THE Anesthetic Pipeline: How It Will Change Your Practice

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THE Anesthetic Pipeline How It Will Change Your
Practice

• Steven L. Shafer, MDProfessor of Anesthesia,
  Stanford UniversityAdjunct Professor of
  Biopharmaceutical Sciences, UCSFIncoming Editor
  in Chief, Anesthesia Analgesia

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Disclosure

• This is a talk about the future.
• Most of the drugs discussed are not approved.
• Ive consulted with AstraZeneca (Propofol),
  Theravance (THRX 918661), Cognetix (Contulakin-G)

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Outline

• Hypnotics
• Novel Propofol Formulations
• A New Rapidly Metabolized hypnotic
• Muscle Relaxants
• A new relaxant
• A new mechanism of relaxant reversal
• Analgesics
• Novel opioids
• Other centrally acting analgesics
• Peripherally acting analgesics

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Hypnotics
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Whats New With Propofol?

• How to improve on propofol
• Less pain on injection
• Less toxic lipid formulation
• Propofol ICU syndrome may be partly caused by
  the long chain triglycerides
• Faster offset
• Less contamination risk

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Propofol Formulations

• Lipuro Propofol
• Propofol in medium chain triglycerides
• Identical PK/PD profile
• Less pain on injection
• Unavailable in the US, perhaps because of the
  lack of EDTA

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Propofol Formulations

• IDD-D Propofol
• Propofol in medium chain triglycerides
• 2 formulation
• Slower onset than Diprivan
• Increased pain on injection
• Increased pain on injection makes this a
  nonstarter in my view

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Propofol Formulations

• Cyclodextrin Propofol
• water-soluble cyclic carbohydrates
• Egan et al Equivalent PK/PD to Diprivan
• Anesthesiology 2001 95A490

Baker MT, Naguib M. . Anesthesiology.
2005103860-76.
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Propofol Formulations

• Propofol micelles
• Formulations are clear
• Associated with substantial increase in pain on
  injection
• Cleofol recently been introduced in India.
• 89 incidence of severe pain on injection
• Venous phlebitis
• Damages infusion sets,
• should only be used for patients who demand a
  pure vegetarian induction agent

Baker MT, Naguib M. . Anesthesiology.
2005103860-76.
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Propofol Prodrug

• Aquavan
• Water soluble
• VERY slow onset 10 minutes or so
• Difficult to titrate
• Being developed for procedural sedation
• Causes a transient unpleasant sensation of
  burning or tingling of moderate severity in the
  anal and genital region.

Baker MT, Naguib M. . Anesthesiology.
2005103860-76.
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Novel GABAergic HypnoticTHRX-918661
Pig EEG study
Beattie et al, SIVA UK, May 2003
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THRX-918661 vs propofol in Rats
Beattie et al, SIVA UK, May 2003
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THRX-918661 vs. propofol in Rats
THRX- 918661
Propofol
3mg/kg i.v.
10mg/kg i.v.
10mg/kg i.v.
30mg/kg i.v.
Beattie et al, SIVA UK, May 2003
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Xenon

• Anesthetic properties known for years
• Found to be neuroprotective (NMDA antagonist)
• e.g., oxygen/glucose deprivation model below
• Being developed by Protexeon

Sanders et al, British Med Bull 2005 71115
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Melatonin hypnosis

• Large doses (312 mg/kg) of IV melatonin in
  antifreeze produce hypnosis similar to thiopental
  and propofol in a rat.

Naguib et al, Anesth Analg 2003 97238
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Melatonin analogs
Shavali et al, Brain Res Bull 2005 64471
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Muscle Relaxants
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Muscle Relaxant GW280430A

• Similar to mivacurium
• Onset similar to succinylcholine
• Lasts for about 15 minutes
• Metabolized by spontaneous formulation of
  cysteine adducts
• Spontaneous in blood
• Closest true replacement for succinylcholine

J Med Chem. 2003 Jun 546(12)2502-15.
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Sugammadex
Anesthesiology. 2006 Apr104(4)667-74.
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Sugammadex

• modified ??-cyclodextrin
• Binds 11 with rocuronium
• Also binds vecuronium

Epemolu et al, Anesthesiology 2003 99632
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Sugammadex

• Very rapid reversal of neuromuscular blockade

Sorgenfrei et al, Anesthesiology 2006104667
-674
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Analgesics
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Fentanyl morph 3E-trans fentanyl
Viscusi et al, JAMA 2004 2911333
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Fentanyl morph 5Inhaled fentanyl aerosol
Mather et al, Br J Clin Pharmacol 1998 4637
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Fentanyl morph 4Inhaled liposomal fentanyl
Hung et al, Anesthesiology 1995 83277-84
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Fentanyl morph 6Effervescent Fentanyl
(OraVescent)
Pather et al, http//www.drugdeliverytech.com/cgi-
bin/articles.cgi?idArticle5
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Sufentanil morph 1Implantable sufentanil
delivery
http//www.drugdeliverytech.com/cgi-bin/articles.c
gi?idArticle115
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Evidence of m opioid subtypes

• Only about 50 cross tolerance between morphine,
  methadone, fentanyl
• Explains why rotating opioids in chronic pain is
  probably a good idea
• CXBK mouse is insensitive to morphine, but has
  normal response to M6G and fentanyl
• Selective response to opioid antagonists
• Morphine-6-glucuronide, the outlier

Gavril Pasternak, Life Sciences 200168, 2213
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Naloxonazine

• Selectively antagonizes morphine analgesia in
  animals
• m1 is considered naloxonazine sensitive
• Does not antagonize morphine-induced ventilatory
  depression or GI effects
• m2 is considered naloxonazine insensitive

Gavril Pasternak, Life Sciences 200168, 2213
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Morphine-6-glucuronide

• Active metabolite of morphine, about 100 fold
  more potent intrathecally, but enters the CNS
  VERY slowly
• Has analgesic activity in the CXBK mouse that is
  insensitive to morphine
• Actions blocked by naloxonazine (hence, m1)
• Has a unique antagonist, 3-O-methylnaxtrexone
• Also antagonizes heroin self administration,
  little affect on morphine
• Subtype of m1
• MOR-1 knockout (exon 1) has normal sensitivity to
  morphine-6-glucuronide

Gavril Pasternak, Life Sciences 200168, 2213
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MOR-1 gene splice variants(geneOPRM)
Gavril Pasternak, http//www.mskcc.org/mskcc/html/
11384.cfm
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DifferentialExpression ofMOR-1 variants

• Each cell expresses just a single spice variant

Gavril Pasternak, http//www.mskcc.org/mskcc/html/
11384.cfm
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Antisense lowers morphine analgesia(no effect on
m6g)
Gavril Pasternak, Life Sciences 200168, 2213
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Antisense lowers m6g analgesia(no effect on
morphine)
Gavril Pasternak, Life Sciences 200168, 2213
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M6G in exon 2 knockout mice
M6G response in exon 2 knockouts
Wildtype M6G response
Romberg et al, BJA 2003 91862
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Morphine-6-glucuronide

• Very slow transit across blood brain barrier.
• Not a substrate for p-glycoprotein, but appears
  to be a substrate for probenecid inhibited
  transporters (Anesthesiology 2004101 1394)
• Recently a peptide based carrier demonstrated 4
  fold increase in uptake and potency (JPET 200512
  epub).
• Some data show higher affinity for ?1, and lower
  affinity for ?2, compared to morphine.
• Some suggestion that M6G is associated with less
  ventilatory depression for the amount of
  analgesia
• (e.g., Romberg et al, Anesthesiology 2004
  100120)

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?1 selective agonists?

• Despite evidence now 25 years old of differential
  response to angatonists, nobody has found a ?1
  selective agonist
• Biggest argument against it Paul Janssen spent
  years looking for one, screening over 70,000
  possible ligands
• Reason for hope perhaps our improved knowledge
  of MOR-1 splice variants will help identify the
  required pharmacofore
• Dont hold your breath

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Next best thinggive opioids, manage side effects

• Treat constipation, ileus with peripheral
  antagonists
• Treat ventilatory depression with 5HT4 agonists

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Peripheral ? antagonistADL 8-2698, alvimopan

• Restricted to the gut
• very little systemic absorption
• unable to cross blood-brain barrier

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Peripheral ? antagonistADL 8-2698, alvimopan
Liu et al, CPT 2001, 6966
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Peripheral ? antagonistADL 8-2698, alvimopan
Liu et al, CPT 2001, 6966
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Methylnaltrexone

• Invented by Leon Goldberg, University of Chicago
• Effective for a variety of opioid side effects
  including
• Opioid induced constipation
• Pruritis
• Post-operative ileus
• Being developed for IV/SQ/Oral
• Progenics
• Phase III trials

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5HT4 agonists

• Cisapride, prucalopride, renzapride, tegaserod,
  SB207710, TC-2749
• Primary development target is as a prokinetic
  agent
• Interesting that 5HT4 agonists reverse two opioid
  side effects ileus and hypoventilation
• TD-2759 (Theravance) is a once daily drug in
  development
• Theravance 2005 investor presentation

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5HT4(a)

• Abundantly expressed in Pre-Boetzinger Complex
• Controls ventilation
• Stimulate adenylyl cyclase
• BIMU8 is a specific agonist of 5HT4(a)
• Novartis endo-N-(8-methyl-8-azabicyclo
  3.2.1oct-3-yl)-2,3-dihydro-(1-methyl)
  ethyl-2-oxo-1H-benzimidazole-1-carboxamide
• Co-locate in PBC with opioid receptors

Manze et al, Science 2003 301226
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5HT4(a)
Manze et al, Science 2003 301226
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BIMU8 reverse fentanyl ventilatory depression
Manzke et al, Science 2003 301226
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Unfortunately

• Based on the Manzke work, the 5HT4 nonspecific
  agonists have been tried for efficacy in
  reversing opioid induced ventilatory depression.
• They dont work.
• Need to await development of 5HT4(a) specific
  agonists.

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Peripheral ? agonists

• High affinity for peripheral ? receptors
• Poor lipophilicity to reduce transfer to CNS
• Potent antinociceptive effects in rat formalin
  injection and acetic writhing test
• In development at Adolor

Kumar et al, Bioorganic and Medicinal Chemistry
Letters 2005151279 Kumar et al, Bioorganic and
Medicinal Chemistry Letters 2005151091 Adolor
Corporation
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Other centrally actinganalgesic drugs
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Cannabinoids

• Dronabinol has modest efficacy as an analgesic in
  multiple sclerosis (Svendsen et al, BMJ
  200431329)
• THC has minimal analgesic activity
• Ajulemic acid, novel cannabinoid with no
  psychotropic effects
• Shown effective in human trial of chronic
  neuropathic pain
• Karst et al, JAMA 2003 2901757
• Mechanism of action appears to be
  anti-inflammation

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Viral cDNA delivery

• Recombinant herpes simplex I vector applied to
  skin
• Permits delivery to dorsal root ganglion via
  application to skin
• Add cDNA for human preproenkephalin
• Get profound antihyperalgesic response
• Can be reversed by i.t. naloxone

Wilson et al, PNAS 1999 963211
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Peripheral targets of analgesic action
Julius, Basbaum, Nature 2001, 13413
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TRPV1

• Transient Receptor Potential V1 (aka VR1)
• Mostly located on C fibers in the periphery
• Sensitive to capsaicin, acid, heat, some lipids
• Opening channel causes influx of calcium

http//www.neurogesx.com/NcPnTRPV1.html
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TRPV1 agonists (capsaicin)

• How capsaicin works
• TRPV1 kept open ??
• Ca entry ?
• Prolonged cell dysfunction ?
• Prolonged analgesia

Malmberg et al, Pain 2004 111360
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Resiniferatoxin

• Resiniferatoxin is a potent TRPV1 agonist
• Diterpene ester from Euphorbia resinifera, a
  cactus
• Causes desensitization without excitation
• Administration induces cytotoxicity by opening up
  calcium channel.
• In high doses selectively ablates TRPV1 nerves
• Currently in clinical trials for overactive
  bladder

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Resiniferatoxin

• Injected perineurally, adjacent to the sciatic
  and saphenous nerves
• Followed by a plantar incision.
• Completely abolished incisional hyperalgesia with
  a concentration dependent duration

Kissin et al, Anesth Analg 2005 100774
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TRPV1 neuroablation

• Resiniferatoxin is a potent TRPV1 agonist
• Administration induces cytotoxicity by opening up
  calcium channel.
• Selectively ablates TRPV1 nerves
• In rats and dogs, inflammatory hyperalgesia is
  blocked
• Touch, proprioception, mechanosensitive, and
  locomotor function remain intact
• Probably requires general anesthesia!

Karai et al, J Clin Invest 2004 1131344
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TRPV1 neuroablation

• Resiniferatoxin trigeminal injection
• Skin burned with ascorbic acid, Evans blue
  injected intravenously
• Eye-wipe in response to capsaicin tested over 1
  year

Karai et al, J Clin Invest 2004 1131344
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TRPV1 neuroablation

• Dogs brought in by owners with poorly controlled
  cancer or arthritis pain.
• Resiniferatoxin injected intrathecally under
  general anesthesia
• Owners graded pet response.

Karai et al, J Clin Invest 2004 1131344
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TRPV1 agonist/antagonist pipeline

• Olvanil is an agonist, developed as an oral
  analgesic
• Phenylacetylrinvanil is an agonist with picomolar
  potency
• Addition of iodine to the phenyl ring creates
  TRPV1 antagonists

Appendino et al, J PET 2005 312561
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Aminoglycoside analgesia?

• Neomycin is a potent antagonist of TRPV1
• Neomycin blocks NMDA receptors
• Neomycin blocks phospholipase C

Raisinghani et al, Pain 2005, 113123
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Conotoxins

• Derived from Conus, a predatory snail
• Highly potent peptides, about 2000 known so far
• ?-conotoxin nicotinic antagonists
• Some are neuromuscular blockers
• Some are central nicotinic antigonists with
  activity in neuropathic pain in animal models
• ?-conotoxin calcium channel antagonists
• Ziconitide (Prialt) approved for IT use in
  chronic or neuropathic pain
• Several others in development
• Contulakin-G Neurotensin agonist
• Phase II trials, IT delivery for acute pain

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Conclusion

• Very promising future for new hypnotics, muscle
  relaxants, and analgesics.
• ALL OF THESE WILL CHANGE YOUR PRACTICE
• Sugammadex will revolutionize the use of muscle
  relaxants
• The new hypnotics will be an important
  incremental change
• Advances in analgesics will contribute to
  significant reductions in patient morbidity and
  mortality after surgery