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WO2009066085A1 - Traitement d'une insuffisance cardiaque avec fraction d'éjection normale - Google Patents

Traitement d'une insuffisance cardiaque avec fraction d'éjection normale Download PDF

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Publication number
WO2009066085A1
WO2009066085A1 PCT/GB2008/003913 GB2008003913W WO2009066085A1 WO 2009066085 A1 WO2009066085 A1 WO 2009066085A1 GB 2008003913 W GB2008003913 W GB 2008003913W WO 2009066085 A1 WO2009066085 A1 WO 2009066085A1
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WIPO (PCT)
Prior art keywords
exercise
patients
perhexiline
diastolic
heart failure
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Ceased
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PCT/GB2008/003913
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English (en)
Inventor
Houman Ashrafian
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Heart Metabolics Ltd
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Heart Metabolics Ltd
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Filing date
Publication date
Application filed by Heart Metabolics Ltd filed Critical Heart Metabolics Ltd
Publication of WO2009066085A1 publication Critical patent/WO2009066085A1/fr
Priority to US12/785,077 priority Critical patent/US8440697B2/en
Anticipated expiration legal-status Critical
Priority to US13/839,313 priority patent/US9468634B2/en
Priority to US13/838,458 priority patent/US9457017B2/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the invention relates to treatment of heart failure with normal left ventricular (LV) ejection fraction syndrome (HFnEF).
  • LV left ventricular
  • HFnEF ejection fraction syndrome
  • HF with normal left ventricular (LV) ejection fraction syndrome HFnEF
  • HFpEF HF with preserved left ventricular ejection fraction syndrome
  • HFnEF patients manifest subtle systolic dysfunction but the principal abnormality in most is a disorder of active relaxation and/or passive filling of the LV.
  • resting measures of active relaxation and filling relate poorly to symptoms and exercise capacity therefore no 'gold standard' diagnostic echocardiographic test exists for HFnEF.
  • Effective ventricular filling results from a highly energy dependent active relaxation process and from passive filling which is dependent on loading conditions as well as the intrinsic (passive) properties of the LV. Since both these parameters change markedly during exercise due to sympathetic activation, it is not surprising that these resting parameters are so poorly predictive of exercise capacity and symptoms.
  • Perhexiline (2-(2,2-dicyclohexylethyl) piperidine) is a known anti-anginal agent that operates principally by virtue of its ability to shift metabolism in the heart from free fatty acid metabolism to glucose, which is more energy efficient.
  • WO-A-2005/087233 discloses the use of perhexiline for the treatment of chronic heart failure (CHF) where the CHF is a result of an initial inciting influence of ischaemia or where the CHF is a result of an initial non-ischaemic inciting influence.
  • CHF chronic heart failure
  • a method of treating HFnEF which comprises administering to an animal in need thereof an effective amount of perhexiline, or a pharmaceutically acceptable salt thereof, to treat said HFnEF.
  • the animal is preferably a mammal and most preferably a human.
  • perhexiline or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of HfnEF.
  • a treatment programme for treating HFnEF which involves the co-use or co-administration of perhexiline or pharmaceutically acceptable salt thereof with one or more other compounds that are advantageous in treating HFnEF or the symptoms thereof, for example a diuretic, an angiotensin receptor blocker or a calcium channel blocker.
  • FIG 1 displays variables correlating with Aerobic Exercise Capacity (V ⁇ 2max).
  • Figure 2 shows MR images of a patient with HFpEF lying prone over a 31 P surface coil (Panel A) and the corresponding localized 31 P MR spectra from the left ventricle (Panel B).
  • Panel C is Individual PCr/ ⁇ ATP ratio in Patients with HfpEF and Controls.
  • the perhexiline exists in the form of a salt of perhexiline, preferably the maleate salt.
  • the perhexiline may be used at doses titrated to achieve therapeutic but non-toxic plasma perhexiline levels (Kennedy JA,
  • Typical doses for a normal patient would be 100mg to 300mg daily, although smaller doses may be appropriate for patients who are slow metabolisers of perhexiline.
  • Physiologically acceptable formulations such as salts, of the compound perhexiline, may be used in the invention.
  • a medicament may be formulated for administration in any convenient way and the invention therefore also includes within its scope use of the medicament in a conventional manner in a mixture with one or more physiologically acceptable carriers or excipients.
  • the carriers should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the medicament may be formulated for oral, buccal, parental, intravenous or rectal administration. Additionally, or alternatively, the medicament may be formulated in a more conventional form such as a tablet, capsule, syrup, elixir or any other known oral dosage form.
  • LV left ventricular
  • HFnEF normal LV ejection fraction
  • nTTPF Vasculo- ventricular coupling
  • PCr/ATP ratio Cardiac energetic status
  • HFpEF patients were prospectively recruited from heart failure clinics. Also studied were twenty age-gender-matched healthy controls with no cardiac history or diabetes mellitus. Study participants had clinical examination, 12- lead electrocardiogram, pulmonary function test, echocardiogram, metabolic exercise test, MUGA studies and a subgroup underwent cardiac 31 P MRS studies to assess cardiac energetic status. All controls had a normal cardiovascular examination, 12- Iead electrocardiogram and echocardiogram. HFpEF patients were defined in accordance with ACC/AHA recommendation (1): i) symptoms and signs of heart failure, ii) ejection fraction >50%, iii) no valvular abnormalities.
  • patients should have iv) VCtemax ⁇ 80% of age and gender predicted with a pattern of gas exchange on metabolic exercise testing indicating a cardiac cause for limitation, v) absence of objective evidence of lung disease on formal lung function testing and/or absence of arterial desaturation during exercise and with a ventilatory reserve at peak exercise ⁇ 15L. Patients with rhythm other than sinus were excluded.
  • Echocardiography was performed with participants in the left lateral decubitus position with a Vivid 7 echocardiographic machine using a 2.5-MHz transducer. Cardiac quantifications were determined in accordance with European Association of Echocardiography.
  • Left ventricular hypertrophy was defined as a left ventricular mass indexed to body surface area that exceeded 88 g/rri2 for women and 102 g/nri2 for men.
  • LV end-systolic elastance (Ees) was determined using the non-invasive single-beat technique.
  • Arterial elastance (Ea) was calculated as the ratio of LV end-systolic pressure/stroke volume. Studies were stored digitally and analyzed offline.
  • Localized iterative 1st order shimming was performed including the entire heart using the unsuppressed water signal acquired with the body coil.
  • a short axis cine scan was acquired to optimise shimming and Fo determination.
  • a 3-D voxel of acquisition was planned to include the left ventricle.
  • the repetition time was 10000 ms with 136 averages and 512 samples.
  • Acquisition was ECG gated and the trigger delay was set to acquire in diastole. Total scan time was 23 minutes.
  • Java magnetic resonance user interface v3.0 (jMRUI) was used for analysis. (5) Using the preprocessing operations within jMRUI, signals were fourier transformed, phase corrected and apodized by 15Hz.
  • AMARES advanced method of accurate, robust and efficient spectroscopic fitting
  • PCr phosphorcreatine
  • ATP adenosine triphosphate
  • phosphodiesters 2, 3- bisphosphoglycerate
  • PCr and ⁇ -ATP was used to determine the PCr/ATP ratio which is a measure of cardiac energetic state (6).
  • MUGA Multiple Uptake Gated Acquisition Scan
  • LV ejection fraction and diastolic filling were assessed by equilibrium R-wave gated blood pool scintigraphy at rest and during graded semi erect exercise on a cycle ergometer as previously described. (8,9) Three minutes of data were acquired at rest and during exercise after a 30-second period for stabilisation of heart rate at the commencement of each stage. Exercise was performed at 50% workloads of heart rate reserve. Data were analysed using LinkMedical MAPS software, Sun Microsystems (Hampshire, UK).
  • Peak left ventricular filling rate in terms of end- diastolic count per second (EDC/s) and time to peak filling normalised for R-R interval (nTTPF) in milliseconds after end systole were calculated from the first derivative of the diastolic activity-time curve.
  • Venous blood samples were obtained for weighing and for counting of blood gamma activity during each scan in order to correct for physical and physiological decay as well as for determination of relative volume changes. (10) The validity of these radionuclide measures of diastolic filling at high heart rates has been established previously. (11)
  • EDVI end-diastolic volume index
  • ESVI end-systolic volume index
  • SVI stroke volume index
  • cardiac index cardiac index.
  • V ⁇ 2max Aerobic Exercise Capacity
  • Panel A V ⁇ 2max correlated negatively with Exercise-induced Changes in nTTPF.
  • Panel B VChmax correlated negatively with Exercise-induced Changes in Vasculo- Ventricular Coupling Ratio.
  • Panel C V ⁇ 2tnax correlated directly with Exercise-induced Changes in Heart Rate. Black circles indicate patients with HFpEF, and Open circles represents healthy controls. When patients on beta blockers were excluded from analysis, the level of significance were similar.
  • Panel A shows an MR images of a patient with HFpEF lying prone over a 31 P surface coil and the corresponding localized 31 P MR spectra from the left ventricle is shown in panel B.
  • the resonances derive from PCr and the v-, ⁇ -, and ⁇ - phosphate Resonances of the ATP.
  • NYHA denotes New York Heart Association
  • ACE angiotensin-converting enzyme ARB angiotensin Il receptor blockers
  • BMI body mass index SBP systolic blood pressure
  • DBP diastolic blood pressure MABP mean arterial blood pressure
  • LA left atrium E/E' mitral E-wave velocity-E' tissue velocity (PW-TDI) at basal inferoseptum ratio
  • Ees denotes Left Ventricular End-Systolic Elastance
  • Ea is Arterial elastance.
  • the bodymass index is the weight in kilograms divided by the square of the height in meters.
  • Predictors ⁇ HR, fPredictors: ⁇ HR and ⁇ WC coupling ratio
  • Predictors ⁇ HR, ⁇ WC coupling ratio and age
  • Predictors ⁇ HR, ⁇ WC coupling ratio, age and ⁇ TTPF.
  • Multivariate analysis was adjusted for the variable that some patients were on betablockers.
  • the tissue Doppler E/E' at the basal infero-septum (a measure of left ventricular end-diastolic pressure) (14), was significantly higher in patients than controls. There was also a trend (non-significant) to higher Ees in patients than in the control group.
  • HFpEF patients also had significantly reduced V ⁇ 2max and reduced peak HR on metabolic exercise testing.
  • nTTPF is determined by the rate of active relaxation (15) and by transmural pressure gradient at the time of mitral valve opening. nTTPF was similar at rest in HFpEF patients and controls. During exercise it shortened in controls, but lengthened in patients (Table 2). There was a negative correlation between VCtemax and ⁇ nTTPF
  • HFpEF HFpEF.
  • the principal findings are: a) HFpEF patients manifest a significant reduction in PCr/ATP ratio at rest, indicating a resting defect in myocardial energetics, b) As a corollary, during exercise, the energetically demanding active relaxation stage of diastole lengthens in patients (vs. a shortening in controls) and there is also a failure of contractile function to increase in patients. These abnormalities result in a lower stroke volume on exercise, c) Consistent with previous studies, HFpEF patients demonstrate chronotropic incompetence on exercise. (16- 18)
  • the independent predictors of impaired exercise capacity were abnormal ventricular-arterial coupling on exercise, a reduced HR response on exercise and a 'paradoxical' slowing of the rate of LV active relaxation on exercise (manifest as a prolongation of nTTPF).
  • V ⁇ 2max is largely determined by cardiac output on exercise and the latter is simply the product of HR and SV.
  • a detrimental effect of an impaired HR might appear logical.
  • a larger diastolic filling period might be expected to be beneficial, by increasing SV.
  • the physiological increase in the rate of LV active relaxation during exercise is a consequence of sympathetic activation, via cAMP-dependent protein kinase (PKA) mediated phosphorylation of key proteins including Troponin I, Sarco/Endoplasmic Reticulum Ca 2+ -ATPase (SERCA) and Titin.
  • PKA cAMP-dependent protein kinase
  • SERCA Sarco/Endoplasmic Reticulum Ca 2+ -ATPase
  • Titin Titin.
  • the radionuclide exercise protocol involved asking subjects to maintain a HR which was 50% of HR reserve above their resting HR. Since this HR reserve was calibrated to peak HR rate on metabolic exercise testing, the absolute workload was lower in patients. Nonetheless, most of the changes in SV occur in the first part of exercise with subsequent increases in cardiac output being principally due to increases in HR. (47) A small proportion of patients were on ⁇ -blockers which may have affected their cardiovascular response to exercise, however, except where stated, the level of significance remained similar when these patients were excluded from the analysis. MRS and Radionuclide studies also require a regular rhythm, thus patients with atrial fibrillation were excluded from the study.
  • HFpEF Patients have abnormal cardiac energetic status which is expected to contribute to the abnormal active relaxation on exercise and to a failure of LV end- systolic elastance to increase. In addition chronotropic response was markedly impaired on exercise in patients.
  • the independent predictors of exercise capacity in patients with HFpEF are exercise-induced changes in active relaxation, heart rate and ventricular-arterial coupling.
  • HFnEF is defined as:-
  • LVEF 50%, with no evidence of significant valvular disease, no hypertrophic cardiomyopathy, and no evidence of pericardial constriction.
  • Metabolic exercise testing is performed during treadmill exercise testing to measure peak VO2, VO2 at anaerobic threshold and VE/VCO2 slope.
  • LVEF and diastolic filling are assessed by equilibrium R-wave gated blood pool scintigraphy at rest and during graded semi erect exercise on a cycle ergometer.
  • the rest and exercise gated blood pool scintigraphs are analysed by a single operator blinded to the patient's data.
  • Peak LV filling rate in terms of end-diastolic volumes per second (EDV/s) and time to peak filling (TTPF) are calculated from the second derivative of the diastolic activity-time curve.
  • the ⁇ TTPF/ ⁇ HR is calculated at peak and submaximal exercise.
  • Standard echocardiographic views are obtained on held expiration.
  • Transmitral flow profiles, pulmonary vein flows and tissue Doppler (TDI) assessment of mitral annulus velocities (as a measure of long axis systolic and diastolic function) are performed.
  • the E/Ea ratio is calculated as an indirect measure of LVEDP.
  • TDI measurements are also performed in multiple segments to assess radial and longitudinal systolic and diastolic function in multiple segments.
  • Cardiac high-energy phosphate metabolism is measured using 31 P MRS on a 3-Tesla Philips whole-body magnet using a linearly polarized transmit and receive 31 P coil with a diameter of 14 cm. The participants are positioned supine with the coil directly over the precordium. The 31 P spectrum is acquired with a repetition time of 10000 ms and 512 averages. PCr/ATP ratio is determined after correcting the ATP peak for blood contamination.
  • the subjects are randomised to receive either 100 mg of perhexiline a day or placebo.
  • Dose titration and dummy dose titration in the placebo group are performed (based on plasma levels) by an unblended independent observer according to a standard algorithm.

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Abstract

La présente invention concerne la perhéxiline, ou un sel pharmaceutiquement acceptable de cette dernière, en vue de son utilisation pour le traitement d'une insuffisance cardiaque avec fraction d'éjection normale (ICFEN), ainsi qu'une méthode de traitement d'une ICFEN. Le traitement consiste à administrer, à un animal nécessitant ledit traitement, une quantité efficace de perhéxiline ou d'un sel pharmaceutiquement acceptable de cette dernière pour traiter ladite ICFEN. L'invention concerne en outre un programme de traitement permettant de traiter une ICFEN, qui implique l'utilisation ou l'administration conjointe de perhéxiline et d'un ou de plusieurs autres composés qui sont avantageux pour le traitement d'une ICFEN ou de ses symptômes.
PCT/GB2008/003913 2007-11-23 2008-11-24 Traitement d'une insuffisance cardiaque avec fraction d'éjection normale Ceased WO2009066085A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US12/785,077 US8440697B2 (en) 2007-11-23 2010-05-21 Treatment of heart failure
US13/839,313 US9468634B2 (en) 2007-11-23 2013-03-15 Treatment of heart failure
US13/838,458 US9457017B2 (en) 2007-11-23 2013-03-15 Treatment of heart failure

Applications Claiming Priority (4)

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GBGB0723100.4A GB0723100D0 (en) 2007-11-23 2007-11-23 Treatment of HFnEF
GB0723100.4 2007-11-23
US99093307P 2007-11-29 2007-11-29
US60/990,933 2007-11-29

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US12/785,077 Continuation-In-Part US8440697B2 (en) 2007-11-23 2010-05-21 Treatment of heart failure

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010133815A1 (fr) * 2009-05-20 2010-11-25 Heart Metabolics Limited Traitement d'une insuffisance cardiaque à fraction d'éjection normale
US8470806B2 (en) 2004-03-10 2013-06-25 Heart Metabolics Limited Perhexiline for treating chronic heart failure
US8697728B2 (en) 2009-05-13 2014-04-15 The University Of Birmingham Perhexiline for use in the treatment of hypertrophic cardiomyopathy (HCM)
EP2892529A4 (fr) * 2012-09-05 2016-01-20 Adelaide Res &Innovation Pty Ltd Utilisations de (-)-perhexiline

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005087233A1 (fr) * 2004-03-10 2005-09-22 Heart Metabolics Limited Utilisation de perhexiline pour le traitement de l'insuffisance cardiaque chronique

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Publication number Priority date Publication date Assignee Title
WO2005087233A1 (fr) * 2004-03-10 2005-09-22 Heart Metabolics Limited Utilisation de perhexiline pour le traitement de l'insuffisance cardiaque chronique

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METRA ET AL: "Treatment of advanced chronic heart failure with normal left ventricular ejection fraction. Response to the letter by Dr. Martinez-Selles", EUROPEAN JOURNAL OF HEART FAILURE, vol. 9, no. 12, 19 November 2007 (2007-11-19), pages 1224 - 1225, XP022361135, ISSN: 1388-9842 *
METRA M ET AL: "Advanced chronic heart failure: A position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology", EUROPEAN JOURNAL OF HEART FAILURE,, vol. 9, no. 6-7, 10 May 2007 (2007-05-10), pages 684 - 694, XP022069148, ISSN: 1388-9842 *
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8470806B2 (en) 2004-03-10 2013-06-25 Heart Metabolics Limited Perhexiline for treating chronic heart failure
US8697677B2 (en) 2004-03-10 2014-04-15 Heart Metabolics Limited Perhexiline for treating chronic heart failure
US8440697B2 (en) 2007-11-23 2013-05-14 Heart Metabolics Limited Treatment of heart failure
US9457017B2 (en) 2007-11-23 2016-10-04 Heart Metabolics Limited Treatment of heart failure
US9468634B2 (en) 2007-11-23 2016-10-18 Heart Metabolics Limited Treatment of heart failure
US8697728B2 (en) 2009-05-13 2014-04-15 The University Of Birmingham Perhexiline for use in the treatment of hypertrophic cardiomyopathy (HCM)
WO2010133815A1 (fr) * 2009-05-20 2010-11-25 Heart Metabolics Limited Traitement d'une insuffisance cardiaque à fraction d'éjection normale
AU2009346606B2 (en) * 2009-05-20 2016-06-02 Heart Metabolics Limited Treatment of heart failure with normal ejection fraction
EP2892529A4 (fr) * 2012-09-05 2016-01-20 Adelaide Res &Innovation Pty Ltd Utilisations de (-)-perhexiline

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