Mannkind & Torrey Pine Joint U.S. Patent - Treating Pain

[suebeeee1]

www.usatoday.com/story/news/nation/2014/02/02/chronic-pain-treatment/4737647/



"Chronic pain — typically defined as pain lasting more than three to six months — affects 100 million adult Americans, according to a 2011 report from the Institute of Medicine, part of the National Academy of Sciences. In 2010, that was more than 40% of the adult population. It is the leading reason people go to doctors and it costs the nation upwards of $635 billion a year — more than cancer, heart disease and diabetes combined."

This is a BIG deal and one, if alleviated, even minimally, through a non-addicting pain med that could be delivered via Technospere, could be far bigger than the release of Afrezza. 

However, I agree with Sean.  It cannot be an opiate or addictive drug.  The same fast uptake and clearance which is hailed by Afrezza users would be a disaster if an opioid was used in this manner, unless it was used in conjunction with a drug regimine which included a long acting pain med with the inhaled pain killer as a additional "kick" when base line pain management was not enough.  In many ways chronic pain treatment mirrors that of type 1 diabetes treatment.  One has a long acting drug taken several times a day (or something like a Fentanyl patch) along with a short acting, smaller dose opioid given at times when pain is out of control.  

There are various cocktails in which this kind of modality would fit.  The inhalable could be a smaller dose opioid used in this manner.  

And it could be bigger than anything we have seen thus far......

[suebeeee1]

Jun 5, 2015 7:19:38 GMT -5 mnholdem said:

Presentation includes Joint Venture of Torrey Pines Institute for Molecular Studies and MannKind Corporation, starting at page 32:


lifesciencessf.org/resources/docs/Webinars/02-18-14_Webinar_Presentation.pdf

"Rapid Pain Therapeutic Identification and Inhalation Delivery
Patent Filed 2012
Expected Phase I Clinical Trial 2014"

This presentation is well worth a second look!  Very impressive.

[cm5]

Methods and Compositions for Treating Pain
Publication number US9233159 B2
Application number US 14/354,092
Publication date Jan 12, 2016
Filing date Oct 24, 2012
Priority date Oct 24, 2011
Also published as CA2852536A1, 5 More »
Inventors Andrea Leone-Bay, Richard A. Houghten, Joseph J. Guarneri, Grayson W. Stowell
Original Assignee Mannkind Corporation, Torrey Pines Institute For Molecular Studies

An inhalable, analgesic composition comprising microparticles of a diketopiperazine and a peptide comprising less than 20 amino acids; wherein said composition is effective at relieving pain, wherein the peptide is an opioid receptor agonist.

The inhalable analgesic composition of claim 1, wherein the peptide binds to a μ opioid receptor, a δ opioid receptor, or a κ opioid receptor, or combinations of receptors thereof, on cells in the central or peripheral nervous systems.

Disclosed are methods and compositions for treating pain that facilitate delivery of the pain medication while reducing unwanted side effects, such as, for example, addiction, somnolence, tolerance, respiratory depression, and constipation, and the like.

In embodiments the pain to be treated can be, for example, a peripheral neuropathy, a central neuropathy, a traumatic abnormality, a cerebral vascular accident, postoperative pain, dental pain, direct trauma, infection, HIV infection, small pox infection, herpes infection, toxic exposure, exposure to arsenic, exposure to lead, cancer, invasive cancer, congenital defect, phantom limb pain, encephalitis, rheumatoid arthritis, fibromyalgias, spinal root lesions, spinal root impingement, back pain, multiple sclerosis, chronic pain, fibrous tissue pain, muscle pain, tendon pain, ligament pain, pain associated with diarrhea, irritable bowel syndrome, abdominal pain, chronic fatigue syndrome, and spasms.

In embodiments, the methods and compositions can be used for the treatment of pain modulated through cell receptors. In embodiments disclosed herein the methods and compositions can comprise, active agents such as, for example, receptor agonists, antagonists, or the like. In embodiments disclosed herein the methods and compositions can comprise, for example, opioid receptor agonists and/or antagonists, alpha-MSH receptor agonists and/or antagonists, and the like, and can be provided to a subject as the active agents for treating pain. In certain embodiments the active agents act directly or indirectly upon other receptor agonists.

Diketopiperazines, in addition to making aerodynamically suitable microparticles, dissolve rapidly at physiologic pH thereby releasing the active agent for absorption into the circulation. Diketopiperazines can be formed into particles that incorporate a drug or particles onto which a drug can be adsorbed. The combination of a drug and a diketopiperazine can impart improved drug stability. These particles can be administered by various routes of administration. As dry powders these particles can be delivered by inhalation to specific areas of the respiratory system, depending on particle size. Additionally, the particles can be made small enough for incorporation into an intravenous suspension dosage form. Oral delivery is also possible with the particles incorporated into suspensions, tablets or capsules.

Accordingly, dry powder formulations for inhalation comprising peptides can provide opioid-like pain relief with fewer adverse effects than current, commercially available analgesics.

The inhalation powder has been administered to mice by pulmonary insufflation.

In a nonclinical model of acute pain (the 55° C. warm-water tail withdrawal assay), the dry powder formulations comprising the peptides demonstrated analgesic activity comparable to injected morphine without the typical opioid side effects. Unlike mice treated with morphine, those given the dry powder formulations comprising the peptides surprisingly did not exhibit depressed respiration or alterations in spontaneous locomotor activity. Nor did they exhibit a place-conditioning response, a behavior associated with a “reward” after receiving the FDKP/opioid receptor agonist peptide dry powder formulation.

Example 6---A 48 yr. old female patient reports headache pain to her doctor. Following examination of the patient, the doctor prescribes an analgesic composition containing a FDKP/SEQ (D)Phe-(D)Phe-(D)Nle-(D)Arg-NH2 (SEQ ID NO: 2, Compound 2) composition prepared as described in the previous Examples. The analgesic composition is 15% peptide. The analgesic composition is administered with a reusable inhaler calibrated to provide a dose of 5 mg/kg of body weight. The patient reports the elimination of her headache pain.

Example 12---An 8 yr. old male patient reports pain from a broken arm to his doctor. Following examination of the patient, the doctor prescribes an analgesic composition containing a Na2FDKP/Trp-(D)Ser-Ser-Phe-NH2 (SEQ ID NO: 4, Compound 4) composition prepared as described in the previous Examples. The analgesic composition is 25% peptide. The analgesic composition is administered with a reusable inhaler calibrated to provide a dose of 2 mg/kg of body weight. The patient reports the elimination of his pain.

[afrezzamiracle]

It's a shame that such an incredibly exciting and promising compound has been apparently neglected and left to die. If MNKD ever got to firing on all cylinders we'd discover that it has been a sleeping GIANT all along.

[cm5]

It's far from over---www.worldpreclinicalcongress.com/wpc_content.aspx?id=123811&libID=123759

Andrea Leone-Bay on Linkedin
Chief Scientific Officer
Receptor Life Sciences
October 2015 – Present (9 months)
Receptor Life Sciences, Inc. is a pharmaceutical development company based in Seattle, Washington. Receptor is quietly laying the foundation for groundbreaking new products in the specialty pharmaceutical market.

6th Annual    Targeting Pain with Novel Therapeutics
----Translating Success from Preclinical Assays to the Clinic  June 14-17 2016 Boston

In recent years, the World Preclinical Congress (WPC) has turned into a key networking event for those involved in preclinical research. It features conferences, training seminars and short courses that cover the very latest in preclinical strategies and technologies, to enable better and faster decisions in drug discovery. WPC attracts a diverse, global audience, which include experts, as well as people who are new and eager to contribute to the field. Having chemists, biologists, pharmacologists, toxicologists, screening and formulation experts in attendance, creates an interesting cross-disciplinary environment for tackling challenges and sharing expertise. Now in its 15th year the event will continue to highlight ways to improve accuracy and efficiency in preclinical research, while bringing together the people and technologies to make it happen.

At the 2013 Meeting:

9:10 Oral Inhalation of Peripherally-Restricted KOR Agonists Produces Rapid Antinociception in Multiple Pain Models without Opioid Liabilities

Andrea Leone-Bay, Ph.D., Vice President, Pharmaceutical Research & Development, MannKind Corporation

Self-administered, rapid-acting pain medicines without opioid side effects, like addiction and respiratory depression, remain an unmet medical need. We have identified a series novel small peptide peripherally-restricted kappa opioid agonists that meet this need. These new drugs have been combined with a non-invasive, oral inhalation delivery system that provides a very rapid (5 minutes or less), dose-dependent onset of pain relief in several nonclinical pain models.

[kc]

I have not looked at the Torrey Pines website for over a year plus. It is been completely updated totally different than the past.

www.tpims.org/

[kc]

Torrey Pines = RLS? Not for profit organization with relationship to Mintaka. Having a long term relationship with MannKind. RLS providing funding for Oxytocin Mintaka? Matt said that the people behind RLS well known and and funded but did not want to reveal their name until it they want to reveal their name.

Bill and Melinda Gates foundation funding in January 2016 Oxytocin project too Mintaka? Mintaka lead Robin Offord is also Chairman of the board of Torrey Pines?
Andrea Leona-Bay working for RLS ties into the whole deal as she would have been involved with dealing with Torrey Pines over the years.

gcgh.grandchallenges.org/grants?f%5B0%5D=field_challenge%253Afield_short_title%3ASaving%20Lives%20at%20Birth


Reduction of Maternal Death Through Postpartum Hemorrhage: A Highly Heat-Resistant Form of Oxytocin That Does Not Require Injection
GRAND CHALLENGES FOR DEVELOPMENT
SAVING LIVES AT BIRTH
1 JAN 2016
More information about Saving Lives at Birth (Round 5)
SHARE THIS AWARDED GRANT

PRINCIPAL INVESTIGATOR

Robin Offord
ORGANIZATION

The Mintaka Foundation for Medical Research

[kc]

Jun 5, 2016 20:36:07 GMT -5 kc said:

I have not looked at the Torrey Pines website for over a year plus. It is been completely updated totally different than the past.

www.tpims.org/

They sure seem to be engaged In a lot more research in many different areas then they had been in the past. Seems to be much better funded than a struggling research company.

[cm5]

Mannkind's Patents for pain relieving inhaled non-opiate cannot come soon enough------


Former Pharmaceutical Company Employees Arrested For Participating In Fentanyl Kickback Scheme

Pharmaceutical Sales Representatives And Managers Paid Thousands Of Dollars To Doctors In Exchange For Prescribing Of Millions Of Dollars’ Worth Of Fentanyl   

www.justice.gov/usao-sdny/pr/former-pharmaceutical-company-employees-arrested-participating-fentanyl-kickback-scheme

Preet Bharara, the United States Attorney for the Southern District of New York, Diego Rodriguez, Assistant Director-in-Charge of the New York Field Office of the Federal Bureau of Investigation (“FBI”), and Scott Lampert, Special Agent in Charge of the U.S. Department of Health and Human Services, Office of Inspector General’s (“HHS-OIG”) New York Region, announced that JONATHAN ROPER, a former District Manager at a pharmaceutical company (“Pharma Company-1”), and FERNANDO SERRANO, a former sales representative at Pharma Company-1, were charged today with violating the Anti-Kickback Statute in connection with their participation in a scheme to pay doctors thousands of dollars to participate in sham educational programs in order to induce the doctors to prescribe millions of dollars’ worth of a fentanyl-based sublingual spray manufactured by Pharma Company-1 (the “Fentanyl Spray”). ROPER was arrested this morning by FBI agents on Long Island, and SERRANO was arrested this morning by FBI agents in New Jersey. They will be presented before U.S. Magistrate Judge Kevin N. Fox in Manhattan this afternoon.

Manhattan U.S. Attorney Preet Bharara said: “Fentanyl is an incredibly dangerous and highly addictive drug that is finding its way into, and destroying, too many lives in our communities. Because of its deadly power, its legitimate prescription faces significant and severe restrictions. Yet, as alleged, former drug company employees Jonathan Roper and Fernando Serrano corruptly induced doctors to prescribe millions of dollars’ worth of Fentanyl through thousands of dollars in kickbacks disguised as phony educational programs. As alleged, Roper and Serrano helped feed this devastating surge of opioid addictions by tapping into another age-old addiction, greed.”

FBI Assistant Director Diego Rodriguez said: “This case should be something the medical industry and the general public should pay close attention to because it’s one of the reasons we’re experiencing an epidemic of overdoses and deaths in this country. Not only did the defendants in this case allegedly bully sales reps into pushing this highly addictive drug, they paid doctors to prescribe it to patients. The more prescriptions written, the more money the doctors made. Instead of seeing a way to help people who are dealing with extreme pain, they allegedly saw a huge payday that potentially put people’s lives in danger.”

Earlier this year : sirf-online.org/?s=fentanyl  (The Southern Investigative Reporting Foundation launched in 2012 with the goal of providing in-depth financial investigative reporting for the common good)

The Brotherhood of Thieves: Insys Therapeutics

By Roddy Boyd | January 25, 2016

Executives at Insys Therapeutics have continued to pressure its employees to develop new ways to mislead insurance companies into granting coverage to patients prescribed its drug Subsys, even as the Food and Drug Administration's Office of Criminal Investigations issues a stream of subpoenas to former employees. As reported in a December Southern Investigative Reporting Foundation story, Insys' prior authorization unit (also known internally as the insurance reimbursement center) employees were trained and rewarded for saying anything, including purportedly inventing patient diagnoses, to get Subsys approved. The revelations illuminated the answer to the conundrum raised in our previous stories: how does a company marketing a standard Fentanyl spray formulation, under a strict FDA usage protocol, easily double the insurance approval rates of its more established competitors? Internal Insys documents and an audio recording of a PA unit meeting show that as recently as the late autumn executives were frantically brainstorming new ways to get around increasingly stringent pharmacy benefit manager rule enforcement. "[PBMs] had begun to deny Insys' [PA] requests in the early autumn to the point where it was rare to get more than two dozen approvals per week for the unit," said ex-PA staffer Jana Montgomery (a pseudonym) and something that began to accelerate after the CNBC reports came out.

See more: Opiates
www.myajc.com/news/news/crime-law/warnings-missed-for-years-in-case-of-doctor-accuse/nqD8g/

sirf-online.org/2015/07/14/the-darkening-world-of-insys-therapeutics/

www.thefix.com/drug-salesmen-arrested-bribing-doctors-prescribe-fentanyl-spray

www.9news.com/news/investigations/hospitals-fail-to-report-employee-drug-thefts/207018442


And, it's not limited to pain killers (which btw, turns out to be a great moniker for opiates):

www.bloomberg.com/news/articles/2016-03-26/u-s-seeks-records-of-80-000-novartis-sham-events-for-doctors March 26, 2016 — 1:56 PM ED

Drugmaker says government has `exploded' scope of lawsuit

Whistle-blower case claims company wined and dined doctors

The U.S. is asking Novartis AG to provide records of about 80,000 “sham” events in which the government says doctors were wined and dined so they would prescribe the company’s cardiovascular drugs to their patients.

The Swiss drugmaker and the Manhattan U.S. Attorney are engaged in a whistle-blower lawsuit that alleges Novartis provided illegal kickbacks to health-care providers through bogus educational programs at high-end restaurants and sports bars where the drugs were barely discussed.

In a filing Friday, the U.S. said it needs Novartis to provide information to support its allegation that the company defrauded federal health-care programs of hundreds of millions of dollars over a decade by inducing doctors to prescribe its medications through sham speaker events.

“The requested documents go to the core issues in this case: whether educational materials were provided at these events; which doctors actually attended the events; how much money was spent on meals and honoraria; and indeed, most fundamentally, whether the underlying documentation shows that a particular event actually took place,” the government said in its court filing.

BTW, doesn't require a lot of sleuthing to see which doctors are linked with the above and the below---

www.bloomberg.com/news/articles/2016-03-26/u-s-seeks-records-of-80-000-novartis-sham-events-for-doctors

www.justice.gov/opa/pr/warner-chilcott-agrees-plead-guilty-felony-health-care-fraud-scheme-and-pay-125-million

 projects.propublica.org/docdollars/doctors/pid/293095

www.timesunion.com/local/article/Doctors-reap-drug-firm-payments-4568977.php

www.cms.gov/openpayments/about/law-and-policy.html

[cm5]

Another extended release opiate approved by FDA advisory committee:

Arymo Wins FDA Advisors' Support
---Many still hesitant about abuse-deterrent labeling www.medpagetoday.com/publichealthpolicy/fdageneral/59545 

A joint FDA advisory committee voted 18-to-1 in favor of approving extended-release morphine sulfate tablets (Arymo), and generally agreed that it had abuse-deterrent properties via the oral, nasal, and injectable routes

A joint FDA advisory committee voted 18-to-1 in favor of approving extended-release morphine sulfate tablets (Arymo), and generally agreed that it had abuse-deterrent properties via the oral, nasal, and injectable routes.

The anesthetic and analgesic drug products advisory committee (AADPAC) and the drug safety and risk management advisory committee (DSaRM) voted that the morphine pill, developed by Egalet, was harder to abuse via the oral (16-to-3), nasal (18-to-1), and intravenous (18-to-1) routes of abuse.

The committees made their decision on the basis of data from five phase I pharmacokinetic studies and two phase III human abuse liability studies.

If approved, the drug would be indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative therapies are inadequate. There was debate, however, regarding proposed labeling language around its abuse-deterrent properties.

Please see comment posted on MedPage:  

08.05.2016— Dr. MJ
Most forms of pain go away as the body heals. We need to diagnose failure to heal and correct their deficiencies so they do. Pain subsides but withdrawal pain intensifies the longer pain it is masked with narcotics.

I have never seen any studies that differentiate between withdrawal pain and injury induced pain. Too many patients think their pain is due to botched operations or advancing disease when in fact their pain is due to their growing dependence and addiction causing withdrawal if they skip a dose.

It is not surprising that new forms of narcotics fix this withdrawal pain while we ignore the greater problem of failed healing. Instead we produce more people applying for disability insurance. Pain and failed healing can also be caused by malnutrition which should gradually respond to nutrients supplement therapy and life-style changes to cure them.

Instead we perpetuate addiction and make more and more new addicts. Long acting narcotics make it difficult to assess whether their pain ever goes away because withdrawal becomes worse the longer they are treated.

[cm5]

Credit to mango for pulling this together--- see Thread:  Having Trouble Understanding These Two Things
mnkd.proboards.com/thread/5928/having-trouble-understanding

And, I am counting on peppy and mnholdem to "Cut to the Chase!" and condense the below!

Name: MANNKIND CORPORATION, RAYMOND URBANSKI
DBA: MANNKIND CORPORATION
Address: 1 CASPER ST LAB 208 DANBURY, CT 06810-6903
Credential: CSL.0001138
License Type: CONTROLLED SUBSTANCE LABORATORY
Effective Date: 02/22/2016
Expiration Date: 01/31/2017
Status: ACTIVE

Name: MANNKIND CORP
DBA: Address: 1 CASPER ST DANBURY, CT 06810-6903
Credential: CSM.0000766
License Type: MANUFACTURER OF DRUGS, COSMETICS & MEDICAL DEVICES
Effective Date: 07/01/2016
Expiration Date: 06/30/2017
Status: ACTIVE
www.elicense.ct.gov/Lookup/LicenseLookup.aspx
Read more: mnkd.proboards.com/thread/5928/having-trouble-understanding#ixzz4GZ2daYoa

Someone finally spotted it! Also, CT is a medical marijuana state and also a hemp state.

—CT has an active hemp industry or has authorized research. Hemp is a distinct variety of the plant species cannabis sativa L. that contains minimal (less than 1%) amounts of tetrahydrocannabinol (THC), the primary psychoactive ingredient in marijuana.
norml.org/laws/item/connecticut-penalties
Read more: mnkd.proboards.com/thread/5928/having-trouble-understanding#ixzz4GZ2daYoa

Please see the below----and, earlier this year, the below no longer appeared on the program for this symposium/ and, the below Linkedin profile no longer available----

Post by cm5 on Jun 5, 2016 at 6:16pm

Andrea Leone-Bay on Linkedin
Chief Scientific Officer
Receptor Life Sciences
October 2015 – Present (9 months)
Receptor Life Sciences, Inc. is a pharmaceutical development company based in Seattle, Washington. Receptor is quietly laying the foundation for groundbreaking new products in the specialty pharmaceutical market.

6th Annual Targeting Pain with Novel Therapeutics ----Translating Success from Preclinical Assays to the Clinic June 14-17 2016 Boston

Read more: mnkd.proboards.com/thread/2667/mannkind-torrey-joint-patent-treating#ixzz4GZ3Wg8oY

Now, again thanks to mango, Cara Therapeutics:
"Pain treatment has remained essentially unchanged for over 50 years  CARA is pioneering a new approach"

Cara Therapeutics is an emerging biotechnology company focused on developing novel therapeutics to treat human diseases associated with pain, inflammation and pruritus. Cara possesses both near-term clinical development opportunities combined with proprietary approaches to developing first-in-class novel therapeutics.

Cara's most advanced compound, CR845, is currently undergoing clinical testing for acute pain and pruritus. This patented compound possesses analgesic, anti-inflammatory and anti-pruritic activities appropriate for multiple therapeutic applications. In addition, Cara aims to develop a future pipeline of first-in-class molecules at novel analgesic and anti-inflammatory targets using its proprietary drug screening technology.

Cara Therapeutics Inc. 
4 Stamford Plaza
107 Elm Street, 9th Fl.
Stamford, CT 06902
Main Line: 203.406.3700
Fax: [phone]
[e-mail]

Now, see the Glossary page on the Cara site: (with minor editing for clarity)

The cannabinoid receptors are a class of receptors under the G-protein coupled receptor superfamily. Cannabinoid receptors work by inhibiting adenylate cyclase and thereby inhibit production of the second messenger molecule cyclic AMP. They are activated by cannabinoids, found naturally inside the body or introduced as a drug (which may be a synthetic compound or a herbal extract).

Centrally acting opiates are agents that bind to opioid receptors found principally in the central nervous system. There are four broad classes of opioids:
1--endogenous opioid peptides, produced in the body;
2--opium alkaloids, such as morphine (the prototypical opioid) and codeine;
3--semi-synthetic opioids such as heroin and oxycodone;
4--and fully synthetic opioids such as pethidine and methadone that have structures unrelated to the opium alkaloids.

The GPCR superfamily is the largest family of membrane proteins, members of which are involved in all types of stimulus-response pathways, from intercellular communication to physiological senses and consequently, pathological functions. GPCRs are the targets of 40 to 50% of modern medicinal drugs.

G-protein-coupled receptors are transmembrane receptors that transduce an extracellular signal (ligand binding) into an intracellular signal (via G protein activation). GPCRs represent the most successful and therapeutically useful drug targets in modern medicine.

Opiate analgesics can act through three different types of opioid receptors, called mu, delta, and kappa.

Morphine, the most widely used opiate analgesic, acts primarily via activation of the mu opioid receptor located in the central nervous system (CNS). This CNS action induces pain relief but is also associated with a wide array of CNS-mediated side effects including sedation, respiratory depression, and abuse liability.

As a way to avoid these undesirable CNS effects, there has been an effort to develop opioids which selectively activate (agonist) peripheral opioid receptors such as kappa receptors, present on sensory nerves, outside the central nervous system.

A kappa agonist (or kappa opioid agonist) is a substance that binds to a kappa opioid receptor and triggers a response in the cell. The receptors of the human body work by being stimulated or inhibited by natural (such as hormones and neurotransmitters) or synthetic (such as drugs) agonists and antagonists.

Cara's most advanced compound, CR845 = Kappa opiod agonist

BTW, Cara Therapeutics:  Aug 11, 2016 at 12:30 PM ET
Canaccord Genuity 36th Annual Growth Conference  ir.caratherapeutics.com/

Now, keep in mind one of many Mannkind patents:

Methods and Compositions for Treating Pain
Publication number US9233159 B2
Application number US 14/354,092
Publication date Jan 12, 2016
Filing date Oct 24, 2012
Priority date Oct 24, 2011
Inventors Andrea Leone-Bay, Richard A. Houghten, Joseph J. Guarneri, Grayson W. Stowell
Original Assignee Mannkind Corporation, Torrey Pines Institute For Molecular Studies

www.google.com/patents/US9233159

Methods and compositions for treating pain are disclosed. The compositions are based on dry powders comprising microparticles of diketopiperazines and an analgesic active agent. The analgesic in the compositions comprises one or more peptide analgesics or derivatives thereof, which are administered to a subject using a pulmonary inhalation drug delivery system comprising a dry powder inhaler and the analgesic composition. The present compositions produce fewer side effects associated with current opioid therapy.

Now, think about the below, from this prescient review:

Naturally Occurring Antinociceptive Substances from Plants
Calixto1  Department of Pharmacology, CCB, Universidade Federal de Santa Catarina (UFSC), Floriano´polis, SC, Brazil 

Despite the progress that has occurred in recent years in the development of therapy, there is still a need  for effective and potent analgesics, especially for the treatment of chronic pain. One of the most important  analgesic drugs employed in clinical practice today continues to be the alkaloid morphine. In this  review, emphasis will be given to the important contribution and the history of Papaver somniferum,  Salix species, Capsicum species and Cannabis sativa in the development of new analgesics and their importance  in the understanding of the complex pathways related to electrophysiological and molecular  mechanisms associated with pain transmission. Recently discovered antinociceptive substances include  alkaloids, terpenoids and flavonoid. Plant-derived substances have, and will certainly continue to have, a relevant place in the process of drug discovery, particularly in the development of new analgesic drugs.

Copyright # 2000 John Wiley & Sons, Ltd.
Keywords: antinociceptive; Papaver somniferum; Cannabis sativa; Capsicum; alkaloids; terpenoids; flavonoids.

In  1842, O’Shaughnessy, an army physician in India,  published an extensive treatise on the use of cannabis in various medical conditions including as an analgesic. As a result, Cannabis was introduced into European  medicine and subsequently into other areas of Western 
medicine, including the United States.  Preparations such as tincture and extract of Cannabis were recognized for a  long time as official drugs and were listed in the US  Pharmacopoeia from 1850 until 1942. However, although C. sativa remained in the Pharmacopoeia until 1942, its  medical use was essentially abolished in 1937, when the  Marijuana Tax Act was introduced (Lemberger, 1980).
The Cannabis plant contains a complex mixture of substances that include at least 60 different cannabinoids,  many of which have been shown  present pharmacological activities (Burstein, 1997).

Peripheral antinociceptive effects of Cannabis have also recently been identified. Calignano et al., (1998) reported that CB1 and CB2 agonists attenuate nociception at the peripheral level in mice, suggesting that their  effects are distinct but synergistic (Fields and Meng, 1998) Recently, a CB1 receptor knockout mouse was  reported. In these animals, the spontaneous nociceptive
 threshold was not altered, but the THC effect was absent.(Ledent et al., 1999).

www.siteprotocolo.com.br/upload/Analg%C3%A9sico%20Derivado%20de%20Plantas.pdf

Now, back to the above Mannkind patent:

In an exemplary embodiment herewith, the method for treating pain comprises providing to a subject an inhalable pharmaceutical composition comprising a dry powder comprising one or more receptor agonist peptides. The receptor agonists can be, for example, alpha-MSH receptor agonists, or opioid receptor agonists, or the like

In a particular embodiment, the compositions comprise peptides or derivatives thereof that, for example, bind to cell receptors, or directly or indirectly affect cell receptor agonists. These cell receptors can include, for example, opioid receptors, alpha-MSH receptors, and the like. In embodiments the opioid receptors can include, for example, a μ opioid receptors, a δ opioid receptors, a κ opioid receptors, combinations of one or more of the receptors thereof, or all three receptors on cells in the central or peripheral nervous systems. In one embodiment, the peptide can be either δ (delta) opioid receptor agonists or μ opioid receptor agonists. In another embodiment, the peptide can bind nonspecifically to δ opioid, μ opioid or κ opioid receptors, or combinations thereof to bring about reduction or abolishment of the sensation of pain. In one particular embodiment, the composition for treating pain comprises a peptide or a peptide derivative which is substantially a κ opioid receptor-selective agonist. In certain embodiments herewith, the κ opioid receptor-selective agonist peptides and/or derivatives thereof can bind selectively to neurons in the peripheral nervous system

In a particular embodiment, a method of treating pain sensation comprises administering to a subject in need of said treatment a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable amount of μ opioid receptor agonist in a composition comprising 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine or 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine disodium salt. In certain embodiments, the pharmaceutical composition can comprise a pharmaceutically acceptable carrier or other inactive agents. In some embodiments, the μ opioid receptor agonist is a peptide that can cross the blood-brain barrier and can bind to the μ opioid receptor in brain cells. In another aspect of this embodiment, the pharmaceutical composition can comprise a δ opioid receptor agonist in the dry powder. In another aspect of this embodiment, the pharmaceutical composition can comprise a κ opioid receptor agonist in the dry powder. In other embodiments, the peptide can be primarily a κ opioid receptor agonist but also bind to either δ (delta) opioid receptors or μ opioid receptors as an agonist. In another embodiment, the peptide can bind nonspecifically to δ opioid, μ opioid or κ opioid receptors, or combinations thereof to bring about reduction or abolishment of pain sensation. In a particular embodiment, the opioid receptor agonist is a tetrapeptide.

[cm5]

Torrey Pines  www.tpims.org/disease-research/pain-management

The Institute is interested in finding compounds that alleviate pain through signal prevention or by resetting the body to restore the natural capacity to alleviate pain. Pain facilitation, opiate tolerance and addiction can be linked to inter-communication between and neurons and immune cells in the brain.

Dr. Dooley uses her training in combinatorial libraries and fluorescent imaging to research new methods for pain relief, addiction and food regulation, and investigates cells' response to stresses which may lead to a better understanding of pain management, chronic pain, addiction, Parkinson's and Alzheimer's.

Dr. Colette Dooley completed her undergraduate studies with honors in 1987 and earned her Masters of Science degree in Zoology ("Identification of binding sites for Atrial Natriuretic Peptide on Gills of Salmonids"), both at the University College Dublin, Ireland. She joined the Torrey Pines Institute in 1990 as a Research Assistant and her research included developing high throughput radioreceptor screening assays and modifying existing opioid receptor assays for screening with combinatorial libraries. In 1994, she was named a Senior Scientist at TPIMS and supervised five research technicians on projects involving the use of mixture based combinatorial libraries in radioreceptor assays for opioid ligands, melanocortin ligands, melanin concentrating hormone, substance P and orphanin FQ and is now the lead author of a study on compounds that are in clinical trials. These research projects were funded by either NIH or commercial enterprises. In 2000, she pursued her Ph.D. in the Department of Chemistry and Biochemistry at the University of California in San Diego. She trained with Roger Tsien of UCSD who is renowned for discovering calcium sensitive fluorescent dyes and optimizing Green Fluorescent Protein in 1994. She achieved her Ph.D. in Chemistry, with her thesis entitled, "Green Fluorescent Protein Based Indicators of Dynamic Redox Changes and Reactive Oxygen Species" in 2006. Dr. Dooley rejoined TPIMS in their new endeavor in Florida as an Assistant Member.

Among the list of selected publications, see:

Dooley, C. T., Ny, P., Bidlack, J. M., and Houghten, R. A. (1998). Selective ligands for the μ, δ and κ opioid receptors identified from a single tetrapeptide positional scanning combinatorial library. Journal of Biological Chemistry 273, 18848‑18856. PMID: 9668060