Some science behind the scenes

Opioid analgesics other drugs

Other drugs without any record on the eHealthme site of hallucinations are as follows

 Dynorphin

Dynorphin – is actually an endogenous compound, but it has also been synthesised pharmaceutically.  I found no hallucination figures for this compound.  A large number of subtypes exists, for example

  • Dynorphin 1-11; Dynorphin 1-8; Dynorphin 1-17; and dynorphin b al of which are agonists at the kappa, delta and mu receptors. 
  • Dynorphin 1-17-NH2, [Met5]-dynorphin 1-17, [D-Ala2,F5,Phe4]-dynorphin 1-17-NH2, [D-Ala2,F5,Phe4]-dynorphin 1-13-NH2  are all agonists at the kappa receptor

[Source:  Toll, L., Berzetei-Gurske, I. P., Polgar, W. E., Brandt, S. R., Adapa, I. D., Rodriguez, L., Schwartz, R. W., Haggart, D., O'Brien, A., White, A., Kennedy, J. M., Craymer, K., Farrington, L. and Auh, J. S.   (1998)

Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications.
PMID: 9686407]

The Thiambutenes

The Thiambutenes are a series of open-chain opioids also called the thienyl derivative opioids.  The parent compound thiambutene has no analgesic effects, but several compounds from this group are analgesics with around the same potency as morphine.  Diethylthiambutene and Dimethylthiambutene are under international control under Schedule I of the UN Single Convention On Narcotic Drugs 1961, the laws governing habit-forming substances in virtually all countries.  They include 

  • Diethylthiambutene (Thiambutene, Themalon, Diethibutin, N,N-Diethyl-1-methyl-3,3-di-2-thienylallylamine) is mainly used as an anesthetic in veterinary medicine.
  • Dimethylthiambutene (N,N-Dimethyl-1-methyl-3,3-di-2-thienylallylamine, Ohton, Aminobutene, Dimethibutin, Kobaton, Takaton, Dimethibutin) is most often used in veterinary medicine in Japan It is also  Schedule I of the US Controlled Substances Act of 1970 due to high abuse potential and never being introduced clinically in the United States; other countries regulate it much as morphine or diamorphine.
  • Ethylmethylthiambutene (N-ethyl-N-methyl-1-methyl-3,3-di-2-thienylallylamine, Emethibutin) has around 1.3x the potency of morphine
  • Pyrrolidinylthiambutene is an analgesic with around 3/4 of the potency of morphine.   It would be considered an illegal controlled substance analogue in some countries such as the USA, Australia and New Zealand, but is legal in countries not possessing a controlled-substances-analog-act equivalent
  • Tipepidine (Bithiodine, Sotal, Antupex, Asverin) is a centrally-acting cough suppressant of the opioid type. It was developed in Japan in 1959. Its relative weakness and other properties make it a drug which is not controlled in most countries or internationally
Other Drugs of the opioid agonist/antagonist type

 A number of drugs act as  partial opioid receptor agonist/antagonists.  A small number are mu agonists and kappa antagonists 

  • AD-1211, is a mixed agonist-antagonist at opioid receptors with a similar pharmacological profile to pentazocine 
  • Butorphanol (Stadol) is was recently discontinued in the USA by the manufacturer. It was a  ? opioid receptor antagonist and a ? opioid receptor agonist.  Because of its ?-agonist activity, at analgesic doses butorphanol increased pulmonary arterial pressure and cardiac work. Additionally, ?-agonism can cause dysphoria at therapeutic or supertherapeutic doses; this gives butorphanol a lower potential for abuse than other opioid drugs.  It was used to treat migraine, as a supplement for balanced general anesthesia, and management of pain during labor! [yes you are reading this right] . In veterinary use, it was used as a  sedative and analgesic in dogs, cats and horses.  Side effects included  sedation, confusion, and dizziness.  Nausea and vomiting were common. Less common were the gastrointestinal effects of other opioids (mostly constipation).  In horse side effects include seizures, falling, salivation, constipation, and muscle twitching. Butorphanol can cross the placenta, and “it will be present in the milk of lactating mares who are given the drug” [and presumably the milk of lactating mothers who are given it in labor!].  It is still available in some countries  under the trade names Moradol, Beforal Butorphic, Dolorex, Morphasol, Torbugesic, and Torbutrol
  • Ciramadol (WY-15,705) is an opioid analgesic that was developed in the late 1970s It is an agonist for the ?-opioid receptor, but also has [unspecified] antagonistic action.   It has a slightly higher potency and effectiveness as an analgesic than codeine, but is weaker than morphine
  • Cyclorphan is mixed agonist-antagonist related to levorphanol discovered in the late 1960s. It is not marketed as an analgesic because of side effects related to its impact on the kappa opioid receptor, but has found some use as a research chemical on and off since its discovery
  • Cyprenorphine (M-285) is related to buprenorphine, which is used as an analgesic and diprenorphine [see below].  It is a kappa agonist but an antagonist at other sites [unspecified], “like those of buprenorphine”. It produces pronounced dysphoria and hallucinations. 
  • Diprenorphine (diprenorfin, Revivon, M5050) is a kappa antagonist, a delta agonist and a mu antagonist used to reverse the effects of the super-potent opioid analgesics such as etorphine and carfentanil that are used for tranquilizing large animals in veterinary medicine. 
  • Meptazinol (trade name Meptid) is most commonly used to treat pain in obstetrics (childbirth). A partial µ-opioid receptor agonist, its mixed agonist/antagonist activity is intended to give it a lower risk of dependence and abuse than full µ agonists like morphine. 
  • Picenadol (LY-150720) was never commercialised.  One enantiomer is a pure ?-opioid agonist, while the other is an antagonist. This means that the racemic mix of the two enantiomers is a “mixed agonist-antagonist, with relatively low abuse potential, and little of the ?-opioid activity that tends to cause problems with other opioid mixed agonist-antagonists such as pentazocine”.  They think 
  • Profadol was developed in the late 1960s. It acts as a mixed agonist-antagonist of the ?-opioid receptor 
  • Propiram (Algeril, Dirame, Bay 4503) is from the ampromide family of drugs. Propiram exhibits weak opioid antagonist activity on the mu receptor -- quite a bit weaker than its agonist effects . It has  about 10 per cent of the analgesic potency of morphine.  It is currently a Schedule I/Narcotic controlled substance in the United States. 
  • Phenampromide is from the ampromide family of drugs, related to other drugs such as propiram and diampromide. It was invented in the 1960s 
  • Viminol (marketed under the brandname Dividol) is  both an antitussive (cough suppressing) and analgesic. It has six different stereoisomers which have varying properties, with the 2-(R) isomer being a ?-opioid full agonist slightly more potent than morphine, while the 2-(S) isomer is an antagonist. Since vimonol is supplied as a racemic mixture of isomers, the overall effect produces a mixed agonist-antagonist profile 
  • Xorphanol (TR-5379) is an analgesic that has never been marketed commercially, although it is still used in scientific research.  It is a mixed agonist-antagonist at the ?-opioid receptor.  It had the normal side effects, but also produced convulsions at higher doses.
Miscellaneous Analgesics

 Analgesics may bind to the delta opioid receptor but not the mu opioid receptor or vice versa.  Some are also antagonists or bind to the kappa receptor.   The binding sites of each drug are not always known, but the effects are , indicating their affinities. 

  • AH-7921 is an opioid analgesic drug selective for the mu opioid receptor, and having around the same potency as morphine. 
  • Alvimopan (trade name Entereg) is a peripherally acting ?-opioid agonist that acts to counter pain in the gastrointestinal tract. 
  • BDPC - 4-(4-Bromophenyl)-4-(dimethylamino)-1-(2-phenylethyl)cyclohexanol ( Bromadol) is a potent narcotic analgesic 10,000 times the strength of morphine.  It has never been used on human beings 
  • Bezitramide is marketed under the trade name Burgodin.  The drug was removed from sale  in the Netherlands in 2004 after fatal overdose cases.  It is regulated much the same as morphine but is a Schedule II narcotic under the United States' Controlled Substances Act of 1970. 
  • Biphalin is a dimeric enkephalin peptide analog that has equal affinity for ? and ? opioid receptors, and has analgesic activity. When administered intracerebroventricularly, it was 257 times more potent than morphine. It has poor brain penetration, - only about 0.05% of labeled biphalin is found in the CNS when administered by injection, as such ‘ Biphalin produces little physical dependence’, but it can produce similar physical depedence to morphine when given intracerebroventricularly. 
  • Bremazocine is both a delta and  ?-opioid receptor agonist, but a mu opiod antagonist. 
  • Bromadoline is selective for the mu-opioid receptor 
  • C-8813 is a potent ?-opioid agonist with a distinctive chemical structure which is not closely related to other established families of opioid drugs. The trans isomer was found to be around 591x more potent than morphine in animal studies.  C-8813 is claimed to be similarly potent at the ?-opioid receptor, which antagonizes the mu depression of breathing, presumably making the drug safer. C-8813 has never been used in humans. 
  • Clonitazene has approximately three times the potency of morphine 
  • DADLE ([D-Ala2, D-Leu5]-Enkephalin) is a synthetic opioid peptide with analgesic properties. Although it is often considered a selective delta opioid receptor agonist, it also binds to the ?1 subtype of mu opioid receptors.  Treatment with DADLE results in transient depression of mean arterial blood pressure and heart rate 
  • DBOs and Azaprocin are analgesics with approximately 10x plus the potency of morphine, and a fast onset and short duration of action. Azaprocin was discovered in 1963, but has never been marketed.  A large family of opioid analgesic compounds derived from this parent structure have been developed over the last 40 years known as DBOs [diazabicyclo octane] all of them wilh mu opiod receptor affinity, but some also with delta affinity.  DBO (1d) for example  “displayed a mu/delta selectivity and an analgesic activity respectively 25 and 17 fold those of morphine”.  Although a family, the receptors affinities are different some even showing antagonistic action, so one would have to be careful in the selection here.  Compound 1j isomer of 1a which is provided with high mu affinity, but lower analgesic potency, was found to possess a mixed agonist-antagonist activity. [Interaction of 3,8-diazabicyclo (3.2.1) octanes with mu and delta opioid receptors - Cignarella G  et al; Institute of Pharmaceutical Chemistry and Toxicology, Milano, Italy PMID: 2843931] 
  • Dextromoramide (Palfium, Palphium, Jetrium, Dimorlin) is three times more potent than morphine but shorter acting. It is subject to drug prohibition regimes, both internationally through UN treaties, and by the criminal law of individual states. It is now mainly used in terminal care.  It has a particularly strong tendency to induce respiratory depression, especially in patients who have low opioid tolerance, and so can be dangerous when used outside of a hospital setting. Dextromoramide was much favoured by drug abusers in Australia in the 1970s.  The main advantage of the drug was that it had a fast onset of action when taken orally, and that oral dosing produced almost as much effect as injection. It has a high potential for development of dependence and addiction. 
  • Dihydroetorphine is a potent analgesic which is used mainly in China. It is a derivative of etorphine.  Dihydroetorphine however is used in China mainly as a strong painkiller for humans. It is several thousand times stronger than morphine (between 1000x and 12000x more potent depending what method is used for comparison), although it is poorly absorbed when taken orally. Sublingual forms of dihydroetorphine are used in China at doses ranging from 20 to 180µg.  Dihydroetorphine is sometimes used in China as a substitute maintenance drug for opioid addicts, in a similar way to how the related drug buprenorphine is used in western nations 
  • Dipipanone is an extremely strong opioid used for very severe pain in cases where morphine is indicated but cannot be used due to the patient being allergic to morphine . The main preparation of the drug commercially available is mixed with cyclizine. It is now unavailable in most countries of the world either by laws prohibiting its medicinal use, as in the United States, or by being replaced by ‘more modern analgesics’.  Its use is discouraged because of the abuse risk. The combination with cyclizine leads to a very strong rush if the drug is injected, however the tablets contain insoluble binders which led to many limb amputations and some fatalities. During the late 1970s to early 1980s in the UK, many deaths were blamed on misuse of this preparation. 
  • Doxpicomine (Doxpicodin, Doxpizodine) is a mu-opioid receptor agonist  of fairly low potency, with a 400 mg dose of doxpicomine approximately equivalent in pain-killing effect to 8 mg morphine 
  • DPI-3290 is a drug that is used in scientific research. It is a potent analgesic drug,  which produces little respiratory depression.  DPI-3290 acts as an agonist at both ?- and ?-opioid receptors, with an IC50 of 6.2nM at ? and 1.0nM at ? [Ananthan S. Opioid ligands with mixed mu/delta opioid receptor interactions: an emerging approach to novel analgesics. AAPS Journal. 2006 Mar PMID 16584118] 
  • Droxypropine is a cough suppressant 
  • Eseroline is a metabolite of the acetylcholinesterase inhibitor physostigmine but unlike physostigmine, the acetylcholinesterase inhibition produced by eseroline is weak, it produces fairly potent analgesic effects mediated through the ?-opioid receptor. This mixture of activities “gives eseroline an unusual pharmacological profile”  although its uses are limited by side effects such as respiratory depression and neurotoxicity 
  • HZ-2 is a drug which acts as a highly selective ?-opioid agonist.   It is a potent analgesic with around the same potency as morphine, with a long duration of action and high oral bioavailability. Side effects include sedation, nausea and dysphoria as well as diuretic effects 
  • Levomethorphan is the l-stereoisomer of methorphan. It has effects similar to levorphanol but is less potent 
  • Levomoramide is ‘virtually without activity’.  However, despite being ‘inactive’, levomoramide is controlled internationally as a Schedule I drug. 
  • Levophenacylmorphan is  around 10x more potent than morphine. 
  • Levopropoxyphene is an antitussive formerly marketed in the U.S. under the tradename Novrad 
  • Levorphanol (Levo-Dromoran) is used to treat severe pain. Levorphanol has affinity to ?, ?, and ? opioid receptors.  It also has NMDA actions and action at the  sigma receptor, as well as SNRI properties. It has the same properties as morphine with respect to the potential for habituation, tolerance, physical dependence and withdrawal syndrome. It is 4 to 8 times as potent as morphine.   The duration of action varies from 4 hours to as much as 15 hours. 
  • Methopholine tablets were marketed in the United States under the brand name of Versidyne, but the drug was withdrawn from the market in 1965 due to the occurance of ophthalamic side-effects and the discovery that it could produce corneal opacities in dogs. 
  • Nalbuphine is a semi-synthetic opioid used commercially as an analgesic under a variety of trade names, including Nubain. It is a kappa full agonist.  Nalbuphine is used for the relief of “moderate to severe pain”. It is also used as a supplement to balanced anesthesia, for preoperative and postoperative analgesia, and “for obstetrical analgesia during labor and delivery” [sic].  You get all the normal effects of a kappa agonist [see main section] , which are in themselves fairly extensive but “Pseudo-sinusoidal fetal heart rhythm” has also been observed.  The incidence of psychotomimetic effects, such as unreality, depersonalization, delusions, dysphoria and hallucinations has been “shown to be less than that which occurs with pentazocine” [sic] .
  • Norlevorphanol is an opioid analgesic of the morphinan class. It was never marketed
  • Normethadone is a cough suppressant 
  • N-Phenethyl-14-ethoxymetopon is a drug which is a derivative of metopon. It is a potent analgesic, around 60 times stronger than morphine and produces significantly less constipation.  It acts as an agonist at both ?- and ?-opioid receptors, with a Ki of 0.16nM at ? and 3.14nM at ? 
  • Phenadoxone (Heptalgin, Morphidone, Heptazone) was used in the United States after the end of the Second World War but has now been withdrawn from the market and is listed as a Schedule I of the United States' Controlled Substance.  It has a duration of 1 to 4 hours. By comparison, methadone lasts from 3 to 6 hours “although for use in opioid maintenance the dose is different from that used for analgesia and can last for 24 to 72 hours”.  Like its drug subcategory prototype methadone, phenadoxone can be used as the opioid analgesic in Brompton Mixture, aka Brompton cocktail. Phenadoxone is most used at the current time in Denmark and various countries in eastern Europe. 
  • Phenomorphan is not used in medicine, but is a highly potent drug with affinity to the ?-opioid receptor.  It is around 10x more potent than levorphanol 
  • Piritramide (trade names Dipidolor, Piridolan, Pirium and others) has a potency 0.65 to 0.75 times that of morphine. It is used for the treatment of postoperative pain. It is one of the longer-lasting opioids and has a plasma half-life of 3 to 12 hours. It “ tends to cause less respiratory depression than morphine and can take a while to have full effect especially if taken by mouth”.  It is a Schedule I/Narcotic controlled substance in the USA.  Piritramide has “a small but dedicated community of recreational users and it has the street names P, Dip (rhymes with "pipe") and Pierrette”
  • RWJ-394674 is a drug which is used in scientific research. It is a potent, orally active analgesic drug, which produces little respiratory depression. RWJ-394674 itself is a potent and selective agonist for ?-opioid receptors, with a Ki of 0.24 nM at ? and 72 nM at ?. However once inside the body, RWJ-394674 is dealkylated to its metabolite RWJ-413216 which is a potent agonist at the ?-opioid receptor. The effect of RWJ-394674 when administered in vivo thus produces potent agonist effects at both ? and ? receptors through the combined actions of the parent drug and its active metabolite, with the ?-agonist effects counteracting the respiratory depression from the ?-opioid effects, and the only prominent side effect being sedation  [Source Codd EE, et al. The novel, orally active, delta opioid RWJ-394674 is biotransformed to the potent mu opioid RWJ-413216. Journal of Pharmacology and Experimental Therapeutic. 2006 Sep; PMID 16766719 ] 
  • Spiradoline (U-62066) is a highly selective ?-opioid agonist.  It has analgesic, diuretic and antitussive effects.  The main effect in humans is sedation, but significant side effects such as dysphoria and hallucinations have stopped it from being used clinically. 
Miscellaneous Analgesic immobilisers [animals] 
  • 7-PET is a potent analgesic drug, 300 times the potency of morphine by weight. It is related to the more well-known oripavine derivative opioid etorphine 
  • Acetorphine is, up to 8700 times stronger than morphine by weight  It is a derivative of etorphine.  Acetorphine was developed for the same purpose as etorphine itself, namely as a strong tranquillizer for use in immobilizing large animals in veterinary medicine, but was never widely adopted for veterinary use.  Acetorphine is a Schedule I controlled substance in the United States 
  • Etorphine (Immobilon or M99) is has an analgesic potency approximately 1,000-3,000 times that of morphine.  Etorphine is often used to immobilize elephants and other large mammals and is available legally only for veterinary use. Veterinary-strength etorphine is fatal to humans. Etorphine is an agonist at  ?  ? and ? opioid receptors. It also has a weak affinity for the ORL1 nociceptin/ orphanin FQ receptor.
Research drugs
  •  7-Spiroindanyloxymorphone (SIOM) is a drug which is used in scientific research. It is a selective ?-opioid agonist
  • ADL 5859 – is a potent, orally bioavailable delta opioid receptor agonist intended for the treatment of pain
  • Alazocine ((-)-SKF-10,047), or (-)-N-allylnormetazocine ((-)-ANMC), was the first drug discovered to act as a ?1 receptor agonist It has no significant affinity for the ?2 receptor.  It is also  a ?-opioid receptor agonist and to a much lesser extent, an NMDA receptor antagonist
  • Asimadoline (EMD-61753) is a drug which acts as a peripherally selective ?-opioid agonist.  Because of its poor ability to cross the blood-brain barrier, it “has more potential for medical use, and has been researched as a possible treatment for irritable bowel syndrome”
  • BRL-52537 acts as a potent and highly selective ?-opioid agonist It is used for “research into potential treatments for stroke and heart attack as well as more general brain research”
  • BU-48 is a drug which is used in scientific research. BU-48 has only weak analgesic effects , it is believed to act  primarily as a ?-opioid agonist, although this was not confirmed on the IUPHAR database. Its main effects are to produce convulsions
  • BW373U86 is an analgesic drug used in scientific research. It is a selective agonist for the ?-opioid receptor, with approximately 15x stronger affinity for the ?-opioid than the ?-opioid receptor usefulness is limited by producing convulsions at high doses, although the convulsive effect is reduced when it is co-administered with ?-opioid agonists. Another advantage of the combination is that BW373U86 reverses the respiratory depression produced by ?-opioid agonists, without affecting pain relief.  .
  • DAMGO ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin) has high ?-opioid agonist capability, but also kappa opioid agonist action.  It has been used “in experimental settings for the possibility of alleviating or reducing opiate tolerance for patients under the treatment of an opioid”.
  • Dextrallorphan (DXA) is used in scientific research. It acts as a ?1 receptor agonist, ?-opioid receptor agonist, and NMDA receptor antagonist. It has no significant affinity for the ?2, ?-opioid, or ?-opioid receptor, or for the serotonin or norepinephrine transporter
  • DPDPE -  a selective delta opioid receptor agonist used for research
  • DPI-221 is a drug which is used in scientific research. It is a highly selective agonist for the ?-opioid receptor which produces less convulsions than most drugs from this family
  • DPI-287 - is a drug which is used in scientific research. It is a highly selective agonist for the ?-opioid receptor which produces less convulsions than most drugs from this family
  • E2078 – is a kappa full agonist used in research [PMID: 9918595]
  • Enadoline is a drug which acts as a highly selective ?-opioid agonist.  In human studies, it produced visual distortions and feelings of dissociation, reminiscent of the effects of Salvinorin A.  It was looked at as a potential analgesic, but abandoned because of the dose-limiting effects of dysphoria, which could be expected from a ?-opioid agonist.
  • Etonitazene is a highly potent analgesic drug, approximately 1000–1500x the potency of morphine. It is a delta, kappa and mu agonist.  It  is structurally related to clonitazene.   It has a strong dependency potential similar to that of morphine, and a strong tendency to produce respiratory depression, and is “therefore not used in humans. It is however useful in addiction studies on animals” [sic].
  • GR-89696 is a drug which acts as a highly selective ?-opioid agonist It shows selective effects in different animal models and it is thought it may be a subtype-selective agonist for the ?2 subtype
  • ICI-204,448 acts as a potent and peripherally selective ?-opioid agonist, It has anti-itching effects. It is used in research to distinguish centrally from peripherally mediated kappa opioid receptor effects
  • ICI-199,441 is a drug which acts as a potent and selective ?-opioid agonist, and has analgesic effects
  • J-113,397 is a highly selective antagonist for the nociceptin receptor.  It is ‘several hundred times selective for the ORL-1 receptor over other opioid receptors’
  • JTC-801 is a selective antagonist for the nociceptin receptor
  • Ketazocine also known as ketocyclazocine,is a research drug that is an agonist of the  kappa opioid receptor.
  • LPK-26 is a drug which acts as a potent and selective ?-opioid agonist
  • MT-45 (IC-6) has around the same potency as morphine, with almost all analgesic activity residing in the (S) enantiomer.  It has been used as a lead compound from which a large family of potent opioid drugs have been developed, including full agonists, partial agonists and antagonists at the three main opioid receptor subtypes
  • Naloxone benzoylhydrazoneis a kappa agonist but a mu antagonist
  • PL017 – a full mu opiod agonist
  • Ro4-1539 (Furethylnorlevorphanol) is a potent ?-opioid agonist, around 30-60x more potent than the related drug levorphanol in animal experiments. Ro4-1539 had no particular clinical advantages over other available opioid drugs, and was never commercially marketed.
  • ·          SB-612,111 is a selective antagonist for the nociceptin receptor (ORL-1), several times more potent than the older drug J-113,397.
  • ·          SC-17599 is a steroid derivative drug discovered in 1968 which acts as a selective ?-opioid receptor agonist, with little or no affinity for the ?-opioid or ?-opioid receptors. It is slightly less potent than morphine and produces similar effects to morphine in animals but with less sedation
  • SNC-80 is a drug used in scientific research, invented in 1994. It is a highly selective agonist for the ?-opioid receptor.  It produces convulsions at high doses.
  • TAN-67 (SB-205,607) is a drug which is used in scientific research, which is a potent and selective ?-opioid agonist
  • Tifluadom is a selective agonist for the ?-opioid receptor used in research.
  • TRIMU 5 is a selective agonist of the mu opioid receptor
  • U-69,593 acts as a potent and selective ?1-opioid receptor agonist
  • U-50488 is a drug which acts as a highly selective ?-opioid agonist, but without any ?-opioid antagonist effects. It has analgesic, diuretic and antitussive effects, and reverses the memory impairment produced by anticholinergic drugs. U-50488 was one of the first selective kappa agonists invented
  • W-18 - 1-(4-Nitrophenylethyl)piperidylidene-2-(4-chlorophenyl)sulfonamide is a potent ?-opioid agonist with a distinctive chemical structure around 10,000x more potent than morphine in animal studies.  It has never been used in humans

 

Observations

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