A randomised, controlled, crossover study to investigate the pharmacodynamics, pharmacokinetics and safety of 1R,2S-methoxamine hydrochloride (NRL001) in healthy elderly subjects.

AIMS: This study aimed to assess the effects of a single dose of 10 mg NRL001 (the 1R,2S stereoisomer of methoxamine hydrochloride) in a 2 g suppository on pharmacodynamic and pharmacokinetic (PK) variables, and safety, in a healthy elderly population. METHODS: This was a Phase I, single-centre, randomised, double-blind, placebo-controlled crossover study during which subjects received a single 2 g suppository of 10 mg NRL001 and a matching placebo in two separate treatment periods. The main outcome measures were Holter-, vital signs- and electrocardiogram-derived cardiovascular variables; plasma PK analysis; and safety assessments. RESULTS: Twenty-six subjects were dosed with study medication. Statistically significant reductions in Holter-derived heart rate (HR), vital signs-derived HR and diastolic blood pressure (BP) were observed comparing NRL001 with placebo treatment, and also with increasing NRL001 plasma concentration. No statistically significant relationships were observed between NRL001 concentration and systolic BP, mean arterial pressure or QTC interval (both Bazett's and Fridericia's correction). Thirty-nine adverse events were reported in 20 (76.9%) subjects, mostly after dosing with NRL001. CONCLUSION: Administration of NRL001 suppositories led to decreases in HR when compared with placebo data. NRL001 was well tolerated with a good safety profile during the study. Healthy elderly subjects did not show significantly different biological responses to NRL001 suppositories compared with younger healthy volunteers in previous studies.

A double-blind, placebo-controlled, randomised, parallel-group, dose-escalating, repeat dose study in healthy volunteers to evaluate the safety, tolerability, pharmacodynamic effects and pharmacokinetics of the once daily rectal application of NRL001 suppositories for 14 days.

AIMS: The 1R,2S stereoisomer of methoxamine hydrochloride, NRL001, is a highly selective α1-adrenoceptor agonist being developed for the local treatment of non-structural faecal incontinence caused by weak internal anal sphincter tone. This study investigated the steady state pharmacokinetics (PK) and safety of 2 g rectal suppositories containing NRL001 in different strengths (7.5, 10, 12.5 or 15 mg). METHODS: Healthy volunteers aged 18-45 years received 14 daily doses of NRL001 2 g suppositories or matching placebo. In each dose group nine participants received NRL001 and three received placebo. Blood samples to determine NRL001 concentrations were taken on Days 1, 7 and 14. Cardiovascular parameters were collected via electrocardiograms, Holter monitoring (three lead Holter monitor) and vital signs. RESULTS: Forty-eight volunteers were enrolled; 43 completed the study and were included in the PK analysis population. AUC and Cmax broadly increased with increasing dose, Tmax generally occurred between 4.0 and 5.0 h. Although the data did not appear strongly dose proportional, dose proportionality analysis did not provide evidence against dose proportionality as the log(dose) coefficients were not significantly < 1. NRL001 did not accumulate over time for any dose. Increasing NRL001 concentrations were related to changes in vital sign variables, most notably decreased heart rate. The most commonly reported adverse events (AEs) in the active treatment groups were paraesthesia and piloerection. CONCLUSIONS: Treatment with NRL001 was generally well tolerated over 14 days once daily dosing and plasma NRL001 did not accumulate over time. Treatment was associated with changes in vital sign variables, most notably decreased heart rate. AEs commonly reported with NRL001 treatment were events indicative of a systemic α-adrenergic effect.

Ultrasonography of plantar soft tissues thickness in young people with diabetes.

AIMS: The aims of this study were to examine soft tissue changes in the skin and plantar aponeurosis of young people with Type 1 diabetes mellitus (T1DM) and to evaluate any relationship between any soft tissue changes, arch length, limited joint mobility (LJM) and plantar pressure. METHODS: The thickness of the skin on the plantar surface of the foot and plantar aponeurosis were examined using ultrasound in 216 young people with diabetes and 57 controls. Foot length, arch length, joint mobility, peak pressure and pressure time integrals were evaluated. RESULTS: Skin was not significantly thicker in the diabetic subjects. The plantar aponeurosis was significantly thicker in the diabetic subjects and was associated with foot size, male gender and subtalar joint (ST) LJM (P < 0.01). Males were nearly three times more likely to have thickened plantar aponeurosis. CONCLUSION: Soft tissue thickening in young people with T1DM affects the deeper structures on the plantar surface of the foot rather than the skin. Thickening of the plantar aponeurosis was associated with LJM at the ST joint and male gender, but was not associated with plantar pressure or arch height changes. Plantar aponeurosis thickening does not appear to alter foot mechanics in young people with T1DM.

Limited joint mobility in the hands and feet of adolescents with Type 1 diabetes mellitus.

AIMS: Limited joint mobility (LJM) in the foot has not been assessed in adolescents with Type 1 diabetes mellitus (DM) but is associated with neuropathic ulceration in adults. This study was designed to determine the presence of LJM in adolescents with Type 1 DM and its association with microvascular disease. METHODS: The hands, feet and hips were examined in 302 diabetic adolescents and 51 nondiabetic controls (aged 11.5-20 years). LJM was defined as less than the fifth percent reference for controls. RESULTS: Reduced motion was found in 35% of diabetic adolescents at the subtalar (ST) joint, 18% at the first metatarsophalangeal (MTP) joint, 26% at the fifth metacarpophalangeal (MCP) joint and 13% had limited passive extension of the interphalangeal (IP) joints of the hands. Limited passive IP joint extension of the hands was not present in the controls. Limited active IP joint extension, a positive 'prayer sign', occurred in 35% of diabetic adolescents and 14% of controls. Diabetic adolescents showing LJM in any of these areas, except the prayer sign, were more likely to have retinopathy (odds ratio 2.53, CI: 1.53-4.18). Those with LJM in the foot were more likely to have albumin excretion rates >7.5 microg/min (OR 2.06, CI: 1.16-3.68). CONCLUSION: LJM in the feet of adolescents with Type 1 DM is associated with microvascular disease and is a useful routine clinical measure.