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Friday, 25 September 2015

OPN-300 Oxytocin and Autism



This post is about nasal spray drugs and Oxytocin.

Monty, aged 12 with ASD, uses a conventional anti-histamine nasal spray and I do sometimes wonder just how much of the drug reaches its target.  

With inhalers for asthma this is a well known problem and often even adults do not use them correctly; they are proven to work much better when they are fitted with a spacer chamber, that way the drug ends up in your lungs and not stuck to the inside of your mouth.






Many adults with asthma and COPD nowadays use spacers.

So my interest was drawn to a company called Optinose that is developing drugs for nasal delivery using a novel dispenser.  I was particularly surprised that in its small drug pipeline is an oxytocin spray for autism.

If you look on the US National Institute of Health website listing clinical trials of oxytocin and autism, you will find that thirty, yes three zero, studies are listed.


According to their website, Optinose intend to be the first to bring a product to the market approved for autism.











On the clinical trials website you may notice that other trials use an existing drug called Syntocinon that is a synthetic form of Oxytocin already approved for other purposes.






I did mention in an earlier post that the US rights to Syntocinon were sold to a company hoping to develop a therapy for Schizophrenia and Autism.


Retrophin Signs U.S. License Agreement for Syntocinon™ Nasal Spray (Oxytocin)


In Europe Syntocinon is available in most countries as a prescription drug.


The Optinose idea is that their dispenser can much more reliably dispense the correct amount of drug and have it reach the membrane deep inside the nose.  None gets in the mouth and less should get stuck at the entrance to the nose.

Previous trials of Oxytocin have yielded very mixed results.  Perhaps part of this is due to the nature of the spray pump being used?  It is certainly plausible.


The Optinose Spray

The Optinose spray is inserted in one nostril and your mouth.  You blow out through mouth, sealing the nasal cavity in the process, and the spray is forced out into your nose.  This should ensure it goes deep inside to the nasal membrane, where the oxytocin can cross directly into the blood stream.





Click on the link below and then click to play the short video.



As the video points out, this kind of drug delivery can “enable new and improved brain treatments”


They are talking about direct nose-to-brain drug delivery, bypassing the blood brain barrier (BBB).  This is not fantasy and is already quite well studied.

Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood-brain barrier: an excellent platform for brain targeting.

Coming back to Oxytocin ...

Not only is Oxytocin a well-known hormone affecting social behavior, but it also plays a role in switching the neurotransmitter GABA between excitatory and inhibitory.


Oxytocin and GABAA

Oxytocin has a role at birth in the GABA “switch”, but it also has an ongoing role via binding to a particular subunit of GABAA receptors.



We report that the oxytocin-mediated neuroprotective γ-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery is abolished in the valproate and fragile X rodent models of autism. During delivery and subsequently, hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations. Maternal pretreatment with bumetanide restored in offspring control electrophysiological and behavioral phenotypes. Conversely, blocking oxytocin signaling in naïve mothers produced offspring having electrophysiological and behavioral autistic-like features. Our results suggest a chronic deficient chloride regulation in these rodent models of autism and stress the importance of oxytocin-mediated GABAergic inhibition during the delivery process. Our data validate the amelioration observed with bumetanide and oxytocin and point to common pathways in a drug-induced and a genetic rodent model of autism.

Further evidence as to the precise effect of Oxytocin on GABA receptors was found by chance.  It was found that having dosed rats with Oxytocin, they did not get drunk when fed alcohol.





Specifically, oxytocin (1 µg i.c.v.) given before ethanol (1.5 g/kg i.p.) attenuated the sedation and ataxia induced by ethanol in the open-field locomotor test, wire-hanging test, and righting-reflex test in male rats.

Vasopressin, which is a nonapeptide with substantial structural similarity to oxytocin, did not alter ethanol effects at δ-GABAARs. This pattern of results confirms the specificity of the interaction between oxytocin and ethanol at δ-GABAARs

The profound and direct interaction observed between oxytocin and ethanol at the behavioral and cellular level may have relevance for the development of novel therapeutics for alcohol intoxication and dependence.



Is Oxytocin a useful Autism Therapy?

Given the large number of trials and the number of people already taking Oxytocin, some people clearly believe in the therapeutic potential of Oxytocin.

What is clear is that there a numerous modes of action for Oxytocin, some of which relate to GABAA receptors.

So why is it taking so very long for these trials to come to any usable conclusion? Well just looking at the long list of researchers, it includes some of those who have spent twenty years "researching" autism and producing absolutely nothing tangible, just papers concluding more research is needed or even producing, supposedly therapeutic, cartoons (Cambridge University).

We have the usual problem that numerous different dysfunctions lie at the root of “autism” and so only a moderate proportion, at best, would be expected to benefit from any therapy.

In the case of nasal sprays we have the question of how much actually gets delivered to the right place deep inside the nose where there is a very thin membrane that allows the Oxytocin to cross over into the blood.


OPN-300 Clinical Trials

The Phase 1 trial for OPN-300 was actually on healthy adults, and looked at things like dosing.  Low doses were more effective than high doses.  Next follows the trial on people with autism.  




Despite the promise of intranasal oxytocin (OT) for modulating social behavior, recent work has provided mixed results. This may relate to suboptimal drug deposition achieved with conventional nasal sprays, inter-individual differences in nasal physiology and a poor understanding of how intranasal OT is delivered to the brain in humans. Delivering OT using a novel ‘Breath Powered’ nasal device previously shown to enhance deposition in intranasal sites targeted for nose-to-brain transport, we evaluated dose-dependent effects on social cognition, compared response with intravenous (IV) administration of OT, and assessed nasal cavity dimensions using acoustic rhinometry. We adopted a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults completing four single-dose treatments (intranasal 8IU (international units) or 24IU OT, 1IU OT IV and placebo). The primary outcome was social cognition measured by emotional ratings of facial images. Secondary outcomes included the pharmacokinetics of OT, vasopressin and cortisol in blood and the association between nasal cavity dimensions and emotional ratings. Despite the fact that all the treatments produced similar plasma OT increases compared with placebo, there was a main effect of treatment on anger ratings of emotionally ambiguous faces. Pairwise comparisons revealed decreased ratings after 8IU OT in comparison to both placebo and 24IU OT. In addition, there was an inverse relationship between nasal valve dimensions and anger ratings of ambiguous faces after 8-IU OT treatment. These findings provide support for a direct nose-to-brain effect, independent of blood absorption, of low-dose OT delivered from a Breath Powered device.


Importantly, the current findings are the first to suggest that a low dose of OT is more effective than a higher dose in modulating social cognition

Converging biological and behavioral evidence suggests that lower OT doses may be more efficacious than higher doses. For instance, compared with higher doses, lower doses increased peripheral levels of OT in saliva,65 attenuated cortisol stress responses66 and increased eye gaze in patients with Fragile X syndrome.67 In animals, a low dose of OT administered shortly after birth increased partner preference later in life, whereas higher doses did not.68 Similarly, lower doses have been associated with stronger increases in social recognition compared with higher doses.69, 70 The dose–response data reported here provide useful preliminary evidence concerning the optimal dose for social cognition modulation; however, extrapolation from healthy individuals to patients must be with caution. Patients with social-cognitive deficits may respond differently than healthy volunteers, so future studies should explore effects in patient populations to determine the generalizability of these findings to target illnesses. Future work should also further investigate the role of different delivery devices, administration routes, dosages and social cognition tasks on the efficacy of intranasal OT, ideally using larger sample sizes given the limitation of a relatively small sample size in the present study.
In addition, this study provides preliminary evidence that a lower dose (8IU) may offer greater efficacy than a higher dose (24IU) when administered with the Breath Powered device.

There are a number of interpretations regarding why no effect was observed at the 24IU OPN-OT dose, in contrast to the 8IU dose. For example, a higher OT dose is more likely to influence the balance of AVP/OT, as evidenced by the decrease in AVP concentration after 24IU OPN-OT (but not 8IU OPN-OT) observed in the present study, which can modulate social behavior.



OptiNose reports positive results from Phase 1 trial of intranasal oxytocin for autism

Jul 15 2015

OptiNose has announced that a study comparing OPN-300 intranasal oxytocin to intravenous oxytocin for the treatment of autism showed the achievement of similar blood levels but significantly greater social-cognitive effects after intranasal administration. The results were published online July 14, 2015 in Translational Psychiatry.
The randomized, placebo-controlled, double-blind, double-dummy, 4-arm cross-over study involved 16 healthy volunteers who received either intravenous oxytocin or two doses of OPN-300 delivered using OptiNose’s bi-directional breath powered intranasal delivery device. Social-cognitive effects were measured by emotional rating of facial images.
Researcher Ole A. Andreassen of the University of Oslo said, “The OptiNose technology significantly changes the way drug is delivered high up in the nose, and may be the drug delivery solution we’ve been looking for. If we can improve social cognition in healthy people with OPN-300 low-dose oxytocin, then we may be able to address a core symptom suffered by millions of patients worldwide with autism.”
OptiNose Chief Scientific Officer Per Djupesland commented, “Although animal data has been encouraging, many would argue that medication transport from the nasal cavity directly to the brain has not been previously proven in humans. Today’s results are quite promising and bolster our belief that we can enable and enhance the treatment of common brain disorders with OptiNose delivery technology.”
The company says that it is initiating a Phase 2 trial of OPN-300 in autism patients in Norway. OptiNose is also developing intranasal fluticasone for chronic sinusitis and recently reported positive results from a Phase 3 trial of that product.
Read the OptiNose press release.
Read the Translational Psychiatry article.




Conclusion

Some parents already use the Syntocinon version of oxytocin for autism; some tried it in one of the earlier clinical trials and found it did not help.  There is nothing surprising in that. 

The people at OptiNose seem to be a bit more motivated than some of the other oxytocin researchers, in relaxed leafy universities, to actually get to the finishing line.  They are initiating Phase 2 trials of OPN-300 in autism patients in Norway.  Some of the other studies have been going on for several years and are still not finished.

Hopefully we will soon have some data on what percentage of people with “autism” respond to OPN-300 and then we could compare that to the response to Syntocinon.

As we have seen several times before, it seems that smaller doses of oxytocin are more effective than larger doses.  Larger doses seem to change (reduce) vasopressin levels, which will also affect social behavior.

One you start changing the level of one hormone, like oxytocin, you are very likely to affect others.  There are many interrelations and feedback loops.  

Oxytocin may well be part of the solution for some people with autism, but I expect in others it may make them worse.  Hopefully in the later trial(s) they will try and indentify biomarkers for the responder group.








12 comments:

  1. Hi,
    My son is different when he his on syntocinon. Eye contact and verbalisation improve.
    Oxytocin has been a part of his life from the last 3 years and I don't regret it. Has it been life changer? Its not a double blind trial but he has steadily come a long way.
    João Santos

    ReplyDelete
    Replies
    1. Thanks Joao, what dosage do you use? Did you look at the effect of higher and lower doses? How many kg is your son?

      Delete
    2. Hi,
      He is currently 18 kg. I've been dosing 4 UI per nostril twice a day for the last 2 1/2 years (since he was 12 kg). I did try lower for the first months but after a while I went with the commonly used 0.4 UI / kg (on the upper level, since the spray is 4 UI per "poof"). The lower doses (1 - half the one I'm using; 2 - only once a day the one I'm using) also had a noticeable effect.
      I also tried higher doses (1.5 X and 2.0 X) but never did it consistently enough to have an opinion. I always had the feeling it made him a little more moody but its just an unsupported feeling.
      João Santos

      Delete
  2. Oxytocin is a mammalian neurohypophysial hormone. It plays an important role in the neuroanatomy of intimacy. I did agree that the spraying way would affect the amount of drug to take effect.

    ReplyDelete
  3. Optinose is recruiting adult males for their autism trial.
    https://clinicaltrials.gov/ct2/show/study/NCT02414503#contacts

    ReplyDelete
  4. Vitamin A, from fish oil (without vitamin D) makes my child more social. Empathy, eye contact, presence - everything is better. I found this:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146614/

    https://www.dropbox.com/s/onh4sse6gze7whv/OXITOCIN%20I%20RETINOL%20-%20CEO%20RAD.doc?dl=0

    ReplyDelete
    Replies
    1. Maja, very clever. CD38 transcription is reduced in autism which reduces oxytocin. Instead of giving oxytocin, increase CD38 transcription. One of the metabolites of vitamin A does just that, as you showed in your paper. That would suggest that Joao, our reader from Portugal, might choose to follow your example and give more vitamin A.

      How much vitamin A is in the fish oil you give daily?

      Delete
    2. Two or tree weeks after I stopped to use multivitamin, I noticed some possible signs of vit A deficiency like hyperkeratosis in the upper arms, insecure when walking in the night, deterioration of strabismus, itchy eyes. She become full of resistance, wild, in fog, not cooperative...
      So, I gave her around 3-4000 IU daily. It is pure vitamin A from fish oil (from NOW, 10 000 IU), in softgels. I squeeze 2 drops in the juice (softgel contains around 5 drops).
      After only one day strabismus improved. After three days skin manifestations improved. After one week she become gentle as a lamb, more communicative and more willing to be cuddled.
      That was so obviously, that I started to explore vit A, and find the connection with oxytocin.
      I am still confused with all this, have to think it over again. Level of retinol in serum is hard to be measured, I suppose that she can use more vit A...

      Delete
  5. I have been looking at the oxytocin links/GABA switch/chloride channels etc. At delivery of my daughter, I had a "retained placenta" - I wonder if the oxytocin rise that occurs in labour was in some ways not efficient which caused the placenta to not come out naturally - which could link to the GABA switch not being activated during labour etc. I could not find studies in humans, but did find one that was done on horses and my hunch was correct: https://www.deepdyve.com/lp/wiley/expression-of-oxytocin-receptors-is-greatly-reduced-in-the-placenta-of-PNqv02AsvY. I will be starting bumetanide soon, we see our meds next week and I will press for it. My daughter is 15 kg, would 1 mg once daily be a good start?

    ReplyDelete
    Replies
    1. I would agree that 1mg once a day is a good place to start. You also need to add back potassium and fluids lost in diuresis. Your doctor should be able to monitor all this.

      Delete
  6. Yet another paper on oxytocin:

    Neurite Outgrowth Stimulated by Oxytocin Is Modulated by Inhibition of the Calcium Voltage-Gated Channels.
    https://www.ncbi.nlm.nih.gov/pubmed/28493233

    "present data indicate that oxytocin may contribute to the regulation of scaffolding proteins expression known to be associated with clusters of calcium channels at the cell membrane. It appears that oxytocin stimulated neurite outgrowth is, at least, in part dependent on the voltage-gated calcium channels."

    SHANK3 is also mentioned.

    /Ling

    ReplyDelete

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