Midazolam plasma levels after the administration of a galenic nasal spray formulation in healthy volunteers

Introduction Acute coronary syndrome is characterized by the active, inflamed and unstable atherosclerotic plaque that is vulnerable to rupture, predisposing to lumen occlusion and varying extents of myocardial injury. Plasma microRNA have been examined in the hope of identifying an easily accessible biomarker for acute coronary syndrome. But so far studies have taken a candidate approach and screened only for miRNA that are potentially released from the injured myocardium. Even so, data from these studies are inconsistent and a consensus is yet to be reached. Aim We set out to screen for circulating plasma microRNAs to serve as biomarkers for patients with Acute Coronary Syndrome. Methods and results We selected patients who suffered from 2 ends of the severity spectrum of acute coronary syndrome vs age-matched healthy controls. These were 20 μsevere” (STEMI: troponin-positive with subsequent rapid deterioration in left ventricular function or death within 5 years), 20 μmild” (unstable angina: troponin-negative with sustained normal left ventricular function and survival at 5 years), and 20 normal healthy volunteers. Blood samples were obtained from patients within 2 weeks of the acute event. We took a non-constrained approach and screened using an array panel consisting of 379 miRNA. We found 32 miRNA that were significantly upregulated (29/32) or downregulated (3/32) in the comparison between patient vs. control (sum of t-statistic>2). We have made a preliminary analysis of these in relation to a full panel of other classical biomarkers and patient clinical details. We selected 4 candidate microRNAs (miR-27b, -103, -323-3p, -652) and proceeded to test the plasma levels of these in a validation cohort of 100 troponin-positive, 100 troponin-negative patients and 100 normal healthy volunteers. miR 27b, -323-3p, -652 were significantly upregulated in disease and hence robustly validated. Conclusion miR 27b, -323-3p, -652 strongly associates with the event of acute coronary syndrome. Further work will be required to determine the origin and physiological function of these candidate miRNA, and whether their plasma levels can be used for prognostication purposes.

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Nasal Administration and Plasma Pharmacokinetics of Parathyroid Hormone Peptide PTH 1-34 for the Treatment of Osteoporosis

Pharmaceutics ◽

10.3390/pharmaceutics11060265 ◽

2019 ◽

Vol 11 (6) ◽

pp. 265 ◽

Cited By ~ 2

Author(s):

Richard G. Pearson ◽

Tahir Masud ◽

Elaine Blackshaw ◽

Andrew Naylor ◽

Michael Hinchcliffe ◽

...

Keyword(s):

Nasal Spray ◽

Subcutaneous Injection ◽

Relative Bioavailability ◽

Nasal Delivery ◽

Absolute Bioavailability ◽

Preclinical Model ◽

Permeation Enhancer ◽

Treatment Of Osteoporosis ◽

Plasma Pharmacokinetics ◽

Spray Formulation

Nasal delivery of large peptides such as parathyroid 1-34 (PTH 1-34) can benefit from a permeation enhancer to promote absorption across the nasal mucosa into the bloodstream. Previously, we have published an encouraging bioavailability (78%), relative to subcutaneous injection in a small animal preclinical model, for a liquid nasal spray formulation containing the permeation enhancer polyethylene glycol (15)-hydroxystearate (Solutol® HS15). We report here the plasma pharmacokinetics of PTH 1-34 in healthy human volunteers receiving the liquid nasal spray formulation containing Solutol® HS15. For comparison, data for a commercially manufactured teriparatide formulation delivered via subcutaneous injection pen are also presented. Tc-99m-DTPA gamma scintigraphy monitored the deposition of the nasal spray in the nasal cavity and clearance via the inferior meatus and nasopharynx. The 50% clearance time was 17.8 min (minimum 10.9, maximum 74.3 min). For PTH 1-34, mean plasma Cmax of 5 pg/mL and 253 pg/mL were obtained for the nasal spray and subcutaneous injection respectively; relative bioavailability of the nasal spray was ≤1%. Subsequently, we investigated the pharmacokinetics of the liquid nasal spray formulation as well as a dry powder nasal formulation also containing Solutol® HS15 in a crossover study in an established ovine model. In this preclinical model, the relative bioavailability of liquid and powder nasal formulations was 1.4% and 1.0% respectively. The absolute bioavailability of subcutaneously administered PTH 1-34 (mean 77%, range 55–108%) in sheep was in agreement with published human data for teriparatide (up to 95%). These findings have important implications in the search for alternative routes of administration of peptides for the treatment of osteoporosis, and in terms of improving translation from animal models to humans.

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Effect of Oral Aspirin on Plasma Levels of Vitamin K-Dependent Clotting Factors – Studies in Healthy Volunteers

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647530 ◽

1988 ◽

Vol 59 (03) ◽

pp. 540-540 ◽

Cited By ~ 4

Author(s):

M Cattaneo ◽

A D’Angelo ◽

M T Canciani ◽

D Asti ◽

S Viganò-D’Angelo ◽

...

Keyword(s):

Healthy Volunteers ◽

Vitamin K ◽

Plasma Levels ◽

Clotting Factors ◽

Oral Aspirin

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Pharmacokinetic and Pharmacodynamic Properties of a Micro-Dose Nasal Spray Formulation of Desmopressin (AV002) in Healthy Water-Loaded Subjects

Pharmaceutical Research ◽

10.1007/s11095-019-2628-1 ◽

2019 ◽

Vol 36 (6) ◽

Author(s):

Karl-Erik Andersson ◽

James Longstreth ◽

Benjamin M. Brucker ◽

Lysanne Campeau ◽

Linda Cheng ◽

...

Keyword(s):

Nasal Spray ◽

Spray Formulation

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Granulocyte colony-stimulating factor administration to healthy volunteers: analysis of the immediate activating effects on circulating neutrophils

Blood ◽

10.1182/blood.v84.11.3885.bloodjournal84113885 ◽

1994 ◽

Vol 84 (11) ◽

pp. 3885-3894 ◽

Cited By ~ 129

Author(s):

M de Haas ◽

JM Kerst ◽

CE van der Schoot ◽

J Calafat ◽

CE Hack ◽

...

Keyword(s):

Healthy Volunteers ◽

Plasma Levels ◽

Subcutaneous Administration ◽

Secretory Vesicles ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Specific Granules ◽

Stimulating Factor

In four healthy volunteers, we analyzed in detail the immediate in vivo effects on circulating neutrophils of subcutaneous administration of 300 micrograms of granulocyte colony-stimulating factor (G-CSF). Neutrophil activation was assessed by measurement of degranulation. Mobilization of secretory vesicles was shown by a decrease in leukocyte alkaline phosphatase content of the circulating neutrophils. Furthermore, shortly postinjection, Fc gamma RIII was found to be upregulated from an intracellular pool that we identified by immunoelectron microscopy as secretory vesicles. Intravascular release of specific granules was shown by increased plasma levels of lactoferrin and by upregulation of the expression of CD66b and CD11b on circulating neutrophils. Moreover, measurement of fourfold elevated plasma levels of elastase, bound to its physiologic inhibitor alpha 1- antitrypsin, indicated mobilization of azurophil granules. However, no expression of CD63, a marker of azurophil granules, was observed on circulating neutrophils. G-CSF--induced mobilization of secretory vesicles and specific granules could be mimicked in whole blood cultures in vitro, in contrast to release of azurophil granules. Therefore, we postulate that the most activated neutrophils leave the circulation, as observed shortly postinjection, and undergo subsequent stimulation in the endothelial microenvironment, resulting in mobilization of azurophil granules. Our data demonstrate that G-CSF should be regarded as a potent immediate activator of neutrophils in vivo.

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Effect of ouabain on pressor responsiveness in normal man

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1994.267.5.e642 ◽

1994 ◽

Vol 267 (5) ◽

pp. E642-E647

Author(s):

G. B. Pidgeon ◽

A. M. Richards ◽

M. G. Nicholls ◽

R. R. Bailey ◽

K. L. Lynn ◽

...

Keyword(s):

Heart Rate ◽

Healthy Volunteers ◽

Plasma Levels ◽

Plasma Renin ◽

Ang Ii ◽

Short Term ◽

Vasoactive Hormones ◽

Normal Man ◽

The Mean ◽

Mean Heart Rate

To assess the effects of ouabain on pressor and vasoactive hormone responsiveness, 10 healthy volunteers were pretreated with ouabain (0.5 mg i.v. 42 and 18 h before study) or placebo before pressor challenge with angiotensin II (ANG II; 2, 4, and 8 ng.kg-1.min-1 for 30 min/dose) and norepinephrine (NE; 5, 15, and 45 ng.kg-1.min-1 for 15 min/dose). There were no differences at baseline between the two study days regarding mean arterial pressure (MAP) or heart rate. Baseline pulse pressure, however, was significantly greater after ouabain (47 +/- 3 vs. 41 +/- 1 mmHg; P < 0.05). The mean maximum increments in MAP during ANG II and NE infusions were 17.5 +/- 1.1 and 10.5 +/- 1.3 (SE) mmHg, respectively, after ouabain and 19.2 +/- 1.3 and 10.4 +/- 1.5 mmHg after placebo (not significant). The mean heart rate was lower during both infusion periods on the ouabain study day compared with control (P < 0.05). Baseline plasma levels of ANG II, aldosterone, plasma renin activity, atrial and brain natriuretic peptide, guanosine 3',5'-cyclic monophosphate, NE, and epinephrine and achieved levels during the two infusions were similar on the two study days. We conclude that short-term ouabain administration does not alter pressor responsiveness or plasma levels of vasoactive hormones in healthy volunteers.

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