Intranasal cabergoline: pharmacokinetic and pharmacodynamic studies
Authors: Ambikanandan Misra
Gitanjali Sharma
Pushpa Mishra
Anil Kumar Mishra
Journal: AAPS PharmSciTech (2009)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: cabergoline; intranasal microemulsion; brain drug delivery; biodistribution; technetium-99m
Affiliations: Pharmacy Department, Faculty of Technology and Engineering, The Maharaja Sayajirao University of Baroda, Kalabhavan, Post Box No.51, Vadodara, 390 001, Gujarat, India.

Abstract:  Aims of this investigation were to prepare and characterize cabergoline intranasal microemulsion formulations, determine brain drug delivery through biodistribution using technetium-99m (99mTc) as a tracer, and assess its performance pharmacodynamically in weight control. Cabergoline microemulsions of different compositions were prepared by water titration method and characterized for globule size and zeta potential. Microemulsion with maximum drug solubilization and stability was considered optimal and taken for further studies with or without addition of mucoadhesive agent. Pharmacokinetics of optimized 99mTc-labeled cabergoline formulations and 99mTc-labeled drug solution were studied by estimating radioactivity in brain and blood of albino rats post intranasal, intravenous, and oral administrations. To confirm localization of drug in brain following intranasal, intravenous, and oral administrations, gamma scintigraphy imaging was also performed. To assess weight control performance of formulations, body weight, white adipose tissue mass, serum lipids, leptin, and prolactin were determined before and after 40 days of intranasal administrations of these formulations to Wistar rats. Microemulsions were found to be stable both physically and chemically when stored at various stress conditions. Brain/blood uptake ratios, drug targeting efficiency, and direct drug transport were found to be highest for drug mucoadhesive microemulsion followed by drug microemulsion and drug solution post-intranasal administration compared to intravenous drug microemulsion. Significant (p&lt;0.05) reduction in assessed pharmacodynamic parameters was observed after intranasal administration of mucoadhesive microemulsion against control group. The results of the studies conclusively demonstrate that intranasal microemulsion formulations developed in this investigation are stable and can deliver cabergoline selectively and in higher amounts to the brain compared to both drug administrations as a solution intranasally or microemulsion intravenously. The results also demonstrate reduction in weight, adipose tissue mass, serum lipids, and serum prolactin after intranasal administration of drug microemulsion. Hence, long-term studies in at least two more animal models followed by extensive clinical evaluation can safely result into a product for clinical use. 

Retracted: No

PubPeer comments:
 Not sure why the authors felt the need to do this, but in one image, one particle has been copied twice more - i.e. there are three exactly identical particles in this image. Panel a of Fig. 2:  The right-hand image with the three identical particles highlighted:  , 
  This is Fig 5a. There is a dark spot with no background. , 
 Supplementary Fig 12. Another NT control lane without background.  , 
 More from Supplementary Figure 12  , 
 Supplementary Figure 12a  , 
 Figure 4b  , 
 Fig 4g  , 
 Fig 4a  , 
 Fig 5b  , 
 The Southerns are tough to interpret because the probe used and the location where HindIII cuts in the construct is never given. Thus, plant DNA-transgene junctions have not been satisfactorily shown. It is very easy to stain any pollen blue if the pH of the solution is off. No segregation ratios are shown. There is no way of knowing if that red dye sticks to DNA. It is possible the dye is moving but the DNA beads are not. There are no controls-- eg, dye only control or DNA only control. Overall, the work falls short of the criteria usually demanded by journals that routinely publish transgenic work. , 
 A Twitter thread discussing replication attempts: https: twitter.com aeharkess status 1023763311308021760 Alex Harkess @aeharkess Jul 29 Has anyone gotten pollen magnetofection to work? Didn t work in our lab, and just found the pubpeer link with image manipulation missing controls. Bummer... https: blog.pubpeer.com publications DA5062D071C5813708B4F9B511F9E5 u2026 Alex Rajewski @Rajewski Jul 30 We couldn t get the pollen out of the filter paper. I wrote the authors but they gave a form response and then didn t response after that. I was gonna try something finer like nitrocellulose but the image manipulation doesn t my hopes... John Fowler @jefowlerjr Jul 30 We have not gotten any response to an email request for a protocol; and have not been able to repeat the transient expression results with lily pollen (only one try, though). lewsey lab @lewseylab Jul 30 We re about to give it a go, but I ve heard from a couple of people now that it did not work in their hands. Nat Graham @natnotgnat Aug 1 Tried in maize, no results. You find pretty quickly that GUS is a terrible reporter as anything will turn blue if you leave in the solution. Also, the pollen medium burst all my pollen. Malia Gehan @maliagehan Jul 31 we were really sad to see the pubpeer link too, but are going to give it a go in quinoa anyway since we have the supplies at the Center. Margaret Frank @Margare41291282 Jul 31 I tried the protocol with loads of tomato pollen. I thought I had a positive result, but I think it was just transient expression, because I recovered ZERO transformants. Tried a second time and had no pollen expression : ( Idan Efroni @efronilab Aug 1 We tried in tomato and gave up after having no success even with transient. Background blue GUS staining in pollen is very common. , 
 Did anyone ever get this protocol to work?? , 
 #11 Here is the detailed protocol authors published. Though they only claim it to work in cotton in that protocol: https: link.springer.com protocol 10.1007 978-1-4939-8952-2_4 , 
 #1 Even a little bit of repeated background in a TEM image is not good. See left-hand edge.  , 
 The more one looks at that panel, the more duplications emerge.  , 
 Failed replication attempt here: https: www.biorxiv.org content 10.1101 2020.05.01.071266v1. ,