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Henry Ford Hospital Medical Journal Volume 34 Number 3 Article 11 9-1986 New Positive Inotropic Agents Syed M. Jafri James A. Bristol Follow this and additional works at: https://scholarlycommons.henryford.com/hfhmedjournal Part of the Life Sciences Commons, Medical Specialties Commons, and the Public Health Commons Recommended Citation Jafri, Syed M. and Bristol, James A. (1986) "New Positive Inotropic Agents," Henry Ford Hospital Medical Journal : Vol. 34 : No. 3 , 188-192. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol34/iss3/11 This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. New Positive Inotropic Agents Syed M. Jafri, MD,* and James A. Bristol, PhD^ Current therapy for heart failure remains inadequate. New positive inotropic agents that augment myocardial contractility have been introduced. The positive inotropic effects ofthese nonglycoside, nonsympathomimetic agents are due, at least in part, to inhibition of cardiac phosphodiesterase activity and hence to an increase in myocardial cyclic AMP levels. These agents also have vasodilator properties through their effects on the enzyme phosphodiesterase in the vascular smooth muscle. Recent developments in the preclinical pharmacology, mechanism of action, and clinical experience with these new inotrope vasodilators are presented in this review. The role these drugs will play in revising our therapeutic strategy in congestive heart failure remains to be defined. (Henry Ford H osp MedJ 1986;34:188-92) urrent therapy for heart failure is aimed at improving 19,205); and 4,5-dihydro-3(2H)-pyridazinones of which im- Cmyocardial contractility by reducing volume overload or azodan (CI-914) and CI-930 are the most prominent examples. systemic vascular resistance. Digitalis glycosides and sym­ Thorough characterizadon of preclinical pharmacology includ­ pathomimetic drugs have long been used to improve the contrac­ ing positive inotropic efficacy and studies designed to elucidate tile state of the myocardium. The efficacy of chronic digitalis the mechanism of action have been reported for these agents and therapy in patients with heart failure and sinus rhythm has re­ are summarized here briefly. cendy been challenged (1), and sympathomimetic agents are limited by their chronotropic side-effects and their need for in­ Amrinone and milrinone travenous administration, The preclinical pharmacology of amrinone and milrinone The requirements of a clinically useful inotropic agent have has been studied extensively (5,6). The two agents have sim­ been summarized in a recent review by Braunwald and Colucci ilar properties, with milrinone characterized as 10 to 30 dmes (2). An ideal agent should produce hemodynamic improvement more potent than amrinone. The cardiovascular responses to (both at rest and with exercise), have persistent clinical and he­ amrinone have been evaluated in vitro and in vivo in dogs, cats, modynamic effects, be well tolerated and relatively free of side- monkeys, and man. In vitro treatment of isolated cat atria effects, and prolong survival. No such agent cunently exists. and papillary muscles with amrinone (3 to 1000 p-g/mL) pro­ Several "new" positive inotropic agents are undergoing trials, duces dose-dependent increases in atrial and papillary muscle- including a new class of nonglycoside, nonsympathomimetic developed tension (5). Intravenous administration of 1 to 10 dmgs. mg/kg of amrinone to anesthetized dogs produces dose-related Most inotropic agents stimulate myocardial contractility by increases in contractility (dP/dtmax), slight increases in heart either inhibition of Na + /K+ ATPase, activation of membrane- rate, and slight decreases in blood pressure (5). Oral doses of bound adenylcyclase, or inhibition of cyclic AMP phos­ amrinone to conscious dogs (1 to 10 mg/kg) produce an increase phodiesterase (3). Recently, a new class of dmgs which increase in cardiac contractile force with a long duration of acdon. Simi­ calcium sensitivity of the myofilaments partly by increasing the larly, intravenous administration of 0.01 to 0.1 mg/kg of affinity of troponin to calcium has been described (4). This re­ milrinone to anesthetized dogs produces significant changes in view focuses primarily on one class of these newer inotropic contractility (23% to 87%), whereas heart rate and blood pres­ agents that have phosphodiesterase inhibitory properties and po­ sure are relatively unaffected (6). Oral doses of milrinone (0.1 to tential as therapeutic agents in the management of patients with 1.0 mg/kg) to conscious dogs produce a dose-related increase in heart failure. contractility. Preclinical Evaluation of Positive Inotropic Efficacy of Phosphodiesterase Inhibitors Submitted for publication: July 11. 1986. The newer agents being developed for treatment of heart Accepted for publication: August 21, 1986. •Formeriy Division of Cardiovascular Medicine, Henry Ford Hospital. Currently from failure generally fall into three main classes of chemical stmc­ Noninvasive Laboratory, Detroit Receiving Hospital, Detroit, Ml. ture: 2(lH)-pyridones, also referred to as bipyridines, which tDepartment of Chemistry. Warner-Lambert/Parke-Davis Pharmaceutical Research, Ann Arbor, Ml. include amrinone and milrinone; 2H-imidazol-2-ones which Address correspondence lo Dr Lakier, Heart and Vascular Institute, Division of Car­ include enoximone (MDL 17,043) and piroximone (MDL diovascular Medicine, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202. 188 Henry Ford Hosp Med J—Vol 34, No 3, 1986 Positive Inotropic Agents—Jafri & Bristol Table 1 Table 2 Positive Inotropic Effects of New Agents for Inhibition of Guinea Pig Cardiac Phosphodiesterase by Congestive Heart Failure in Conscious Dogs New Cardiotonic Agents: Theophylline and Papaverine (14) Compound (Reference) Dose (mg/kg) % Increase Contractility IC50 (^jtmoI/L) Amrinone (II) 10.0 45 PDEI PDE II PDE III Milrinone (11) 1.0 45 Agent cAMP cGMP cAMP cGMP cAMP Enoximone (7) 10.0 49 Amrinone >1000 >1000 720 580 46 Piroximone (8) 3.0 54 Milrinone 310 340 22U 200 2.5 Imazodan (11) 1.0 40 Enoximone >1000 >I0OO 860 450 14 CI-930 (II) 0.1 42 Imazodan >I000 >I0OO 750 530 8.2 CI-930 820 >IOOO 400 360 2.9 Papaverine 24 27 6.0 5.1 3.8 Theophylline 230 310 210 170 340 Enoximone and piroximone myocardial cell and the consequent increase in intracellular The in vivo and in vitro pharmacology for enoximone and pir­ cAMP serve to open the calcium slow channel. The increased oximone have been extensively evaluated (7,8). In the anesthe­ intracellular concentration of calcium entering from the slow tized dog, enoximone (7) and piroximone (8) (0.1 to 10 mg/kg) channel causes the release of additional calcium stored in the result in a dose-related positive inotropic response accompanied sarcoplasmic reticulum, which in tum initiates contraction via by a minor increase in heart rate and a minor decrease in blood interaction with the contractile protein, troponin C. pressure. These hemodynamic changes were not altered by Recently, several different molecular forms (isozymes) of alpha or beta blockade (9,10). Both compounds lead to a phosphodiesterase have been separated from tissues of several vasodilatory response in the canine pump-perfused hindlimb species and characterized kinetically (16). In cardiac tissue iso­ preparation. This acdon was not attenuated by alpha, beta, cho­ lated from guinea pigs, three molecular forms of phos­ linergic, or histaminergic blockade, thus indicating that these phodiesterase exist. compounds produce vasorelaxation by a direct mechanism Classical inhibitors of phosphodiesterase (PDE), ie, (9,10). Oral administradon of enoximone (7) and piroximone (8) theophylline, isobutylmethylxanthine (IBMX), and papaver­ to conscious dogs produces a dose-related increase in contrac­ ine, inhibit nonselecdvely all three forms of PDE. Of consider­ tility, with piroximone being approximately three times as po­ able interest and significance was the discovery that the new car­ tent as enoximone (Table I). diotonic agents described in this review inhibit selectively the cyclic AMP specific form (PDE III) relative to their effects on Imazodan (CI-914) and CI-930 PDE 1 and 11. The effects of several cardiotonics on inhibition of Studies on imazodan (11-14) and CI-930 (11) have been re­ cardiac PDE 111 are compared in Table 2 (17). ported. Imazodan has a dose-related increase in positive ino­ By applying a linear regression analysis, an excellent conela­ tropic activity in excised guinea pig atrial and rabbit papillary tion between inhibition of PDE III in vitro and positive inotropic muscle preparations. In anesthetized dogs, imazodan (0.001 to activity in vivo across several stmctural classes was identified. 1.0 mg/kg intravenously) increases myocardial contractility of This conelation strongly suggests that inhibition of cardiac PDE 10% to 150% and decreases aortic blood pressure up to 31%. 111 represents a principal component of the positive inotropic ac­ Minimal heart rate changes occuned relative to the positive ino­ tion of these classes of compounds (11). Furthermore, all of the tropic responses. The positive inotropic responses were not newer agents described possess vascular relaxant effects which blocked by propranolol. Forelimb perfusion studies in the anes­ may be associated with inhibition of one of
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    Therapeutic (“normal”), toxic, and comatose-fatal blood-plasma concentrations (mg/L) in man Substance Blood-plasma concentration (mg/L) t½ (h) Ref. therapeutic (“normal”) toxic (from) comatose-fatal (from) Abacavir (ABC) 0.9-3.9308 appr. 1.5 [1,2] Acamprosate appr. 0.25-0.7231 1311 13-20232 [3], [4], [5] Acebutolol1 0.2-2 (0.5-1.26)1 15-20 3-11 [6], [7], [8] Acecainide see (N-Acetyl-) Procainamide Acecarbromal(um) 10-20 (sum) 25-30 Acemetacin see Indomet(h)acin Acenocoumarol 0.03-0.1197 0.1-0.15 3-11 [9], [3], [10], [11] Acetaldehyde 0-30 100-125 [10], [11] Acetaminophen see Paracetamol Acetazolamide (4-) 10-20267 25-30 2-6 (-13) [3], [12], [13], [14], [11] Acetohexamide 20-70 500 1.3 [15] Acetone (2-) 5-20 100-400; 20008 550 (6-)8-31 [11], [16], [17] Acetonitrile 0.77 32 [11] Acetyldigoxin 0.0005-0.00083 0.0025-0.003 0.005 40-70 [18], [19], [20], [21], [22], [23], [24], [25], [26], [27] 1 Substance Blood-plasma concentration (mg/L) t½ (h) Ref. therapeutic (“normal”) toxic (from) comatose-fatal (from) Acetylsalicylic acid (ASS, ASA) 20-2002 300-3502 (400-) 5002 3-202; 37 [28], [29], [30], [31], [32], [33], [34] Acitretin appr. 0.01-0.05112 2-46 [35], [36] Acrivastine -0.07 1-2 [8] Acyclovir 0.4-1.5203 2-583 [37], [3], [38], [39], [10] Adalimumab (TNF-antibody) appr. 5-9 146 [40] Adipiodone(-meglumine) 850-1200 0.5 [41] Äthanol see Ethanol -139 Agomelatine 0.007-0.3310 0.6311 1-2 [4] Ajmaline (0.1-) 0.53-2.21 (?) 5.58 1.3-1.6, 5-6 [3], [42] Albendazole 0.5-1.592 8-992 [43], [44], [45], [46] Albuterol see Salbutamol Alcuronium 0.3-3353 3.3±1.3 [47] Aldrin -0.0015 0.0035 50-1676 (as dieldrin) [11], [48] Alendronate (Alendronic acid) < 0.005322 -6 [49], [50], [51] Alfentanil 0.03-0.64 0.6-2.396 [52], [53], [54], [55] Alfuzosine 0.003-0.06 3-9 [8] 2 Substance Blood-plasma concentration (mg/L) t½ (h) Ref.
  • (12) Patent Application Publication (10) Pub. No.: US 2007/0208029 A1 Barlow Et Al

    (12) Patent Application Publication (10) Pub. No.: US 2007/0208029 A1 Barlow Et Al

    US 20070208029A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0208029 A1 Barlow et al. (43) Pub. Date: Sep. 6, 2007 (54) MODULATION OF NEUROGENESIS BY PDE Related U.S. Application Data INHIBITION (60) Provisional application No. 60/729,366, filed on Oct. (75) Inventors: Carrolee Barlow, Del Mar, CA (US); 21, 2005. Provisional application No. 60/784,605, Todd A. Carter, San Diego, CA (US); filed on Mar. 21, 2006. Provisional application No. Kym I. Lorrain, San Diego, CA (US); 60/807,594, filed on Jul. 17, 2006. Jammieson C. Pires, San Diego, CA (US); Kai Treuner, San Diego, CA Publication Classification (US) (51) Int. Cl. A6II 3 L/506 (2006.01) Correspondence Address: A6II 3 L/40 (2006.01) TOWNSEND AND TOWNSEND AND CREW, A6II 3/4I (2006.01) LLP (52) U.S. Cl. .............. 514/252.15: 514/252.16; 514/381: TWO EMBARCADERO CENTER 514/649; 514/423: 514/424 EIGHTH FLOOR (57) ABSTRACT SAN FRANCISCO, CA 94111-3834 (US) The instant disclosure describes methods for treating dis eases and conditions of the central and peripheral nervous (73) Assignee: BrainCells, Inc., San Diego, CA (US) system by stimulating or increasing neurogenesis. The dis closure includes compositions and methods based on use of (21) Appl. No.: 11/551,667 a PDE agent, optionally in combination with one or more other neurogenic agents, to stimulate or activate the forma (22) Filed: Oct. 20, 2006 tion of new nerve cells. Patent Application Publication Sep. 6, 2007 Sheet 1 of 6 US 2007/0208029 A1 Figure 1: Human Neurogenesis Assay: budilast + Captopril Neuronal Differentiation budilast + Captopril ' ' ' 'Captopril " " " 'budilast 10 Captopril Concentration 10-8.5 10-8.0 10-7.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 10-4.5 10-40 ammammam 10-9.0 10-8.5 10-8-0 10-75 10-7.0 10-6.5 10-6.0 10-5.5 10-50 10-4.5 Conc (M) Ibudilast Concentration Patent Application Publication Sep.