U.S. patent application number 14/186554 was filed with the patent office on 2014-07-10 for perhexiline for use in the treatment of hypertrophic cardiomyopathy (hcm).
This patent application is currently assigned to The University of Birmingham. The applicant listed for this patent is The University of Birmingham. Invention is credited to Houman ASHRAFIAN, Michael Paul FRENNEAUX.
Application Number | 20140194466 14/186554 |
Document ID | / |
Family ID | 40833905 |
Filed Date | 2014-07-10 |
United States Patent
Application |
20140194466 |
Kind Code |
A1 |
ASHRAFIAN; Houman ; et
al. |
July 10, 2014 |
PERHEXILINE FOR USE IN THE TREATMENT OF HYPERTROPHIC CARDIOMYOPATHY
(HCM)
Abstract
The invention relates to perhexiline, or a pharmaceutically
acceptable salt or enantiomer thereof, for use in the treatment of
hypertrophic cardiomyopathy, as well as to a method of treating
HCM, which comprises administering to an animal in need thereof an
effective amount of perhexiline, or a pharmaceutically acceptable
salt or enantiomer thereof, to treat said HCM. The invention
further relates to a treatment programme for treating HCM, which
involves the co-use or co-administration of perhexiline with one or
more other compounds that are advantageous in treating HCM or the
symptoms thereof.
Inventors: |
ASHRAFIAN; Houman; (London,
GB) ; FRENNEAUX; Michael Paul; (Aberdeenshire,
GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The University of Birmingham |
Birmingham |
|
GB |
|
|
Assignee: |
The University of
Birmingham
Birmingham
GB
|
Family ID: |
40833905 |
Appl. No.: |
14/186554 |
Filed: |
February 21, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13319986 |
Jan 27, 2012 |
8697728 |
|
|
PCT/GB10/50070 |
May 11, 2010 |
|
|
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14186554 |
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Current U.S.
Class: |
514/317 |
Current CPC
Class: |
A61P 9/00 20180101; A61K
31/4458 20130101; A61P 9/02 20180101; A61P 43/00 20180101; A61K
31/366 20130101; A61K 31/445 20130101; A61P 9/04 20180101 |
Class at
Publication: |
514/317 |
International
Class: |
A61K 31/4458 20060101
A61K031/4458; A61K 31/366 20060101 A61K031/366 |
Foreign Application Data
Date |
Code |
Application Number |
May 13, 2009 |
GB |
0908193.6 |
Claims
1. A method for treating hypertrophic cardiomyopathy in a mammal in
need thereof, comprising: diagnosing the mammal as having
hypertrophic cardiomyopathy or at least one of a symptomatic
component, feature or condition thereof; and administering to said
mammal a therapeutically-effective amount of (-)-perhexiline.
2. The method of claim 1, wherein the therapeutically-effective
amount of (-)-perhexiline is sufficient to reduce or ameliorate the
hypertrophic cardiomyopathy or at least one of a symptomatic
component, feature or condition thereof in the mammal.
3. The method of claim 1, wherein the (-)-perhexiline is in the
form of a pharmaceutically acceptable salt.
4. The method of claim 2, wherein the (-)-perhexiline is in the
form of a maleate salt.
5. The method of claim 1, wherein the mammal is a human.
6. The method of claim 1, further comprising co-administering to
said mammal at least one therapeutic compound.
7. The method of claim 1, further comprising co-administering to
said mammal at least one therapeutic compound advantageous in
treating hypertrophic cardiomyopathy or at least one of a
symptomatic component, feature or condition thereof.
8. The method of claim 6, wherein the therapeutic compound is
selected from a member of the group consisting of Alpha Blockers,
Beta Blockers, Calcium Channel Blockers, Diuretics, Ace
(Angiotensin-Converting Enzyme) Inhibitors, Arb (Angiotensin II
Receptor Blockers), Spironolactone, Nitrate, Warfarin, Verapamil,
Insulin, Amiodarone, Lisinopril, Ramipril, Perindopril, Enalapril,
Trandolapril, At2 Receptor Blockers, Losartan, Valsartan,
Irbersartan, Carvedilol, Bisoprolol, Metoprolol, Atenolol, Aspirin,
Clopidogrel, Oral Hypoglycaemics, Disopyramide, and Statins.
9. A method for treating a mammal having at least one of a
symptomatic component, feature or condition associated with
hypertrophic cardiomyopathy, comprising: diagnosing the mammal as
having at least one of a symptomatic component, feature or
condition associated with hypertrophic cardiomyopathy; and
administering to said mammal a therapeutically-effective amount of
(-)-perhexiline.
10. The method of claim 9, wherein the symptomatic component,
feature or condition is member of the group consisting of dyspnoea
(shortness of breath), chest pain, fatigue, palpitation and
syncope.
11. The method of claim 9, wherein the mammal is further diagnosed
as having a member of the group consisting of reduced left
ventricular ejection fraction (LVEF), reduced E:EA ratio,
abnormally rapid skeletal muscle phosphocreatine depletion with
delayed recovery, reduced systolic velocity (PSV), diminished
exercise capacity or tolerance, diminished peak oxygen consumption
(VO.sub.2max) during exercise, diastolic dysfunction at rest and
during exercise as measured by Time to Peak LV Filling (nTTPF), no
significant LVOT obstruction at rest (gradient<30 mmHg), and
impaired myocardial energetic state (PCr/.gamma.ATP ratio).
12. The method of claim 9, wherein the extent of hypertrophic
cardiomyopathy in the mammal is diagnosed in accordance with a New
York Heart Association (NYHA) classification.
13. The method of claim 9, further comprising: determining a NYHA
classification score (breathlessness) of the mammal before and
after administration of perhexline, wherein a decreased NYHA score
after administration of perhexline indicates a reduction in the
extent of hypertrophic cardiomyopathy or at least one of a
symptomatic component, feature or condition thereof in the
mammal.
14. The method of claim 13, wherein the NYHA classification score
of the mammal after administration of (-)-perhexiline decreases
from Class III to Class II.
15. The method of claim 9, wherein the extent of hypertrophic
cardiomyopathy in the mammal is diagnosed in accordance with a
Minnesota Living with Heart Failure Questionnaire (MLHFQ)
score.
16. The method of claim 15, further comprising determining a MLHFQ
(quality of life) score of the mammal before and after
administration of (-)-perhexiline, wherein a decreased MLHFQ score
after administration of (-)-perhexiline indicates a reduction in
the extent of hypertrophic cardiomyopathy or at least one of a
symptomatic component, feature or condition thereof in the
mammal.
17. The method of claim 9, further comprising determining peak
oxygen consumption (VO.sub.2max) in the mammal during exercise
wherein an increase in peak oxygen consumption (VO.sub.2max) in the
mammal after administration of (-)-perhexiline indicates a
reduction in the extent of hypertrophic cardiomyopathy or at least
one of a symptomatic component, feature or condition thereof in the
animal.
18. The method of claim 9, wherein (-)-perhexiline is administered
in an amount of 300 mg or less per day.
19. The method of claim 9, wherein (-)-perhexiline is administered
in an amount of 100 mg or less per day.
20. The method of claim 9, wherein (-)-perhexiline is administered
in an amount of 100 mg to 300 mg per day.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/319,986, filed Jan. 27, 2012, which is a National Stage
Entry for International Application No. PCT/GB2010/050770, filed
May 11, 2010, which claims the benefit of priority of GB 0908193.6,
filed May 13, 2009. The entire contents of each of the foregoing
applications identified above are incorporated herein by
reference.
BACKGROUND
[0002] The invention relates to treatment of hypertrophic
cardiomyopathy (HCM) in animal subjects, in particular humans.
Hypertrophic cardiomyopathy, characterised by unexplained cardiac
hypertrophy, is the commonest inherited cardiac condition
(prevalence .about.0.2%). The clinical manifestations of HCM can
range from the complete absence of symptoms to dyspnoea, chest
pains, palpitations, and syncope; HCM's first presentation may even
be as sudden cardiac death. Left ventricular outflow tract
obstruction that accounts for some of these symptoms in a
proportion of HCM patients, may be amenable to drug therapies and
to interventions such as surgical septal myectomy or alcohol septal
ablation. However, less progress has been made, in the treatment of
the substantial number of patients with HCM without obstruction, in
whom dyspnoea appears to be primarily due to diastolic dysfunction.
Evidence supporting the benefit of the negative chrono-inotropes
(eg, beta-blockers, verapamil, disopyramide), which are extensively
used by these patients, is limited mandating a better understanding
of the mechanisms underlying HCM with the intention of identifying
novel therapies.
[0003] HCM is a disease of the perturbed sarcomere, with >400
mutations having been identified in genes encoding cardiac
contractile proteins (e.g. .beta.-myosin heavy chain, cardiac
myosin-binding protein-C, .alpha.-tropomyosin, cardiac troponin T
and I). HCM-causing mutations increase sarcomeric Ca.sup.2+
sensitivity, ATPase activity and the energetic "tension cost" of
myocyte contraction. These biophysical considerations have led to
the proposal that the pathophysiology of HCM is attributable, at
least in part, to excessive sarcomeric energy use. Supporting this
proposal, myocardial energy defects have been associated with HCM,
in both animal and human disease. Indeed, consistent with a
functional role for this energy deficiency, LV relaxation (an
energy requiring process), has been observed to be aberrant in
HCM.
[0004] 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.
[0005] 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.
SUMMARY
[0006] According to a first aspect of the present invention, there
is provided a method of treating hypertrophic cardiomyopathy (HCM),
which comprises administering to an animal in need thereof an
effective amount of perhexiline, or a pharmaceutically acceptable
salt thereof, to treat said HCM. The animal is preferably a mammal
and most preferably a human.
[0007] The HCM treated may be obstructive HCM or non-obstructive
HCM.
[0008] According to another aspect of the present invention,
perhexiline, or a pharmaceutically acceptable salt thereof, is
provided for use in the treatment of HCM.
[0009] According to a further aspect of the invention there is
provided a treatment programme for treating HCM, 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 HCM or the symptoms thereof, for example a
calcium channel blocker such as verapamil, or a beta blocker.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 is a flow chart of a study carried out to establish a
causative role for energy deficiency and to evaluate the impact of
perhexiline on cardiac energy status in HCM.
[0011] FIGS. 2A-2D represent the baseline data of HCM vs controls,
more particularly:
[0012] FIG. 2A represents the peak oxygen consumption (peak
V.sub.O2) results;
[0013] FIG. 2B represents the diastolic ventricular filling results
(nTTPF, normalized for heart rate Time To Peak Filling) and shows
that PCr/ATP ratio (a measure of cardiac energetic state) is lower
in HCM patients versus controls.;
[0014] FIG. 2C is an example of .sup.31P cardiac spectra of a HCM
patient in which Point C indicates centre of phosphorus coil, VOI;
voxel of interest, 2,3-DPG indicates 2,3-diphosphoglycerate; PDE,
phosphodiesters; PCr, phosphocreatine; .alpha., .beta., .gamma.
indicate the three phosphorus nuclei of ATP, and shows that nTTPF
(a measure of the rate of active relaxation of the LV) is
essentially unchanged on exercise in the controls bu abnormally
slows in the HCM patients; and
[0015] FIG. 2D represent the myocardial energetic results
(PCr/.gamma. ATP ratio) and shows that exercise capacity (peak VO2)
is lower in HCM patients versus controls.
[0016] FIGS. 3A and 3B respectively represent the effect of Placebo
and Perhexiline on peak oxygen consumption (peak V.sub.O2), p=0.003
and myocardial energetic (PCr/.gamma. ATP ratio), p=0.003, where
the p value represents the significant difference between
perhexiline and placebo response. Peak VO2 (exercise capacity)
increases with Perhexiline (FIG. 3A). Perhexiline improves PCr/ATP
ratio (energetic status of heart), but this was unchanged in the
placebo group (FIG. 3B).
[0017] FIGS. 3C and 3D respectively represent nTTPF changes in the
placebo group (3C) and the perhexiline group (3D), p=0.03, where
the p value represents the significant difference between
perhexiline and placebo response. In the placebo group nTTPF (a
measure of the rate of LV active relaxation) abnormally lengthened
at baseline and on treatment. The response in healthy controls is
shown in dotted lines. Perhexiline (FIG. 3D) normalises the
response to similar to that seen in healthy controls (also shown in
dotted lines).
[0018] FIG. 3E and 3F illustrate that NYHA (New York Heart
Association) score (of breathlessness) falls (improves) with
perhexiline (3E) and Minnesota Living with Heart Failure
Questionnaire (MLHFQ) score falls (=improved quality of life) on
perhexiline (3F).
[0019] FIG. 4 illustrate the causative role for energy deficiency
in the pathophysiology of HCM.
DETAILED DESCRIPTION OF EXAMPLE EMBODIMENTS
[0020] In aspects of the present invention, 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 J A,
Kiosoglous A J, Murphy G A, Pelle M A, Horowitz J D. "Effect of
perhexiline and oxfenicine on myocardial function and metabolism
during low-flow ischemia/reperfusion in the isolated rat heart", J
Cardiovasc Pharmacol 2000; 36(6):794-801). Typical doses for a
normal patient would be 100 mg to 300 mg daily, although smaller
doses may be appropriate for patients who are slow metabolizers of
perhexiline.
[0021] Physiologically acceptable formulations, such as salts, of
the compound perhexiline, may be used in the invention.
Additionally, 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. Preferably, 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.
[0022] Perhexiline exists as two enantiomers, (+)-perhexiline and
(-)- perhexiline which are known to be metabolized differently
based on patient genotype. It has further been proposed that the
atypical kinetics observed in the inhibition of both cardiac and
liver derived CPT-1 may have been due to different inhibition
affinities of each enantiomer of perhexiline for both the muscle
and liver isoforms of CPT-1, and that (+)-perhexiline and
(-)-perhexiline may exhibit differential selectivity for target
enzymes in cardiac and hepatic tissues.
[0023] In accordance with the invention, perhexiline may be used as
a racemic mixture (typically a 50:50 mixture of the enantiomers),
or as one or other of the (+)-perhexiline and (-)-perhexiline
enantiomers, or as a mixture of the two enantiomers in any
ratio.
[0024] Based on relative pharmacodynamic activities of the
individual enantiomers, therapeutic drug monitoring may be employed
based on specific enantiomer target concentration ranges in plasma
for the racemic preparation of perhexiline, or by developing a
target concentration for a chiral preparation.
[0025] As indicated, the preferred subject for treatment is a
human. However, the treatment may be a veterinary one. For example,
treatment of cats suffering from feline HCM is contemplated.
[0026] The invention is illustrated by the following non-limiting
examples.
EXAMPLE
[0027] A study was carried out to establish a causative role for
energy deficiency and to evaluate the impact of perhexiline on
cardiac energy status in HCM.
[0028] The study was approved by the South Birmingham Research
Ethics Committee and the investigation conforms with the principles
outlined in the Declaration of Helsinki. All study participants
provided written informed consent. The study was a randomized,
double blind, placebo-controlled parallel-group design of minimum 3
months duration. FIG. 1 represents a flow chart of the study. The
pre-defined primary end point was peak oxygen consumption (peak
VO2). Pre-defined secondary end points were symptomatic status,
resting myocardial energetics (PCr/.gamma.-ATP ratio) and diastolic
function at rest and during exercise (nTTPF). 33 controls of
similar age and gender distribution were recruited for comparison
with baseline data of HCM patients. All controls had no history or
symptoms of any cardiovascular disease with normal ECG and
echocardiogram (LVEF.gtoreq.55%).
[0029] Patients were recruited from dedicated cardiomyopathy
clinics at The Heart Hospital, University College London Hospitals,
London and Queen Elizabeth Hospital, Birmingham, UK between 2006
and 2008. Inclusion criteria were 18 to 80 years old symptomatic
HCM patients (predominant symptom breathlessness) in sinus rhythm
with reduced peak VO2 (<75% of predicted for age and gender) and
no significant LVOT obstruction at rest (gradient<30 mmHg).
Exclusion criteria were presence of epicardial coronary artery
disease, abnormal liver function test, concomitant use of
amiodarone or selective serotonin reuptake inhibitors (due to
potential drug interactions with perhexiline), peripheral
neuropathy and women of childbearing potential. Diabetic patients
were also excluded to maintain the blindness of the study as
Perhexiline may lead to a reduction in plasma glucose in such
patients necessitating a reduction in anti-diabetic therapy. 46
consecutive consenting patients who met these entry criteria were
recruited into the study.
[0030] Patients were subjected to a number of tests and assessments
as follows.
Cardiopulmonary Exercise Test
[0031] This was performed using a Schiller CS-200 Ergo-Spiro
exercise machine which was calibrated before every study. Subjects
underwent spirometry and this was followed by symptom-limited erect
treadmill exercise testing using a standard ramp protocol with
simultaneous respiratory gas analysis (Bruce R A, McDonough J R.
Stress testing in screening for cardiovascular disease. Bull N Y
Acad Med 1969; 45(12):1288-1305.; Davies N J, Denison D M. The
measurement of metabolic gas exchange and minute volume by mass
spectrometry alone. Respir Physiol 1979;36(2):261-267). Peak oxygen
consumption (peak VO2) was defined as the highest VO2 achieved
during exercise and was expressed in ml/min/kg.
Symptomatic Status Assessment
[0032] All HCM patients filled in Minnesota Living with Heart
Failure Questionnaire and were also assessed for NHYA class.
[0033] Transthoracic Echocardiography
[0034] Echocardiography was performed with participants in the left
lateral decubitus position with a Vivid 7 echocardiographic machine
(GE Healthcare) and a 2.5-MHz transducer. Resting scans were
acquired in standard apical 4-chamber and apical 2-chamber. LV
volumes were obtained by biplane echocardiography, and LVEF was
derived from a modified Simpson's formula (Lang R M, Bierig M,
Devereux R B et al. Recommendations for chamber quantification: a
report from the American Society of Echocardiography's Guidelines
and Standards Committee and the Chamber Quantification Writing
Group, developed in conjunction with the European Association of
Echocardiography, a branch of the European Society of Cardiology. J
Am Soc Echocardiogr 2005;18(12):1440-1463.) Pulse wave doppler
sample volume was used to assess resting LVOTO gradient.
Radionuclide Ventriculography
[0035] Diastolic filling were assessed by equilibrium R-wave gated
blood pool scintigraphy using a standard technique at rest and
during graded semi erect exercise on a cycle ergometer (Atherton J
J, Moore T D, Lele S S et al. Diastolic ventricular interaction in
chronic heart failure. Lancet 1997;349 (9067):1720-1724; Lele S S,
Macfarlane D, Morrison S, Thomson H, Khafagi F, Frenneaux M.
Determinants of exercise capacity in patients with coronary artery
disease and mild to moderate systolic dysfunction. Role of heart
rate and diastolic filling abnormalities. Eur Heart J
1996;17(2):204-212). 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 were measured
at rest and during exercise (50% of heart rate reserve). The
validity of these radionuclide measures of diastolic filling at
high heart rates has been established previously (Atherton et al.
and Lele et al., see above).
31 P cardiac Magnetic Resonance Spectroscopy (MRS)
[0036] In vivo myocardial energetics were measured using a MRS at
3-Tesla Phillips Achieva 3T scanner (Shivu G N, Abozguia K, Phan T
T, Ahmed I, Henning A, Frenneaux M. (31)P magnetic resonance
spectroscopy to measure in vivo cardiac energetics in normal
myocardium and hypertrophic cardiomyopathy: Experiences at 3T. Eur
J Radiol 2008). A Java magnetic resonance user interface v3.0
(jMRUI) was used for analysis (see Naressi A, Couturier C, Castang
I, de Beer R, Graveron-Demilly D. Java-based graphical user
interface for MRUI, a software package for quantitation of in
vivo/medical magnetic resonance spectroscopy signals. Comput Biol
Med 2001;31(4):269-286)). PCr and .gamma.-ATP peaks was used to
determine the PCr/.gamma.-ATP ratio which is a measure of the
cardiac energetic state (Neubauer S, Krahe T, Schindler R et al.
31P magnetic resonance spectroscopy in dilated cardiomyopathy and
coronary artery disease. Altered cardiac high-energy phosphate
metabolism in heart failure. Circulation 1992;86(6):1810-1818).
Data were analyzed by an investigator who was blinded to the
participants' clinical status. Carmeo-Rao ratio was used to assess
signal to noise ratio. A typical example of cardiac 31P MRS spectra
from a patient with HCM is shown in FIG. 2C.
Intervention
[0037] Following baseline studies, patients were randomized in a
double-blind fashion to receive either perhexiline (n=25) or
placebo (n=21) 100 mg OD. Serum perhexiline levels were obtained at
1 and 4 weeks after initiation of the drug. Dose adjustments were
advised by an unblinded physician according to serum level to
achieve therapeutic level and to avoid drug toxicity. Identical
dosage adjustments were also made for randomly allocated
placebo-treated patients by the unblinded observer to ensure that
blinding of the investigators was maintained. At the end of study,
patients were re-evaluated as described earlier.
[0038] Data were analyzed using SPSS ver. 15.0 for Window and
Microsoft Office Excel 2007, and expressed as Mean.+-.Standard
Deviation (SD). Comparison of continuous variables between
Perhexiline and Placebo baseline data were determined by unpaired
Student's t-test (2-tail) if variables were normally distributed
and the Mann-Whitney U-test if the data were non-normally
distributed. ANCOVA with baseline values as covariates was
performed to test for the significance of differences in the
perhexiline versus placebo group after treatment. For the primary
end point, the sample size required to detect a change in peak Vo2
of 3 ml/kg/min versus placebo group with a power of 90% and
probability of 5% is 44. 30 patients will be required to identify a
5% change in cardiac PCr/ATP ratio with a power of 90% and a p
value of <0.05. 40 patients will be required to detect a change
25% in nTTPF with power of 0.99 with probability of 5%. Therefore,
we aimed to study 50 patients including the drop-outs, 32 of them
will take part in the MRS study.
[0039] The characteristics and treatment of participants are shown
in Table 1 below. V.sub.O.sub.2; refers to peak oxygen consumption,
ACE: refers to angiotensin-converting enzyme, and ARB refers to
angiotensin II receptor blockers.
TABLE-US-00001 TABLE 1 The clinical characteristics of HCM patients
and controls. HCM HCM HCM Controls P value (Perhexiline) (Placebo)
P value Age [years] 55 .+-. 0.26 52 .+-. 0.46 0.2 56 .+-. 0.46 54
.+-. 0.64 0.42 Number (Male) 46 (34) 33 (20) 0.64 25 (19) 21 (17)
0.69 Heart Rate [bpm] 69 .+-. 0.27 82 .+-. 0.47 <0.001* 69 .+-.
0.53 69 .+-. 0.52 0.97 Systolic BP [mm Hg] 126 .+-. 0.64 126 .+-.
0.44 0.93 123 .+-. 0.84 130 .+-. 0.92 0.2 Diastolic BP [mm Hg] 76
.+-. 0.25 78 .+-. 0.34 0.33 74 .+-. 0.45 78 .+-. 0.57 0.24 Peak
Vo.sub.2 [ml/kg/min] 23 .+-. 0.12 38 .+-. 0.24 <0.0001* 22.2
.+-. 0.2 23.56 .+-. 0.27 0.42 Resting nTTPF (sec) 0.17 .+-. 0.002
0.18 .+-. 0.003 0.44 0.19 .+-. 0.003 0.17 .+-. 0.004 0.52 PCr/yATP
ratio 1.28 .+-. 0.01 2.26 .+-. 0.02 <0.0001* 1.27 .+-. 0.02 1.29
.+-. 0.01 0.86 Drug therapy--no. Beta-blocker 17 0 -- 10 7 0.21
CC-blocker 24 0 -- 11 8 0.53 Diuretic 10 0 -- 4 5 0.49 ACE
inhibitor 6 0 -- 3 2 0.84 ARB 4 0 -- 3 1 0.41 Warfarin 5 0 -- 2 3
0.48 Statin 15 0 -- 7 7 0.9 *indicates statistical significance
Baseline Data (HCM Versus Controls)
[0040] The clinical characteristics and cardiopulmonary exercise
test results of all the HCM patients and controls are shown in
Table 1. The groups were well matched with respect to age and
gender. Heart rate was lower in the HCM group compared to controls
due to medication use (beta blockers and/or calcium channel
blockers).
[0041] The resting cardiac PCr/.gamma.ATP ratio was lower in HCM
patients than in controls (1.28.+-.0.01vs 2.26.+-.0.02,
p<0.0001) (see FIGS. 2A and B), and this remained so after
excluding patients taking beta blocker therapy (p<0.0001). At
rest, nTTPF, a sensitive marker of LV relaxation, was similar in
HCM patients and controls (0.17.+-.0.002 vs 0.18.+-.0.003 sec,
p=0.44). During submaximal exercise (at a workload that achieved
50% of heart rate reserve) it remained relatively constant in
controls (from 0.18.+-.0.003 sec to 0.16.+-.0.002 sec,
[.delta.nTTPF=-0.02.+-.0.003 sec]), but lengthened in patients
(from 0.17.+-.0.002 to 0.34.+-.0.002 sec,
[.delta.nTTPF=+0.17.+-.0.002 sec]) p<0.0001, (FIG. 2C). This
pattern persisted after exclusion of patients on beta blockers and
remained significantly different from controls (p<0.0001).
Patients exhibited marked exercise limitation compared to controls
(23.+-.0.12 vs 38.+-.0.24 ml/kg/min, p<0.0001) (FIG. 2D).
[0042] Randomized, Double Blinded, Placebo-Controlled
Parallel-Group
[0043] The perhexiline and placebo groups were well matched (see
Table 1). Only one patient (on placebo) did not complete the study
due to poor compliance. Side effects were restricted to transient
nausea (n=3) and dizziness (n=2) in the perhexiline group and
transient nausea (n=2) and headache (n=1) in the placebo group
during the first week of treatment. There were no deaths during the
study period.
Myocardial Energetics
[0044] The PCr/.gamma.ATP ratio increased with perhexiline
(1.27.+-.0.02 to 1.73.+-.0.02) as compared with placebo
(1.29.+-.0.01 to 1.23.+-.0.01), p=0.003 (see FIG. 3A). The mean
Cramer-Rao ratios for PCr and .gamma.ATP were 7.5% and 10.8%
respectively. The effect of perhexiline on PCr/.gamma.ATP ratio
remained significant after inclusion of the 3 patients with Cramer
Rao ratios>20 from the analysis (p=0.02).
[0045] Diastolic Ventricular Filling
[0046] Whereas the placebo group showed similar prolongation of
nTTPF during exercise before and after therapy (0.17.+-.0.004 to
0.35.+-.0.005 [.delta.nTTPF 0.18.+-.0.006 sec] and 0.23.+-.0.006 to
0.35.+-.0.005 sec [.delta.nTTPF 0.12.+-.0.006 sec], respectively),
in the perhexiline group there was a substantial improvement on
therapy with nTTPF at rest and exercise similar (0.19.+-.0.003 to
0.19.+-.0.004 sec [.delta.nTTPF 0.00.+-.0.003 sec]) p=0.03 between
the perhexiline and placebo response (see FIGS. 3B and 3C).
Symptomatic Status
[0047] More patients in the perhexiline group than in the placebo
group had improvements in NYHA classification (67 percent vs. 30
percent) and fewer had worsening (8 percent vs. 20 percent)
(p<0.001). Minnesota Living with Heart Failure Questionnaire
score showed an improvement (fall in score) in the perhexiline
group (from 36.13.+-.0.94 to 28.+-.0.75) but did not change in the
placebo group (p<0.001) (see FIGS. 3D and 3E).
[0048] Exercise Capacity (Peak Oxygen Consumption)
[0049] Peak V.sub.O2 at baseline was similar in the perhexiline and
placebo groups (Table 1). After treatment, Peak V.sub.O2 fell by
-1.23 ml/kg/min in the placebo group (from 23.56.+-.0.27 to
22.32.+-.0.27 ml/kg/min) but increased by 2.09 ml/kg/min in the
perhexiline group (from 22.2.+-.0.2 to 24.29.+-.0.2 ml/kg/min),
p=0.003 (see FIG. 3F).
Discussion Of Results
[0050] The study indicates that patients with symptomatic HCM
manifest a cardiac energy defect at rest (reduced PCr/.gamma.ATP
ratio). This defect was accompanied by a slowing of the
energy-requiring early diastolic LV active relaxation during
exercise (prolongation of nTTPF). The metabolic modulator
perhexiline resulted in significant myocardial energy augmentation.
Supporting a causative role for energy deficiency in the
pathophysiology of HCM, this energy augmentation was accompanied by
striking normalisation of HCM's characteristic "paradoxical"
nTTPF-prolongation in exercise. These biochemical and physiological
improvements translated into significant subjective (NYHA
classification and QoL score) and objective (V.sub.O2) clinical
benefits in symptomatic HCM patients already on optimal medical
therapy (see FIG. 4).
[0051] The subject headings used herein are included only for the
ease of reference of the reader and should not be used to limit the
subject matter found throughout the disclosure or the claims. The
subject headings should not be used in construing the scope of the
claims or the claim limitations.
[0052] Future patent applications may be filed on the basis of the
present application, for example by claiming priority from the
present application, by claiming a divisional status and/or by
claiming a continuation status. It is to be understood that the
following claims are provided by way of example only, and are not
intended to limit the scope of what may be claimed in any such
future application. Nor should the claims be considered to limit
the understanding of (or exclude other understandings of) the
present disclosure. Features may be added to or omitted from the
example claims at a later date.
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