Pharmacokinetic and pharmacodynamic comparison of subcutaneous versus intramuscular leuprolide acetate formulations in male subjects.

BACKGROUND: The aim of this study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of two distinct formulations of leuprolide acetate (LA); subcutaneous (SC) injection and intramuscular (IM) injection. METHODS: A total of 32 healthy men were randomized to receive a single 7.5 mg injection of SC-LA (n = 16) or IM-LA (n = 16) in this phase I, open-label, parallel-group study. PK was assessed via LA concentrations, and PD via serum luteinizing hormone (LH) and testosterone (T) concentrations. RESULTS: The initial surge of LA was higher for IM-LA than SC-LA (Cmax 27 ± 4.9 versus 19 ± 8.0 ng/ml, respectively), with a shorter tmax (1.0 ± 0.4 versus 2.1 ± 0.8 h). The duration of quantifiable LA concentration was longer for SC-LA (up to 56 versus 42 days for SC-LA and IM-LA, respectively). Median LH concentrations in both groups rapidly increased, followed by gradual decrease. However, SC-LA demonstrated a longer duration of LH suppression, with median levels remaining below 1.0 IU/l through Day 56 compared with IM-LA where LH started to rise by Day 35. Consequently, serum T began to increase by Day 42 in the IM-LA group, with only four subjects maintaining levels ⩽50 ng/dl, compared with 14 subjects in the SC-LA group. By Day 56, 13 SC-LA subjects maintained serum T levels ⩽50 ng/dl. Both SC-LA and IM-LA were well tolerated. CONCLUSIONS: Both formulations demonstrated consistent delivery of drug over 1 month; however, SC-LA provided a longer duration of action than expected based on the dosing interval. This profile suggests that SC-LA will provide effective suppression of T over a longer period of time, permitting greater injection scheduling flexibility.

Cardiac safety of Modified Vaccinia Ankara for vaccination against smallpox in a young, healthy study population.

BACKGROUND: Conventional smallpox vaccines based on replicating vaccinia virus (VV) strains (e.g. Lister Elstree, NYCBOH) are associated with a high incidence of myo-/pericarditis, a severe inflammatory cardiac complication. A new smallpox vaccine candidate based on a non-replicating Modified Vaccinia Ankara (MVA) poxvirus has been assessed for cardiac safety in a large placebo-controlled clinical trial. METHODS: Cardiac safety of one and two doses of MVA compared to placebo was assessed in 745 healthy subjects. Vaccinia-naïve subjects received either one dose of MVA and one dose of placebo, two doses of MVA, or two doses of placebo by subcutaneous injection four weeks apart; vaccinia-experienced subjects received a single dose of MVA. Solicited and unsolicited adverse events (AE) and cardiac safety parameters (recorded as Adverse Events of Special Interest, AESI) were monitored after each injection. RESULTS: A total of 5 possibly related AESI (3 cases of palpitations, 2 of tachycardia) were reported during the study. No case of myo- or pericarditis occurred. One possibly related serious AE (SAE) was reported during the 6-month follow-up period (sarcoidosis). The most frequently observed AEs were injection site reactions. CONCLUSIONS: Vaccination with MVA was safe and well tolerated and did not increase the risk for development of myo-/pericarditis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00316524.

Omalizumab protects against allergen- induced bronchoconstriction in allergic (immunoglobulin E-mediated) asthma.

BACKGROUND: Omalizumab has been shown to suppress responses to inhaled allergens in allergic asthma patients with pretreatment immunoglobulin E (IgE) ≤700 IU/ml. To extend current dosing tables, we evaluated the potential of high omalizumab doses to block allergen-induced bronchoconstriction in patients with higher IgE levels. METHODS: Asthmatic adults (18-65 years; body weight 40-150 kg) were divided into groups according to screening IgE (group 1: 30-300 IU/ml; group 2: 700-2,000 IU/ml) and randomized 2:1 to omalizumab/placebo every 2 or 4 weeks for 12-14 weeks. Allergen bronchoprovocation (ABP) testing was performed before treatment and at weeks 8 and 16. The primary efficacy endpoint, the early-phase allergic response (EAR), was defined as the maximum percentage drop in forced expiratory volume in 1 s during the first 30 min after ABP. Serum free IgE was determined as a pharmacodynamic endpoint, and the exhaled fractional concentration of nitric oxide (FE(NO)) was an exploratory endpoint. RESULTS: Fifty patients were included in the study. Omalizumab improved EAR; at week 8, EAR was 23.1% for placebo, 9.3% in group 1 (p = 0.018 versus placebo) and 5.6% in group 2 (p < 0.001). At week 16, EAR was 20%, 11.8% (p = 0.087) and 5.1% (p < 0.001), respectively. Free IgE decreased in groups 1 and 2 and remained <50 ng/ml in all patients during weeks 6-16. Omalizumab completely suppressed FE(NO) increases after ABP in both groups. CONCLUSIONS: Omalizumab blocked early asthmatic responses over a broad range of IgE/body weight combinations. Extending the dosing tables enables omalizumab to benefit a wider range of patients.

Pharmacokinetics and safety of aclidinium bromide in younger and elderly patients with chronic obstructive pulmonary disease.

OBJECTIVE: To investigate the pharmacokinetics, safety and tolerability of aclidinium bromide 200 µg and 400 µg after a single dose and repeated once-daily doses in younger and elderly patients with moderate or severe chronic obstructive pulmonary disease (COPD). METHODS: Younger (40-59 years; n = 12) and elderly (≥ 70 years; n = 12) patients were treated with aclidinium via the Genuair® inhaler. Patients received once-daily aclidinium 200 µg for 3 days; after a 7-day washout period, patients received once-daily aclidinium 400 µg for 3 days. Pharmacokinetic analyses were conducted on plasma and urine on Days 1 and 3 of both treatment periods. Safety and tolerability were assessed. RESULTS: Aclidinium showed similar linear and time-independent pharmacokinetics in younger and elderly patients at each dose level and day of treatment. For both age groups at each dose level and day, aclidinium appeared rapidly in the plasma with a median tmax between 10 and 15 min; concentrations of aclidinium in the plasma declined rapidly with a t1/2 between 1 and 3 h. Plasma exposure with the 400 µg dose was ~ 2-fold higher than for the 200 µg dose in both age groups on both days. For both age groups, urinary excretion of aclidinium over 24 h was < 0.15% of the dose at each dose and day. Aclidinium 200 µg and 400 µg were safe and well tolerated in both age groups. CONCLUSION: These data suggest that no dose adjustment of aclidinium is required when treating elderly patients with COPD.

Effects of consumption of a fermented dairy product containing the probiotic Lactobacillus casei DN-114 001 on common respiratory and gastrointestinal infections in shift workers in a randomized controlled trial.

OBJECTIVE: The risk of infection may be increased in people under stress such as shift workers. This study examined the effect of a fermented dairy product containing the probiotic Lactobacillus casei DN-114 001 (verum) on the incidence of respiratory and gastrointestinal common infectious diseases (CIDs) and on immune functions in healthy shift workers. METHODS: The study was single-center, randomized, double-blind, and controlled. Volunteers received 200 g/day of verum (n = 500) or control product (n = 500) for 3 months; 1-month follow-up was carried out. RESULTS: The cumulated number of CIDs (primary outcome) was not significantly different between groups. Because the Poisson distribution of the primary parameter did not fully fit the observed data, a post hoc categorical analysis was applied and showed a significantly lower cumulated number of CIDs in the verum group during the product consumption phase (odds ratio [OR] = 0.75, 95% confidence interval [CI] 0.59-0.95, p = 0.017). Verum also reduced the proportion of volunteers experiencing at least 1 CID (43% vs. 51%, p = 0.005), increased the time to the first occurrence of CID (p = 0.017) in the whole population, and reduced the cumulated number of CIDs in the subgroup of smokers (p = 0.033). In the course of CID, cumulated duration of fever was lower in the verum group (in the whole study phase) (p = 0.022), and an increase in leukocyte, neutrophil, and natural killer (NK) cell counts and activity (p = 0.047 to p < 0.001) was observed compared with control group. Verum was safe and well tolerated. CONCLUSION: The results indicate that daily consumption of a fermented dairy product containing Lactobacillus casei DN-114 001 could reduce the risk of common infections in stressed individuals such as shift workers.

Reduction of dietary fat absorption by the novel gastrointestinal lipase inhibitor cetilistat in healthy volunteers.

AIMS: To assess the efficacy, pharmacodynamics, safety and tolerability of a range of doses of cetilistat, a novel inhibitor of gastrointestinal lipases, in healthy volunteers. METHODS: Three Phase I, randomized, placebo-controlled, parallel-group studies were conducted. Enrolled subjects in the three studies (n = 99) received a controlled calorie diet (total intake 2160 calories daily, 30% from fat). Twenty-four subjects were randomized to placebo and 66 were randomized to the following cetilistat doses: 50 mg three times daily [t.i.d. (n = 7)], 60 mg t.i.d. (n = 9), 100 mg t.i.d. (n = 7), 120 mg t.i.d. (n = 9), 150 mg t.i.d. (n = 16), 240 mg t.i.d. (n = 9) and 300 mg t.i.d. (n = 9). Nine subjects received the approved orlistat dose (120 mg t.i.d.). Treatment was for 5 days, with a 2-day run-in period and 1-day post-treatment follow-up. The primary outcome measure was daily faecal fat excretion. Secondary outcomes included plasma lipid levels, tolerability [gastrointestinal adverse events (AEs)] and safety. RESULTS: Cetilistat increased faecal fat excretion relative to baseline at all doses. Cetilistat was well tolerated, with gastrointestinal AEs the most common (51%). Steatorrhoea (oily stool) was more frequent in the orlistat group (4.11 events per subject) than in any cetilistat dose group (0.14-1.81 events per subject). Most AEs (98%) were mild or moderate in intensity. CONCLUSIONS: Cetilistat increased dietary fat excretion in healthy volunteers receiving a controlled calorie diet. Cetilistat was well tolerated at all doses examined and tolerability appeared to be improved relative to orlistat. Faecal fat excretion in the cetilistat groups was at least comparable to the orlistat 120 mg t.i.d. group.

Evaluation of the CCK-4 model as a challenge paradigm in a population of healthy volunteers within a proof-of-concept study.

RATIONALE: Experimental panic induction with cholecystokinin-tetrapeptide (CCK-4) has been established as a model to study the pathophysiology of panic disorder and might serve as a tool to asses the antipanic potential of novel anxiolytic compounds. However, assessment of CCK-4-induced panic does not follow consistent rules. OBJECTIVES: To provide a basis for the use of the CCK-4 model in proof-of-concept studies, we investigated CCK-4-induced panic according to different criteria in 85 healthy volunteers who underwent a CCK-4 bolus injection. METHODS: We assessed panicker/non-panicker ratios according to different panic criteria and explored whether differences in cardiovascular and neuroendocrine responses to CCK-4 paralleled subjective panic responses. Subjective panic responses were measured with the Acute Panic Inventory (API) and the Panic Symptom Scale (PSS). Heart rate, blood pressure, adrenocorticotropic hormone (ACTH) and cortisol were assessed concomitantly. RESULTS: The API-derived panic rate was 10.6% higher than that derived from the PSS. CCK-4 induced an increase in heart rate, systolic blood pressure and ACTH/cortisol plasma levels, which did not differ between panickers and non-panickers. CONCLUSIONS: The panic criterion applied appears to be of major importance for the panic rate achieved, whereas CCK-4-induced cardiovascular and hormonal alterations are not valuable as an objective "read out". The CCK-4 challenge might serve as a useful model to study putative anxiolytic effects of novel compounds during the early phase of drug development if the challenge procedure is carried out according to strictly comparable conditions.

Comparative pharmacokinetics and pharmacodynamics of a new sustained-release growth hormone (GH), LB03002, versus daily GH in adults with GH deficiency.

CONTEXT: LB03002 is a novel sustained-release GH preparation administered once weekly. OBJECTIVE: Our objective was to examine the pharmacokinetics, pharmacodynamics, and safety of LB03002 vs. daily GH. DESIGN AND SETTING: This open-label, crossover study compared the pharmacokinetics and pharmacodynamics of LB03002 and daily GH. PATIENTS AND OTHER PARTICIPANTS: Six male and three female patients with adult GH deficiency participated in the single-center study. INTERVENTION: Subjects were on stable daily GH treatment before the study. After a 4-wk washout with no GH, five weekly doses of LB03002 were given. MAIN OUTCOME MEASURE: GH and IGF-I concentrations were measured during the last dose of daily GH and during the first and fifth weekly doses of LB03002. RESULTS: The observed maximal serum GH concentration was approximately doubled after LB03002 (6.1 +/- 3.2 and 4.5 +/- 2.2 microg/liter at first and fifth doses) compared with daily GH (2.7 +/- 2.2 microg/liter). A sustained increase in GH concentration for more than 48 h was observed with LB03002, such that dose-normalized area under the curve (AUC) was not significantly different between daily GH and LB03002. Mean maximal serum IGF-I concentration was 34-41% greater with LB03002 than with daily GH, and AUC was 7-fold greater. However, normalized to GH dose, AUC for IGF-I was comparable. Adverse events and local reactions were acceptable, and there were no evident safety concerns with LB03002. CONCLUSIONS: Multiple weekly doses of LB03002 appeared safe and well tolerated. Comparable GH bioavailability and sustained IGF-I elevations support the use of once-weekly LB03002 to replace daily GH therapy.

Saterinone: A New Dual-Action Drug in the Acute Management of Chronic Heart Failure.

A new dual-action drug called saterinone combines both alpha-1 blocking vasodilatory property and phosphodiesterase III inhibition--mediated inotropism. A placebo-controlled, randomized, double-blind study was performed in 12 patients with severe congestive heart failure. Either 2 &mgr;g center dot kg center dot min(minus sign1) saterinone (n = 8) or placebo (n = 4) was injected intravenously over 3 h at rest. On-line hemodynamic measurement utilizing intra-arterial blood pressure monitoring and two-dimensional (2D) echocardiography were performed at basal time; then 30, 60, 120 and 180 min after infusion. The parameters measured were blood pressure (mmHg), systemic vascular resistance (SVR dynes center dot cm(5) center dot min(minus sign1)), pulmonary artery pressure (PAP mmHg), mean pulmonary capillary wedge pressure (PCWP mmHg) and cardiac index (CI 1 min/m(2)) using right heart catheterization and end-systolic volume (ESV ml) and end-diastolic volumes (EDV ml), ejection fraction (EF%) using 2D echocardiography. Placebo had no significant effects on any of the parameters (p = NS). Saterinone decreased SVR by 37% (p < 0.001), PAPm by 24% (p < 0.05), PCWP by 35% (p < 0.05), ESV by 27% (p < 0.01) and increased CI by 32% (p < 0.05) and EF by 45% (p < 0.05). Saterinone appears to be a potent drug that produces improvements in both cardiac hemodynamics and LV functional parameters. Further study with this interesting agent is indicated.