Exenatide - pharmacokinetics, pharmacodynamics, safety and tolerability in patients ≥ 75 years of age with Type 2 diabetes.

OBJECTIVE: This study evaluated pharmacokinetics, pharmacodynamics,safety, and tolerability of single doses of exenatide in elderly Type 2 diabetes (T2D)patients. METHODS: This placebo-controlled,patient-blind, crossover study compared elderly patients (≥ 75 y, n = 15) to controls( ≥ 45 to ≤ 65y, n = 15) with T2D. Patients were randomized to single subcutaneous doses of exenatide 5µg, placebo or exenatide 10 µg (Sequence 1) or placebo, exenatide 5 µg or exenatide 10 µg (Sequence 2) before a standardized breakfast over three consecutive days. Serial blood samples were collected for plasma exenatide and serum glucose concentrations.Pharmacokinetic data from this study were also integrated with those from six other clinical pharmacology studies to further evaluate the impact of age on plasma exenatide apparent clearance (CL/F) (139 controls ( ≤ 65 y); 28 elderly patients (> 65 y)). RESULTS: Mean ± SD ages for control and elderly patients were 57 ± 6 y and 78 ± 3 y, respectively.All elderly patients had renal impairment at baseline, as compared with one third of controls. Dose-normalized plasma exenatide maximum concentration and exposure were greater in elderly patients, but between-age group differences were neither statistically significant nor considered clinically relevant. The integrated pharmacokinetic analysis showed a significant linear relationship between plasma exenatide CL/F and renal clearance (test of slope = 0, p < 0.001),with no additional effect from age. Exenatide dose-dependently blunted postprandial serum glucose excursions in both age groups. No hypoglycemia or serious adverse events were reported, and exenatide was generally well tolerated in both age groups. CONCLUSIONS: Exenatide dose adjustments should be determined by renal function rather than age in elderly T2D patients.

A thorough QT study to evaluate the effects of singledose exenatide 10 µg on cardiac repolarization in healthy subjects.

OBJECTIVE: This was a singledose, randomized, positive- and placebo-controlled, double-dummy, double-blinded, 3-period crossover thorough QT study of exenatide, a glucagon-like peptide-1 receptor agonist for the treatment of Type 2 diabetes that enhances insulin secretion in a glucose- dependent fashion. METHODS: Healthy subjects (n = 70) underwent an initial tolerability screening, receiving subcutaneous exenatide 10 µg daily for 3 consecutive days. Subjects who passed tolerability screening (n = 62) received exenatide 10 µg, placebo, and moxifloxacin (400 mg orally; positive control) separated by washout periods of approximately 5 days. Twelve-lead electrocardiograms and blood samples for plasma exenatide, glucose, and insulin were collected. QT intervals were heart rate-corrected using Fridericia's correction (QTcF) and an individual correction (QTcI) and were analyzed as change from predose (ΔQTcF, or ΔQTcI). The relationships between the QTc interval and plasma exenatide, glucose, and insulin concentrations were also explored. RESULTS: Based on ΔQTcF and ΔQTcI assessments, exenatide 10 µg did not show a clinically significant prolongation of QT compared with placebo; the upper bound of the 2-sided 90% confidence interval (CI) for the largest mean difference from placebo was < 10 msec with both corrections. A positive slope was observed between plasma exenatide and ΔΔQTcF (0.02 (95% CI 0.01, 0.03), p < 0.001); no significant slope was observed between plasma exenatide concentrations and ΔΔQTcI (0.01 (95% CI 0.00, 0.02), p = 0.064). The plasma exenatide versus QTc analyses may be confounded by exenatide's glucose-lowering effect. A negative slope was observed between plasma glucose and [delta]QTcF (-1.5 (95% CI -2.2, -0.7), p < 0.001) and between plasma glucose and ΔQTcI (-1.6 (95% CI -2.3, -0.9), p < 0.0001). Plasma insulin and ΔQTcF were not correlated. CONCLUSION: This study demonstrated that single-dose exenatide 10 µg was not associated with clinically meaningful prolongation of the QTc interval.

The regulation of CD11b integrin levels on human blood leukocytes and leukotriene B4-stimulated skin by a specific leukotriene B4 receptor antagonist (LY293111).

CD11b is part of the beta2-integrin Mac-1 and plays an important role in neutrophil adhesion. Leukotriene B4 (LTB4) is an active upregulator of neutrophil CD11b-expression, acts as a potent chemoattractant to neutrophils and is also known to upmodulate epidermal proliferation. We performed a placebo-controlled study on LY293111, an oral LTB4 receptor antagonist. Twenty healthy male volunteers were randomised over three treatment groups that received placebo, 48 mg, or 200 mg drug twice daily for 10 days. Before and after treatment, flow cytometrical CD11b assessment was performed on in vitro LTB4-stimulated peripheral blood neutrophils. Additionally, skin biopsies were taken at 24 and 72 h after epicutaneous LTB4 application, before and after treatment. The effects on skin were assessed immunohistochemically using various markers. All observed effects were dose related. CD11b upregulation on blood neutrophils was significantly suppressed in both treatment groups compared to placebo. In skin, a significant suppression of inflammation and hyperproliferation occurred. Pronounced inhibition was observed on neutrophil migration into the epidermis and the inflammatory infiltrate was decreased. A similar but weaker response was seen in the dermis. The number of cycling cells as well as suprabasal keratin-16 expression were decreased in both treatment groups. LY293111 proved to be a potent inhibitor of LTB4-induced cutaneous inflammation and hyperproliferation. The potent antiinflammatory effect in vivo and the fact that in the present study the compound showed no clinically significant side effects make it an interesting drug in the future treatment of inflammatory conditions predominated by neutrophils.

Hemlock water dropwort poisoning--a review.

Hemlock water dropwort (Oenanthe crocata) is probably the most poisonous plant in the British Isles. The roots are the most toxic part of the plant and have been eaten in mistake for the roots of several other plant species with often fatal results. A recent nonfatal case of poisoning is reported and previous cases reviewed. Present evidence suggests that barbiturates, particularly short-acting agents are life saving and are the drugs of choice in the treatment of the convulsions.

Sodium and renin in the hypertension of early renal disease.

1. Plasma renin activity, response to saralasin and exchangeable sodium have been measured in 43 patients with early renal disease. 2. Blood pressure was directly proportional to plasma renin activity. However, mean plasma renin activity was lower in patients with renal disease than in normal controls. 3. Blood pressure fell in response to saralasin infusion in proportion to the pre-infusion plasma renin activity. 4. Exchangeable sodium in hypertensive patients with renal disease did not exceed that in normotensive patients in contrast to earlier reports. Discrepancies may arise from the difficulty in interpreting measured exchangeable sodium in relation to body build.

Effect of a leukotriene B4 receptor antagonist, LY293111, on allergen induced responses in asthma.

BACKGROUND: Leukotriene (LT) B4 is a potent neutrophil chemoattractant and also stimulates eosinophils in vitro, but its role in asthmatic inflammation is unknown. METHODS: The effect of the novel LTB4 receptor antagonist, LY293111, was examined using allergen challenge as a model for asthmatic inflammation in 12 atopic asthmatic subjects in a double blind placebo controlled crossover trial. Subjects with an established early (EAR) and late asthmatic response (LAR) to allergen at screening received oral LY293111 in a dose of 112 mg three times daily for seven days or placebo before further allergen challenge. Each treatment was separated by a washout period of 28 days. Individuals underwent histamine challenge one hour before and three hours after allergen challenge. Bronchoalveolar lavage (BAL) fluid was obtained at bronchoscopy 24 hours after allergen challenge. RESULTS: There was no difference in baseline lung function, EAR, LAR, or in airway responsiveness to histamine before and after allergen between placebo and LY293111. By contrast, treatment with LY293111 significantly reduced the number of neutrophils in BAL fluid expressed as both absolute cell numbers and percentage cell differential counts: absolute cell counts, median (range) 0.04 (0.02-0.15) x 10(6) after LY293111, 0.09 (0.02-0.43) x 10(6) after placebo; percentage differential cell counts 0.35 (0.1-2.0) after LY293111, 0.80 (0.1-3.6) after placebo (p < 0.05). Eosinophils, macrophages, and lymphocytes in BAL fluid did not differ between treatments. There was a significant reduction in the concentration of myeloperoxidase (MPO) with both placebo (16 (6.6) ng/ml) and LY293111 (3.5 (1.8) ng/ml) and of LTB4 (placebo 4.6 (1.2) pg/ml, LY293111 2.2 (0.2) pg/ml). Concentrations of LTC4 and interleukin 8 were reduced, although not significantly, whereas concentrations of interleukin 6, GM-CSF, and TNF-alpha were unchanged by LY293111. CONCLUSIONS: These results demonstrate an influence of LTB4 on neutrophil influx and activation in the airway following allergen challenge. Despite this anti-inflammatory effect, there was no measured physiological benefit and this questions the functional role of the neutrophil in the pathophysiology of allergen induced asthma.