Effects of desloratadine,diphenhydramine, and placebo on driving performance and psychomotor performance measurements

Introduction First-generation antihistamines taken for relief of allergic rhinitis are sedating and pose potential risks for those driving a car or operating machinery. Desloratadine is a potent, selective, histamine H₁-receptor antagonist that does not easily cross the blood–brain barrier. It is nonsedating at therapeutic doses and should not affect driving or psychomotor performance.Objective This study compared the acute effects of desloratadine with diphenhydramine (active control) and placebo on the performance of healthy subjects evaluated with standard over-the-road driving tests (primary objective). The subjects performances were also evaluated (secondary objective) with the use of conventional performance tests.Methods Eighteen men and women received a single dose of desloratadine 5 mg, diphenhydramine 50 mg, or placebo during each period of this randomized, double-blind, three-way, crossover study. Two hours post-dosing, subjects operated a specially instrumented vehicle in a 90-min test designed to measure their ability (1) to maintain constant speed and lateral position while following another vehicle at a constant distance and (2) to respond to brake signals. Additionally, a full battery of performance tests was administered.Results No significant differences were noted between desloratadine and placebo in standard deviation of lateral position (SDLP), whereas diphenhydramine treatment significantly increased SDLP (P<0.001 for both comparisons). Brake reaction time was significantly faster following treatment with desloratadine than diphenhydramine (473.72 ms vs 541.22 ms; P<0.001) or placebo (512.06 ms; P=0.033). No differences were seen among treatments in deviation of speed or distance to the lead car. The majority of performance tests showed no significant differences among groups.Conclusion Desloratadine at a therapeutic dose does not impair driving performance.     

Zopiclone as positive control in studies examining the residual effects of hypnotic drugs on driving ability

Zopiclone (7.5 mg) is frequently used as a positive control in studies that examine the residual effects of hypnotic drugs on driving ability and related skills. This review summarizes studies examining the effects of zopiclone, and discusses its usefulness as a comparator drug for investigations of residual effects of novel sleep medication. A literature review (Pubmed and Embase) was conducted searching for studies that tested zopiclone on driving. Cross references were checked for additional papers. Eight studies utilizing the standardized on-the-road driving test consistently showed that in the morning following bedtime administration zopiclone (7.5 mg) significantly impaired driving performance. A total of 191 healthy volunteers were tested after placebo and zopiclone (7.5 mg). Meta analyses showed no significant differences in driving performance after zopiclone (7.5 mg) between adult and elderly healthy volunteers. The combined effect size (ES) and 95% confidence interval (95%CI) for healthy volunteers was 0.782 (0.620, 0.944). Relative to placebo, an average increment of 3.0 cm in Standard Deviation of Lateral Position (SDLP) was observed when treated with zopiclone (7.5 mg). This deviation was higher than the increment in SDLP reported for drivers with a blood alcohol concentration of 0.05% (+2.4 cm). Results from driving simulators and psychometric tests are consistent with the on-road driving test results. In conclusion, zopiclone (7.5 mg) is a reliable positive control, that consistently shows significant and meaningful impairment on the on-the-road driving test.     

Lack of effect of single and repeated doses of levocetirizine,a new antihistamine drug,on cognitive and psychomotor functions in healthy volunteers

Aims  Levocetirizine (R-cetirizine), is the active enantiomer of cetirizine, an antihistamine indicated in the treatment of allergic rhinitis and chronic idiopathic urticaria. The purpose of this trial was to analyse the effects of levocetirizine single and multiple doses on CNS using integrated measures of cognitive and psychometric performance.
Methods  A battery of psychometric tests was used: critical flicker fusion (CFF), choice reaction time (CRT), body sway (BS), learning memory test (LMT) and subjective assessments of alertness compared with placebo. Nineteen (19) healthy male volunteers received either levocetirizine 5 mg (therapeutic dose), diphenhydramine 50 mg or placebo once daily for 5 consecutive days (3-way cross-over). Diphenhydramine was used as a positive control. CFF tests were performed on days 1 and 5 at baseline and up to 24 h following drug intake. Subjects used the Bond-Lader visual analogue scales (VAS) to assess their mood and vigilance.
Results  In contrast to diphenhydramine, when compared with placebo, levocetirizine did not modify the CFF (primary endpoint), regardless of the dosing scheme (−1.62 Hz [−2.61, −0.64] and −0.81 Hz [−1.80, 0.19], respectively, 3 h after dosing on day 1). CRT was decreased with both levocetirizine and placebo up to 5 h after dosing on day 1 and up to 3 h after dosing on day 5. Body sway data were similar with levocetirizine and placebo but increased with diphenhydramine. LMT was similar in all three groups. No relevant difference between placebo and levocetirizine was recorded by the subjects on their assessment of alertness using the VAS, whilst decreased alertness was reported following diphenhydramine 50 mg.
Conclusions  This study showed that levocetirizine does not produce any deleterious effect on cognitive and psychometric functions compared with placebo in healthy male volunteers.     

Acute and subchronic effects of amitriptyline 25mg on actual driving in chronic neuropathic pain patients

The acute and subchronic effects of low doses nocturnally administered amitriptyline were compared to placebo in a double-blind crossover randomized study on driving ability and driving-related skills involving seven chronic neuropathic pain patients. Performance testing occurred at the first and last day of each 15-day drug administration period, which was preceded by a 6-day washout phase. A standardized method of measuring driving ability, the on-the-road driving test, was performed on all visits. Patients were instructed to drive with a steady lateral position while maintaining a constant speed of 95 km/h. The primary outcome of the driving test is the Standard Deviation of Lateral Position (SDLP, cm), which is an index of weaving of the car. At the first treatment day, driving performance was significantly impaired in patients after nocturnal administration of 25 mg amitriptyline compared to placebo. The increase in SDLP of 3 cm was higher than the increment generally observed with a blood alcohol concentration of 0.5 mg/ml or higher, the legal limit for driving in many countries. Also, reaction times on a memory test were significantly increased, indicating worse performance after acute treatment of amitriptyline compared to placebo. In contrast, after 2 weeks of treatment, no significant differences were found between amitriptyline and placebo, suggesting that tolerance had developed to the impairing effects of amitriptyline.     

Effects of sumatriptan and eletriptan on diseased epicardial coronary arteries

Background: Triptans are contraindicated in patients with known or suspected coronary artery disease (CAD); however, few studies have evaluated triptans in patients with obstructive CAD to quantify the vasoconstrictive effect on diseased coronary vessels. Methods: Patients undergoing percutaneous transluminal coronary angioplasty for symptomatic single-vessel CAD were randomised to one of three parallel cohorts to receive (1) 6 mg intravenously (IV) infused eletriptan plus subcutaneous (SC) placebo, (2) IV infused placebo plus 6 mg SC sumatriptan or (3) IV infused placebo plus SC placebo, as simultaneous administrations in a double-blind manner. Serial arteriograms, hemodynamic indices, electrocardiography and triptan plasma concentrations were obtained. Results:. Fifteen minutes after triptan challenge, median (95% confidence interval) changes in coronary artery diameter (CADM) at the focal point of the stenosed segment were: dilation of 2.6% (−5.0, 11.4), eletriptan 6 mg IV (n=18); constriction of 6.8% (−12.6, 0.4), sumatriptan 6 mg SC (n=17), and constriction of 4.5% (−7.0, 7.9), placebo (n=10). One patient had angiographic evidence of a new thrombus at the stenosis site, necessitating termination of study infusion and successful stenting of the lesion. There was no correlation between effects on CADM and triptan concentration, or between hemodynamic or electrocardiograph changes and the presence (n=13) or absence (n=33) of chest pain. Conclusions: Triptans had very little effect on diseased epicardial coronary arteries in a small group of angina sufferers with established CAD. Results should be interpreted cautiously since there may be instances where even modest triptan-associated epicardial constriction is sufficient to precipitate myocardial ischemia in patients with severe obstructive CAD.     

Lack of interaction between orlistat and oral contraceptives

Objectives: Orlistat, a potent and selective inhibitor of gastrointestinal lipases, is designed for the treatment of obesity. A double-blind, randomised, placebo-controlled, 2-way crossover study investigated the possible influence of orlistat on the ovulation-suppressing action of combination oral contraceptives (OC). Methods: After an 8-day run-in prior to the first of two consecutive menstrual cycles (Day 1 was the first day of menstruation), two groups of 10 healthy women, 20–27 years of age and on a stable regimen with OCs, received either 120 mg orlistat t.i.d. or placebo t.i.d. on Days 1–23 of the first cycle, and, separated by a placebo washout period on Days 24–28, the alternative treatment on Days 1–23 of the second cycle. In both cycles, serum luteinizing hormone (LH) was measured on Days 12–16 and progesterone on Days 12, 16, 19–23. Results: The geometric means of time-averaged concentrations (Days 12–16 for LH and Days 19–23 for progesterone) in the cycles with orlistat and placebo, respectively, and the one-sided 95% confidence region for the mean in the cycle with orlistat were 1.92, 2.03 and < 2.23 IU l⁻¹ for LH and 0.147, 0.145 and < 0.176 μg l⁻¹ for progesterone. The one-sided 95% confidence region for the ratio (orlistat/placebo) of geometric means was < 1.06 for LH and < 1.11 for progesterone. Conclusion: During normal ovulation the peak serum concentration of LH is above 30 IU l⁻¹ around Day 14 of the cycle, and that of progesterone exceeds 3 μg l⁻¹ around day 21. The 95% confidence regions for the means, as well as all individual concentrations, were below these limits. It was concluded that orlistat did not influence the ovulation suppressing action of oral contraceptives. Received: 18 April 1995/Accepted in received form: 6 November 1995     

Levocetirizine does not prolong the QT/QTc interval in healthy subjects: results from a thorough QT study

Objective To conduct a thorough QT study of levocetirizine, a non-sedating antihistamine, in accordance with International Conference on Harmonisation (ICH) E14 guidance. Methods The study was designed as a single-dose, placebo and positive-controlled, four-way crossover, randomised trial in which 52 healthy male and female subjects participated. Levocetirizine (5 and 30 mg) and placebo were administered double-blind, and the positive control, moxifloxacin (400 mg), was open-label. Electrocardiograms (ECGs) were obtained by continuous Holter monitoring at various time points (three per time point) during a 24-h period at baseline and after each treatment. The ECGs were read centrally in a blinded manner. QT intervals were corrected for heart rate using a gender- and study-specific correction (QT_cSS) and Fridericia’s correction (QT_cF). The largest QTc time-matched and baseline-subtracted difference between each active drug and the placebo (largest ΔΔQT_cSS) was derived from a mixed-effect analysis of variance. Results The one-sided 95% upper limits of the largest ΔΔQT_cSS for levocetirizine were 5.7 ms (5 mg) and 3.9 ms (30 mg), with mean estimates of 2.9 and 1.1 ms, respectively. Similar results were obtained for the ΔΔQT_cF data. Statistically, moxifloxacin significantly lengthened the QT_cSS, with a one-sided 95% lower limit of the largest ΔΔQT_cSS of 10.5 ms and a mean estimate of 13.4 ms. There was no relationship between the measured ΔQT_cSS and the plasma concentration of levocetirizine, whereas a statistically significant linear relationship was observed with the plasma concentration of moxifloxacin [slope estimate 0.004 ms/(ng/mL); 95% confidence interval: 0.003–0.005]. Conclusions Overall, the results of this thorough QT study indicate that the methodology of the trial was valid and sensitive enough to demonstrate the absence of effect of levocetirizine at both therapeutic (5 mg) and supra-therapeutic (30 mg) doses on cardiac repolarisation.     

Methylphenidate significantly improves driving performance of adults with attention-deficit hyperactivity disorder: a randomized crossover trial

Although patients with attention-deficit hyperactivity disorder (ADHD) have reported improved driving performance on methylphenidate, limited evidence exists to support an effect of treatment on driving performance and some regions prohibit driving on methylphenidate. A randomized, crossover trial examining the effects of methylphenidate versus placebo on highway driving in 18 adults with ADHD was carried out. After three days of no treatment, patients received either their usual methylphenidate dose (mean: 14.7 mg; range: 10-30 mg) or placebo and then the opposite treatment after a six to seven days washout period. Patients performed a 100 km driving test during normal traffic, 1.5 h after treatment administration. Standard deviation of lateral position (SDLP), the weaving of the car, was the primary outcome measure. Secondary outcome measurements included the standard deviation of speed and patient reports of driving performance. Driving performance was significantly better in the methylphenidate than in the placebo condition, as reflected by the SDLP difference (2.3 cm, 95% CI = 0.8-3.8, P = 0.004). Variation in speed was similar on treatment and on placebo (-0.05 km/h, 95% CI = -0.4 to 0.2, P = 0.70). Among adults with ADHD, with a history of a positive clinical response to methylphenidate, methylphenidate significantly improves driving performance.     

Comparative effects of enoximone and theophylline on plasma catecholamines and haemodynamics in cardiosurgical patients

Summary The release of endogenous catecholamines in aorto-coronary bypass graft patients receiving either 0.5 mg/kg enoximone (n=10), 4.0 mg/kg theophylline (n=10) or saline solution (control,n=10) has been studied, as well as certain haemodynamic parameters. Adrenaline (A) and noradrenaline (NA) concentrations were not significantly changed by the administration of enoximone. Theophylline caused a small increase in NA (+ 40% in the 1st min) and a marked increase in A (approximately + 7000% in the 1st min), which still remained elevated at the end of the investigation period (+ 220% in the 30th min). The major haemodynamic effects of enoximone were a significant increase in cardiac index (CI; + 35%) and a decrease in pulmonary capillary wedge pressure (PCWP; −27%), pulmonary artery pressure (PAP; −21%), RVEDV and RVESV, while the heart rate (HR) remained almost unchanged. The dominant haemodynamic effects of theophylline were an increase in HR (+ 26%; arrhythmia in 3 patients), PAP (+ 22%), and RVEDV (+ 19%), while REVESV (+ 26%), MAP (−16%), CI (−14%), and RVEF (−15%) fell significantly. It is concluded that the haemodynamic actions of enoximone are not mediated by catecholamine release, whereas the adverse cardiovascular effects of theophylline might partly be explained by the significant increase in plasma adrenaline.     

Marijuana,alcohol and actual driving performance

The objective of the current study was to assess the separate and combined effects of marijuana and alcohol on actual driving performance. Eighteen subjects were treated with drugs and placebo according to a balanced, 6-way, crossover design. On separate evenings they were given weight calibrated Delta(9)-tetrahydrocannabinol (THC) doses of 0, 100 and 200 &mgr;g/kg with and without an alcohol dose sufficient for achieving blood alcohol concentrations (BAC) of 0.04 g/dl while performing a Road Tracking and Car Following Test in normal traffic. Main outcome measures were standard deviation of lateral position (SDLP), time driven out of lane (TOL), reaction time (RT) and standard deviation of headway (SDH). Both THC doses alone, and alcohol alone, significantly impaired the subjects performances in both driving tests. Performance deficits were minor after alcohol and moderate after both THC doses. Combining THC with alcohol dramatically impaired driving performance. Alcohol combined with THC 100 and 200 &mgr;g/kg produced a rise in SDLP the equivalent of that associated with BAC=0.09 and 0.14 g/dl, respectively. Mean TOL rose exponentially with SDLP. Relative to placebo mean RT lengthened by 1.6 s under the combined influence of alcohol and THC 200 &mgr;g/kg. Changes in SDH ranged between 0.9 and 3.8 m. Low doses of THC moderately impair driving performance when given alone but severely impair driving performance in combination with a low dose of alcohol. Copyright 2000 John Wiley & Sons, Ltd.     

Use of the 'nutriceutical', bovine colostrum,for the treatment of distal colitis: results from an initial study

BACKGROUND: Bovine colostrum is a rich source of nutrients, antibodies and growth factors. AIM: To examine the efficacy of colostrum enemas in the treatment of distal colitis using a randomized, double-blind, controlled protocol. METHODS: Fourteen patients (eight female), with a mean age of 45 years (range, 16-75 years) and mild to moderately severe distal colitis (Powell-Tuck scoring system), received colostrum enema (100 mL of 10% solution) or placebo (albumin solution) b.d. for 4 weeks. Both groups also received mesalazine (1.6 g/day) or, if already taking it, had a dose increment of 1.6 g/day. Disease activity was documented at 0, 2 and 4 weeks. RESULTS: After 4 weeks, the colostrum group showed a mean reduction in symptom score of - 2.9 (95% confidence interval (CI), - 5.4 to - 0.3), whereas the placebo group showed a mean response of + 0.5 (95% CI, - 2.4 to +3.4). The histological score improved in five of the eight patients in the colostrum group (mean response, - 0.9; 95% CI, - 1.69 to - 0.03), whereas the histological scores only improved in two of the six patients in the placebo group (mean response, 0.2; 95% CI, - 2.4 to +2.6). CONCLUSIONS: Bovine colostrum enema shows potential as a novel therapy for left-sided colitis with additional benefits over using mesalazine alone. Further studies appear to be warranted.     

The extrapulmonary effects of increasing doses of formoterol in patients with asthma

Objective: To assess the cardiovascular and metabolic responses to increasing doses of formoterol administered from a dry powder inhaler. Methods: Twenty patients with mild to moderate asthma were given 12, 24, 48 and 96 μg of formoterol or a matched placebo on separate days. The doses were administered using a randomised, cross-over, double-blind design. The effects on heart rate, blood pressure, electromechanical systole (QS₂I), the electrocardiographic QTc interval, plasma potassium (K); blood glucose and FEV₁ were assessed prior to, and for 9 h following each dose. Results: There was no difference between the maximum effects of formoterol 12 μg and placebo; the 24 μg dose significantly decreased plasma K (−0.2 mmol · l⁻¹) and increased blood glucose (1.8 mmol · l⁻¹) compared to placebo. The two highest doses affected most of the variables with the 96 μg dose being significantly different from placebo for all indices, heart rate (9 beats · min⁻¹), systol BP (4 mmHg), diastolic BP (−3 mmHg), QS₂I (−11 ms), QTc (17 ms), plasma K (−0.5 mmol · l⁻¹) and blood glucose (2.6 mmol · l⁻¹). All doses of formoterol increased FEV₁. Conclusion: Although there were dose-dependent effects on the extrapulmonary measurements, only the effects at the highest dose may be of clinical significance. Received: 17 June 1997 / Accepted in revised form: 12 November 1997     

Lapses of attention as outcome measure of the on-the-road driving test

Background

Lapses are brief periods of inattention and reduced alertness which may be a risk factor for car crashes. The Dutch on-the-road driving test is applied to examine effects of CNS drugs on driving, using the standard deviation of lateral position (SDLP) as primary outcome measure. This paper examines the utility of an alternative outcome measure, lapses, to determine the degree to which CNS drugs impair driving.

Methods

Data from two double-blind, placebo-controlled on-the-road driving studies that examined the residual effects of hypnotic drugs were reanalyzed. The treatments were zaleplon and zolpidem tested 4 h after middle-of-the-night administration, and ramelteon and zopiclone tested 8.5 h after bedtime administration. In addition to SDLP, outcome measures related to lapses (number, total duration, and maximum deviation) were computed. A lapse was defined as a continuous change in lateral position of greater than 100 cm, lasting for at least 4 s.

Results

Both SDLP and lapses were able to detect significant driving impairment after middle-of-the-night administration of zolpidem (10 and 20 mg) and bedtime administration of ramelteon (8 mg) and zopiclone (7.5 mg) relative to placebo. Both measures found no differences from placebo after middle-of-the-night administration of zaleplon (10 and 20 mg). The number of lapses was more sensitive in differentiating treatment from placebo than the maximum deviation of a lapse or their duration. After considering different lapse duration criteria, a lapse was redefined as a continuous change in lateral position of greater than 100 cm, lasting for at least 8 s. This change in definition did not significantly alter the outcome of the statistical analyses.

Conclusions

In addition to SDLP, the number of lapses is a useful outcome measure to identify treatments that impair driving. Future research should determine the unique contributions of SDLP and lapses in defining the potential risk of CNS drugs on driving.     

Adrenal suppression with high doses of inhaled fluticasone propionate and triamcinolone acetonide in healthy volunteers

Study objective: This study was conducted to compare the adrenal suppression of inhaled fluticasone propionate and triamcinolone acetonide in healthy volunteers, both given via their respective pressurised metered dose inhaler (pMDI) devices at high doses within the manufacturers recommended dose range. Design: We used a single (investigator) blind, randomised, crossover design comparing a total daily dose of 1.625 mg fluticasone propionate delivered via a pMDI, 1.60 mg daily of triamcinolone acetonide delivered via a pMDI with integrated spacer, or placebo pMDI; each drug was given in two divided doses at 0800 hours and 2200 hours over a 24-h period. Each drug treatment was separated by a 1-week washout. Patients: Twelve normal subjects mean age 27.5 years were studied. Measurements: Blood samples were taken for 0800 hours plasma cortisol, i.e. 10 h following the second dose. Ten hour urine collections (2200 hours until 0800 hours) were taken for urinary cortisol and creatinine excretion. Results: For the 0800 hours plasma cortisol (geometric mean, nmol · l⁻¹) compared with placebo (353) fluticasone propionate (138) produced significant (P<0.05) suppression (2.57-fold difference), whereas triamcinolone acetonide (263) did not (1.34-fold difference). Fluticasone propionate produced a 1.91-fold greater adrenal suppression than triamcinolone acetonide (95% CI 1.10 to 3.33). Individual subjects with abnormally low 0800 hours cortisol values <150 nmol · l⁻¹ (<5.4 μg/dl) were n=4 for fluticasone propionate and n=0 for triamcinolone acetonide. Overnight urinary cortisol/creatinine ratio (geometric mean, nmol/mmol) did not show any difference between fluticasone propionate (1.48) and triamcinolone acetonide (1.60), with both producing significant suppression versus placebo (4.01): triamcinolone acetonide 2.50-fold difference (95% CI 1.45–4.24); fluticasone propionate 2.71-fold difference (95% CI 1.57–4.69). Conclusion: Fluticasone propionate 1.625 mg/day (pMDI) produced an approximately two-fold greater adrenal suppression of 0800 hours plasma cortisol than triamcinolone acetonide 1.60 mg per day (Oral Inhaler) when given twice daily, and one third of subjects with fluticasone had abnormally low 0800 hours cortisol values <150 nmol · l⁻¹ (<5.4 μg · dl⁻¹). There were no differences between the drugs for urinary cortisol excretion. Further dose-ranging studies are required at steady-state in asthmatic subjects in order to see whether differences occur at lower doses on the steep part of the dose–response curve for both plasma and urinary cortisol suppression. Received: 28 January 1997 / Accepted in revised form: 11 April 1997     

Effect of erythromycin and itraconazole on the pharmacokinetics of intravenous lignocaine

Objective: We have studied the possible interaction of erythromycin and itraconazole, both inhibitors of cytochrome P450 3A4 isoenzyme (CYP3A4), with intravenous lignocaine in nine healthy volunteers using a randomized cross-over study design. Methods: The subjects were given oral placebo, erythromycin (500 mg three times a day) or itraconazole (200 mg once a day) for 4 days. Intravenous lignocaine 1.5 mg · kg⁻¹ was given with an infusion for 60 min on the fourth day of pretreatment with placebo, erythromycin or itraconazole. Timed plasma samples were collected until 11 h. The concentrations of lignocaine and its metabolite monoethylglycinexylidide (MEGX) were measured by gas chromatography. Results: The area under the lignocaine concentration-time curve was similar during all three phases but erythromycin significantly increased the elimination half-life of lignocaine from 2.5 to 2.9 (0.7) h compared with placebo. Following itraconazole administration, t_1/2 was 2.6 h. The values for plasma clearance and volume of distribution at steady state were similar during all the phases. Compared with placebo and itraconazole, erythromycin significantly increased MEGX peak concentrations by approximately 40% and AUC_(0–11 h) by 45–60%. Conclusion: The plasma decay of lignocaine administered intravenously is virtually unaffected by the concomitant administration of erythromycin and itraconazole. However, erythromycin increases the concentrations of MEGX, which indicates that erythromycin either increases the relative amount of lignocaine metabolized via N-de-ethylation or decreases the further metabolism of MEGX. Further studies are necessary to elucidate the clinical significance of the erythromycin-induced elevated concentrations of MEGX during prolonged intravenous infusions of lignocaine. Received: 8 January 1998 / Accepted in revised form: 8 June 1998     

Total cholesterol,high density lipoprotein and triglyceride for cardiovascular disease in elderly patients treated with metformin

Metformin reduces total cholesterol level, low density lipoprotein cholesterol (LDL-C) level, blood glucose level and increases high density lipoprotein cholesterol (HDL-C) level associated with cardiovascular disease. We evaluated effect of metformin on lipid profile in Korean patients with type 2 diabetes aged 64 yeras or older. We retrospectively examined 307 outpatients treated with metformin in a hospital setting with a follow-up period of 4.7 years. Metformin was not associated with the improvement in total cholesterol level (adjusted mean difference; 30.6 mg/dl, 95% CI: 24.9 to 36.4) and HDL-C level (adjusted mean difference; 2.6 mg/dl, 95% CI: 0.09 to 4.64) but may be associated with improvement in triglyceride level (adjusted mean difference; 41.5 mg/dl, 95% CI: 24.7 to 58.3). In comparison to the placebo groups (Kooy et al., 2009), there was a 1.5-fold decrease in triglyceride level and a 2-fold decrease in HDL-C level in our study. The frequency of Scr level that increased above the defined level [Scr ≥ 1.5 mg/dl for male, ≥1.4 mg/dl for female] was 6.7% [mean difference of elevated Scr: −0.9 mg/dl, 95% CI: −0.41 to −1.44, p < 0.002]. To confirm the efficacy of metformin use on triglyceride level and HDL-C level associated with the risk of cardiovascular disease in patient with diabetes, further placebo-controlled investigations are required.     

The interaction of paracetamol with frusemide.

Following the administration of paracetamol (1 g 4 times per day) or placebo to 10 healthy female volunteers for 2 days, the pharmacological effects of intravenous frusemide (20 mg) were observed after a final dose of either paracetamol or placebo. Paracetamol pre-treatment had no effect on frusemide-induced diuresis or natriuresis. There was a significant reduction in the basal output of prostaglandin E2 (PGE2) with paracetamol pre-treatment (18.4 +/- 15.4 vs 7.6 +/- 5.0 ng h-1, P < 0.05; 95% confidence interval of the difference 0.2 to 21.8). Frusemide induced a transient increase in the urinary excretion rate of PGE2 and although this effect was reduced by paracetamol (46.6 +/- 50.9 vs 23.2 +/- 13.8) the differences in the change of excretion rate from baseline were not statistically significant (95% confidence interval of the difference -17.8 to 15.7). The basal level of 6-keto prostaglandin F1 alpha (PGF1 alpha) was less with paracetamol pre-treatment (61.7 +/- 41.1 vs 38.7 +/- 26.1 ng h-1, NS; 95% confidence interval of the difference -16.6 to 62.6) and the cumulative urinary output of PGF1 alpha in the 6 h after frusemide administration was significantly reduced (305.9 +/- 179.4 vs 181.8 +/- 100.2 ng h-1, P < 0.05; 95% confidence interval of the difference 32.2 to 216). The frusemide-induced rise in plasma renin activity was significantly less with paracetamol than placebo at 60 min (4.3 +/- 2.9 vs 2.7 +/- 1.9 ng ml-1 h-1, P < 0.01; 95% confidence interval of the difference 0.4 to 2.7).     

The effectiveness, safety and epidemiology of the use of acarbose in the treatment of patients with type II diabetes mellitus A model of medicine-based evidence

Objective: To assess the efficacy, safety and extent of perceived indications of acarbose, a new antidiabetic agent, under routine clinical practice conditions in an unselected Northern Italian population of type II diabetic patients. Methods: The study population was assigned to three different groups according to the physician's clinical judgement: group A (acarbose considered as an elective treatment); group B (acarbose considered to be of uncertain benefit); group C (acarbose deemed not to be appropriate). Group B patients were randomized either to continue their standard treatment or to add acarbose to it. Patients with type II diabetes mellitus were recruited from 17 diabetes outpatient clinics from one Italian region (Lombardy). A total of 1027 patients were recruited (group A: 283; group C: 494; group B: 250, of whom 124 were randomly assigned to standard treatment + acarbose and 126 to standard treatment alone). Acarbose was administered for 1 year at a median dose of 100 mg 3 times daily. Drug efficacy was evaluated in terms of mean HbA1c, pre- and post-prandial glycaemic values. Additional endpoints were the proportion of patients with HbA1c levels below 8% at the end of the study period and the proportion of subjects who needed a modification in the standard treatment. The safety and tolerability profiles of the drug were also investigated. Data on HbA1c, fasting and post-prandial blood glucose levels were analysed over time using repeated-measures analysis [Generalized Estimating Equation (GEE) models]. Results: The analysis of Group B showed that, after treatment for 1 year, the mean reduction in HbA1c levels in the acarbose group with respect to the control group was 0.30% (95% confidence limits −0.60 +0.02; P = 0.07), while the mean reduction in post-prandial glycaemia was 17 mg · dl⁻¹ (95% c.l. −33.5 −0.8; P = 0.04). No difference resulted for fasting blood glucose levels. When looking at the baseline HbA1c levels, it emerged that the mean benefit associated with the use of acarbose was 0.14% (95% c.l. −0.6 +0.28; P = 0.5) in patients with HbA1c levels below 8%, 0.28% (95% c.l. −0.6 +0.05; P = 0.09) in those with values between 8% and 9.9% and 0.65% (95% c.l. −1.36 +0.06; P = 0.07) in those with values ≥10%. Only patients treated with diet ± oral anti-diabetic agents (OAA) benefited from acarbose treatment (mean benefit = 0.37%, 95% c.l. −0.65 −0.08), while no effect was shown for insulin-treated subjects. The proportion of patients with HbA1c below 8% increased from 31% to 44% in the acarbose group and from 40% to 45% in the control group (absolute difference between baseline and end-of-study values = 8.0% in favour of acarbose-treated patients; P = 0.058). Patients treated with acarbose were significantly more likely to undergo a dose reduction in concomitant diabetic treatments compared with the control group; they were also less likely to require an increase in the dose of standard treatment and to start insulin during the study period. One third of the patients could not assume the drug for the whole study period, mainly due to gastrointestinal side-effects. Conclusions: The design adopted in this study allowed an integrated evaluation of the overall effectiveness of acarbose in clinical practice. The benefits of the drug in an unselected population of non-insulin-dependent diabetes mellitus (NIDDM) patients are significant but of marginal clinical relevance. Only a better definition of the subgroups of patients who are more likely to benefit from long-term treatment, particularly through possible postponement of secondary OAA failure, will allow a reliable definition of the cost-effectiveness of this complementary component of anti-diabetic strategy. Received: 14 July 1998 / Accepted in revised form: 23 November 1998     

The cardiac effects of terfenadine after inhibition of its metabolism by grapefruit juice

Objective: To determine whether the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine are affected by the concomitant administration of grapefruit juice. Methods: Six healthy volunteers were recruited for a balanced cross-over study. Each volunteer received 120 mg terfenadine 30 min after drinking 300 ml of either water or freshly squeezed grapefruit juice. The alternative treatment was administered on the second study day 2 weeks later. Measurements of the area under the terfenadine plasma concentration-time curve (AUC), maximum terfenadine concentration (C_max) and the time to maximum concentration (t_max) were made, and the corrected QT (QTc) interval was measured from the surface electrocardiogram. Results: Terfenadine was quantifiable in plasma in all 6 subjects on both study days for up to 24 h post-dosing. The AUC of terfenadine was significantly increased by concomitant grapefruit administration (median values 40.6 vs 16.3 ng · ml⁻¹ · h), as was the C_max (median values 7.2 vs 2.1 ng · ml⁻¹). The t_max was not significantly increased and there was no significant change in the median QTc interval despite the increased terfenadine levels. The 95% confidence interval for the difference in the change in QTc interval at C_max was −13 to +38 ms. Conclusion: Administration of grapefruit juice concomitantly with terfenadine may lead to an increase in terfenadine bioavailability, but the increase observed in this study did not lead to significant cardiotoxicity in normal subjects. However, this does not exclude the risk of cardiotoxicity in high-risk subjects given greater doses of grapefruit juice over longer periods of time. Received: 14 October 1996 / Accepted in revised form: 10 December 1996     

Concomitant administration of the α-glucosidase inhibitor voglibose (AO-128) does not alter the pharmacokinetics of glibenclamide

Objective: Voglibose is a new and potent inhibitor of α-glucosidases used for treatment of diabetes mellitus. It increases gastro-intestinal motility and could thus affect absorption of other concurrently administered antidiabetic drugs. The aim of this study was to investigate whether or not voglibose modifies the pharmacokinetics of glibenclamide, a widely used oral antidiabetic, and the glibenclamide-induced decrease in fasting serum glucose. Methods: Twelve healthy male subjects were included in this double-blind cross-over study and received a single 1.75-mg dose of glibenclamide on the 8th day of continuous administration of either placebo (reference) or voglibose 5 mg t.i.d. (test). Blood samples were taken to determine the pharmacokinetic characteristics of gliben-clamide and the test/reference ratios were evaluated according to bioequivalence criteria. Additional blood samples were taken to measure serum glucose on the same day. Results: The concentration–time course of glibenclamide under concomitant voglibose administration was similar to that under placebo. The equivalence ratio (test/reference) for the pharmacokinetic characteristics AUC_normwas 1.03 (geometric mean; 0.95–1.11, 90% confidence interval) and C_max,norm1.01 (0.94–1.08). The parameters were within the accepted range of 0.8–1.25 (AUC) or 0.7–1.43 (C_max), thus fulfilling equivalence criteria and indicating no effect of voglibose on glibenclamide kinetics. The glibenclamide-induced decrease in fasting serum glucose concentration was similarly independent of placebo or voglibose co-administration. Conclusions: Voglibose did not interact with glibenclamide on a pharmacokinetic level. Concomitant treatment was well tolerated and has been proven to be safe for further clinical use. Received: 28 February 1997 / Accepted in revised form: 8 May 1997