Receptor Life Science

[peppy]

Quote: Whether it is "probable" or merely "possible" that they do other deals that bring cash in time, it is the possibility of running out of money that is the big thing wrong with the picture. If the cash flow risk is resolved, the share price will surely rebound sharply.

Reply: we did see 2007 to 2009, that running out of money, shorters will jump on. (Banks and all)

Lucky for the US Market 3 trillion US dollars plus was printed and put into quantitative easing.

[peppy]

Mar 20, 2017 17:37:27 GMT -5 sayhey24 said:

Mar 19, 2017 14:36:43 GMT -5 dreamboatcruise said:

Matt, CEO of Mannkind, put out a list of the APIs RLS is developing?  I have not seen this "white paper".  Does someone have a copy of this?

GWPH is far ahead of RLS, but if FDA approves any cannabis based drugs there isn't a reason they wouldn't approve more than one as they do for any other class of drugs.

Mannkind does on their website - here you go

Technosphere technology is to be used as a vehicle to deliver regulated doses of a proprietary compound to treat a variety of medical conditions, including chronic pain, spasticity and inflammatory diseases such as rheumatoid arthritis.

Technosphere’s value proposition is the immediate delivery of a consistent and precise dosage of the prescribed amount of an active therapeutic compound, while reducing unwanted side effects.

www.mannkindcorp.com/Collateral/Documents/English-US/TS%20licensing%20FAQ.pdf

IMO, the RLS plan is to go head to head with GWPH and IMO GWPH has dosing issues.  "Sativex, via an oromucosal pump spray, has proved to be well tolerated and successfully self-administered and self-titrated in both healthy volunteers and patient cohorts. Clinical assessment of this combined cannabinoid medicine has demonstrated efficacy in patients with intractable pain (chronic neuropathic pain, pain due to brachial plexus nerve injury, allodynic peripheral neuropathic pain, and advanced cancer pain), rheumatoid arthritis and MS (bladder problems, spasticity and central pain), with no significant intoxication-like symptoms, tolerance or withdrawal syndrome (Perez 2006)."  www.ncbi.nlm.nih.gov/pmc/articles/PMC2626929/

Quote: Technosphere technology is to be used as a vehicle to deliver regulated doses of a proprietary compound to treat a variety of medical conditions, including chronic pain, spasticity and inflammatory diseases such as rheumatoid arthritis.

Reply: compare contrast rheumatoid arthritis medications; Enbrel by Amgen. The television advertisement shows a person playing golf.

content.screencast.com/users/mpeppy/folders/Jing/media/80d22348-7009-4d08-81fc-667c893ac084/2017-03-20_2234.png

Amgen is not running out of money.

--------------------------------------------------------------------------------------------------------------------------------------

"CBD definitely blocks the inflammation with clinical score. at 5mg/kg in clinical score."

Cannabinoid System in Neuroprotection, Raphael Mechoulam,PhD
www.youtube.com/watch?v=ZI2VT2kOfnM
work done in Israel.
www.screencast.com/t/4zpsWatIJ

[peppy]

You All know I latched on to the Epilepsy testimonials as the RLS biggy.

Look what are Fine Man on the Street Mango dig up for our entertainment pleasure.

Mangos post:

First, here are the meanings of the abbreviations within the article so it will be less confusing

MV = membrane vesicle

EV = extracellular vesicle

CB1 = cannabinoid receptor 1 / type-1 cannabinod receptor
(G-coupled protein)

CB2 = cannabinoid receptor 2 / type-2 cannabinoid receptor
(G-coupled protein)

AEA = arachidonoylethanolamine, also known as Anandamide. This is an endogenous cannabinoid

2-AG = 2-arachidonoylglycerol, an endogenous cannabinoid

eCB = endocannabinoid

ECS = endocannabinoid system


Active endocannabinoids are secreted on extracellular membrane vesicles

• Our findings, by providing evidence for the activation of CB1 in GABAergic neurons by microglia-derived MVs, suggest that microglia may crucially regulate positioning and circuit formation of CB1-expressing interneurons through secretion of AEA-storing EVs during brain development.

• Here, we show that endocannabinoids are secreted through extracellular membrane vesicles produced by microglial cells.

• We demonstrate that microglial extracellular vesicles carry on their surface N-arachidonoylethanolamine (AEA), which is able to stimulate type-1 cannabinoid receptors (CB1), and inhibit presynaptic transmission, in target GABAergic neurons. This is the first demonstration of a functional role of extracellular vesicular transport of endocannabinoids.

• Retrograde signaling is the principal mode by which eCBs modulate synaptic function. N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), the most active eCBs as yet discovered, are synthesized in the postsynaptic compartment of neurons and act retrogradely to inhibit GABA or glutamate release from presynaptic terminals; this process is mediated by activation of type-1 cannabinoid (CB1) receptor 3, 5.

• However, there is also evidence suggesting that eCBs indirectly signal at the synapse via glial cells by triggering gliotransmission 6 and that glial cells directly produce eCBs 7.

• Indeed, microglia release eCBs 8, 9, 10 and produce in vitro 20-fold higher amounts than neurons or astrocytes, likely representing the main source of these substances in the inflamed brain 11. Microglia also respond to eCBs through functional type-1 (CB1) and type-2 (CB2) cannabinoid receptors, which likely regulate microglia behavior and phenotype 11.

• Additionally, we now show that microglial MVs directly suppress the GABAergic tone through CB1 activation on interneurons, thereby contributing to alteration of excitation/inhibition balance.

• Conflict of interest

The authors declare that they have no conflict of interest.

• Source

www.ncbi.nlm.nih.gov/pmc/articles/PMC4328748/?report=reader

Here is what I say:

The mechanism of action, why it works for epilepsy.

• Retrograde signaling is the principal mode by which eCBs modulate synaptic function. N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), the most active eCBs as yet discovered, are synthesized in the postsynaptic compartment of neurons and act retrogradely to inhibit GABA or glutamate release from presynaptic terminals; this process is mediated by activation of type-1 cannabinoid (CB1) receptor 3, 5.


Interesting source
• Source
www.ncbi.nlm.nih.gov/pmc/articles/PMC4328748/?report=reader

The definition needed is RETROGRADE.

ret·ro·grade
adjective: retrograde
1.
directed or moving backward.
"a retrograde flow"
synonyms: backward, backwards, reverse, rearward
"retrograde motion"

[peppy]

Mar 24, 2017 5:48:07 GMT -5 peppy said:

You All know I latched on to the Epilepsy testimonials as the RLS biggy.

Look what are Fine Man on the Street Mango dig up for our entertainment pleasure.

Mangos post:

First, here are the meanings of the abbreviations within the article so it will be less confusing

MV = membrane vesicle

EV = extracellular vesicle

CB1 = cannabinoid receptor 1 / type-1 cannabinod receptor
(G-coupled protein)

CB2 = cannabinoid receptor 2 / type-2 cannabinoid receptor
(G-coupled protein)

AEA = arachidonoylethanolamine, also known as Anandamide. This is an endogenous cannabinoid

2-AG = 2-arachidonoylglycerol, an endogenous cannabinoid

eCB = endocannabinoid

ECS = endocannabinoid system


Active endocannabinoids are secreted on extracellular membrane vesicles

• Our findings, by providing evidence for the activation of CB1 in GABAergic neurons by microglia-derived MVs, suggest that microglia may crucially regulate positioning and circuit formation of CB1-expressing interneurons through secretion of AEA-storing EVs during brain development.

• Here, we show that endocannabinoids are secreted through extracellular membrane vesicles produced by microglial cells.

• We demonstrate that microglial extracellular vesicles carry on their surface N-arachidonoylethanolamine (AEA), which is able to stimulate type-1 cannabinoid receptors (CB1), and inhibit presynaptic transmission, in target GABAergic neurons. This is the first demonstration of a functional role of extracellular vesicular transport of endocannabinoids.

• Retrograde signaling is the principal mode by which eCBs modulate synaptic function. N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), the most active eCBs as yet discovered, are synthesized in the postsynaptic compartment of neurons and act retrogradely to inhibit GABA or glutamate release from presynaptic terminals; this process is mediated by activation of type-1 cannabinoid (CB1) receptor 3, 5.

• However, there is also evidence suggesting that eCBs indirectly signal at the synapse via glial cells by triggering gliotransmission 6 and that glial cells directly produce eCBs 7.

• Indeed, microglia release eCBs 8, 9, 10 and produce in vitro 20-fold higher amounts than neurons or astrocytes, likely representing the main source of these substances in the inflamed brain 11. Microglia also respond to eCBs through functional type-1 (CB1) and type-2 (CB2) cannabinoid receptors, which likely regulate microglia behavior and phenotype 11.

• Additionally, we now show that microglial MVs directly suppress the GABAergic tone through CB1 activation on interneurons, thereby contributing to alteration of excitation/inhibition balance.

• Conflict of interest

The authors declare that they have no conflict of interest.

• Source

www.ncbi.nlm.nih.gov/pmc/articles/PMC4328748/?report=reader

Here is what I say:

The mechanism of action, why it works for epilepsy.

• Retrograde signaling is the principal mode by which eCBs modulate synaptic function. N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), the most active eCBs as yet discovered, are synthesized in the postsynaptic compartment of neurons and act retrogradely to inhibit GABA or glutamate release from presynaptic terminals; this process is mediated by activation of type-1 cannabinoid (CB1) receptor 3, 5.


Interesting source
• Source
www.ncbi.nlm.nih.gov/pmc/articles/PMC4328748/?report=reader

The definition needed is RETROGRADE.

ret·ro·grade
adjective: retrograde
1.
directed or moving backward.
"a retrograde flow"
synonyms: backward, backwards, reverse, rearward
"retrograde motion"

Mango just asked me how?

here is my reply

the resting potential.

Epilisey, a electronic charge disorder.

The retrograding, the delay of the charge transmission, the seizures stop.

the - 70 mv to + 30 mv charge is delayed.

faculty.washington.edu/chudler/ap.html

[peppy]

www.alchimiaweb.com/blogfr/wp-content/uploads/2015/11/Russo-Cannabis-and-Cannabidiol-in-Pediatric-Epilepsy-2015.pdf

[Deleted]

peppy you up late hitting the rls pipe?

[peppy]

Mar 26, 2017 0:11:06 GMT -5 @reverselo said:

peppy you up late hitting the rls pipe?

lot's of love for mannkind  on this board.

Mango feeding me some good links.

I hadn't seen this historical presentation before.

Heh, cannabis on Sumerian  text, with hemp fiber used in the making of the tablets, aye?

Then it gets better, cannabis used as a treatment for epilepsy since the beginning of recorded time?

puts Richard Nixon schedule 1 and Reagans confiscation laws and privately run prisons into context.

"Tin soldiers and Nixon coming, we are finally on our own."

A bit like the hood wink of health insurance policies that do not include hospitalization.

Here is another study of interest:

Cannabinoid 2 Receptor Agonist Improves
Systemic Sensitivity to Insulin in High-Fat
Diet/Streptozotocin-Induced Diabetic Mice

www.karger.com/Article/Pdf/453171

[peppy]

The second annual Personalized Cannabinoid Medicine Conference (CannMed) will be held at The Joseph B. Martin Conference Center at The Harvard School of Medicine on April 9-11, 2017. The event is drawing international attention as cannabis research and legalization continues to grow exponentially.

CannMed 2017 will kick-off on Sunday, April 9, with tours of the Courtagen Life Sciences/ Medicinal Genomics laboratory, and conference presentations on cannabis science and delivery will include:

•Featured address via Skype from world-renowned cannabis researcher, Dr. Raphael Mechoulam.


•How the FDA's Expectations of Respiratory Drug Delivery Create Parallel Challenges for the Vaping and Medicinal Cannabis Industries.


•Delivery of Cannabinoids to the Bloodstream via Inhalation of Dry Powder Aerosols or Sublingual Absorption of Dry Powder Compressed Wafers.

www.healthcarepackaging.com/article/trends-and-issues/medical-marijuana/cannabis-news-cannmed-conference-machinery-and-more

(Mango)

[mango]

• From the Most Recent Form 10-K:

On January 20, 2016, we entered into the CLA with Receptor pursuant to which we performed initial formulation studies on compounds identified by Receptor. Following successful completion of the studies, Receptor exercised its option to acquire an exclusive license to develop, manufacture and commercialize inhalation formulations of these compounds utilizing our technology.
See Note 8 — Collaboration Arrangements of the Notes to Consolidated Financial Statements included in “Part II, Item 8 — Financial Statements and Supplementary Data” for additional information related to the accounting for the CLA.

8. Collaboration Arrangements
Receptor Collaboration and License Agreement — On January 20, 2016, the Company entered into a Collaboration and License Agreement (the “CLA”) with Receptor Life Sciences, Inc. (“Receptor”) pursuant to which the Company performed initial formulation studies on compounds identified by Receptor. Following successful completion of the studies, Receptor obtained the option to acquire an exclusive license to develop, manufacture and commercialize certain products that use MannKind’s technology to deliver the compounds via oral inhalation.

The Company received $0.4 million in nonrefundable payments in 2016 prior to Receptor exercising the option. On December 30, 2016, Receptor exercised the option and paid the Company a $1.0 million nonrefundable option exercise and license fee. Under the CLA, the Company may receive the following additional payments:

• Nonrefundable milestone payments upon the completion of certain technology transfer activities and the achievement of specified sales targets.

• Royalties upon Receptor’s and its sublicensee’s sale of the product.

• Milestones upon total worldwide sales reaching certain agreed upon levels.

The Company evaluated the accounting for the payments received in 2016 under the multiple element accounting guidance and determined that the $0.4 million in payments received prior to Receptor exercising its option are separable from the other elements of the agreement and represented payments to offset costs incurred. Therefore, those payments reduced the Company’s research and development expense in 2016. The $1.0 million license fee received in 2016 does not have standalone value from the follow-on transfer of technology. Therefore, the license fee was recorded in deferred payments from collaboration at December 31, 2016 and will be recognized in net revenue — collaboration over four years. See Note 2 — Summary of Significant Accounting Policies for additional information on the Company’s accounting for multiple element arrangements.

Cash used in operating activities in 2016 of $78.1 was primarily driven by an excess of cash used in operations of approximately $105.1 million over cash received from operations of approximately $29.4 million. Cash received of approximately $29.4 million represented $19.4 million from sales of insulin to Sanofi, $4.8 million from Afrezza product sales, $2.7 million from sales of insulin to a third party, $1.4 million from our collaboration with Receptor and $1.1 million from other sources. Cash used in operations of approximately $105.1 million represented by $69.5 million in cash used for selling, general and administrative expenses, cost of goods sold, and research and development, a $12.1 million decrease in accounts payable between December 31, 2015 and December 31, 2016, $11.6 million in purchases of inventory from Amphastar, $9.0 million in interest paid and a $2.5 million increase in inventory between December 31, 2015 and December 31, 2016.

MannKind's Most Recent Form 10-K



• From the First Form 10-K to Mention Receptor Life Sciences:

In January 2016, we entered into a collaboration and license agreement with a newly formed entity, Receptor Life Sciences, Inc., pursuant to which Receptor is evaluating the feasibility of developing multiple inhaled therapeutic products using our technology to explore their potential to treat conditions such as chronic pain, neurologic diseases and inflammatory disorders.

First Form 10-K to Mention Receptor



Going to stick with my original thoughts that the pdf is a load of BS and Receptor is using Technosphere for inhaled therapeutic products. 

[mango]

I wonder what is up with the mention of collaboration over four years...

The Company evaluated the accounting for the payments received in 2016 under the multiple element accounting guidance and determined that the $0.4 million in payments received prior to Receptor exercising its option are separable from the other elements of the agreement and represented payments to offset costs incurred. Therefore, those payments reduced the Company’s research and development expense in 2016. The $1.0 million license fee received in 2016 does not have standalone value from the follow-on transfer of technology. Therefore, the license fee was recorded in deferred payments from collaboration at December 31, 2016 and will be recognized in net revenue — collaboration over four years. See Note 2 — Summary of Significant Accounting Policies for additional information on the Company’s accounting for multiple element arrangements.

[madog365]

Figured i would keep this thread up to date - Seems like the partnership is going strong.

From the the 1Q -10Q

On March 15, 2017, the Company entered into a Manufacturing and Supply Agreement with Receptor pursuant to which the Company will provide certain raw
materials to Receptor. On March 16, 2017, the Company agreed to provide certain additional research and formulation consulting services to Receptor.

[nylefty]

May 11, 2017 15:54:05 GMT -5 madog365 said:

Figured i would keep this thread up to date - Seems like the partnership is going strong.

From the the 1Q -10Q

On March 15, 2017, the Company entered into a Manufacturing and Supply Agreement with Receptor pursuant to which the Company will provide certain raw
materials to Receptor. On March 16, 2017, the Company agreed to provide certain additional research and formulation consulting services to Receptor.

Certain raw materials?  What could those be?

[peppy]

May 11, 2017 17:02:39 GMT -5 nylefty said:

May 11, 2017 15:54:05 GMT -5 madog365 said:

Figured i would keep this thread up to date - Seems like the partnership is going strong.

From the the 1Q -10Q

On March 15, 2017, the Company entered into a Manufacturing and Supply Agreement with Receptor pursuant to which the Company will provide certain raw
materials to Receptor. On March 16, 2017, the Company agreed to provide certain additional research and formulation consulting services to Receptor.

Certain raw materials?  What could those be?

My guess is:

www.mannkindcorp.com/Collateral/Documents/English-US/Innovation%20In%20Drug%20Delivery%20by%20Inhalation.pdf

[ssiegel]

May 11, 2017 15:54:05 GMT -5 madog365 said:

Figured i would keep this thread up to date - Seems like the partnership is going strong.

From the the 1Q -10Q

On March 15, 2017, the Company entered into a Manufacturing and Supply Agreement with Receptor pursuant to which the Company will provide certain raw
materials to Receptor. On March 16, 2017, the Company agreed to provide certain additional research and formulation consulting services to Receptor.

Does "provide" mean they'll sell or they'll give?

[madog365]

May 11, 2017 17:51:33 GMT -5 ssiegel said:

May 11, 2017 15:54:05 GMT -5 madog365 said:

Figured i would keep this thread up to date - Seems like the partnership is going strong.

From the the 1Q -10Q

On March 15, 2017, the Company entered into a Manufacturing and Supply Agreement with Receptor pursuant to which the Company will provide certain raw
materials to Receptor. On March 16, 2017, the Company agreed to provide certain additional research and formulation consulting services to Receptor.

Does "provide" mean they'll sell or they'll give?

It's a good question, my assumption would be that they are revenue producing agreements (who gives away materials and consulting services for free?) - But for whatever reason Mannkind did not consider them material, maybe they are part of the next scheduled payment.