NoscapineFrom Wikipedia, the free encyclopedia

Noscapine

Systematic (IUPAC) name

(3S)- 6,7-Dimethoxy-3-[(5R)-5,6,7,8-tetrahydro- 4-methoxy- 6-methyl- 1,3-dioxolo (4,5-g)isoquinolin-5-yl]- 1(3H)-isobenzofuranone

Clinical data

AHFS/Drugs.comInternational Drug Names

Pregnancy cat.Contraindicated

Legal statusrx only

Pharmacokinetic data

Bioavailability~30%

Half-life1.5 to 4h (mean 2.5)

Identifiers

CAS number128-62-1Y

ATC codeR05DA07

PubChemCID 275196

ChemSpider242139Y

UNII8V32U4AOQUY

KEGGD01036Y

ChEBICHEBI:73237N

ChEMBLCHEMBL364713Y

SynonymsNarcotine

Chemical data

FormulaC22H23NO7

Mol. mass413.421

N

Noscapine (also known as Narcotine, Nectodon, Nospen, Anarcotine and (archaic) Opiane) is a benzylisoquinoline alkaloid from plants of the Papaveraceae family, without painkilling properties. This agent is primarily used for its antitussive (cough-suppressing) effects.Contents 1 History 2 Structure analysis 3 Mechanism of action 4 Dosage 5 Cancer and stroke treatment 6 Abuse 7 Noscapine in heroin 8 Possible side effects 9 Interactions 10 See also 11 ReferencesHistoryNoscapine was first isolated and characterized in chemical breakdown and properties in 1817 under the denomination of "Narcotine" by Pierre Robiquet, a French chemist in Paris. Robiquet conducted over 20 years between 1815 and 1835 a series of studies in the enhancement of methods for the isolation of morphine, and also isolated in 1832 another very important component of raw opium, that he called codeine, today's probably most widely used opium-originating component.Structure analysisThe lactone ring is unstable and opens in basic media. The opposite reaction is presented in acidic media. The bond C1-C3' is also unstable. This is the bond connecting the two optically active carbon atoms. In aqueous solution of sulfuric acid and heating it dissociates into cotarnine (4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline) and opic acid (6-formyl-2,3-dimethoxybenzoic acid). When noscapine is reduced with zinc/HCl, the bond C1-C3' saturates and the molecule dissociates into hydrocotarnine (2-hydroxycotarnine) and meconine (6,7-dimethoxyisobenzofuran-1(3H)-one).Mechanism of actionNoscapine's antitussive effects appear to be primarily mediated by its sigma receptor agonist activity. Evidence for this mechanism is suggested by experimental evidence in rats. Pretreatment with rimcazole, a sigma specific antagonist, causes a dose-dependent reduction in antitussive activity of noscapine.

DosageThe recommended dose for over-the-counter cough treatment varies from country to country; for example, in The Netherlands, 1530 mg per 8 hours is recommended for adults, whereas in Sweden it is 50 mg per 8 hours. Cancer and stroke treatmentNoscapine is currently under investigation for use in the treatment of several cancers and hypoxic ischemia in stroke patients. In cancer treatment, noscapine appears to interfere with microtubule function, and thus the division of cancer cells in a way similar to the taxanes. Early animal studies in treatment of prostate cancer are promising. Typical doses in cancer treatment are about 100-fold those in cough treatment. In stroke patients, noscapine blocks the bradykinine b-2 receptors. A 2003 study in Iran showed a dramatic decrease in mortality in ten acute ischemic stroke patients treated with noscapine. Noscapine is non-addictive, widely available, has a low side-effect incidence, and is easily administered orally, thus it has been used as an off-label therapy for some cancers. Conceptual studies find great promise for noscapine as a treatment in drug-resistant glioblastoma multiforme. Other medical researchers have evaluated novel noscapine derivatives as active tubulin-binding antineoplastic agents. AbuseThere are anecdotal reports of over-the-counter drug abuse in several countries, being readily available from local pharmacies without a prescription. The effects, beginning around 45 to 120 mins after consumption, are similar to dextromethorphan and alcohol intoxication. Unlike dextromethorphan, noscapine is not an NMDA receptor antagonist. Noscapine in heroinNoscapine can survive the manufacturing processes of heroin and can be found in street heroin. This is useful for law enforcement agencies, as the amounts of contaminants can identify the source of seized drugs. In 2005 in Lige, Belgium, the average noscapine concentration was around 8%.Noscapine has also been used to identify drug users who are taking street heroin at the same time as prescribed diamorphine. Since the diamorphine in street heroin is the same as the pharmaceutical diamorphine, examination of the contaminants is the only way to test whether street heroin has been used. Other contaminants used in urine samples alongside noscapine include papaverine and acetylcodeine. Noscapine is metabolised by the body, and is itself rarely found in urine, instead being present as the primary metabolites, cotarnine and meconine. Detection is performed by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry (LCMS) but can also use a variety of other analytical techniques.Possible side effects Loss of coordination Hallucinations (auditory and visual) Loss of sexual drive Swelling of prostate Loss of appetite Dilated pupils Increased heart rate Shaking and muscle spasms Chest pains Increased alertness Loss of any sleepiness Loss of stereoscopic visionThe effects shown above are not permanent.InteractionsNoscapine can increase the effects of centrally sedating substances such as alcohol and hypnotics.The drug should not be taken with any MAOIs (monoamine oxidase inhibitors), as unknown and potentially fatal effects may occur.Noscapine should not be taken in conjunction with warfarin as the anticoagulant effects of warfarin may be increased. See also Narceine, a lesser known but related opium alkaloid. Norco (medication), a commonly prescribed opiate painkiller

LevopropoxypheneFrom Wikipedia, the free encyclopedia

Levopropoxyphene

IUPAC name[hide](1R,2S)-1-benzyl-3-(dimethylamino)-2-methyl-1-phenylpropyl propionate

Other names[hide][(2R,3S)-4-dimethylamino-3-methyl-1,2-diphenyl-butan-2-yl]propanoate

Identifiers

CAS number2338-37-6N

PubChem200742

ChemSpider21234163N

ChEMBLCHEMBL1213351N

Jmol-3D imagesImage 1

O=C(O[C@](c1ccccc1)(Cc2ccccc2)[C@@H](C)CN(C)C)CC

InChI=1S/C22H29NO2/c1-5-21(24)25-22(18(2)17-23(3)4,20-14-10-7-11-15-20)16-19-12-8-6-9-13-19/h6-15,18H,5,16-17H2,1-4H3NKey: XLMALTXPSGQGBX-UHFFFAOYSA-NN

InChI=1/C22H29NO2/c1-5-21(24)25-22(18(2)17-23(3)4,20-14-10-7-11-15-20)16-19-12-8-6-9-13-19/h6-15,18H,5,16-17H2,1-4H3/t18-,22-/m1/s1Key: XLMALTXPSGQGBX-XMSQKQJNBJ

Properties

Molecular formulaC22H29NO2

Molar mass339.47 g mol1

Except where noted otherwise, data are given for materials in their standard state (at 25C (77F), 100kPa)

Levopropoxyphene is an antitussive. It is an optical isomer of dextropropoxyphene. The racemic mixture is called propoxyphene. Only the dextro-isomer (dextropropoxyphene) has an analgesic effect; the levo-isomer appears to exert only an antitussive effect. It was formerly marketed in the U.S. by Eli Lilly under the tradename Novrad as an antitussive.

DextromethorphanFrom Wikipedia, the free encyclopediaNot to be confused with dexamethasone.Dextromethorphan

Systematic (IUPAC) name

(4bS,8aR,9S)-3-methoxy-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene

Clinical data

Trade namesRobitussin, Delsym, DM, DexAlone, Duract

AHFS/Drugs.commonograph

MedlinePlusa682492

Pregnancy cat.A (AU) C (US)

Legal statusPharmacy Only (S2) (AU) OTC (CA) OTC (UK) OTC (US)

DependenceliabilityLow

RoutesOral

Pharmacokinetic data

Bioavailability11%

MetabolismHepatic (liver) enzymes: major CYP2D6, minor CYP3A4, and minor CYP3A5

Half-life3-5 hours

ExcretionRenal

Identifiers

CAS number125-71-3Y

ATC codeR05DA09

PubChemCID 15978238

DrugBankDB00514

ChemSpider13109865Y

UNII7355X3ROTSY

KEGGD03742Y

ChEMBLCHEMBL52440Y

Chemical data

FormulaC18H25NO

Mol. mass271.40 g/mol

SMILES[show] COC1=CC([C@]23[C@@H](CCCC3)[C@@]4([H])N(C)CC2)=C(C4)C=C1

InChI[show] InChI=1S/C18H25NO/c1-19-10-9-18-8-4-3-5-15(18)17(19)11-13-6-7-14(20-2)12-16(13)18/h6-7,12,15,17H,3-5,8-11H2,1-2H3/t15-,17+,18+/m1/s1YKey:MKXZASYAUGDDCJ-NJAFHUGGSA-NY

Physical data

Melt. point111C (232F)

Dextromethorphan (DXM or DM) is an antitussive (cough suppressant) drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, including generic labels and store brands, Benylin DM, Mucinex DM, Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, TheraFlu, and others. Dextromethorphan has also found other uses in medicine, ranging from pain relief to psychological applications. It is sold in syrup, tablet, spray, and lozenge forms. In its pure form, dextromethorphan occurs as a white powder. DXM is also used recreationally. When exceeding label-specified maximum dosages, dextromethorphan acts as a dissociative hallucinogen. Its mechanism of action is via multiple effects, including actions as a nonselective serotonin reuptake inhibitor and a sigma-1 receptor agonist. The major metabolite of DXM, dextrorphan, also acts as an NMDA receptor antagonist. In high doses this produces effects similar to, yet distinct from, the dissociative states created by other dissociative anaesthetic such as ketamine and phencyclidine. As well, the metabolite 3-methoxymorphinan of dextrorphan (thus a second-level metabolite of DXM) produces local anesthetic effects in rats with potency above dextrorphan, but below that of DXM. Contents 1 Medical use 2 Recreational use 3 Adverse effects 3.1 Contraindications 3.2 Drug interactions 3.3 Food interactions 3.4 Lab testing 4 Chemistry 5 Pharmacology 5.1 Pharmacodynamics 5.2 Pharmacokinetics 5.3 Metabolism 6 History 7 See also 8 References 9 External linksMedical useThe primary use of dextromethorphan is as a cough suppressant, for the temporary relief of cough caused by minor throat and bronchial irritation (such as commonly accompanies the flu and common cold), as well as those resulting from inhaled particle irritants.A 2004 study showed that dextromethorphan was no more effective for children than a placebo. Studies conducted by the American Academy of Pediatrics show that dextromethorphan is not superior to a placebo in providing nocturnal symptom relief for children with cough and sleep difficulty due to upper respiratory infections. A combination of dextromethorphan and quinidine, a CYP2D6 inhibitor, has been shown to alleviate symptoms of easy laughing and crying (pseudobulbar affect) in patients with amyotrophic lateral sclerosis and multiple sclerosis. Dextromethorphan is also being investigated as a possible treatment for neuropathic pain and pain associated with fibromyalgia. In 2010, the FDA approved the combination product dextromethorphan/quinidine (Nuedexta) for the treatment of pseudobulbar affect (PBA).Dextromethorphan has been shown to be effective in treating opioid withdrawal. At doses of 2mg/kg in rats all signs of opioid withdrawal were eliminated.

Recreational use

Dextromethorphan gel capsules

Main article: Recreational use of dextromethorphanOver-the-counter preparations containing dextromethorphan have been used in manners inconsistent with their labeling, often as a recreational drug. At doses much higher than medically recommended, dextromethorphan is classified as a dissociative hallucinogen, possessing certain effects that are somewhat similar to the dissociative agents ketamine and phencyclidine. It may produce distortions of the visual field - feelings of dissociation, distorted bodily perception, and excitement, as well as a loss of sense of time. Some users report stimulant-like euphoria, particularly in response to music. Dextromethorphan usually provides its recreational effects in a non-linear fashion, so that they are experienced in significantly varied stages. These stages are commonly referred to as "plateaus".Adverse effectsSide-effects of dextromethorphan use can include: At normal doses: body rash/itching (see below) nausea drowsiness dizziness Closed-eye hallucination Difficulty breathingAt dosages 3 to 10 times the recommended therapeutic dose: Increased energy Increased confidence Slight Nauseousness Restlessness Insomnia "speeding"/talking fast Feelings of increased strength Enlargened pupils/glazed eyes (but not red)At dosages 15 to 75 times the recommended therapeutic dose: hallucinations dissociation vomiting blurred vision and/or double vision bloodshot eyes dilated pupils sweating fever bruxia hypotension hypertension tachycardia shallow respiration diarrhea urinary retention muscle spasms Sedation euphoria Paresthesia blackouts sight loss inability to focus eyes skin rash

Dextromethorphan can also cause other gastrointestinal disturbances. Dextromethorphan had been thought to cause Olney's Lesions when administered intravenously; however, this was later proven inconclusive, due to lack of research on humans. Tests were performed on rats, giving them 50 mg and up every day up to a month. Neurotoxic changes, including vacuolation, have been observed in posterior cingulate and retrosplenial cortices of rats administered other NMDA antagonists such as PCP, but not with dextromethorphan. In many documented cases, dextromethorphan has produced psychological dependence in people who used it recreationally. However, it does not produce physical addiction, according to the WHO Committee on Drug Dependence.

ContraindicationsBecause dextromethorphan can trigger a histamine release (allergic reaction), atopic children, who are especially susceptible to allergic reactions, should be administered dextromethorphan only if absolutely necessary, and only under the strict supervision of a healthcare professional. Drug interactionsDextromethorphan should not be taken with monoamine oxidase inhibitors (MAOIs) due to the potential for serotonin syndrome, which is a potentially life-threatening condition that can occur rapidly, due to a buildup of an excessive amount of serotonin in the body. Dextromethorphan can also cause serotonin syndrome when used with SSRI medicines, an interaction which has been documented in clinical cases where dextromethorphan is taken at recreational doses. It has been suggested that the link between therapeutic dosages of dextromethorphan and serotonin syndrome is less conclusive. Food interactionsCaution should be exercised when taking dextromethorphan when drinking grapefruit juice or eating grapefruits, as compounds in grapefruit affect a number of drugs, including dextromethorphan, through the inhibition of the cytochrome p450 system in the liver and can lead to excessive accumulation and prolonged effects. It is generally recommended that grapefruits and grapefruit juices (especially white grapefruit juice, but also including other citrus fruits such as bergamot and lime, as well as a number of non-citrus fruits) be avoided while using dextromethorphan and numerous other medications.Lab testingTesting for this drug is done either by blood or by urine. Blood can be either serum or plasma, serum in a plain red top 2mL preferred. Urine requires only 2mL minimum.ChemistryDextromethorphan is the dextrorotatory enantiomer of levomethorphan, which is the methyl ether of levorphanol, both opioid analgesics. It is named according to IUPAC rules as (+)-3-methoxy-17-methyl-9,13,14-morphinan. As the pure free base, dextromethorphan occurs as an odorless, white to slightly yellow crystalline powder. It is freely soluble in chloroform and insoluble in water. Dextromethorphan is commonly available as the monohydrated hydrobromide salt, however some newer extended-release formulations contain dextromethorphan bound to an ion exchange resin based on polystyrene sulfonic acid. Dextromethorphan's specific rotation in water is +27.6 (20C, Sodium D-line).[citation needed]

PharmacologyPharmacodynamicsDextromethorphan has been shown to possess the following properties, mainly in binding assays to various receptors of animal tissues. Low Ki values mean strong binding or high affinity; high Ki values mean weak binding to the target or low affinity: Uncompetitive NMDA receptor (PCP site) antagonist (Ki = 7,253 nM). 1 and 2 sigma receptor agonist (Ki = 205 nM and 11,060 nM, respectively). In a comparative investigation of dimemorfan, dextromethorphan and dextrorphan in mouse cells, dextromethorpan binds with relatively high affinity to Sigma-1 receptors and with very low affinity to Sigma-2 receptors. 34-, 42-, and 7-nACh receptor (Ki = in the M range) antagonist. Dextromethorphan binds to nicotinic receptors in frog eggs (Xenopus oocytes), human embryonic kidney cells and mouse tissue. It inhibits the antinociceptive (pain killing) action of nicotine in the tail-flick test in mice, where mouse tails are exposed to heat, which makes the mouse flick its tail if it feels pain. -, -, and -opioid receptor agonist (Ki = 1,280 nM, 11,500 nM, and 7,000 nM, respectively). SERT and NET inhibitor (Ki = 23 nM and 240 nM, respectively). NADPH oxidase inhibitor. Its affinities for some of the sites listed are relatively very low and are probably insignificant, such as binding to NMDA receptors and opioid receptors, even at high recreational doses. Instead of acting as a direct antagonist of the NMDA receptor itself, it is likely that dextromethorphan functions as a prodrug to its nearly 10-fold more potent metabolite dextrorphan, and this is the true mediator of its dissociative effects. It is not entirely clear what role, if any, (+)-3-methoxymorphinan, dextromethorphan's other major metabolite, plays in its effects. PharmacokineticsFollowing oral administration, dextromethorphan is rapidly absorbed from the gastrointestinal tract, where it enters the bloodstream and crosses the bloodbrain barrier.At therapeutic doses, dextromethorphan acts centrally (meaning that it acts on the brain) as opposed to locally (on the respiratory tract). It elevates the threshold for coughing, without inhibiting ciliary activity. Dextromethorphan is rapidly absorbed from the gastrointestinal tract and converted into the active metabolite dextrorphan in the liver by the cytochrome P450 enzyme CYP2D6. The average dosage necessary for effective antitussive therapy is between 10mg and 45mg, depending on the individual. The International Society for the Study of Cough recommend "an adequate first dose of medication is 60 mg in the adult and repeat dosing should be infrequent rather than the qds recommended." The duration of action after oral administration is approximately three to eight hours for dextromethorphan-hydrobromide, and ten to twelve hours for dextromethorphan-polistirex. Approximately 1 in 10 of the caucasian population has little or no CYP2D6 enzyme activity leading to long lived high drug levels. Because administration of dextromethorphan can trigger a histamine release (an allergic reaction), its use in atopic children is very limited. MetabolismThe first-pass through the hepatic portal vein results in some of the drug's being metabolized by O-demethylation into an active metabolite of dextromethorphan called dextrorphan (DXO). DXO is the 3-hydroxy derivative of dextromethorphan. The therapeutic activity of dextromethorphan is believed to be caused by both the drug and this metabolite. Dextromethorphan also undergoes N-demethylation (to 3-methoxymorphinan or MEM),[38] and partial conjugation with glucuronic acid and sulfate ions. Hours after dextromethorphan therapy, (in humans) the metabolites (+)-3-hydroxy-N-methylmorphinan, (+)-3-morphinan, and traces of the unchanged drug are detectable in the urine. A major metabolic catalyst involved is the cytochrome P450 enzyme known as 2D6, or CYP2D6. A significant portion of the population has a functional deficiency in this enzyme and are known as poor CYP2D6 metabolizers. O-demethylation of DXM to DXO contributes to 100% of the DXO formed during DXM metabolism.[38] As CYP2D6 is a major metabolic pathway in the inactivation of dextromethorphan, the duration of action and effects of dextromethorphan can be increased by as much as three times in such poor metabolizers. In one study on 252 Americans, 84.3% were found to be "fast" (extensive) metabolizers, 6.8% to be "intermediate" metabolizers, and 8.8% were "slow" metabolizers of DXM. There are a number of known alleles for CYP2D6, including several completely inactive variants. The distribution of alleles is uneven amongst ethnic groups; see also CYP2D6 - Ethnic factors in variability.A large number of medications are potent inhibitors of CYP2D6. Some types of medications known to inhibit CYP2D6 include certain SSRI and tricyclic antidepressants, some antipsychotics, and the commonly-available antihistamine diphenhydramine. There exists, therefore, the potential of interactions between dextromethorphan and medications that inhibit this enzyme, particularly in slow metabolizers.DXM is also metabolized by CYP3A4. N-demethylation is primarily accomplished by CYP3A4, contributing to at least 90% of the MEM formed as a primary metabolite of DXM.A number of other CYP enzymes are implicated as minor pathways of DXM metabolism. CYP2B6 is actually more effective than CYP3A4 at N-demethylation of DXM, but, since the average individual has a much lower CYP2B6 content in his/her liver relative to CYP3A4, most N-demethylation of DXM is catalyzed by CYP3A4.

HistoryDextromethorphan was identified as one of three compounds tested as part of US Navy and CIA-funded research that sought a "nonaddictive substitute for codeine"; it is implied that the compound was first found to have clinical potential in this study. It was first patented in 1949. The U.S. Food and Drug Administration (FDA) approved dextromethorphan as a prescription antitussive drug on September 24, 1954, and subsequently as an over-the-counter cough suppressant in 1958. This filled the need for a cough suppressant lacking the sedative side-effects, stronger potential for misuse, and physically addictive properties of codeine phosphate, the most widely used cough medication at the time. During the 1960s and 1970s, dextromethorphan became available in an over-the-counter tablet form by the brand name Romilar. In 1973, Romilar was taken off the shelves after a burst in sales because of frequent misuse, and was replaced by cough syrup in an attempt to cut down on abuse. As of January 1, 2012, dextromethorphan is prohibited for sale to minors in the state of California, except with a doctor's prescription.