Min In Volunteers Research Articles

Smart mucoadhesive buccal chitosan/ HPMC scaffold for sore throat: In vitro, ex vivo and pharmacokinetic profiling in humans

Sore throat (ST) is exacerbated distress of throat which causes irritation during drinking and swallowing. It is conventionally treated with throat soothing lozenges or spray for symptomatic control. However, it may effectively be cured by providing sustained delivery of locally acting antiseptic and anesthetic agents for local relief. Therefore, aim of the current research was to deliver tibezonium iodide (TBN) and lignocaine hydrochloride (LGN) for the relief of sore throat as a smart mucoadhesive buccal delivery. The gel scaffolds were developed using homogenization technique and evaluated for solid-state, mucoadhesive and pharmacokinetic parameters in volunteers. Results obtained for FTIR, DSC and XRPD revealed no abnormal peak and incompatibility between ingredients in physical mixture. Sodium alginate (SA) alone or blended with chitosan (CHI) exhibited better swelling (106.1% in MG6) but did not show sustained release, mucoadhesive strength (MS) and time (FT) profile compared with CHI and hydroxyl propyl methyl cellulose HPMC based formulations. The MS and FT were improved when CHI and HPMC were combined. The desired 6 h complete in vitro release was exhibited when CHI and HPMC were formulated at a concentration of 4 and 2% w/v, respectively. It also depicted MS and FT values of 28.34 g and 249.4 min, respectively. In volunteers, the in vivo residence time (RT) was found to be 341.82 min in volunteers. The maximum salivary concentrations (Cmax) for LGN and TBN were calculated to be 40.83 and 20.2 μg/mL at 4 h (tmax), respectively. Conclusively, LGN and TBN can delivered together to release locally till 6 h as smart buccal scaffold alternative to lozenges for sore throat.

Sleep Phase Delay in Cystic Fibrosis: A Potential New Manifestation of Cystic Fibrosis Transmembrane Regulator Dysfunction

Cystic fibrosis (CF) transmembrane regulator (CFTR) protein dysfunction causes CF. Improving survival allows detection of increasingly subtle disease manifestations. CFTR dysfunction in the central nervous system (CNS) may disturb circadian rhythm and thus sleep phase. We studied sleep in adults to better understand potential CNS CFTR dysfunction. We recruited participants from April 2012 through April 2015 and administered the Munich Chronotype Questionnaire (MCTQ). We compared free-day sleep measurements between CF and non-CF participants and investigated associations with CF survival predictors. We recruited 23 female and 22 male adults with CF aged 18 to 46 years and 26 female and 22 male volunteers aged 18 to 45 years. Compared with volunteers without CF, patients with CF had delayed sleep onset (0.612 h; P= .015), midsleep (1.11 h; P< .001), and wake (1.15 h; P< .001) times and prolonged sleep latency (7.21 min; P= .05) and duration (0.489 h; P= .05). Every hour delay in sleep onset was associated with shorter sleep duration by 0.29h in patients with CF and 0.75h in subjects without CF (P= .007) and longer sleep latency by 7.51 min in patients with CF and 1.6 min in volunteers without CF (P= .035). Among patients with CF, FEV1 %predicted, prior acute pulmonary exacerbations, and weight were independent of all free-day sleep measurements. CF in adults is associated with marked delays in sleep phase consistent with circadian rhythm phase delays. Independence from disease characteristics predictive of survival suggests that sleep phase delay is a primary manifestation of CFTR dysfunction in the CNS.

Multi-contrast and three-dimensional assessment of the aortic wall using 3 T MRI

ObjectivesTo develop a 3D-multi-contrast MRI protocol allowing for high resolution imaging of the wall and of atheroma in the thoracic aorta. MethodsEleven healthy volunteers and eleven acute stroke patients with aortic plaques detected by TEE underwent MRI at 3T. The MRI-protocol consisted of a T1w-bright-blood, a T2w- and a PDw-black-blood sequence (spatial resolution=1.15mm3). Image quality was assessed by two blinded investigators using a 3-point score and intra- and inter-rater agreement was tested. In patients, atherosclerotic plaques were graded according to the modified American Heart Association (AHA) classification. ResultsTotal examination time was 35:42±7:48min in volunteers and 41:07±3:15min in patients. Image quality was graded with the highest score in 80–94% of T1w, 89–96% of T2w and 79–86% of PDw datasets. Intra- and inter-rater reliability regarding image quality grading was high. Five stroke patients showed AHA type III lesions, three had AHA type VII and two had type VIII plaques. One patient had a vulnerable appearing AHA VI plaque. Conclusions3D-multi-contrast MR-imaging of the aorta was performed with high image quality and in reasonable time. It allows evaluation of atherosclerotic plaque composition throughout the aortic arch and can be used to identify vulnerable plaques in acute stroke patients.

High‐resolution MRI of uveal melanoma using a microcoil phased array at 7 T

High-field MRI is a promising technique for the characterisation of ocular tumours, both in vivo and after enucleation. For in vivo imaging at 7 T, a dedicated three-element microcoil array was constructed as a high-sensitivity receive-only device. Using a dedicated blink/fixation protocol, high-resolution in vivo images could be acquired within 3 min in volunteers and patients with no requirement for post-acquisition image registration. Quantitative measures of axial length, aqueous depth and lens thickness in a healthy volunteer were found to agree well with standard ocular biometric techniques. In a patient with uveal melanoma, in vivo MRI gave excellent tumour/aqueous body contrast. Ex vivo imaging of the enucleated eye showed significant heterogeneity within the tumour.

Effect of timing of morphine administration during remifentanil‐based anaesthesia on early recovery from anaesthesia and postoperative pain

Since the time to peak analgesic effect of intravenous morphine can be longer than 40-60 min in volunteers, the goal of this study was to evaluate the effect of the timing of intraoperative morphine administration on early postoperative pain. A total of 120 adult patients undergoing laparoscopic cholecystectomy were studied. Anaesthesia was induced with remifentanil and etomidate and maintained with remifentanil and sevoflurane/nitrous oxide. Morphine 150 micrograms kg-1 was given randomly at three different times during surgery, and a fourth group received placebo. Times to eyes opening and extubation were measured, and pain was evaluated in the post-anaesthesia care unit (PACU) using a visual analogue scale (VAS). Morphine 2-3 mg was given when the VAS score was > or = 50 mm. The four groups were, according to the time elapsed from morphine administration to the end of surgery, group 1 (n = 30): placebo; group 2 (n = 33): < 20 min; group 3 (n = 30): 20-40 min; group 4 (n = 27): > 40 min. Recovery from anaesthesia and pain scores were similar in all groups. However, mean (SD) morphine consumption was 5.7 (4.7) mg in group 1, 4.4 (4.2) mg in group 2, 4.7 (4.7) mg in group 3, and 2.2 (4.0) mg in group 4 (P < 0.05, group 1 vs 4). Morphine was required in only 38% of patients in group 4 compared with 83%, 67% and 69% in groups 1, 2, and 3, respectively (P < 0.01, group 1 vs 4). The timing of intraoperative morphine administration did not affect the early recovery from anaesthesia. However, the reduction in the number of patients requiring morphine in the PACU when morphine had been given more than 40 min before the end of surgery supports this practice, rather than administration closer to the end of surgery.

EFFICACY AND PHARMACOKINETICS OF NEUTRALASE[trade mark sign] IN CABG

Introduction. Neutralase[trade mark sign] (heparinase I) is a 42.5 kD enzyme which neutralizes heparin by cleaving it into primarily di- and tetrasaccharide fragments. [1] The activated clotting time (ACT) of heparinized volunteers returned to baseline after Neutralase administration, [2] leading to this phase II dose ranging study in elective coronary artery bypass graft (CABG) patients. Methods. Six institutions enrolled 49 patients with IRB approval into 3 sequential dosing groups in an open-label design: 5 mcg/kg (n=12), 7 mcg/kg (n=25) and 10 mcg/kg (n=12). Porcine mucosal heparin anticoagulation was reversed with bolus Neutralase at cardiopulmonary bypass (CPB) conclusion. Measurements included ACT (3 min prior to bolus and 3, 6, and 9 min thereafter), Neutralase blood concentrations, anti-Factor IIa and Xa activity (multiple timepoints) and chest tube drainage (CTD) over 24 hrs. An analysis-of-variance model with treatment as a main effect was used in assessing mean ACT and median (mean rank) chest tube drainage. Results. Figure 1 demonstrates a dose response relationship for ACT return to baseline at 9 min. Neutralase rapidly and completely eliminated anti-IIa activity, and decreased anti-Xa activity to 20% at 9 min and 6% at 12 hrs. Mean (SD) plasma half-life was 12.1 (2.9) min compared to 6.6 (2.1) min in volunteers. Figure 2 displays 12 hr CTD data.Figure 1Figure 2Discussion. The data support 7 mcg/kg as an appropriate dose for investigational clinical use after CPB: 5 mcg/kg yields more bleeding, while 10 mcg/kg yields an equivalent blood loss; and both 7 and 10 mcg/kg are clinically adequate for heparin reversal.

Pharmacokinetic studies of ceftazidime in serum, bone, bile, tissue fluid and peritoneal fluid

After a single iv bolus injection of 2 g ceftazidime, concentrations were measured in serum and urine in volunteers and in serum, bone, bile and tissue fluid in patients. The serum half-life was 171 min in volunteers ( n = 6, average age 26 years) and 221 min in patients ( n = 12, average age 58 years). The peripheral volumes of distribution were also different, being 7.81 in volunteers and 11.31 in patients. Urinary recovery from the volunteers averaged 92% of the dose. Bone samples free from blood and taken from the femoral head, the pelvis or the femoral shaft contained an average of 24.1 mg ceftazidime per litre of organic bone at 30 min after injection and 19.7 mg/l at 2 h. Samples of fluid from the periprosthetic space after hip replacement contained 25.6 mg/l at 2 h and were above 8 mg/l at 10 h. Bile concentrations reached 36.4mg/l at 90 min and were above 8 mg/l for over 8 h. Peritoneal fluid samples contained 27.6 mg/l at 1 h and 8.0 mg/l at 8 h. These concentrations are considered sufficient to treat most aerobic infections associated with surgery.

Pharmacokinetic studies of ceftazidime in serum, bone, bile, tissue fluid and peritoneal fluid

After a single iv bolus injection of 2 g ceftazidime, concentrations were measured in serum and urine in volunteers and in serum, bone, bile and tissue fluid in patients. The serum half-life was 171 min in volunteers (n=6, average age 26 years) and 221 min in patients (n=12, average age 58 years). The peripheral volumes of distribution were also different, being 7.81 in volunteers and 11.31 in patients. Urinary recovery from the volunteers averaged 92% of the dose. Bone samples free from blood and taken from the femoral head, the pelvis or the femoral shaft contained an average of 24.1 mg ceftazidime per litre of organic bone at 30 min after injection and 19.7 mg/l at 2 h. Samples of fluid from the periprosthetic space after hip replacement contained 25.6 mg/l at 2 h and were above 8 mg/l at 10 h. Bile concentrations reached 36.4 mg/l at 90 min and were above 8 mg/l for over 8 h. Peritoneal fluid samples contained 27.6 mg/l at 1 h and 8.0 mg/l at 8 h. These concentrations are considered sufficient to treat most aerobic infections associated with surgery.