Steroidal hormones for the treatment and prevention of wave burst arrhythmia

Abstract

The invention relates to a new method for the prevention and treatment of wave burst arrhythmia by administering a gestagen having an androgenic effect.

Claims

1. A method for treating torsades de pointes comprising administering to a patient a compound of general formula (I): ##STR00008## wherein R1 is chosen from H, CH.sub.3, CH.sub.2—CH.sub.3, CH═CH.sub.2, and C≡CH; R2 is chosen from CH.sub.3, CH.sub.2—CH.sub.3, CH═CH.sub.2, and C≡CH; R3 is chosen from —H, —CH.sub.3, =CH.sub.2, wherein the bond between the carbon of the ring and R3 is a double bond, and ≡CH, wherein the bond between the carbon of the ring and R3 is a triple bond; and R4 is chosen from —H, —OH and =O, wherein the bond between the carbon of the ring and R4 is a double bond; wherein the compound of general formula (I) is chosen from levonorgestrel, norethisterone, desogestrel, etonogestrel, 19-nortestosterone, medroxyprogesterone, or medroxyprogesterone acetate.

2. The method of claim 1, wherein the method comprises preventing the occurrence of episodes of torsades de pointes.

3. The method of claim 1, wherein the method comprises preventing sudden death in a diabetic patient.

4. The method of claim 1, wherein the patient has a predisposition to the occurrence of torsades de pointes.

5. The method of claim 4, wherein the patient is following a treatment with a QT-increasing drug.

6. The method of claim 1, wherein the compound of general formula (I) is administered to the patient after an episode of torsade de pointes.

7. The method of claim 6, wherein the compound of general formula (I) is administered to the patient for a period of less than or equal to 15 days.

8. The method of claim 1, wherein compound of general formula (I) is administered to the patient in a daily amount between 30 pg and 3 mg.

9. The method of claim 1, wherein compound of general formula (I) is administered to the patient in a daily amount between 30 pg and 300 pg.

10. The method of claim 1, wherein compound of general formula (I) is administered orally to the patient.

11. The method of claim 1, wherein compound of general formula (I) is administered by injection to the patient.

12. The method of claim 1, wherein the patient is female.

13. The method of claim 1, further comprising administering an androgen to the patient.

14. The method of claim 13, wherein the androgen is chosen from testosterone, dehydroepiandrosterone, Δ4-androstenedione, androsterone, and dihydrotestosterone.

15. The method of claim 3, further comprising administering IGF-I to the patient.

16. The method of claim 3, further comprising administering an androgen to the patient, wherein the patient is male.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1: characteristics of the patients having received sotalol, and of their method of contraception. H3 represents the value three hours after administration of sotalol.

(2) Statistics: ns represents p>0.1. Various tests (Chi.sup.2 test with trend, one-way ANOVA with Tukey or Kruskal-Wallis post-test with Dunn's post-test) were used. The quantitative data are presented as a mean±standard error or median with interquartile range.

(3) *(no hormones vs drospirenone), **(levonorgestrel vs drospirenone), # (desogestrel vs gestodene), § (levonorgestrel vs no hormones), ‡ (gestodene vs no hormone).

(4) The PC1 value is obtained by analysis by main components of the variables ΔQTc (%), ΔTpTe (%) and ΔTAmp (%) and quantitatively reflects the IKr inhibition obtained three hours after taking sotalol.

(5) FIG. 2: PC1 value three hours after administration of 80 mg of sotalol as a function of the pill type. The statistics (significant values) were obtained by means of a Kruskal-Wallis test with Dunn's post test. Significance with threshold: p<0.05.

(6) FIG. 3: Value of the difference in QTc (ms) three hours after administration of 80 ms of sotalol as a function of the pill type. The statistics (significant values) were obtained by ANOVA with Tukey post-test, p<0.01.

(7) FIG. 4: number and proportion of patients with a double T-wave peak induced by sotalol as a function of the type of contraception.

EXAMPLES

Example 1—Development of a Marker Representative of Inhibition of the IKr Potassium Channel

(8) Results obtained on a cohort of 995 volunteers in good health, from 18 to 60 years old, of European or North African origin, were used for the development of a marker representative of inhibition of the IKr potassium channel.

(9) The results were obtained on an exploration cohort, having served to identify the marker described below, and a replication cohort having served to verify the results obtained on the exploration cohort.

(10) Briefly, the electrocardiogram (ECG) of the patients (each one in triplicate, for 10 seconds) was recorded after 10 minutes at rest lying on their back. A single oral dose of 80 mg of sotalol was then given to the patients and the ECG monitoring was continued. Three hours after the sotalol had been taken, the ECG was again recorded (in triplicate) after the subjects had remained lying on their back for 10 minutes.

(11) ECG Analysis

(12) The increase in the QT by sotalol represents the equivalent of the congenital iatrogenic form of long QT syndrome LQT2; the appearance of the conventional differences between the basal trace and the trace three hours after taking sotalol was verified on the ECG.

(13) The QTcF (QT corrected using Fridericia's formula), TpTe (interval between the first peak and the end of the T wave), TAmp (amplitude of the first peak of the T wave) and the presence of double peaks in the T wave (called notches) were quantified. The Fridericia correction (QTcF) was used to correct the QT with respect to the heart rate, in accordance with the ICH guidelines E14.

(14) The analysis of the ECG data was carried out with the CARDIABASE software (Group Banook, Nancy, France).

(15) TpTe was measured using the tangent method, in triplicate, on a representative heart beat (averaged representation of an ECG of 10 seconds) on the V3, V4 and V5 derivations. In the event of a double peak of the T wave (notch), the peak taken into consideration was the first peak, even if the amplitude of the T wave was smaller for this peak. The average value obtained was retained. In the event of it being impossible to measure TpTe on V3, V4 or V5, the measurement was instead carried out on V2 (for V3), or V6 (for V4/V5).

(16) In order to measure TAmp, positioning was on the site of the maximum amplitude of the first peak of the T wave on a representative beat (averaged representation of an ECG of 10 seconds) on the DII, V2 and V3 leads. The average of the TAmp values resulting from these three leads, and measured on three different ECGs of 10 seconds (in triplicate), was calculated and retained. If it was not possible to measure a TAmp on one of these leads (in particular because of a low value (<0.1 mV)), the V4 lead was used.

(17) QTcF was measured using the tangent method on the DII lead for three consecutive beats and the average value of an evaluation in triplicate was retained.

(18) It was possible to verify that the measurements remained consistent and reproducible between the evaluators.

(19) For these parameters, the difference between the value obtained at H3 and the basal value was measured. This difference was expressed as percentage relative to the basal value, and the calculations were carried out such that the value calculated is positive.

(20) The following calculations were therefore carried out:
ΔQTcF (%)=(QTcF at H3−QTcF basal)/(QTcF basal)×100
ΔTpTe (%)=(TpTe at H3−TpTe basal)/(TpTe basal)×100
ΔTAmp (%)=(TAmp basal−TAmp at H3)/(TAmp basal)×100

(21) In order to evaluate the double peaks (notches), all the ECGs were evaluated independently by two investigators. The patients were described as notchers or non-notchers, in the event of agreements between the two investigators. In the event of disagreement in the evaluation, the subjects were not included in these groups (only ten subjects in the evaluation cohort and eight subjects in the replication cohort could thus not be classified).

(22) Principal Component Analysis

(23) A principal component analysis was carried out on the calculated values ΔQTcF, ΔTpTe and ΔTAmp, which made it possible to generate three non-correlated alternative markers PC1, PC2 and PC3, taking better account of the information carried by the three initial correlated values. The statistical analyses were carried out with the R software (https://www.r-project.org/). Principal component analysis (PCA) is a method which makes it possible to convert correlated variables into new variables which are not correlated with one another.

(24) Results

(25) Sotalol-Induced Changes in the Electrocardiogram

(26) The changes observed in the electrocardiogram three hours after administration of sotalol suggest an inhibition of the IKr channel, with results and observations similar in the exploration and replication cohorts, regardless of the qualitative or quantitative parameters evaluated.

(27) In agreement with previous studies, sotalol also induces absolute and relative changes in the duration of QTcF (21.4±14 ms and 5.5±3.5% respectively).

(28) Typical changes in the shape of the T wave were also observed, with an increase in TpTe (14.2±15.6 vs 15.9±20.5%, p=ns (not significant)) and a decrease in TAmp (13.6±15.7 vs 12.8±15.3%, p=ns) respectively between the exploration and replication cohorts.

(29) However, a large inter-subject variability was observed in all the changes observed. The variations in TpTe, TAmp and QTcF between H3 and the basal level exhibit an autocorrelation in the same proportion between the two cohorts.

(30) Finally, 40 (8%) or 51 (10%) subjects exhibited a double peak (notch) in each of the two cohorts. They were almost exclusively women, and these patients had a higher ΔTpTe, ΔQTcF and ΔTAmp than those observed for the non-notchers (patients without double peak).

(31) Principal Component Analysis

(32) The principal component analysis made it possible to generate three new quantitative values, linked to the sotalol-induced modifications of ventricular repolarization.

(33) The first component (PC1) explaining approximately 65-67% of the phenotypic variance reflects the typical modifications after inhibition of the IKr channel, that is to say the increase in TpTe and QTcF and the decrease in TAmp (Table 1).

(34) The PC1 variable under consideration is the variable which correlates best with each of ΔQTc, ΔTAmp and ΔTpTe. This signifies that the correlation coefficient that can be calculated for PC1 with each of ΔQTc, ΔTAmp and ΔTpTe is greater (in absolute value) than the correlation coefficient that is calculated for the other principal components of PC2 and PC3 for ΔQTc, ΔTAmp or ΔTpTe in question. Table 1 of the examples clearly shows that the absolute value of the correlation coefficient of PC1 is greater than the absolute value of the correlation coefficient of PC2 and PC3, calculated for each of ΔQTc, ΔTAmp and ΔTpTe.

(35) Depending on how the principal component analysis is carried out, PC1 can correlate positively or negatively with ΔQTc, ΔTAmp and ΔTpTe described above. The PC1 value is very clearly associated with the appearance of ECG sign determining an inhibition of IKr, and presumed to be associated with an increased risk of episode of torsade de pointes with long QT.

(36) In the context of the calculation carried out in this study which made it possible to demonstrate the PC1 marker, PC1 correlates negatively with ΔQTc, ΔTAmp and ΔTpTe.

(37) Consequently, the increase in these values leads to a decrease in PC1.

(38) A significant decrease in the PC1 value (p<10.sup.−4) was observed in the patients exhibiting a double peak (notchers) compared with the patients not exhibiting this double peak (non-notchers) in one or other of the exploration (−2.5±1.5 vs 0.3±1.1) or replication (−2.3±1.8 vs 0.3±1.1) cohorts.

(39) The PC1 value is therefore a quantitative alternative value of the inhibition of IKr.

(40) The other principal components (PC2 and PC3) explained, respectively, approximately 19-21% and 14% of the phenotypic variance.

(41) TABLE-US-00001 TABLE 1 Correlations (r) between ΔTAmp, ΔTpTe, ΔQTcF and the principal components in the exploration cohort (n = 489, upper part of the table) or the replication cohort (n = 495, lower part of the table) Correlation(r) ΔTAmp ΔTpTe ΔQTcF PC1 PC2 PC3 ΔTAmp 1 0.59 0.40 −0.83 0.36 −0.43 ΔTpTe 0.58 1 0.45 −0.85 0.23 0.47 ΔQTcF 0.47 0.46 1 −0.73 −0.68 −0.06 PC1 −0.84 −0.84 −0.78 1 0 0 PC2 0.28 0.3 −.063 0 1 0 PC3 −0.46 0.45 0.01 0 0 1

(42) It is clearly observed that PC1 correlates in the same sense with ΔTAmp, ΔTpTe and ΔQTcF (correlated negatively in this example), which is not the case for PC2 or PC3.

(43) It is also observed that the absolute value of the correlation coefficients of PC1 with ΔTAmp, ΔTpTe and ΔQTcF is greater than that of PC2 or PC3 with these values.

(44) Conclusion

(45) As expected, an increase in TpTe and QTcF and a decrease in TAmp were observed between the basal level and three hours after taking sotalol.

(46) The new PC1 value obtained by principal component analysis of ΔQTcF, ΔTpTe and ΔTAmp explains most of the total variance of the “A” data (ΔQTcF, ΔTpTe and ΔTAmp) and is thus associated with the common mechanism of increase in QTcF and TpTe, associated with the decrease in TAmp.

(47) Consequently, PC1 is a quantitative and integrative marker for drug-induced IKr inhibition.

Example 2—Levonorgestrel and Desogestrel have a Rather Protective Action on the Inhibition of the IKr Potassium Channel

(48) Population

(49) The study was carried out on 615 women in good health, of European or North African type, between the ages of 18 and 60, with a QTcF<450 ms, and no known disease or chronic, or chronic treatment, except a contraception, and without any family history of congenital long QT syndrome, arrhythmia, or sudden death.

(50) Measurement and Calculation of the Various QTcF, TAmp and TpTe Data

(51) The QTcF, TAmp and TpTe were measured according to the same protocol as for example 1, before and three hours after administration of a single oral dose of sotalol at 80 mg.

(52) The ΔQTcF, ΔTpTe and ΔTAmp were also calculated.

(53) Principal Component Analysis

(54) A principal component analysis was carried out on ΔQTcF, ΔTpTe and ΔTAmp (XLStat software, Addinsoft) in order to generate three new decorrelated values PC1, PC2 and PC3.

(55) Results

(56) The PC1 variable thus obtained (of which the absolute value of the correlation coefficients with ΔTAmp, ΔTpTe, and ΔQTcF is greater than that of the correlation coefficients for PC2 or PC3 with these values) explains 63% of the phenotypic variance observed (characterized by the increase in QTcF and TpTe and the decrease in TAmp). In this embodiment, PC1 correlates positively in the same sense as ΔQTcF, ΔTpTe and ΔTAmp, that is to say that it increases when these values increase (Table 2).

(57) TABLE-US-00002 TABLE 2 Correlation between the variables and the factors obtained after PCA, and contribution of each of these factors to the total variance (n = 498). PC1 PC2 PC3 ΔQTcF (%) 0.71 0.71 −0.06 ΔTpTe (%) 0.85 −0.24 0.48 ΔTAmp (%) 0.83 −0.36 −0.44 Contribution to the total variance 63.2% 22.7% 14.1%

(58) FIG. 1 shows the various characteristics of the patients having received sotalol, and also the contraceptive hormone.

(59) The following are observed: The basal levels of QTcF, and the sotalol concentrations in the plasma three hours after administration, and also the kalemia, were not different between the subgroups as a function of the type of contraception. The increase in QTcF for the patients taking drospirenone was greater than that observed for the patients without hormonal contraception (6.6±2.6 msec) or taking levonorgestrel (7.0±2.7 msec) (FIG. 3). The patients taking drospirenone and gestodene exhibited a greater incidence (p<0.01) of double peaks (notches) three hours after administration of Sotalol (25.8% and 23.5% respectively) than the patients taking desogestrel (7.3%), levonorgestrel (16.4%) or without hormonal contraception (13.4%) (FIG. 4). The value of PC1 was significantly higher in the drospirenone group than in the group of patients without oral contraception (respectively 0.56 [−0.13; 1.5] and 0.09 [−0.58; 1.1], p<0.05) (FIG. 2). The value of PC1 was more moderate in the desogestrel group and levonorgestrel group (respectively 0.27 [−0.47; 1.2] and 0.22 [−0.54; 1.2]) (FIG. 2).

(60) It is therefore seen that not all the methods of oral contraception are identical with regard to the risks of inhibition of the IKr channel induced by taking drugs.

(61) Drospirenone exhibits the greatest risk of drug-induced IKr inhibition, while levonorgestrel, and desogestrel, appear to be neutral, levonorgestrel instead being protective with regard to the increase in QT and desogestrel instead being protective with regard to the appearance of a double peak (notch) of the T wave.

(62) The inventors put forward the hypothesis that this is due to both the progestogenic and the androgenic effect of these two hormones, compared with drospirenone, which does not have an androgenic effect (Table 3).

(63) If the doses of estrogens (ethinyl estradiol) administered at the same time as these progestogens are decreased or eliminated, the protective effect of these progestogens would be all the more marked.

(64) TABLE-US-00003 TABLE 3 Characteristics of the various oral pills for hormonal contraception Levonorgestrel Desogestrel Gestodene Drospirenone Number of patients 137 41 51 62 Concomitant use of EE  99 78 100 100 (%) EE dose min/max* 20-35  20-30  15-35 20-30 (μg/day) PG dose min/max* 30-175 75-150 60-75 3000 (μg/day) Pill 2.sup.nd 3.sup.rd 4.sup.th generation Progestogenic High High Intermediate activity Androgenicity High Intermediate/variable Anti-androgenic Abbreviations: EE: ethinyl estradiol, PG: progestogen, *in the event of concomitant use of EE, except on the days with placebo or without pills

Example 3—Treatment of a Torsade De Pointes by Administration of Testosterone

(65) Peripheral hypogonadism was identified in a man suffering from ischemic cardiopathy and from Erdheim-Chester disease with arrhythmic storm on torsades de pointes with long QT and notching (double peak (notch) of the T wave) promoted by iatrogenesis and bradycardia with more than seven episodes in less than one week.

(66) Testosterone (Androtardyl, testosterone enantate 250 mg/ml) was administered to the patient in amounts which made it possible to maintain a testosterone level making it possible to correct his hypogonadism, the bradycardia was corrected and an implantable defibrillator was implanted as secondary prevention.

(67) Following the introduction of testosterone, the circulating concentration of bioavailable testosterone and his repolarization became normalized.

(68) Three months following the introduction of testosterone, the monitoring of the defibrillator confirmed the absence of recurrence of torsades de pointes despite the reintroduction of QTc-prolonging drug (Vemurafenob) which the patient required for his background health (Erdheim-Chester).

(69) This clinical case is in favor of the effectiveness of a hormonal modulation for the treatment and prevention of torsades de pointes.

(70) Conclusion

(71) Example 3 is the first demonstration that testosterone, beyond its discussed effect on QTc, is capable of treating a patient presenting a torsades de pointes arrhythmic storm.

(72) Example 2 shows that the progestogenic pills with androgenic effect can be used to prevent episodes of torsade de pointes, since they control inhibition of the IKr channel, as demonstrated by the small increase in the value of the PC1 marker. Thus, this example clearly shows a protective effect of these pills, in the presence of a joint administration of a drug which increases the risk of torsades de pointes.

(73) Because of the properties of the progestogenic pills with androgenic effect shown in example 2 and the clinical result of example 3, the use of the progestogenic pills with androgenic effect can be envisioned, in particular in women, for the treatment of torsades de pointes, during the treatment of a patient who has just suffered an episode of torsade de pointes, or who is experiencing arrhythmic storm.

(74) However, it is preferable to decrease the amount of estrogen in these pills, and to administer pills based on pure progestogens, as described above, in order to amplify the effect due to these molecules.