Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin.

AIM: Assess the pharmacodynamics of lixisenatide once daily (QD) versus liraglutide QD in type 2 diabetes insufficiently controlled on metformin. METHODS: In this 28-day, randomized, open-label, parallel-group, multicentre study (NCT01175473), patients (mean HbA1c 7.3%) received subcutaneous lixisenatide QD (10 µg weeks 1-2, then 20 µg; n = 77) or liraglutide QD (0.6 mg week 1, 1.2 mg week 2, then 1.8 mg; n = 71) 30 min before breakfast. Primary endpoint was change in postprandial plasma glucose (PPG) exposure from baseline to day 28 during a breakfast test meal. RESULTS: Lixisenatide reduced PPG significantly more than liraglutide [mean change in AUC(0:30-4:30h) : -12.6 vs. -4.0 h·mmol/L, respectively; p < 0.0001 (0:30 h = start of meal)]. Change in maximum PPG excursion was -3.9 mmol/l vs. -1.4 mmol/l, respectively (p < 0.0001). More lixisenatide-treated patients achieved 2-h PPG <7.8 mmol/l (69% vs. 29%). Changes in fasting plasma glucose were greater with liraglutide (-0.3 vs. -1.3 mmol/l, p < 0.0001). Lixisenatide provided greater decreases in postprandial glucagon (p < 0.05), insulin (p < 0.0001) and C-peptide (p < 0.0001). Mean HbA1c decreased in both treatment groups (from 7.2% to 6.9% with lixisenatide vs. 7.4% to 6.9% with liraglutide) as did body weight (-1.6 kg vs. -2.4 kg, respectively). Overall incidence of adverse events was lower with lixisenatide (55%) versus liraglutide (65%), with no serious events or hypoglycaemia reported. CONCLUSIONS: Once daily prebreakfast lixisenatide provided a significantly greater reduction in PPG (AUC) during a morning test meal versus prebreakfast liraglutide. Lixisenatide provided significant decreases in postprandial insulin, C-peptide (vs. an increase with liraglutide) and glucagon, and better gastrointestinal tolerability than liraglutide.

Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial.

Alpha-lipoic acid (ALA), a naturally occuring compound and a radical scavenger was shown to enhance glucose transport and utilization in different experimental and animal models. Clinical studies described an increase of insulin sensitivity after acute and short-term (10 d) parenteral administration of ALA. The effects of a 4-week oral treatment with alpha-lipoic acid were evaluated in a placebo-controlled, multicenter pilot study to determine see whether oral treatment also improves insulin sensitivity. Seventy-four patients with type-2 diabetes were randomized to either placebo (n = 19); or active treatment in various doses of 600 mg once daily (n = 19), twice daily (1200 mg; n = 18), or thrice daily (1800 mg; n = 18) alpha-lipoic acid. An isoglycemic glucose-clamp was done on days 0 (pre) and 29 (post). In this explorative study, analysis was done according to the number of subjects showing an improvement of insulin sensitivity after treatment. Furthermore, the effects of active vs. placebo treatment on insulin sensitivity was compared. All four groups were comparable and had a similar degree of hyperglycemia and insulin sensitivity at baseline. When compared to placebo, significantly more subjects had an increase in insulin-stimulated glucose disposal (MCR) after ALA treatment in each group. As there was no dose effect seen in the three different alpha-lipoic acid groups, all subjects receiving ALA were combined in the "active" group and then compared to placebo. This revealed significantly different changes in MCR after treatment (+27% vs. placebo; p < .01). This placebo-controlled explorative study confirms previous observations of an increase of insulin sensitivity in type-2 diabetes after acute and chronic intravenous administration of ALA. The results suggest that oral administration of alpha-lipoic acid can improve insulin sensitivity in patients with type-2 diabetes. The encouraging findings of this pilot trial need to be substantiated by further investigations.

Gastric emptying in patients with insulin dependent diabetes mellitus and bioavailability of thioctic acid-enantiomers.

The objective of this study was to determine the impact of prolonged gastric emptying in patients with insulin dependent diabetes mellitus (IDDM) on the bioavailability of the R(+)- and S(-)-thioctic acid (TA) enantiomers. Gastric emptying time (GET) was assessed in 30 healthy volunteers and 22 patients with IDDM using sequential ultrasonography after a standardized solid-liquid test meal. Pharmacokinetics and absolute bioavailability (F) of the TA-enantiomers were studied using a randomized, open two-way crossover design with administrations of oral and intravenous single doses of 200 mg rac-TA. GET in healthy subjects was 134.7+/-21.6 min, the normal range was calculated from 88.3 to 181.1 min. The mean GET in all IDDM patients was significantly prolonged (178.2+/-28.1 min; P<0.001). Only 50% of the patients (n=11) were found to have normal GET (group A), the other half of the population (n=11) were considered to have delayed GET (group B). Mean GET values were 156.9+/-21.5 in group A (P=0.028) and 199.4+/-13.9 min in group B, respectively, suggesting that gastric motility is significantly different from non-diabetic controls even in patients with apparently normal gastric emptying. Times to peak plasma concentrations (t(max)) of both TA-enantiomers were similar in both groups and thus, unrelated to measures of gastric emptying. In contrast, maximum concentrations (C(max)) and area-under-the-curve values (AUC) of both enantiomers were reduced by about 30% in patients with delayed GET. Although these differences resulted in statistical significance for the AUC of both enantiomers (P<0.05), linear regression analysis showed only modest correlation between GET and the extent of TA-enantiomer absorption (r2=0.31 and 0.22 for R(+)-/S(-)-TA, respectively). The study suggests that prolonged gastric emptying is frequently present in IDDM. Delayed gastric emptying, however, does not substantially affect the rate and extent of absorption of both TA-enantiomers.

Tolerability and in vivo performance of a novel freon-free metered dose inhaler for a fixed combinational product of reproterol and disodium cromoglycate.

The present study was conducted to describe and compare the in vivo performance (systemic exposure), clinical and laboratory safety of a fixed combinational product of inhaled reproterol (CAS 54063-54-6) plus disodium cromoglycate (DSCG; CAS 15826-37-6) using a novel freon (CFC)-free metered dose inhaler (MDI), which uses 1,1,1,2,3,3,3-heptafluoropropane (HFA-227; CAS 431-89-0) as propellant and polyoxyethylene glyceryl trioleate (Tagat TO; CAS 68958-64-5) as surfactant relative to the conventional freon-driven MDI Allergospasmin in healthy male and female volunteers. Twenty-four young male and female healthy subjects were randomly allocated in gender-balanced fashion to 4 parallel treatment groups with single and repeated dosing of either reproterol + DSCG by HFA- or CFC-MDI (each time N = 8) or placebo by HFA- or CFC-MDI (each time N = 4) using matched placebo devices thus allowing a double-blind (with regard to placebo) approach. Treatments consisted of a single morning dose of 2 actuations followed 4 days later by a 1 week treatment course of 2 actuations four times daily. Subjects were investigated extensively in terms of blood pressure, pulse rate, electrocardiography, spirometry, respiratory rate, body temperature, laboratory safety (haematology, clinical chemistry, urinalysis) and clinical well-being. There were no treatment, compound or device related effects for any of the tolerability and safety end points. The treatments were well tolerated. In particular, there was no irritative cough or any sign of broncho-irritation on application. Adverse events were reported in a total of 9 subjects: 3/8, 4/8, 0/4 and 2/4 subjects treated with reproterol + DSCG by HFA-MDI, reproterol + DSCG by CFC-MDI, placebo by HFA-MDI and placebo by CFC-MDI, respectively. Of these, 6 events in 6 subjects receiving the active treatments were considered probably or definitely related to the test drug administration (i.e. adverse drug reactions): after reproterol + DSCG one subject in each treatment group (HFA-MDI and CFC-MDI) complained of an unpleasant bitter taste immediately after application; one further subject in each group complained of headache. Under treatment with reproterol + DSCG by CFC-MDI one male subject complained of mild transient nausea with onset on day 5. Under treatment with reproterol + DSCG by HFA-MDI one female subject complained of mild dizziness and mildly disturbed (blurred) vision with onset on day 1. All adverse events occurred only transitory and required no treatment. Systemic exposure, evaluated by the plasma concentrations of DSCG at 1 h after application, was slightly higher with the HFA-MDI compared to the CFC-MDI. It is concluded that the safety, tolerability and in vivo performance of the newly developed freon-free MDI is at least as well tolerable as the already marketed freon-driven conventional formulation.

[Time factors in endoscopic studies. A survey in West Germany]. / Zeitaufwand für endoskopische Untersuchungen. Eine Umfrage in der Bundesrepublik Deutschland.

In order to obtain representative data for the orientation of personal requirements in endoscopic units, 650 hospitals in the FRG were asked to have an exact look at the times they needed for endoscopic procedures during an period of 14 days. 25% of the contacted hospitals answered to this request and thus the times required for more than 14,000 endoscopic procedures for both, doctors and medical staff, could be analysed. Results revealed that most of the sophisticated procedures such as colonoscopy, ERCP (especially when they included therapeutic endoscopical methods) varied largely in time. This was caused by different factors such as the patient dependent variables, and the course of the procedure including observation of safety and hygiene standards. Average values of times needed for endoscopic procedures were as follows (time in minutes): (Table: see text). The data given above might be of value for the estimation of actual personal and time requirements in endoscopic units.

Pharmacokinetics of naftopidil, a novel anti-hypertensive drug, in patients with hepatic dysfunction.

The pharmacokinetics of naftopidil, a novel alpha-1 adrenoceptor-blocking antihypertensive, were investigated in ten patients (9M/1F) with hepatic dysfunction after oral administration (50 mg, tablet) and after an intravenous infusion of 5.0 mg over 2 minutes. Results were compared to a control group of 12 healthy subjects (6M/6F) of a previous investigation, which was carried out according to the identical study protocol. The pharmacokinetic parameters obtained for the i.v. administration were comparable in both groups (half life 3.6 +/- 3.4 hours in liver-impaired subjects versus 3.3 +/- 2.1 hours in controls; clearance 11.9 +/- 4.7 ml/minute/kg versus 11.0 +/- 1.6 ml/minute/kg). Following oral administration the plasma levels and half-life times of naftopidil were significantly increased in liver impairment (t1/2 16.6 +/- 19.3 hours versus 5.4 +/- 3.2 hours in controls; P = 0.012). Mean values for the absolute bioavailability in patients with hepatic dysfunction were significantly higher (mean 75%, median 53%, range 13.4-211.0%) compared to healthy subjects (mean 17%, median 16%, range 6.7-29.6%, P = 0.001). Reduction of functional hepatic blood flow in chronic liver disease or, as evidenced in one case as a consequence of shunt surgery, is the probable cause of the observed alteration in naftopidil kinetics. This phenomenon occurred only following the oral 50 mg dose whereas the intravenous 5 mg dose obviously still could be normally handled. Naftopidil demethylation and hydroxylation were both less and non-uniformly affected. The pharmacokinetic findings suggest that in patients with severe hepatic impairment or evidence for marked changes in hepatic blood flow the dose of naftopidil may require adjustment to the lower end of the therapeutic range and/or may be limited to once daily. However, before definite conclusions can be drawn, further steady-state studies are required. Despite the pharmacokinetic discrepancies no difference in drug tolerability was seen between patients and healthy subjects.

Retigabine N-glucuronidation and its potential role in enterohepatic circulation.

The metabolism of retigabine in humans and dogs is dominated by N-glucuronidation (), whereas in rats, a multitude of metabolites of this new anticonvulsant is observed (). The comparison of the in vivo and in vitro kinetics of retigabine N-glucuronidation in these species identified a constant ratio between retigabine and retigabine N-glucuronide in vivo in humans and dog. An enterohepatic circulation of retigabine in these species is likely to be the result of reversible glucuronidation-deglucuronidation reactions. Rats did not show such a phenomenon, indicating that enterohepatic circulation of retigabine via retigabine N-glucuronide does not occur in this species. In the rat, 90% of retigabine N-glucuronidation is catalyzed by UDP-glucuronosyltransferase (UGT)1A1 and UGT1A2, whereas family 2 UGT enzymes contribute also. Of ten recombinant human UGTs, only UGTs 1A1, 1A3, 1A4, and 1A9 catalyzed the N-glucuronidation of retigabine. From the known substrate specificities of UGT1A4 toward lamotrigine and bilirubin and our activity and inhibition data, we conclude that UGT1A4 is a major retigabine N-glucuronosyl transferase in vivo and significantly contributes to the enterohepatic cycling of the drug.