DOCSLIB.ORG

Synthesis and Positive Inotropic Activity of [1,2,4]Triazolo[4,3-A] Quinoxaline Derivatives Bearing Substituted Benzylpiperazine and Benzoylpiperazine Moieties

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Synthesis and Positive Inotropic Activity of [1,2,4]Triazolo[4,3-A] Quinoxaline Derivatives Bearing Substituted Benzylpiperazine and Benzoylpiperazine Moieties molecules Article Synthesis and Positive Inotropic Activity of [1,2,4]Triazolo[4,3-a] Quinoxaline Derivatives Bearing Substituted Benzylpiperazine and Benzoylpiperazine Moieties Xue-Kun Liu 1,†, Long-Xu Ma 2,†, Zhi-Yu Wei 2, Xun Cui 3, Shi Zhan 4, Xiu-Mei Yin 2,* and Hu-Ri Piao 2,* 1 Tonghua Normal University , College of Pharmaceutical and Food Science, Tonghua 134002, China; [email protected] 2 Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133000, China; [email protected] (L.-X.M.); [email protected] (Z.-Y.W.) 3 College of Medicine, Yanbian University, Yanji 133000, China; [email protected] 4 State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, College of Chemistry, Jilin University, Changchun 130000, China; [email protected] * Correspondences: [email protected] (X.-M.Y.); [email protected] (H.-R.P.); Tel.: +86-433-243-6019 (X.-M.Y.); +86-433-243-5003 (H.-R.P.); Fax: +86-433-243-5026 (X.-M.Y.); +86-433-243-5026 (H.-R.P.) † These authors contributed equally to this work. Academic Editor: Derek J. McPhee Received: 15 January 2017; Accepted: 8 February 2017; Published: 11 February 2017 Abstract: In an attempt to search for more potent positive inotropic agents, two series of [1,2,4]triazolo[4,3-a] quinoxaline derivatives bearing substituted benzylpiperazine and benzoylpiperazine moieties were synthesized and their positive inotropic activities evaluated by measuring left atrial stroke volume in isolated rabbit heart preparations. Several compounds showed favorable activities compared with the standard drug, milrinone. Compound 6c was the most potent agent, with an increased stroke volume of 12.53% ± 0.30% (milrinone: 2.46% ± 0.07%) at 3 × 10−5 M. The chronotropic effects of compounds having considerable inotropic effects were also evaluated. Keywords: [1,2,4]triazolo[4,3-a] quinoxaline; positive inotropic activity; stroke volume; atrium; milrinone 1. Introduction Glycosides such as digoxin are frequently prescribed cardiotonic agents used for the treatment of congestive heart failure (CHF). Unlike other CHF drugs, they do not increase mortality. However, the narrow safety margins associated with the use of digitalis compounds are serious problems because of the high frequency and severity of digitalis intoxication [1]. The discovery of amrinone led to the synthesis of several agents holding promise for CHF treatment as non-sympathomimetic, non-glycoside agents [2]. The phosphodiesterase-inhibiting agent milrinone has vasodilator and inotropic properties. It was approved for the treatment of CHF more than a decade ago. Nevertheless, the significant ventricular arrhythmias and tachycardia associated with elevated levels of cyclic adenosine monophosphate limit the use of milrinone [3] as well as a newer agent, vesnarinone [4,5]. Therefore, newer positive inotropic agents with fewer side effects are needed [6]. Previously, we reported the identification of a [1,2,4]triazolo[3,4-a]phthalazine derivative (compound A) with remarkable positive inotropic activities that could elicit an increased stroke Molecules 2017, 22, 273; doi:10.3390/molecules22020273 www.mdpi.com/journal/molecules Molecules 2017, 22, 273 2 of 9 adenosine monophosphate limit the use of milrinone [3] as well as a newer agent, vesnarinone [4,5]. MoleculesTherefore,2017, newer22, 273 positive inotropic agents with fewer side effects are needed [6]. 2 of 9 Previously, we reported the identification of a [1,2,4]triazolo[3,4-a]phthalazine derivative (compound A) with remarkable positive inotropic activities that could elicit an increased stroke volumevolume of of 9.92% 9.92%± ± 0.09% (Figure1 1))[ [7].7]. To To further further optimize optimize compound compound AA, ,based based on on the the principles principles of ofbioisosterism, bioisosterism, we we replaced replaced the [1,2,4]triazolo[3,4-a]phthalazine groupgroup withwith aa [1,2,4]triazolo[4,3- [1,2,4]triazolo[4,3-a]a] quinoxalinequinoxaline group, group, and and simultaneously simultaneously changed changed the the substituents substituents on on the the phenyl phenyl ring ring of of the the benzyl benzyl moietymoiety at at the the 4-position 4-position of of the the piperazine piperazine ring, ring Thus,, Thus, 11 11 novel novel compounds compounds of of [1,2,4]triazolo[4,3- [1,2,4]triazolo[4,3-a]a] quinoxalinequinoxaline derivativesderivatives bearingbearing substitutedsubstituted benzylpiperazinebenzylpiperazine moietiesmoieties (6a(6a––kk)) werewere synthesized.synthesized. Moreover,Moreover, to to investigate investigate the the effects effects of of benzylpiperazine benzylpiperazine on on activity, activity, we we introduced introduced a a carbonyl carbonyl group group atat the theα α-position-position of of the the benzyl benzyl group. group. Thus, Thus a, a series series of of [1,2,4]triazolo[4,3- [1,2,4]triazolo[4,3-a]a quinoxaline] quinoxaline derivatives derivatives bearingbearing substituted substituted benzoylpiperazine benzoylpiperazine moietiesmoieties (7a(7a––ee)) were were also also designed designed and and screened screened for for their their inotropicinotropic activity. activity. FigureFigure 1. 1.Cardiotonic Cardiotonic agents agents used used for the for treatment the treatment of congestive of congestive heart failure heart (CHF) failure and (CHF) the previously and the reportedpreviously compound reportedA compound. A. 2.2. Results Results and and Discussion Discussion 2.1.2.1. Synthesis Synthesis TheThe reaction reaction sequence sequence for for the the synthesis synthesis of of16 16new new quinoxaline quinoxaline derivatives derivatives6a 6a––kkand and7a 7a–e–eis is outlinedoutlined in in Scheme Scheme1. 1. Benzene-1,2-diamine Benzene-1,2-diamine ( 1(1)) was was reacted reacted with with diethyl diethyl oxalate oxalate to to afford afford quinoxaline- quinoxaline- 2,3(12,3(1HH,4,4HH)-dione)-dione (2(2),), whichwhich waswas subsequently subsequently reactedreacted with with refluxing refluxing hydrazine hydrazine hydrate hydrate to to give give 3-hydrazono-3,4-dihydroquinoxalin-2(13-hydrazono-3,4-dihydroquinoxalin-2(1HH)-one)-one ((33).). Compound Compound 44 waswas prepared prepared from from compound compound 3 by3 byreaction reaction with with ethyl ethyl orthoformate. orthoformate. Compound Compound 5 was obtained5 was obtained by reacting by 4 reacting with refluxing4 with phosphorus refluxing phosphorusoxychloride oxychloride (POCl3). (POClThe nucleophilic3). The nucleophilic aromatic aromatic substitution substitution reactions reactions of of5 5 with variousvarious monosubstitutedmonosubstituted piperazines piperazines in in refluxing refluxing acetone acetone in in the the presence presence of of potassium potassium carbonate carbonate afforded afforded compoundscompounds6a 6a––kk.. Finally, Finally, compounds compounds 7a7a––ee werewere obtained obtained in in high high yield yield from from thethe reactions reactions of 5 ofwith5 withappropriate appropriate different different monosubstitute monosubstitutedd piperazines piperazines in refluxing in refluxing acetone acetonein the presence in the presenceof potassium of potassiumcarbonate. carbonate. Newly synt Newlyhesized synthesized derivatives derivatives 6a–k and 6a7a––ke andwere7a characterized–e were characterized by 1H-NMR, by 1 13H-NMR,C-NMR, − 13IRC-NMR, and mass IR spectral and mass data. spectral In general, data. IR In spectral general, data IR in spectral the ranges data ofin 1549–1457 the ranges cm− of1 and 1549–1457 1638–1620 cm cm1−1 andindicated 1638–1620 distinctive cm−1 indicatedfunctional distinctive groups such functional as −C=N and groups −C=O such stand as −forC=N derivatives and −C=O 6a–k stand and 7a for–e, derivativesrespectively.6a –Thek and (M 7a+ 1)–e peaks, respectively. in the mass The spectra (M + 1) for peaks these in compounds the mass spectra were in for agreement these compounds with their weremolecular in agreement formula. with their molecular formula. Molecules 2017 22 Molecules ,2017, 273, 22, 273 3 of 93 of 9 Scheme 1. Synthetic scheme for the synthesis of compound 6a–k and 7a–e. Reagents and conditions: Scheme 1. Synthetic scheme for the synthesis of compound 6a–k and 7a–e. Reagents and conditions: (a)C6H10O4, reflux, 4 h; (b) NH2NH2H2O, reflux, 4 h; (c) CH(OC2H5)3, reflux, 3 h; (d) POCl3, Methylbenzene/DMF,(a) C6H10O4, reflux, reflux, 4 h; 3(b h;) NH (e)2 monosubstitutedNH2H2O, reflux, piperazines,4 h; (c) CH(OC K2CO3,2H5)3, acetone,reflux, 3 reflux, h; (d) 5 POCl h; 3, Methylbenzene/DMF, reflux, 3 h; (e) monosubstituted piperazines, K2CO3, acetone, reflux,5 h; (f) monosubstituted piperazines, K2CO3, acetone, reflux, 8 h. (f) monosubstituted piperazines, K2CO3, acetone, reflux, 8 h. 2.2. Biological Evaluation 2.2. Biological Evaluation Seven of the 16 compounds tested displayed inotropic effects against isolated rabbit heart Seven of the 16 compounds tested displayed inotropic effects against isolated rabbit heart preparations (Table1). Compounds 6c, 6g, 6h, and 7c exhibited more potent effects compared with preparations (Table 1). Compounds 6c, 6g, 6h, and 7c exhibited more potent effects compared with milrinone (2.46% ± 0.3% at 3 × 10−5 M), among which compound 6c showed the most potent activity, milrinone (2.46% ± 0.3% at 3 × 10−5 M), among which compound 6c showed the most potent activity, with an increased stroke volume of 12.53% ± 0.30%. For compounds 6a–k, different substituents on the with an increased stroke volume of 12.53% ± 0.30%. For compounds 6a–k,
Load more

Recommended publications
  • Phosphodiesterase (PDE)
    Phosphodiesterase (PDE) Phosphodiesterase (PDE) is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases. The cyclic nucleotide phosphodiesterases comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They regulate the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains. PDEs are therefore important regulators ofsignal transduction mediated by these second messenger molecules. www.MedChemExpress.com 1 Phosphodiesterase (PDE) Inhibitors, Activators & Modulators (+)-Medioresinol Di-O-β-D-glucopyranoside (R)-(-)-Rolipram Cat. No.: HY-N8209 ((R)-Rolipram; (-)-Rolipram) Cat. No.: HY-16900A (+)-Medioresinol Di-O-β-D-glucopyranoside is a (R)-(-)-Rolipram is the R-enantiomer of Rolipram. lignan glucoside with strong inhibitory activity Rolipram is a selective inhibitor of of 3', 5'-cyclic monophosphate (cyclic AMP) phosphodiesterases PDE4 with IC50 of 3 nM, 130 nM phosphodiesterase. and 240 nM for PDE4A, PDE4B, and PDE4D, respectively. Purity: >98% Purity: 99.91% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 1 mg, 5 mg Size: 10 mM × 1 mL, 10 mg, 50 mg (R)-DNMDP (S)-(+)-Rolipram Cat. No.: HY-122751 ((+)-Rolipram; (S)-Rolipram) Cat. No.: HY-B0392 (R)-DNMDP is a potent and selective cancer cell (S)-(+)-Rolipram ((+)-Rolipram) is a cyclic cytotoxic agent. (R)-DNMDP, the R-form of DNMDP, AMP(cAMP)-specific phosphodiesterase (PDE) binds PDE3A directly.
    [Show full text]
  • Use of Sildenafil in Patients with Cardiovascular Disease
    Arq Bras Cardiol GuimarãesReview et al volume 73, (nº6), 1999 Sildenafil in patients with cardiovascular disease Use of Sildenafil in Patients with Cardiovascular Disease Armênio Costa Guimarães, Marcus Vinícius Bolívar Malachias, Otávio Rizzi Coelho, Emílio Cesar Zilli, Rafael Leite Luna Introduction of phosphodiesterase inhibitors. The erectile action of sildenafil combines increase in arterial flow with reduction Erectile dysfunction, formerly called impotence, is the in the venous flow of cavernous body of penis. Sildenafil inability of the male to achieve or maintain penile erection and leads to relaxation of smooth muscle of penile arteries and thus engage in coitus1. It is common among patients with trabeculae surrounding the sinusoidal spaces, resulting in cardiovascular diseases or their risk factors. This dysfunc- a greater engorgement of cavernous body. The trabeculae tion occurs mainly among individuals with coronary artery of engorged sinusoidal spaces compress the penile disease, after episodes of acute ischemic syndrome, hyper- venules against the tunica albuginea, reducing venous tensive patients underpharmacologic treatment, and among flow, contributing to maintenance of engorgement of patients with heart failure. In approximately 85% of these ca- cavernous body8. Relaxation of this smooth muscle ses, the fear of a cardiac event during coitus constitutes an results from a decrease in intracellular calcium mediated important factor for erectile dysfunction 2-4. by accumulation of the second messenger, the cyclic Discovery of sildenafil citrate has represented a great de- guanosine monophosphate (cGMP), whose production velopment in the treatment of erectile dysfunction; it may results from activation of guanyl cyclase by nitric oxide benefit, among many others, those patients with cardiovascu- produced by the stimulus of endothelial cells generated lar diseases or with their risk factors 5.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,894,970 B2 Tomczuk Et Al
    US008894970B2 (12) United States Patent (10) Patent No.: US 8,894,970 B2 Tomczuk et al. (45) Date of Patent: Nov. 25, 2014 (54) ARGINASE INHIBITORS AND METHODS OF 546/184, 133, 138, 139, 152; 548/560; USE THEREOF 540/484 See application file for complete search history. (75) Inventors: Bruce Edward Tomczuk, Collegeville, PA (US); Gary Lee Olson, (56) References Cited Mountainside, NJ (US); Richard Scott Pottorf, Belle Mead, NJ (US); Lijuan U.S. PATENT DOCUMENTS Jane Wang, Wildwood, MO (US); Bhask Rao Nall h 4.483,853. A 11/1984 Collins et al. naskara Kao Nalagancnu, 5,792,769 A * 8/1998 Lu et al. ...... 514,252.12 Hillsborough, NJ (US); Yanqun Zhang, 5,891,909 A * 4/1999 Soll et al. ...................... 514/517 East Brunswick, NJ (US) 6,037,356 A * 3/2000 Lu et al. ...... ... 514,349 6,133,315 A * 10/2000 Lu et al. ...... 514/517 6,204.263 B1* 3/2001 Lu et al. ...... 514,235.8 (73) Assignee: Corridor Pharmaceuticals, Inc., 6,225,302 B1* 5/2001 Lu et al. ......... ... 514, 183 Towson, MD (US) 6,235,778 B1* 5/2001 Tomczuk et al. 514/517 6,245,763 B1* 6/2001 Lu et al. ......... ... 514,247 (*) Notice: Subject to any disclaimer, the term of this 6,281.206 B1 : 8/2001 Lu et al. ...... ... 514, 183 patent is extended or adjusted under 35 6,326,492 B1* 12/2001 Wang et al. ..................... 544, 63 6,344,466 B2 * 2/2002 Soll et al. ....... ... 514,331 U.S.C. 154(b) by 356 days.
    [Show full text]
  • General Pharmacology
    GENERAL PHARMACOLOGY Winners of “Nobel” prize for their contribution to pharmacology Year Name Contribution 1923 Frederick Banting Discovery of insulin John McLeod 1939 Gerhard Domagk Discovery of antibacterial effects of prontosil 1945 Sir Alexander Fleming Discovery of penicillin & its purification Ernst Boris Chain Sir Howard Walter Florey 1952 Selman Abraham Waksman Discovery of streptomycin 1982 Sir John R.Vane Discovery of prostaglandins 1999 Alfred G.Gilman Discovery of G proteins & their role in signal transduction in cells Martin Rodbell 1999 Arvid Carlson Discovery that dopamine is neurotransmitter in the brain whose depletion leads to symptoms of Parkinson’s disease Drug nomenclature: i. Chemical name ii. Non-proprietary name iii. Proprietary (Brand) name Source of drugs: Natural – plant /animal derivatives Synthetic/semisynthetic Plant Part Drug obtained Pilocarpus microphyllus Leaflets Pilocarpine Atropa belladonna Atropine Datura stramonium Physostigma venenosum dried, ripe seed Physostigmine Ephedra vulgaris Ephedrine Digitalis lanata Digoxin Strychnos toxifera Curare group of drugs Chondrodendron tomentosum Cannabis indica (Marijuana) Various parts are used ∆9Tetrahydrocannabinol (THC) Bhang - the dried leaves Ganja - the dried female inflorescence Charas- is the dried resinous extract from the flowering tops & leaves Papaver somniferum, P album Poppy seed pod/ Capsule Natural opiates such as morphine, codeine, thebaine Cinchona bark Quinine Vinca rosea periwinkle plant Vinca alkaloids Podophyllum peltatum the mayapple
    [Show full text]
  • Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
    US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 6,333,354 B1 Schudt (45) Date of Patent: Dec
    USOO6333354B1 (12) United States Patent (10) Patent No.: US 6,333,354 B1 Schudt (45) Date of Patent: Dec. 25, 2001 (54) SYNERGISTIC COMBINATION OF PDE Buerke et al.: “Synergistic platelet inhibitory effect of the INHIBITORS AND ADENYLATE CYCLASE phosphodiesterase inhibitor piroximone and iloprost: Pros AGONSTS OR GUANYL CYCLYSE taglandins in the Cardiovascular System, 1992, 37/suppl. AGONSTS (71–77).* (75) Inventor: Christian Schudt, Constance (DE) O'Grady et al. “A chemically stable analot 9-beta methyl carbacyclin with Similar effects to epoprostenol proStacyclin (73) Assignee: Byk Gulden Lomberg Chemische prostaglandin in I-2 in man” Br J Clin Pharmacol, 18(6). Fabrik GmbH, Constance (DE) 1984 (921-934).* (*) Notice: Subject to any disclaimer, the term of this Crutchley et al. “Effects of Prostacyclin Analogs on the patent is extended or adjusted under 35 Synthesis of Tissue Factor, Tumor Necrosis Facotr-alpha U.S.C. 154(b) by 0 days. and Interleukin-1beta in Human Monocytic THP-1 Cells”, J Pharmacol and Experimental Therapeutics, 271 (1). 1994. (21) Appl. No.: 09/367,850 446-451. (22) PCT Filed: Feb. 24, 1998 Crutchley et al. “Prostacyclin Analogues Inhibit Tissue (86) PCT No.: PCT/EP98/O1047 Factor Expression in the Human Monocytic Cell Line THP-1 Via a Cyclic AMP-Dependent Mechanism” Arterio S371 Date: Aug. 27, 1999 scler. Thromb, 12(6), 1992. 664-670.* S 102(e) Date: Aug. 27, 1999 Turner et al., Br. J. Pharmacol., “Pulmonary effects of type V cyclic GMP specific phosphodiesterase inhibition in the (87) PCT Pub. No.: WO98/37894 anaesthetized guinea-pig", (1994), 111, pp.
    [Show full text]
  • Mechanism of Drug-Induced Qt Interval Prolongation
    ABSTRACT Torsades de pointes (TdP) is a polymorphic ventricular tachycardia characterized by a distinctive pattern of undulating QRS complexes that twist around the isoelectric line. TdP is usually self-terminating or can subsequently degenerate into ventricular fibrillation, syncope, and sudden death. TdP has been associated with QT interval prolongation of the electrocardiogram; therefore, the QT interval has come to be recognized as a surrogate marker for the risk of TdP. International guidelines have been developed to harmonize both the preclinical and clinical studies for the evaluation of drug-induced TdP. However, currently preclinical in vitro and in vivo methods as well as biomarkers for proarrhythmias have been imperfect in predicting drug-induced TdP in humans. It is clear that relevant biomarkers together with appropriate models are needed to assess the arrhythmic risk of new chemical entities. The goal of the present dissertation is to create rabbit with myocardial failing heart as an in vivo animal model to predict TdP in humans and to determine mechanism(s) underlying TdP in this model. Electrocardiograms were recorded from bipolar transthoracic leads in 7 conscious healthy rabbits previously trained to rest quietly in slings. The RR and QT relationship, ii QT=2.4RR0.72 (r2=0.79, p < 0.001) was obtained by slowed the heart rate with 2.0 mg/kg zatebradine, and the algorithm for removing effect of heart rate on QT is QTc = QT/(RR)0.72. QTc lengthened significantly in all conscious rabbits given intravenous cisapride, dofetilide or haloperidol (p < 0.05), and QTc did not change with DMSO (vehicle control), propranolol or enalaprilat.
    [Show full text]
  • Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DIX to the HTSUS—Continued
    20558 Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DEPARMENT OF THE TREASURY Services, U.S. Customs Service, 1301 TABLE 1.ÐPHARMACEUTICAL APPEN- Constitution Avenue NW, Washington, DIX TO THE HTSUSÐContinued Customs Service D.C. 20229 at (202) 927±1060. CAS No. Pharmaceutical [T.D. 95±33] Dated: April 14, 1995. 52±78±8 ..................... NORETHANDROLONE. A. W. Tennant, 52±86±8 ..................... HALOPERIDOL. Pharmaceutical Tables 1 and 3 of the Director, Office of Laboratories and Scientific 52±88±0 ..................... ATROPINE METHONITRATE. HTSUS 52±90±4 ..................... CYSTEINE. Services. 53±03±2 ..................... PREDNISONE. 53±06±5 ..................... CORTISONE. AGENCY: Customs Service, Department TABLE 1.ÐPHARMACEUTICAL 53±10±1 ..................... HYDROXYDIONE SODIUM SUCCI- of the Treasury. NATE. APPENDIX TO THE HTSUS 53±16±7 ..................... ESTRONE. ACTION: Listing of the products found in 53±18±9 ..................... BIETASERPINE. Table 1 and Table 3 of the CAS No. Pharmaceutical 53±19±0 ..................... MITOTANE. 53±31±6 ..................... MEDIBAZINE. Pharmaceutical Appendix to the N/A ............................. ACTAGARDIN. 53±33±8 ..................... PARAMETHASONE. Harmonized Tariff Schedule of the N/A ............................. ARDACIN. 53±34±9 ..................... FLUPREDNISOLONE. N/A ............................. BICIROMAB. 53±39±4 ..................... OXANDROLONE. United States of America in Chemical N/A ............................. CELUCLORAL. 53±43±0
    [Show full text]
  • Bath Salts Or Methylenedioxypyrovalerone (MDPV)
    New Highs for the New Millennium Brandon J. Warrick MD Assistant Clinical Professor Wayne State University Disclosures • No financial disclosures • All treatments mentioned in this talk are FDA approved. • Treatment dosing may exceed package insert Objectives • What are “Bath Salts”? • What is “Spice or K2”? • Epidemiology • Were did designer drugs come from? • Were are designer drugs going? What are “Bath Salts”? Testimonials • “I don’t believe in the hype so I ordered some offline and received in roughly a week and a half. It came in a 250mg package that ran me roughly 18 dollars with tax and shipping included. I tried roughly 10mg and absolutely loved it. Immediately after ingestion of the bath salts I felt a rush of energy and even a slight euphoria to go along with it. My mind felt like it was working in overdrive and I wanted to talk to anyone about anything I possibly could…” • “At about 1 hour and 10 minutes in I got the strongest urge to redose I have ever felt from a drug, including cocaine.” Physical Properties • White to Light Brown • Hydrophilic • Crumbly powder • Slight odor Michigan; How it Began • First call December 18, 2010 • First Death February 3 2011 • February 2-7 10 cases • Reported – Bay City – Iron Wood – Mt. Clemons PCC & Health Department Need PCC MDCH 24/7 Call Center Yes No Able to give medical advice Yes No Real-time reporting Yes Yes Able to mandate reporting No Yes Able to take legal action No Yes Able to create EPI-X alerts* Yes Yes Able to create HAN* No Yes Able to submit MMWR* No Yes Participates in
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2003/0068365A1 Suvanprakorn Et Al
    US 2003.0068365A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0068365A1 Suvanprakorn et al. (43) Pub. Date: Apr. 10, 2003 (54) COMPOSITIONS AND METHODS FOR Related U.S. Application Data ADMINISTRATION OF ACTIVE AGENTS USING LIPOSOME BEADS (60) Provisional application No. 60/327,643, filed on Oct. 5, 2001. (76) Inventors: Pichit Suvanprakorn, Bangkok (TH); Tanusin Ploysangam, Bangkok (TH); Publication Classification Lerson Tanasugarn, Bangkok (TH); Suwalee Chandrkrachang, Bangkok (51) Int. Cl." .......................... A61K 9/127; A61K 35/78 (TH); Nardo Zaias, Miami Beach, FL (52) U.S. Cl. ............................................ 424/450; 424/725 (US) (57) ABSTRACT Correspondence Address: Law Office of Eric G. Masamori Compositions and methods for administration of active 6520 Ridgewood Drive agents encapsulated within liposome beads to enable a wider Castro Valley, CA 94.552 (US) range of delivery vehicles, to provide longer product shelf life, to allow multiple active agents within the composition, (21) Appl. No.: 10/264,205 to allow the controlled use of the active agents, to provide protected and designable release features and to provide (22) Filed: Oct. 3, 2002 Visual inspection for damage and inconsistency. US 2003/0068365A1 Apr. 10, 2003 COMPOSITIONS AND METHODS FOR toxic degradation of the products, leakage of the drug from ADMINISTRATION OF ACTIVE AGENTS USING the liposome and the modifications of the Size and morphol LPOSOME BEADS ogy of the phospholipid liposome vesicles through aggre gation and fusion. Liposome vesicles are known to be CROSS REFERENCE TO OTHER thermodynamically relatively unstable at room temperature APPLICATIONS and can Spontaneously fuse into larger, leSS Stable altered liposome forms.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • A Abacavir Abacavirum Abakaviiri Abagovomab Abagovomabum
    A abacavir abacavirum abakaviiri abagovomab abagovomabum abagovomabi abamectin abamectinum abamektiini abametapir abametapirum abametapiiri abanoquil abanoquilum abanokiili abaperidone abaperidonum abaperidoni abarelix abarelixum abareliksi abatacept abataceptum abatasepti abciximab abciximabum absiksimabi abecarnil abecarnilum abekarniili abediterol abediterolum abediteroli abetimus abetimusum abetimuusi abexinostat abexinostatum abeksinostaatti abicipar pegol abiciparum pegolum abisipaaripegoli abiraterone abirateronum abirateroni abitesartan abitesartanum abitesartaani ablukast ablukastum ablukasti abrilumab abrilumabum abrilumabi abrineurin abrineurinum abrineuriini abunidazol abunidazolum abunidatsoli acadesine acadesinum akadesiini acamprosate acamprosatum akamprosaatti acarbose acarbosum akarboosi acebrochol acebrocholum asebrokoli aceburic acid acidum aceburicum asebuurihappo acebutolol acebutololum asebutololi acecainide acecainidum asekainidi acecarbromal acecarbromalum asekarbromaali aceclidine aceclidinum aseklidiini aceclofenac aceclofenacum aseklofenaakki acedapsone acedapsonum asedapsoni acediasulfone sodium acediasulfonum natricum asediasulfoninatrium acefluranol acefluranolum asefluranoli acefurtiamine acefurtiaminum asefurtiamiini acefylline clofibrol acefyllinum clofibrolum asefylliiniklofibroli acefylline piperazine acefyllinum piperazinum asefylliinipiperatsiini aceglatone aceglatonum aseglatoni aceglutamide aceglutamidum aseglutamidi acemannan acemannanum asemannaani acemetacin acemetacinum asemetasiini aceneuramic
    [Show full text]