Use of hyaluronidase for the prevention or treatment of arterial hypertension or cardiac insufficiency

Abstract

The present invention relates to the use of hyaluronidase for the prevention and/or treatment of cardiac insufficiency. In addition, the present invention provides a composition and a combined preparation each comprising hyaluronidase and at least one further antihypertensive, and a method of prevention and/or treating cardiac insufficiency in a patient in need thereof, wherein the patient is administered a therapeutically effective amount of hyaluronidase.

Claims

1. A method of treating cardiac insufficiency in an individual, the method comprising administering to the individual an effective amount of hyaluronidase.

2. The method of claim 1, wherein the individual is a non-human animal or a human.

3. The method of claim 1, wherein the hyaluronidase is administered parenterally.

4. The method of claim 1, wherein the hyaluronidase is administered by an enteral route.

5. The method of claim 1, wherein the hyaluronidase is administered in an effective amount of at least 3000 IU per day.

6. The method of claim 1, wherein the hyaluronidase is administered at a frequency of from 1 time per week to 7 times per week.

7. The method of claim 1, wherein the hyaluronidase is administered for a period of time of at least 2 weeks.

8. The method of claim 1, wherein the hyaluronidase dosage is increased over time until a plateau dosage is reached.

9. The method of claim 1, further comprising administering at least one additional antihypertensive agent.

10. The method of claim 9, wherein the at least one further antihypertensive agent is selected from a diuretic, an alpha-adrenergic receptor inhibitor, a beta adrenergic receptor inhibitor, an angiotensin converting enzyme inhibitor, an angiotensin receptor inhibitor, a renin inhibitor, a calcium channel inhibitor, a vasodilatating agent, an antisympathotonic and an imidazoline type 1 receptor agonist.

11. A method of treating cardiac insufficiency in an individual, the method comprising administering to the individual an effective amount of hyaluronidase and at least one additional antihypertensive agent.

12. The method of claim 11, wherein the hyaluronidase and the at least one additional antihypertensive agent are administered simultaneously.

13. The method of claim 11, wherein the hyaluronidase and the at least one additional antihypertensive agent are administered at separate times.

14. A method of treating cardiac insufficiency in a mammalian individual, the method comprising administering to the individual hyaluronidase in an amount of at least 3,000 IU per day.

Description

EXAMPLES

(1) Several patients with arterial hypertension were successfully treated with hyaluronidase.

(2) Shown below are data obtained from five patients.

Example 1: Patient 1 (A.C.)

(3) Patient 1 suffered from coronary heart disease and displayed symptoms of angina pectoris. At that time the patient also suffered from arterial hypertension and displayed systolic blood pressure values of 180-160 mmHg and diastolic blood pressure values ranging from 120-105 mmHg.

(4) Before hyaluronidase treatment was initiated, patient 1 had been treated for arterial hypertension with the following medicaments: 1 tablet per day Belok Zok 100 mg (Metoprolol 100 mg), a ß1-adrenergic receptor antagonist; 1 tablet per day Atacand 16 mg Plus (Candesartan 16 mg+12.5 mg hydrochlorthiazide), an angiotensin II receptor inhibitor; 1 tablet per day Unimax 5/5 (Felodipin 5 mg, a Ca.sup.++ channel antagonist); and 1 tablet per day 5 mg Ramipril (an ACE antagonist).

(5) Based on this regimen the blood pressure could be kept at a normal level. Hyaluronidase treatment was initiated 3 Nov. 1995 by combining the above treatment regimen (Belok Zok 100 mg+Atacand 16 mg Plus+Unimax 5/5) with the following doses regimen of Hyaluronidase:

(6) TABLE-US-00001 Hylase dosage regimen Hylase dosage (Hylase Dessau 1.500 IU product, by RIEMSER Arzneimittel AG), Date intravenous injection 3 Nov. 1995 4.500 IU 4 Nov. 1995 6.000 IU 5 Nov. 1995 7.500 IU

(7) Then, the above co-treatment regimen with (daily administration of each of Belok Zok+Atacand 16 mg Plus+Unimax 5/5 at the dosages indicated above) and hyaluronidase (7.500 IU per day) administered 5× per week for six weeks was continued until the end of December 1995.

(8) From January 1996 on the above treatment regimen could be surprisingly reduced as follows, while at the same time maintaining the blood pressure levels at a normal level (see table 2 below): 0.25 tablet per day Belok Zok 100 mg (Metoprolol 100 mg), a ß1-adrenergic receptor antagonist; 0.5 tablet per day Atacand 16 mg Plus (Candesartan 16 mg+12.5 mg hydrochlorthiazide), an angiotensin II receptor inhibitor; and 5 times a week Hylase Dessau 7.500 IU by intravenous injection.

(9) This regimen was applied from January to May 1996.

(10) From June 1996 on Hylase therapy was discontinued and the patient maintained normal blood pressure levels with the following medication: 0.25 tablet per day Atacand 16 mg (Candesartan 16 mg), an angiotensin II receptor inhibitor.

(11) Thus, hyaluronidase exerted a strong blood pressure-reducing effect which allowed to reduce administration of the other antihypertensives used before hyaluronidase treatment was initiated. From the day hyaluronidase treatment was initiated, patient 1 displayed stable and normal blood pressure values. As a result of the hyaluronidase co-administration the systolic blood pressure value ranged between 130 and 120 mmHg and the diastolic values between 80-65 mmHg.

(12) TABLE-US-00002 TABLE 2 Riva -Rocci values (determined on the upper arm using the Scipione Riva-Rocci method) (RR Values): Blood Pressure systolic pressure/diastolic Date pressure [mmHg] 2 Nov. 1995  150/110 End of November 1995 140/88 End of December 1995 142/79 2 Jan. 2008 137/66 11 Jun. 2008 168/75 17 Jul. 2008 172/79

Example 2: Patient 2 (H.L.)

(13) Immediately before hyaluronidase therapy was initiated, Patient 2 was diagnosed as suffering from arterial hypertension with symptoms of angina pectoris. Patient 2 also suffered from coronary heart disease and a heart catheter-based examination carried out Mar. 10, 2008 confirmed that the heart vessels still showed stenosis and calcification. At that time patient 2 displayed systolic blood pressure values of 190-170 mmHg and diastolic blood pressure values ranging from 125-100 mmHg.

(14) Before hyaluronidase treatment commenced, patient 2 had been treated for arterial hypertension with the following medicaments: 1 tablet per day Atacand 16 mg Plus (Candesartan 16 mg+12.5 mg hydrochlorthiazide), an angiotensin II receptor inhibitor; 1 tablet per day Amlopidin 10 mg, a Ca.sup.++ channel antagonist; and 1 tablet per day Nebilit (Nebivolol 5 mg), a ß1-Adrenergic receptor antagonist.

(15) Hyaluronidase was co-administered by intravenous injection on top of the above regimen from 28 Apr. 2008 to 28 May 2008.

(16) TABLE-US-00003 TABLE 3 Hylase dosage regimen Hylase dosage (Hylase Dessau 1.500 IU product, by RIEMSER Arzneimittel AG), Date intravenous injection 28 Apr. 2008 4.500 IU 29 Apr. 2008 6.000 IU 30 Apr. 2008 7.500 IU 2 May 2008 9.000 IU 3 May 2008 9.000 IU 4 May 2008 9.000 IU 5 May 2008 9.000 IU 6 May 2008 9.000 IU 7 May 2008 9.000 IU 8 May 2008 10.500 IU  9 May 2008 10.500 IU  13 May 2008 10.500 IU  27 May 2008 10.500 IU  28 May 2008 10.500 IU 

(17) As a result of the hyaluronidase therapy the symptoms of angina pectoris disappeared and the blood pressure fell significantly and persistently to a systolic blood pressure value ranging between 140-120 mmHg and diastolic values between 80-60 mmHg.

(18) Moreover, following termination of the Hyaluronidase therapy the above medication regimen used before the hylase co-administration therapy could be reduced to the following treatment: 1 tablet per day Nebilit (Nebivolol 5 mg), 0.5 tablets, a ß1-Adrenergic receptor antagonist;

(19) Using only Nebilit medication, the patient steadily displayed normal diastolic blood pressure values of less than 80 mmHg. The patient still displayed the normal blood pressure values in the months following the termination of the antihypertensives/hyaluronidase administration.

(20) TABLE-US-00004 TABLE 4 RR Values: Blood Pressure systolic pressure/diastolic Date pressure [mmHg] 6 May 2008 108/73 7 May 2008 120/74 13 May 2008 115/75 20 May 2008 136/79

(21) Thus, Hyaluronidase exerted long-lasting and strong blood pressure-reducing effect which allowed to dramatically reduce the administration of the other antihypertensives used before hyaluronidase treatment was initiated.

Example 3: Patient 3 (Z.M.)

(22) The patient was diagnosed as suffering from, coronary heart disease, obstructive disease, condition after myocard infarct, general arteriosclerosis.

(23) Before hyaluronidase treatment was initiated, patient 3 had been treated for hypertension with the following medicaments: 1 tablet per day Belok Zok mite (11.88 mg); 1 tablet per day Enalapril (10 mg); 1 tablet every 3 days Plavix (75 mg Clopidogrel); and 1 tablet per day Norvasc (5 mg).

(24) At that time the patient displayed systolic blood pressure values of 156-147 mmHg and diastolic blood pressure values ranging from 80-66 mmHg.

(25) Hyaluronidase co-administration on top of the above treatment and was carried out from 19 Jun. 2008 to 30 Jun. 2008 by intravenous injection using the following dosage regimen for hylase:

(26) TABLE-US-00005 TABLE 5 Hylase dosage regimen Hylase dosage (Hylase Dessau 1.500 IU product, by RIEMSER Arzneimittel AG), Date intravenous injection 19 Jun. 2008  4.500 IU 20 Jun. 2008  6.000 IU 21 Jun. 2008  7.500 IU 22 Jun. 2008  9.000 IU 23 Jun. 2008 10.500 IU 24 Jun. 2008 12.000 IU 25 Jun. 2008 12.000 IU 26 Jun. 2008 12.000 IU 27 Jun. 2008 15.000 IU 28 Jun. 2008 15.000 IU 29 Jun. 2008 15.000 IU 30 Jun. 2008 15.000 IU
Medication after Hyaluronidase Therapy was Discontinued: 1× every 3 days Plavix 75 mg (Clopidogrel), a thrombozyte aggregation inhibitor.

(27) Thus, due to the Hyaluronidase therapy the administration of blood pressure reducing-medicaments could be discontinued while maintaining normal blood pressure levels.

(28) TABLE-US-00006 TABLE 6 RR- Values Blood Pressure systolic pressure/diastolic Date pressure [mmHg] 8 May 2008 156/80 9 May 2008 147/66 19 Jun. 2008 153/64 20 Jun. 2008 134/61 24 Jun. 2008 163/67 25 Jun. 2008 157/70 27 Jun. 2008 135/66 25 Jul. 2008 130/70

Example 4: Patient 4 (N.H.)

(29) The patient was diagnosed as suffering from arteriosclerosis, arterial hypertension, and obesity. At that time the patient displayed systolic blood pressure values of 160-140 mmHg and diastolic blood pressure values ranging from 110-100 mmHg.

(30) Medication Before Hyaluronidase Therapy was Initiated

(31) 1× per day Atacand 16 mg, an angiotensin II receptor inhibitor; and 1× per day Atenolol 25 mg (beta adrenergic receptor inhibitor)

(32) Hyaluronidase co-administration was carried out from 10 Jul. 2007 to 9 Nov. 2007. On top of the above treatment regimen, hylase was administered according to the following dosage regimen:

(33) TABLE-US-00007 TABLE 7 Hylase dosage regimen Hylase dosage (Hylase Dessau 1.500 IU product, by RIEMSER Arzneimittel AG), Date intravenous injection 10 Oct. 2007 6.000 11 Oct. 2007 7.500 14 Oct. 2007 9.000 15 Oct. 2007 10.500 5 Nov. 2007 10.500 6 Nov. 2007 10.500 7 Nov. 2007 12.000 8 Nov. 2007 12.000 9 Nov. 2007 12.000
Medication after Hyaluronidase Therapy was Terminated 1× per day Atenolol 25 mg

(34) As a result of the Hyaluronidase administration the systolic blood pressure value ranged between 130 and 120 mmHg and the diastolic values between 80-70 mmHg and the administration of antihypertensives could be was dramatically reduced.

(35) TABLE-US-00008 TABLE 8 RR Values: Blood Pressure systolic pressure/diastolic Date pressure [mmHg] 7 Aug. 2007 132/69 8 Aug. 2007 111/58 9 Oct. 2007 126/81 10 Oct. 2007 123/87 11 Oct. 2007 120/80 6 Nov. 2007 122/74 7 Nov. 2007 147/77 8 Nov. 2007 123/78 9 Nov. 2007 122/80 1 Aug. 2008 110/68

Example 5: Patient 5 (T.F.)

(36) The patient was diagnosed as suffering from coronary heart disease, arterial hypertension, condition after pericarditis, aortic valve stenosis, hypertrophic cardiomyopathy, arterial fibrillation and condition after apoplexy.

(37) Medication Before Hyaluronidase Therapy was Initiated

(38) 1 tablet per day of Atacand 16/12.5 mg; 1 tablet per day Diblocin Pb 4 mg; and 1 tablet per day Belok Zok Mite 47.5 mg.

(39) At that time the patient displayed systolic blood pressure values of 174-152 mmHg and diastolic blood pressure values ranging from 107-98 mmHg.

(40) Hyaluronidase co-administration on top of the above regimen was initiated 9 Dec. 2002 and was continued until 17 Dec. 2002.

(41) TABLE-US-00009 TABLE 9 Hylase dosage regimen Hylase dosage (Hylase Dessau 1.500 IU product, by RIEMSER Arzneimittel AG), Date intravenous injection 9 Dec. 2002 4.500 IU 10 Dec. 2002 6.000 IU 11 Dec. 2002 7.500 IU 12 Dec. 2002 9.000 IU 13 Dec. 2002 10.500 IU  14 Dec. 2002 12.000 IU  16 Dec. 2002 12.000 IU  17 Dec. 2002 13.500 IU 
Medication after Hyaluronidase Therapy was Discontinued (from 18 Dec. 2002 on): 0.5 tablet per day Belok Zok Mite 47.5 mg.

(42) As a result of the hyaluronidase administration the systolic blood pressure value ranged between 188-128 mmHg and the diastolic values between 94-69 mmHg.

(43) TABLE-US-00010 TABLE 10 RR Values: Blood Pressure systolic pressure/diastolic Date pressure [mmHg] 15 Jan. 2002  174/103 2 Dec. 2002 153/96 3 Dec. 2002  152/107 9 Dec. 2002 170/98 12 Dec. 2002 145/88 30 Jan. 2003 128/83 13 Feb. 2003 143/85 14 Apr. 2003 113/69 2 Aug. 2004 148/80