The use of modeling and simulation to guide clinical development of olmesartan medoxomil in pediatric subjects.

Modeling and simulation were used extensively in the development of an indication for the use of olmesartan medoxomil in pediatric patients with hypertension. Simulations based on models developed in adult patients indicated that two dose groups were sufficient to estimate a dose-response relationship, thereby reducing by one-third the number of subjects required for the phase III pediatric study. Model-based predictions for blood pressure reduction agreed with the observed results of the subsequent phase III study, showing statistically significant dose-response relationships with respect to both systolic and diastolic blood pressure. Previously established pharmacokinetic and exposure-response relationships in adults, adjusted for the influence of body weight on clearance (wt(0.80)), were confirmed in the pediatric population. Together, these findings support an olmesartan dosing recommendation in pediatric subjects aged 6 to 16 years of 10 mg for subjects weighing <35 kg and 20 mg for those weighing ≥35 kg.

Long-term efficacy of a combination of amlodipine and olmesartan medoxomil ± hydrochlorothiazide in patients with hypertension stratified by age, race and diabetes status: a substudy of the COACH trial.

A prespecified subgroup analysis of a 44-week open-label extension study is presented. The efficacy and safety of the combination of amlodipine (AML) + olmesartan medoxomil (OM), with and without the addition of hydrochlorothiazide (HCTZ), were investigated in patients aged ≥65 and <65 years, Blacks and non-Blacks and patients with and without type 2 diabetes. After an 8-week double-blind, placebo-controlled portion of the study, patients initiated therapy on AML 5 + OM 40 mg per day, were uptitrated stepwise to AML 10 + OM 40 mg per day, with the addition of HCTZ 12.5 mg, and 25 mg if blood pressure (BP) goal was not achieved (<140/90 or <130/80 mm Hg for patients with diabetes). Endpoints included the change from baseline in mean seated systolic BP, mean seated diastolic BP and achievement of BP goal. BP decreased from baseline for all treatments in each prespecified subgroup. By the end of the study, BP goal was achieved in 61.0% of patients aged ≥65 years, 68.1% of patients aged <65 years, 63.3% of Blacks, 67.8% of non-Blacks, 26.9% of patients with diabetes and 72.9% of patients without diabetes. The combination of AML + OM ± HCTZ was efficacious, safe and well tolerated by these subgroups.

Efficacy and tolerability of amlodipine plus olmesartan medoxomil in patients with difficult-to-treat hypertension.

Hypertension is particularly prevalent in patients aged ≥65 years, those with a body mass index ≥30 kg m(-2), Blacks and those with type II diabetes. Here we report a prespecified secondary analysis of the efficacy of amlodipine (10 mg day(-1)), olmesartan medoxomil (40 mg day(-1)), a combination of the two and placebo in these subgroups. Patients were randomized to treatment for 8 weeks. The primary efficacy endpoint was the change from baseline in mean seated diastolic blood pressure (DBP). Secondary efficacy endpoints included the change from baseline in mean seated systolic BP (SBP), proportions of patients achieving BP goal (<140/90 mm Hg or <130/80 mm Hg in patients with diabetes), and the number and percentage of patients achieving a range of BP targets. Safety and tolerability of amlodipine 5 and 10 mg, olmesartan medoxomil 10, 20 and 40 mg, and all possible combinations of the two were also assessed. For each prespecified subgroup, all active treatments resulted in significant BP reductions from baseline (P<0.05). The antihypertensive effect of the combination of amlodipine+olmesartan medoxomil was generally greater than the constituent amlodipine or olmesartan medoxomil monotherapies, regardless of subgroup. In general, more patients receiving combination therapy achieved BP goal than those treated with monotherapies. The safety and tolerability of combinations were similar to monotherapies across the subgroups. These results suggest that the combination of amlodipine+olmesartan medoxomil provides a safe and effective option for the treatment of hypertension in challenging patient populations.

The triple neurokinin-receptor antagonist CS-003 inhibits neurokinin A-induced bronchoconstriction in patients with asthma.

Neurokinin A (NKA) causes bronchoconstriction in asthmatic patients. In vitro both NK1 and NK2 receptors can mediate airway contraction. Moreover in guinea pigs, NK3 receptors facilitate cholinergic neurotransmission. Dual tachykinin NK1/NK2 receptor antagonism results in prevention of NKA-induced bronchoconstriction. We have now examined the effect of a single dose of the triple tachykinin receptor antagonist CS-003 on NKA-induced bronchoconstriction in asthmatics. A double blind, crossover, placebo-controlled trial in 16 mild asthmatics was performed. One single dose of CS-003 (200 mg, solution in distilled water) or matched placebo was given orally on the assessment days. NKA-provocation tests were performed pre-dose and 1, 8 and 24 h after dosing. There was a significant shift to the right of the dose-response curve at 1 and 8 h after intake of CS-003. PC20 was not reached in 12/16 patients at 1h post-dose and in 5/16 patients at 8 h post-dose. This did not occur under placebo treatment. A single dose of 200 mg CS-003 protected significantly against NKA-induced bronchoconstriction at 1 and 8h post-dose in mild asthmatics.

A study in patients with erectile dysfunction comparing different formulations of prostaglandin E1. Alprostadil Study Group.

PURPOSE: Prostaglandin E1 sterile powder and sterile solution are 2 new formulations of exogenous prostaglandin E1 that are more convenient for auto-injection therapy for erectile dysfunction than the presently used pediatric sterile solution. Therefore, the pharmacodynamic profiles of intracavernous prostaglandin E1 sterile powder and nonalcohol sterile solution were compared with the pediatric sterile solution in men with erectile dysfunction who were known to be stable responders to intracavernous prostaglandin E1. MATERIALS AND METHODS: Based on the dose used at home, patients were randomized to 1 of 5 dose groups: 0 microgram. (placebo), 2.5 micrograms., 5 micrograms., 10 micrograms. or 20 micrograms. Each patient received a single injection of the same dose of each of the 3 formulations. The primary pharmacodynamic end points were clinical evaluation of erectile response, RigiScan real-time evaluation of erectile response and patient evaluation of erectile response. RESULTS: No significant differences were identified among the formulations for any of these end points, either by comparison among all active doses or by comparison at each prostaglandin E1 dose level. There was also little or no intra-patient variation in dose response and the inter-dose variation in response between patients was not significant. Pharmacodynamic end points were well intercorrelated, although assessment of erectile response by the patients tended to be more positive than that by RigiScan or clinical evaluation. There were no major side effects. Penile pain on injection and/or during erection occurred in 9 to 17% of the patients according to the formulations. However, penile pain was also reported by 11% of the placebo-treated patients. CONCLUSIONS;: The 3 formulations of prostaglandin E1 showed equivalence and were safe for the treatment of erectile dysfunction with respect to side effects.

Effect of oxygen administration on the breathing pattern during haemodialysis in man.

During haemodialysis (HD), allowing important CO2- unloading, an irregular breathing pattern (BP) is frequently observed. This has been attributed to a decrease in central chemoreceptor firing, with a greater contribution of the peripheral chemoreceptors in the chemical drive to breathe. To provide further evidence for these findings we studied five patients with end-stage renal failure in chronic HD. They underwent HD with a cuprophane membrane and acetate-containing dialysate. Ventilation was measured continuously using respiratory inductance plethysmography. Oxygen was administered for 30 min, using nasal cannulae, at a rate of 6 l.min-1, starting 130 min after the onset of the HD. Blood gases were taken from the arterial line. During the initial air breathing, arterial oxygen tension (PaO2) decreased from 12.3 +/- 1.2 kPa (92.8 +/- 8.9 mmHg) at 0 min to 10.5 +/- 1.8 kPa (79.0 +/- 13.3 mmHg) at 2 h (p less than 0.01) (mean +/- SD). All patients showed irregular breathing with 1.4 +/- 0.6 apnoeas exceeding 10 s per 10 min after 2 h. Minute ventilation decreased from 6.8 +/- 1.9 l.min-1 at 0 min to 5.4 +/- 1.3 l.min-1 at 2 h (p less than 0.05). During the O2 breathing, PaO2 increased to 26.3 +/- 4.0 kPa (197.8 +/- 30.3 mmHg) (p less than 0.001), while arterial carbon dioxide tension (PaCO2) remained unchanged. The irregular BP previously observed vanished completely. The mean number of apnoeas exceeding 10 s per 10 min decreased to 0.08 +/- 0.12 during O2 (p less than 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of acetate on ventilation in haemodialysis patients.

This study evaluates the direct effect of acetate upon ventilation during acetate-haemodialysis. Eight patients with end-stage renal failure who were receiving chronic haemodialysis treatment underwent acetate infusion for 1 h on a day outside a haemodialysis session. Ventilation was continuously measured using respiratory inductance plethysmography, starting 20 min before the infusion. Arterial blood samples were drawn and expired gases were analysed at regular intervals. After 1 h of acetate infusion, arterial pH increased rapidly and significantly from 7.38 +/- 0.01 to 7.49 +/- 0.01, the VCO2 and VO2 slightly decreased and increased respectively, resulting in a reduced respiratory exchange ratio from 0.81 +/- 0.04 to 0.69 +/- 0.05. Ventilation slightly decreased only after 60 min, whereas the breathing pattern remained normal; neither apnoea periods nor periodic breathing were observed. We conclude that the hypoventilation and irregular breathing encountered in acetate-cuprophane haemodialysis is related to CO2/HCO3- unloading and the occurrence of complement-activation-induced hypoxaemia rather than to the small changes in VCO2, VO2 during metabolism of acetate.

Ventilation and breathing patterns during hemodialysis-induced carbon dioxide unloading.

Important CO2 unloading occurs during hemodialysis (HD) when acetate-buffered dialysate is used. This is accompanied by alveolar hypoventilation. To gain more insight into the mechanisms of this alveolar hypoventilation, breathing patterns were studied in 5 patients with end-stage renal failure during HD using acetate-buffered dialysate, which induces CO2 unloading, or bicarbonate without CO2 loss. Ventilation was continuously measured with calibrated respiratory inductance plethysmography using techniques of multiple linear regression analysis. At regular intervals, arterial blood gas was sampled and expired air was analyzed. Breathing patterns were analyzed for VE, VT, TI, TE, and VT/TI. All data were compared with the respective starting value and with the respective value in the other setup. A greater decrease in ventilation was seen during HD with an acetate-containing dialysate because of irregular breathing patterns that resulted in a prolongation of expiratory time. Important variations in tidal volumes, striking apnea periods, and occasional periodic breathing were observed. We suggest that these irregularities are due to CO2 unloading leading to the point where ventilation is totally mediated through the output of the peripheral chemoreceptors.

Biocompatibility of a polycarbonate membrane. A preliminary report.

In this preliminary study, the biocompatibility of a new dialysis membrane, polycarbonate, was studied. The bioincompatible effect of this membrane is less pronounced compared to cuprophane.