder volume tended to decrease (p = 0.085) during the nifedipine treatment but not with placebo. Serum liver chemistry remained within normal range. CONCLUSIONS: This small study shows that nifedipine may decrease slightly biliary pain intensity and duration, and contrary to previous findings in healthy volunteers, it seems to decrease resting gallbladder volume in patients with symptomatic uncomplicated gallbladder stones, but did not reduce the need of traditional pain medication partly because of increased need for headache. Thus it is not a feasible choice for routine use against biliary pain in symptomatic gallbladder stones, which is why the study was not continued to reach statistical significance in respect to biliary pain.

[125I]calcitonin gene-related peptide binding in membranes of the ciliary body-iris block.

Calcitonin gene-related peptide (CGRP) is a mediator of intraocular inflammatory responses, but it may also affect aqueous humour dynamics. The aim of the present work was to characterize CGRP binding sites in the eyes of various mammals. The binding of radiolabelled human CGRP to membranes from the ciliary body-iris (c+i) block of porcine eye showed characteristics expected of an interaction with a receptor site: it was reversible, saturable and displaced by rat CGRP and calcitonin. Studies with CGRP fragments demonstrated the importance of rather long carboxy-terminal sequences of the CGRP molecule for high-affinity binding to the receptor. Rat islet amyloid polypeptide (IAPP), which has about 50% structural similarity to CGRP, displaced radioligand binding nearly as efficiently as CGRP, while human IAPP was about twenty-fold less potent. No displaceable CGRP binding could be reliably demonstrated by the present method in c+i membranes from cat, rabbit and bovine eyes, thus indicating differences in the number or localization of CGRP receptors between different mammalian species.

Association between serum lipids, glucose tolerance, and insulin sensitivity during 12 months of celiprolol treatment.

The study was undertaken to evaluate the development and association of parameters related to the metabolic syndrome during celiprolol treatment. Hyperinsulinemic euglycemic clamp and independent oral glucose tolerance tests (OGTT) were performed on 25 nondiabetic patients with controlled hypertension and dyslipidemia. The tests were carried out during the patients' previous antihypertensive monotherapy (beta- or Ca-blocker, or an ACE inhibitor), and after 6 and 12 months of celiprolol treatment. About one third of patients were randomized to a control group in which treatment was kept unchanged. Insulin sensitivity index (ISI), measured by the euglycemic clamp test, increased 35% in the celiprolol group at 6 months and remained at that level at 12 months, independent of the previous treatment (p = 0.03, compared to the change in the control group). During a 2 hour OGTT, incremental glucose area under the curve (AUC) decreased from 4.5 to 1.9 hr x mmol/l during 6 months of celiprolol treatment, and decreased further to 1.5 hr x mmol/l at 12 months (p < 0.001). Insulin AUC decreased from 113 to 72 hr x mU/l, and decreased further to 68 hr x mU/l (p < 0.01). All insulin parameters in OGTT were highly significant (p < 0.0001) and inversely associated with ISI. Insulin AUC had the best linear correlation with ISI (r = -0.682, p < 0.0001). Glucose parameters in OGTT correlated only weakly and inversely with insulin sensitivity. From the fasting serum lipids, triglycerides showed an inverse (p < 0.001) and HDL a weak (p < 0.05) positive association with ISI. Four out of 20 metabolic, clinical, and demographic parameters proved to be independently significant predictors for ISI in multiple regression analysis. These were insulin AUC, fasting insulin levels, triglyceride values, and age. The coefficient of determination in this four-parameter linear model was 69%. In this preliminary, observer-masked trial with a limited control group, celiprolol improved the impaired insulin sensitivity and glucose tolerance of dyslipidemic hypertensive patients. A fairly predictive model can be formulated to evaluate the peripheral insulin sensitivity of hypertensive patients with suspected metabolic syndrome using OGTT with serum insulin determinations.

Long-term celiprolol therapy lowers fasting plasma leptin levels. Celiprolol Multicenter Study Group.

The effects of celiprolol on fasting plasma leptin levels, glucose tolerance, and insulin sensitivity were studied in a randomized, investigator-masked, and parallel clinical trial. Modified oral glucose tolerance tests (OGTT) were performed during the previous antihypertensive monotherapy (beta- or Ca-blocker, or ACE inhibitor), and 6 and 12 months after randomization to celiprolol (200-400 mg daily) or to control group, where the therapy was kept unchanged. One hundred sixty-nine dyslipidemic and hypertensive nondiabetics with an age range of 42-65 years and an average body mass index of 28.4 kg/m2 completed the study according to the protocol. The mean circulating leptin level decreased from 7.5 to 6.6 ng/mL in men (p < 0.05) and from 23.0 to 19.7 ng/mL in women during the 12-month celiprolol treatment. The incremental glucose area under the curve (AUC) in the 2-hour OGTT decreased from 3.8 to 3.0 h* mmol/L (p < 0.01), and insulin AUC decreased from 134 to 99 h* mU/L (p < 0.01). The insulin sensitivity index increased by 22% (p < 0.01) and the serum triglyceride level decreased by 15% in the celiprolol group. Changes in serum cholesterol were clinically insignificant. In the control group, no significant change was seen in any measured variable. A decrease in leptin levels in the celiprolol group was associated with improved insulin sensitivity, while the weight of the moderately obese patients did not change. The clinical significance of a 14% decrease in fasting plasma leptin level remains to be elucidated. The results suggest amelioration of leptin resistance during long-term celiprolol therapy.

Ubiquinone supplementation during lovastatin treatment: effect on LDL oxidation ex vivo.

A randomized, double-masked, placebo-controlled cross-over trial was carried out to evaluate whether ubiquinone supplementation (180 mg daily) corrects impaired defence against initiation of oxidation of low density lipoprotein (LDL) related to effective (60 mg daily) lovastatin treatment. Nineteen men with coronary heart disease and hypercholesterolemia received lovastatin with or without ubiquinone during 6-week periods after wash-out. The depletion times for LDL ubiquinol and reduced alpha-tocopherol were determined during oxidation induced by 2,2-azobis(2,4-dimethylvaleronitrile) (AMVN). Copper-mediated oxidation of LDL isolated by rapid density-gradient ultracentrifugation was used to measure the lag time to the propagation phase of conjugated diene formation. Compared to mere lovastatin therapy, ubiquinone supplementation lead to a 4.4-fold concentration of LDL ubiquinol (P < 0.0001). In spite of the 49% lengthening in depletion time (P < 0.0001) of LDL ubiquinol, the lag time in copper-mediated oxidation increased only by 5% (P = 0.02). Ubiquinone loading had no statistically significant effect on LDL alpha-tocopherol redox kinetics during high radical flux ex vivo. The faster depletion of LDL ubiquinol and shortened lag time in conjugated diene formation during high-dose lovastatin therapy may, at least partially, be restored with ubiquinone supplementation. However, the observed improvement in LDL antioxidative capacity was scarce, and the clinical relevance of ubiquinone supplementation during statin therapy remains open.

Effects of lovastatin therapy on susceptibility of LDL to oxidation during alpha-tocopherol supplementation.

A randomized, double-masked, crossover clinical trial was carried out to evaluate whether lovastatin therapy (60 mg daily) affects the initiation of oxidation of low density lipoprotein (LDL) in cardiac patients on alpha-tocopherol supplementation therapy (450 IU daily). Twenty-eight men with verified coronary heart disease and hypercholesterolemia received alpha-tocopherol with lovastatin or with dummy tablets in random order. The two 6-week, active-treatment periods were preceded by a washout period of at least 8 weeks. The oxidizability of LDL was determined by 2 methods ex vivo. The depletion times for LDL ubiquinol and LDL alpha-tocopherol were determined in timed samples taken during oxidation induced by 2, 2-azobis(2,4-dimethylvaleronitrile). Copper-mediated oxidation of LDL isolated by rapid density-gradient ultracentrifugation was used to measure the lag time to the propagation phase of conjugated-diene formation. alpha-Tocopherol supplementation led to a 1.9-fold concentration of reduced alpha-tocopherol in LDL (P<0.0001) and to a 2.0-fold longer depletion time (P<0.0001) of alpha-tocopherol compared with determinations after the washout period. A 43% prolongation (P<0.0001) was seen in the lag time of conjugated-diene formation. Lovastatin decreased the depletion time of reduced alpha-tocopherol in metal ion-independent oxidation by 44% and shortened the lag time of conjugated-diene formation in metal ion-dependent oxidation by 7%. In conclusion, alpha-tocopherol supplementation significantly increased the antioxidative capacity of LDL when measured ex vivo, which was partially abolished by concomitant lovastatin therapy.

Second derivative of developed tension in classifying cardiotonics with respect to their mechanisms of action: drugs affecting cAMP metabolism.

The second derivative of developed tension (T", d2T/dt2) has not come into common use in the analysis of cardiac contractility, although it has been shown to give additional information on the myocardial contraction-relaxation cycle (CRC). In the present study a new way to use T" in the analysis of myocardial mechanics, including the time course of T", is described. Profiles of the T" of the some drugs with established cardiotonic effects are presented. Experiments were carried out in spontaneously beating whole rat atria preparations. The effects of changing contraction frequency on the measured parameters were studied with electrically paced left atria. Qualitative inotropic effects of 1-methyl-3-isobutylxanthine (MIX), theophylline, caffeine, milrinone, isoprenaline and forskolin were studied. Concentrations equieffective with respect to the force of contraction were tested. Inotropic profiles were evaluated at the time of maximal force of contraction. We found that methylxanthines have a mechanical behaviour quite distinct from other inotropic agents acting via cAMP. The effects of MIX were similar to those of theophylline in all respects. A tendency to increase the active relaxation phase of T" was a property common to methylxanthines. Caffeine also prolonged the phases of contraction, whereas MIX and theophylline have opposite effects. Milrinone in turn mimics the effects of isoprenaline and forskolin; abbreviation of the relaxation phase of T" was the feature most typical of them. Caffeine was the only agent which did not shorten the duration of CRC. The method proved valuable in basic research on drug effects on cardiac contractility.

Pharmacokinetics of chlorambucil in patients with chronic lymphocytic leukaemia: comparison of different days, cycles and doses.

The effects of repeated treatment cycles and different doses on intraindividual variation in oral bioavailability of chlorambucil and its first, active, and more toxic metabolite, phenylacetic acid mustard, were studied. Chlorambucil and phenylacetic acid mustard concentrations were measured with HPLC on Day 1 and on Day 4 in 15 timed blood samples from 11 chronic lymphocytic leukaemia patients receiving chlorambucil therapy cycles. Bioavailability was evaluated also after the first chlorambucil doses of six consecutive treatment cycles repeated every 4 weeks with increasing chlorambucil doses starting with 0.8 mg/kg/4 days, and increased by 0.1 mg/kg/4 days cycle. Area under the concentration-time-curve (AUC) from t=0 to infinite was in average 3.2 hr* microg/ml for the first cycle, and decreased by 17% in four days (P<0.05). The mean distribution half-life of chlorambucil was 0.49 hr and the terminal elimination half-life 2.45 hr. The bioavailability of chlorambucil decreased further when 4-day treatment cycles were repeated. For the fifth cycle, dose-corrected AUC for the first 2 hr was 33% smaller than that for the first cycle (P for trend <0.01). Data suggest accelerated metabolism and elimination of chlorambucil and phenylacetic acid mustard, but reduced oral bioavailability of chlorambucil cannot be excluded. However, except for AUC, none of the pharmacokinetic parameters of chlorambucil changed significantly during the first 4-day treatment period. The maximal plasma concentration and AUC of phenylacetic acid mustard did not change significantly during repeated treatment cycles. According to this trial a dose adjustment of chlorambucil is not necessary during a short-term course, but may be necessary when treatment cycles are repeated. An average increase in the chlorambucil dose of 10% per cycle maintains similar plasma concentration of chlorambucil.

Topical lomefloxacin twice daily compared with fucidic acid in acute bacterial conjunctivitis.

Forty-five patients with presumed acute bacterial conjunctivitis were treated in an investigator-masked randomized multicenter study with either lomefloxacin 0.3% or fucidic acid 1% eye drops twice daily. Clinical signs and symptoms were rated by slit-lamp examination and conjunctival swab cultures were performed to evaluate clinical and microbiological efficacy. A total of 57 ocular isolates were tested for susceptibility to nine antibiotics. A significant decrease in clinical symptomatology was achieved by both treatments with a gradual improvement over the treatment period of 7-9 days. Bacteriological recovery was frequently achieved already at the first control visit (day 3-5), but the recovery rate was statistically significant (p = 0.014) only in the lomefloxacin group. The relatively high in vitro resistance rate (46%) to fucidic acid was not reflected by lower clinical efficacy. Two unrelated adverse events (one in each treatment group) and minimal local intolerance problems were observed in both treatment groups. A significantly higher incidence of burning sensation was observed with fucidic acid than with lomefloxacin (p < 0.01). All four treatment failures in the study occurred in the fucidic acid group. Lomefloxacin 0.3% ophthalmic solution demonstrated a high efficacy and good tolerance in the management of acute bacterial conjunctivitis.

A randomized, double-blind, placebo-controlled study of moclobemide and amitriptyline in the treatment of fibromyalgia in females without psychiatric disorder.

OBJECTIVE: To study the usefulness of moclobemide and amitriptyline in the treatment of fibromyalgia (FM) in females without psychiatric disorder. METHODS: In the present four centre, 12 week study, 130 female FM patients not suffering from psychiatric disorders were randomized to receive amitriptyline (AMI; 25 37.5 mg), moclobemide (MOCLO; 450-600 mg) or identical placebo. RESULTS: Seventy-four, 54 and 49 per cent of patients on AMI, MOCLO and placebo, respectively, were judged as responders. The patients on AMI also managed best regarding the respective improvements during the trial in general health, pain, sleep quality and quantity, and fatigue on visual analogue scales (VAS), the areas of the Nottingham Health Profile (NHP), as well as in the three Sheehan's functional disability scales. In the within-group comparisons, MOCLO also improved pain assessed both on VAS and on the NHP pain dimension, but the improvement was invalidated by the poor success of the drug with regard to sleep. The tolerabilities of all three drugs were comparable. CONCLUSION: The study indicates that MOCLO may not be helpful in FM patients free from clinically meaningful psychiatric problems.

Insulin sensitivity in a long-term crossover trial with celiprolol and other antihypertensive agents.

The effects of a vasodilating beta-blocker, celiprolol, on insulin sensitivity and cardiovascular risk factors were compared with those of another beta1-selective adrenoceptor blocker, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors. A randomized 21-month crossover trial was carried out with 25 patients with dyslipidemia receiving antihypertensive monotherapy. The study consisted of a 3-month active run-in period and two treatment periods, during which the patients received celiprolol (200-400 mg daily) or the control drug for 12 and 6 months in a crossover manner. A hyperinsulinemic euglycemic clamp and an oral glucose tolerance test (OGTT) were performed every 6 months. According to the clamp tests, the insulin-sensitivity index increased on average by 32% (p < 0.0001) during celiprolol treatment compared with that with the other antihypertensive agents, including ACE inhibitors. In OGTT, area under the incremental glucose curve decreased by 36% (p = 0.002) during celiprolol treatment, whereas insulin secretion diminished on average by 26% (p = 0.006). The mean decrease in fasting serum triglycerides was 11% (NS), whereas the high-density lipoprotein to low-density lipoprotein (HDL/LDL) ratio increased by 15% (p = 0.012). The results suggest that celiprolol improves insulin sensitivity of hypertensive patients with dyslipidemia in long-term therapy.

Transurethral prostatectomy in patients with preoperative bacteriuria: double-blind study with oral fleroxacin and cefalexin.

We compared oral fleroxacin and cefalexin in the prevention of postoperative infectious complications after transurethral prostatectomy (TURP) in patients with preoperative bacteriuria. 95 patients underwent TURP due to benign prostatic hyperplasia with preoperative bacteriuria. The therapy consisted of 7 days of oral fleroxacin 400 mg once a day or cefalexin 500 mg three times daily. After 2 weeks, 62% of the urine samples were sterile in the fleroxacin groups but only 37% in the cefalexin group (p = 0.047). Patients in the cefalexin group had also statistically significantly more symptoms of urinary tract infections. After 6 weeks, the bacterial eradication rate was 53% in the fleroxacin group and 37% in the cefalexin group. There were no septicemias. TURP can be performed with reasonable safety with this oral antibiotic therapy.