DE2048926C2 - Antihypertensive combination preparation - Google Patents

Description

and inositol nicotinate of formula II

-OC-O

OC-O

CO-

O - CO

in a weight ratio of 3.15: 300 to 1: 30,000.

2. Antihypertensive agent according to claim 1 containing reserpine and inositol nicotinate in one Weight ratio of 1: 1,000.

3. Antihypertensive agent according to claim 1, characterized

characterized in that, in addition to reserpine and inositol nicotinate, it also contains the saluretic active ingredient Contains mefruside.

4. Antihypertensive agent, characterized in that it contains 1 part reserpine, 1000 parts inositol nicotinate and contains 100 parts of mefruside.

The present invention relates to a new combination of active ingredients which consists of a known antihypertensive agent and a known vascular dilator exists and has a particularly high and long-lasting effect.

It is already known that sympathetic inhibitors like reserpine, by influencing the regulatory mechanisms of the circulatory system, lowering blood pressure Have effect, and it is also known that compounds such as inositol nicotinate, papaverine, 1,4-dihydropyridines et al. cause peripheral vascular dilation. The reduction in peripheral vascular resistance however, when vascular dilators are used alone in therapeutic doses, a Counter-regulatory increase in cardiac output mediated via the sympathetic nervous system is balanced out, so that these substances alone are unsuitable as antihypertensive drugs. It therefore makes sense to take small doses of one peripheral vasodilators that do not yet lower blood pressure with small doses of a sympathetic inhibitor to combine, which for their part also do not yet lower blood pressure.

The active ingredients inositol nicotinate and mefruside are known as peripheral vascular dilators and antihypertensive drugs (cf. “Red List”, 1969, page 707, LIPOKAP-SUL® and “Red List”, 1969, page 130), BAYCA-RO N®).

It is also known that combinations of reserpine with certain vasodilating substances show a synergistic effect. So show z. B. contain combinations with papaverine or papaverine Substances with reserpine have a potentiating effect (cf. B. Helwig, Moderne Arzneimittel, 1967, p. 686 and M. A. Crespo, La Semana Medica 121, 1962, pp. 2082 ff [C. A. 59,685Ib]), but the reduction in blood pressure achieved is short-lived. One for this reason

the need for more frequent application is undesirable and also causes the blood pressure to fluctuate continuously result. In contrast, the combination of reserpine according to the invention shows with Inositol nicotinate a uniform and long-lasting (up to 24 hours) antihypertensive effect.

It has been found that the new combination of active ingredients from reserpine of formula I.

H ₃ CO

OOC

H ₃ CCOO

OCH ₃

and inositol nicotinate of formula II

i Voc-o

O-CO

in a weight ratio of 3.15: 300 to 1: 30,000 has a particularly strong and long-lasting antihypertensive effect.

The antihypertensive effectiveness of the active ingredient combination according to the invention is surprising much higher than the sum of the effects of the individual active ingredients. So shows z. B. on rats with experimental hypertension a dose of 0.01 mg / kg p. o. Reserpine given in isolation, a medium one maximum blood pressure reduction of only 12 mm / Hg from baseline, and a dose of 300 mg / kg Inositol nicotinate p. o. no significant decrease in blood pressure while using a combination of the two Active ingredients in the same dose reduced blood pressure by 31.4 mm / Hg compared to the initial value is achieved (see Tables 1 to 3). So there is a real synergism. The active ingredient combinations thus represent a valuable addition to technology.

The use of inositol nicotinate in the combination according to the invention with reserpine is advantageous because they are compared to the well-known combination with the similarly acting papaverine causes a more even and longer-lasting blood pressure lowering and on the other hand in comparison to other vascular dilators that work through the sympathetic system, another additional method for Represents lowering of blood pressure.

With knowledge of the state of the art, it is extremely surprising and could not be foreseen that the combination of reserpine with inositol nicotinate shows this superior effect. Furthermore it was not obvious to the person skilled in the art from the multitude of known and different vascular dilators to select precisely the inositol nicotinate as the optimal combination partner with a superior effect. The active ingredient combination according to the invention should

So the antihypertensive agent reserpine and the vasodilator agent inositol nicotinate in weight ratio 3.15: 300 to 1: 30,000. Of particular interest is a weight ratio of 1: 1,000.

The active ingredient combination according to the invention is due to its dosage, effect and tolerability very suitable for initial and long-term therapy of primary and secondary hypertension.

The new active ingredient combinations can be converted into the customary formulations in a known manner such as tablets, capsules, coated tablets, pills, granules, solutions, emulsions, suspensions, are preferred in capsules, tablets, coated tablets, solutions and suspensions, which may be replaced by inert, non-toxic, pharmaceutically suitable excipients and / or other active ingredients that can be mixed in, preferably Saluretica (e.g. Mefrusid), which is known to provide the necessary dose of the antihypertensive

reduce and improve its tolerance, supplemented.

Formulation examples:

(a) Capsules containing 150 mg inositol nicotinate and 0.15 mg reserpine.

(b) Capsules containing 150 mg inositol nicotinate, 15 mg mefruside and 0.15 mg reserpine.

The new active ingredient combinations can be used in the usual way, preferably orally. Of the Dosage range is approximately between 10 mg and 1 g per day. The temporal distribution is because of the long lasting effect very variable, e.g. 1-2 capsules or tablets 1 to 3 times a day.

The following animal experiments confirm experiments the potentiating effect of the active ingredient combinations. The tests are carried out on Hypertension rats (WILSON, C. AND BYROM, F. B., The Lancet 1939 I, pp. 136 to 139), with the blood pressure is measured according to the method specified by BREUNINGER (BREUNINGER, H., Arzneimittelforschung 6, pp. 222 to 225, 1956).

The combination effectiveness is determined by a known method (K. STOEPEL, H. KALLER and G. KRONEBERG, Naunyn-Schmidebergs Arch. Pharmak. Exp. Path. 262, 189 - 196 (1969) determined quantitatively.

A. I trials with reserpine and
Inositol nicotinate in hypertensive rats

Readings

The maximum decrease in blood pressure measured in the course of the 24-hour experiments is used for statistical processing of each individual animal compared to its initial value in mm Hg. Because of the individual responsiveness of the animals, this Maximum not always reached at the same point in time, so that individual maximum and maximum effect of the entire group, as it is used for the representation, do not always coincide.

For the graphical representations, measured values are averaged over the η animals of the test group at the same point in time. The resulting maximum effect is not identical to the mean maximum effect calculated for the statistical processing, which results from averaging the individual effect maxima of the λ animals per group ίο regardless of the time of measurement.

Combination attempts

To assess the effectiveness of the combination, each active ingredient is assessed individually on the one hand and on the other investigated the combination of active ingredients. For the quantitative determination of the combination effectiveness Dose-effect curves drawn up:

(a) for inositol nicotinate alone: Table 1

(b) for reserpine alone: Table 2

(c) for reserpine with simultaneous application of 300 mg / kg inositol nicotinate p. top .: Table 3

Table 1

Effect of inositol nicotinate on hypertensive rats. Blood pressure measurement on the tail without blood. Mean values of η animals in mm HG

Inositol nicotinate η Oh lh 2h 4h 6h 24 hours Dose in mg / kg p. O. 100 5 238 239 240 239 226 239 300 6th 258 260 256 249 244 256 300 6th 236 242 242 233 228 242

Inosiitol nicotinate causes hypertension rats up to a dose of 300 mg / kg p.o. no significant graphic 40 lowering of blood pressure.

Table 2

Effect of reserpine on hypertensive rats. Blood pressure measurement on the tail without blood. Maximum decrease in mm Hg compared to the initial value.

Ο, ΰϊ mg / kg 0.03 i 5 mg / kg 0.1 Iflg / kg η it C ^ / i, " p.o. 3 K _mrt / Ir «
- », υ tii £ / n ^ p.o. p.o. p.o. p.o. 43 P.O. 3 24 27 27 32 38 82 4th 85 42 37 43 42 67 22nd 16 32 29 17th 53 43 8th 15th 28 19th 61 72 61 13th 28 70 30th 25th 72 51 0 20th 27 27 63 55 50 10 32 5 28 34 46 43 26th 55 38 26th 39 15th 29 40 43 16 51 13th 47 51 41 35 58 0 37 24 23 54 75 15th 43 16 14th 66

x = 12.2

χ = 30.0 χ = 35.7

χ = 45.0

χ = 57.4

Table 3

Effect of reserpine with simultaneous application of 300 mg / kg inositol nicotinate p. o. on

High pressure rats.

Blood pressure measurement on the tail without blood. Maximum decrease in mm Hg compared to

Baseline.

0.01 mg / kg 0.0315 mg / kg 0.1 mg / kg 0.315 mg / kg 1.0 mg / kg 3.15 mg / kg p.o. p.o. p.o. p.o. p.o. p.O. 42 31 22nd 14th 101 93 20th 46 43 55 51 61 38 51 48 22nd 96 80 42 59 37 36 110 55 48 36 61 64 94 42 14th ! 6 33 55 55 83 20th 16 32 64 27 100 32 46 38 55 26th 74 24 53 26th 51 58 59 23 27 37 34 60 59 26th 51 24 7th 48 55 48 16 34 42

χ = 31.4

χ = 37.3

χ = 36.5

χ = 40.9

χ = 64.0

χ = 69.2

Table 3 shows that the combination of reserpine and inositol nicotinate has a surprising potentiating effect Has an effect on the antihypertensive effects of reserpine. This potentierer.de effect can with Can be statistically proven with the help of regression analysis.

For both dose-effect curves, the regression line Y = a + b- χ was calculated using the general form of regression analysis and the relative effectiveness R was determined with its confidence limits:

Reserpine:
Reserpine +
Inositol nicotinate:

Y = 4.63 +14.22 ■ χ Y = 11.70 +15.52 · χ

40

The regression lines are shown in FIG. 1 shown graphically.

The two regression coefficients b _y / _x (14.22 and 15.22) do not differ significantly from one another, ie the two regression lines run parallel. Thus, a common regression coefficient b and a relative effectiveness R with an upper and lower confidence limit can be calculated:

b =! 4.84

R = 4.68 (1.91-13.67)

The lower confidence limit for R is 1.91, above 1.0. This means: The distance between the two regression lines is statistically secured (p0.05). The effect of reserpine is significantly increased by the simultaneous administration of doses of inositoinicotinate that are ineffective for blood pressure (for the statistical calculations and the formulas used: see Burn, JH: Biological Standardization. Oxford University Press London, New York, Toronto 1952; p. 48 ff.)

The graphic representation in FIG. 2 of the measured values averaged over the η animals of the group at the same point in time in each case (for definition see under measured values) clearly shows this enhancement of the effect even with this type of representation.

A. II. Experiments with awake carotid sling dogs

In hypertensive rats it could be shown that the antihypertensive effect of reserpine was carried out concomitant administration of inositol nicotinate doses which are ineffective against blood pressure. To complement and Confirmation of this finding was carried out on 3 conscious, trained carotid sling dogs using the method the circulatory analysis according to WEZLER-BÖGER carried out further investigations.

literature

WEZLER, K. and BÖGER, A .:

The dynamics of the arterial system. Erg. Physiol.

41,212-606 (1939)
WEZLER, K. and THAUER, R .:

Bloodless stroke and minute volume determination on the dog without anesthesia. Z. Circulatory Research.

33,486-498 (1941)
SCHROEDER ₁ W .:

Methodology of continuous circulatory analysis on dogs.

Arch. F. Circulatory Research. 15.33-38 (1949)
BRECHT, K. and BOUCKE, H .:

For measuring the arterial pulse in humans with the infrared microphone. Pflüger's Arch.

Physiol. 257,490-494 (1953)

In preliminary tests, a limit dose was initially determined for reserpine, at which just one weak effect is noticeable. This limit dose for reserpine is 0.1 mg / kg p. o. The blood pressure drops after this dose decreases only slightly, the greatest change is in the behavior of the peripheral vascular resistance recognizable. The maximum effect is between 6 and 30 hours after application, 48 hours p. a. the effect of this dose has worn off again.

Inositol nicotinate does not lower blood pressure even at high doses. At a dose of 300 mg / kg p. o. is in some of the dogs a weak vasodilatory effect in an increase in heart rate and

10

a drop in peripheral vascular resistance recognizable.

The experimental plan was designed so that each of the three dogs in alternating order and in the Absland of several days

a)
b)
c)

0.1 mg / kg reserpine p. O.

300 mg / kg inositol nicotinate and the combination of these two doses

Table 4 a

Orally in gelatin capsules.

Blood pressure, heart rate and femoral pulse were then recorded at the same time intervals and taken from the Measured values of the heartbeat volume, cardiac output, volume elasticity of the Windkessel and the peripheral Calculated vascular resistance.

The results are shown in Tables 4-6a-c contain.

Circulatory analysis according to WEZLER-BÖGER on the awake carotid sling dog. Effect of 0.1 mg / kg reserpine p.o.

Dog 292 9

24

48

Table 4 b

Hours p.a.

Blood pressure 144/108 139/103 137/100 140/104 140/104 mm Hg Heart rate 45 52 53 58 38 P / min Stroke volume 0.040 0.044 0.045 0.054 0.045 1 Minute volume 1.82 2.33 2.36 3.14 1.73 l / min Volume elasticity 2410 2160 2180 1790 2170 dyn · cm " ⁵ peripheral resistance 5390 4140 4030 3130 5660 dyn ■ see cm ⁵

te
(Jl
f? Circulatory analysis according to WEZLER-BÖGER on the awake carotid sling dog. Table 4 c 0 6th O. 24 30th 48 Hours p.a. F. Effect of 300 mg / kg inositol nicotinate p. 150/110 144/104 150/112 150/112 152/115 mm Hg I. Dog 292 9 51 38 61 66 50 P / min i Blood pressure 0.044 0.045 0.041 0.045 0.041 1 Heart rate 2.18 1.74 2.53 2.97 2.03 ! / Min fei
i Stroke volume 2420 2350 2440 2240 2460 dyn · cm i Minute volume 4560 5690 4130 3,570 5270 dyn · see I. Volume elasticity cm ⁵ «; peripheral resistance 1

Circulatory analysis according to WEZLER-BÖGER on the awake carotid sling dog. Effect of 0.1 mg / kg reserpine p. o. at simultaneous application of 300 mg / kg inositol nicotinate p. O.

Dog 292 9

24

30th

72

96

Hours p.a.

Blood pressure

Heart rate

Stroke volume

Minute volume

Volume elasticity

peripheral

152/110 144/94 132/91 137/93 135/93 152/108 154/107 mn: ed

resistance

0.037

1.70

3020

6170

0.057 3.04 2320

56

0.049

2.73

2280

3270

51

0.051

2.61

2290

3530

46
0.045 2.08 2450 d 3 QfI

50

0.047

2.33

2470

4460

51 0.041 2.11 3030

4QdD

P / min 1

l / min dyn-cm " ⁵ dyn · see ■ α

Table 5 a

Circulatory analysis according to WEZLER-BÖGER on the awake carotid sling dog. Effect of 0.1 mg / kg reserpine p. O.

Dog 314 6 0 6th 24 48 Hours p.a. Blood pressure
Heart rate
Stroke volume
Minute volume
Volume elasticity
peripheral resistance 159/119
51
0.033
1.67
3250
6630 154/116
63
0.036
2.31
2790
4660 166/125
49
0.037
1.81
2920
6400 160/119
56
0.039
2.20
2790
5040 mm Hg
P / min
1
l / min
dyn · cm " ⁵
dyn-see cm ⁵

11th Table 5 b 20th Table 5 c 0 6th 48 926 12th 48 6th 24 30th 48 72 0 6th 24 30th 48 Hours p.a. 0 6th 24 30th 48 Hours p.a. 10970 5470 7240 dyn-see 162/116
49
0.032
1.60
3 780
6930 151/110
46
0.026
1.17
4240
8880 167/126
46
0.033
1.51
3 320
7720 162/113
45
0.038
1.72
3470
6410 135/92
55
0.039
2.17
2880
4160 137/97
73
0.032
2.35
3290
3980 140/96
53
0.037
1.98
3140
4800 151/113
50
0.030
1.47
3 370
7 160 158/120
50
0.028
1.44
3,570
7710 149/109
65
0.030
1.98
3 510
5210 150/111
67
0.032
2.13
3240
4880 148/112
56
0.031
1.75
3070
5930 154/116
48
0.029
1.41
3440
7630 mm Hg
P / min
1
l / min
dyn-cm- ⁵
dyn-see-cm " ⁵ 142/108
61
0.020
1.21
4530 143/108 143/109 143/106 148/110 mm Hg
71 56 78 58 p / min
0.021 0.017 0.023 0.024 1
1.49 0.92 1.81 1.42 l / min
4440 5450 4210 4130 dyn-cm " ⁵ r-rnS Circulation analysis according to WEZLER-BÖGER
300 mg / kg inositol nicotinate po on watch 8270 6710 Dog 314 i> 24 Carotid snare dog. Effect of Circulatory analysis according to WEZLER-BÖGER on the awake carotid sling dog. Effect of
simultaneous application of 300 mg / kg inositol nicotinate po Circulatory analysis according to WEZLER-BÖGER on the awake carotid sling dog.
Effect of 0.1 mg / kg reserpine po 0.1 mg / kg reserpine p.o. at Blood pressure
Heart rate
Stroke volume
Minute volume
Volume elasticity
peripheral resistance 166/124
46
0.033
1.52
3340
7620 30th Dog 314 6 0 Dog 317 9 96 hours p.a. 161/118
53
0.027
1.45
4190
7 680 Blood pressure 170/118
Heart rate 51
Stroke volume 0.039
Minute volume 1.99
Volume elasticity 3 340
peripheral Resistance 5870 Blood pressure
Heart rate
Stroke volume
Minute volume
Volume elasticity
peripheral resistance 158/114 mm Hg
49 p / min
0.037 1
1.78 l / min
3 230 dyncm-5
6090 dyn-sec-cm-5 Table 6 a Table 6 b Hours p.a. mm Hg
P / min
1
l / min
dyn · cm " ⁵
dyn · see · cm " ⁵ Circulatory analysis according to WEZLER-BÖGER on the awake carotid sling dog. Effect of
0.1 mg / kg inositol nicotinate po Dog 317 9 Blood pressure
Heart rate
Stroke volume
Minute volume
Volume elasticity peripheral resistance

Table 6 c f

Circulatory analysis according to WEZLER-BÖGER on the awake carotid sling dog. Effect of 0.1 mg / kg reserpine ρ. ο. at ϊ: simultaneous application of 300 mg / kg inositol nicotinate p. o. ;;

Dog 317 9

24

48 72

96

192

Hours p.a.

blood pressure

Heart rate

Stroke volume

Minute volume

Volume elasticity

peripheral resistance

149/110 133/97 131/92 133/97 136/93 144/103 143/99 mm Hg

0.022

1.18

4650

8730

81

0.025

2.01

3860

4560

69

0.026

1.81

3950

4920

69

0.025

1.69

3900

5430 70

0.019

1.31

6150

7000

61

0.022

1.37

4860

7190

0.021

1.33

5550

7100

P / min

l / min

dyn · cm " ⁵

dyn-sec-cm " ⁵

The results are the same for all three dogs. While after the administration of the individual components the above circulatory changes in varying intensity and described in the preliminary experiments Persisted, but above all no significant decrease in blood pressure was observed by the simultaneous administration of doses of the two compounds, the systolic and ineffective against blood pressure diastolic blood pressure sustained and significantly reduced. This decrease is mainly due to an increased drop in peripheral vascular resistance. Rise as an expression of counter-regulation Heart rate and cardiac output increased only slightly, while the cardiac stroke volume in 2 of the animals remains almost unchanged. The long duration of action of the combination is noticeable. Lowering of blood pressure and reduction in peripheral vascular resistance last significantly longer than after administration of the individual components.

The experiments on conscious dogs confirm the findings on hypertensive rats and also provide them Information about the mechanism of action of the combination.

To demonstrate the superior effect of the combination according to the invention compared to the known Combination of reserpine and papaverine were used in dogs and rats with artificial renal Treated high pressure with both combinations, a surprising advantage for the invention Combination resulted, as the following explanations show.

B. I. Experiments on high pressure dogs

(a) Preliminary tests with papaverine

50

In the preliminary tests with papaverine it came about Dose 100 mg / kg p. o. severe vomiting, motor restlessness, tachypnea and panting in both animals about 30 to 60 minutes after application. A proper measurement of blood pressure and heart rate was not possible.

The dose reduced by a factor of log 2.0 from 31.5 mg / kg p. o. was well tolerated. With none of the four animals showed a significant decrease in blood pressure at this dose, two of the four animals showed a slight increase in heart rate 1-4 hours after application.

(b) reserpine + inositol nicotinate

protracted lowering of systolic (PS) and diastolic blood pressure (PD). The maximum of the Effect Lasts 26-30 hours after the combined administration. The effect is still 48 hours after application has not completely subsided, the mean arterial pressure (PM) is still 19% at this point in time below baseline.

The heart rate (FR) increases slightly within the first hours after administration, normalizes but in the further course.

With these experiments, the findings described under A II can also be used on dogs with renal High pressure to be confirmed. They have been repeated for a direct comparison with the following To enable combination experiments with papaverine.

(c) reserpine + papaverine at the same time

With the combined administration of 0.1 mg / kg reserpine p. o. and 31.5 mg / kg papaverine p. o. it comes to a weak, but above all only short-term, lowering of the systolic and diastolic blood pressure (PS and PD). The mean arterial pressure (PM) is two hours after the simultaneous application of both Substances only decreased by a maximum of 9% (PM%). The is already 6 hours after application Blood pressure has risen to its initial level and remains there for 24-48 hours after administration unchanged.

B. II. Experiments on hypertensive rats

The limit dose determined in the preliminary tests for papaverine is 100 mg / kg p. o. 300 mg / kg p. o. are already toxic. The limit dose that can be applied does not lower the blood pressure of hypertensive rats.

Table 7 shows the measured values for the dose-effect curve of reserpine alone and Table 8 for simultaneous application of 100 mg / kg papaverine p. o. compiled. From the mean values is clearly shows that papaverine is not able to increase the reserpine effect. Because of the Uniqueness of the results was based on the biometric calculation of the combination effectiveness and on the graphic representation is omitted.

Table 7

Effect of reserpine on hypertension. Bloodless Measurement of blood pressure on the tail. Maximum reductions in mm Hg compared to the initial value.

With the combined administration of the blood pressure 65 0.01 mg / kgp.o. 0.1 mg / kg p.o. 1.0 mg / kg p.o.

effective limit dose of 0.1 mg / kg reserpine p. o. and

the dose of 2 13 54, which is also ineffective for blood pressure

300 mg / kg inositol nicotinate p. o. there is a 4 28 50

continuation

0.0! mg / kg ρ. ο.

0.1 mg / kg p.o.

1.0 mg / kg p.o.

2 24 42

0 28 37

2 28 38

0 26 46

χ = 1.7 χ = 24.5 χ = 44.5

Table 8

Effect of reserpine with simultaneous application of 100 mg / kg papaverine p. o. high pressure rats. Bloodless Measurement of blood pressure on the tail. Maximum reductions in mm Hg compared to the initial value.

Reserpine 0.01 mg / kg 0.1 mg / kg 1.0 mg / kg p.o. p.o. p.o. Papaverine 100 mg / kg 100 mg / kg 100 mg / kg p.o. p.o. p.o. 2 19th 45 3 24 39 6th 26th 41 2 26th 38 11th 26th 46 5 22nd 57 5 31 30th 0 18th 58 0 21 32 0 23 34

χ = 23.6

Clinical studies on humans with the combination of reserpine and inositol nicotinate according to the invention, which also contains the saluretic Mefrusid, also confirm the progressive Effect of the combination according to the invention. The capsules administered here each contained

0.15 mg reserpine
150 mg inositol nicotinate
15 mg of mefruside

A total of 2,425 patients were treated with the combination product listed above. The duration of treatment was up to 12 months. Long-term observations of 148 cases are longer than 6 months before.

In the case of the various forms of hypertension, the combination preparation was predominantly used in a one-off manner Dose of 1 capsule per used. Tolerance is good. In 92% of the patients it was seen no side effect at all; side effects were reported in 8%; in 33% it was Therapy discontinued Orthostatic disorders occurred compared to more subjective complaints on the part of the Gastrointestinal tract strong back.

ίο An intra-individual comparison between the above A combination of three and a combination of two without inosital nicotinate showed that one of the Combination preparation according to the invention required significantly lower doses in order to produce a good one Treatment success to come.

The verdict on the preparation is extremely favorable. It was a very good and in 79.3% of the cases good success, with 12.0% a satisfactory success. It is in good agreement with these findings that the treating physicians assessed the combination preparation according to the invention predominantly better than the previous therapy.

Description of the FIG. 1 and 2

F i g. 1 contains the dose-response curves for reserpine alone (curve I) and the combination of reserpine-inositol nicotinate, in which inositol nicotinate always in one Amount of 300 mg / kg rat is given (curve II) determined on hypertensive rats. The ordinate gives the maximum decrease in blood pressure in mm Hg. The amounts of reserpine administered orally (p. O.) Are on the abscissa applied in mg / kg rat.

F i g. 2 contains the graphical representations of the measured values of the combination effectiveness of reserpine and inositol nicotinate obtained by blood pressure measurement on the tail of hypertensive rats (Average values for every 12 animals). On the abscissa is the Time in hours (h) after application (post appl.) And on the ordinate the reduction in blood pressure compared to the Initial value plotted in mm Hg. Curve Ia represents the drop in blood pressure on application of 0.01 mg Reserpine per kg rat, curve Ib shows the blood pressure lowering on application of 0.1 mg reserpine per kg rat and curve Ic represents the lowering of blood pressure upon application of 1.0 mg reserpine per kg rat Curves marked I la -c represent the lowering of blood pressure caused by application of a combination of 300 mg inositol nicotinate per kg Rat and the amount of reserpine indicated in each case by la -c.

25th

30th

35

1 sheet of drawings

Claims (1)

Patent claims: 1. Antihypertensive in the form of capsules, tablets, coated tablets, solutions, emulsions, or suspensions Granules containing a combination of reserpine of the formula I. H ₃ CO OOC H ₃ CCOO OCH ₃