Composition and method for treating glaucoma

An antiglaucoma composition containing as the active component a s-/-/-2,3 dihydroxy-9,10,11-trimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo (a,f) quinolizine hydrochloride of the general formula: ##STR1## where R.sub.1 .dbd.R.sub.2 .dbd.R.sub.3 .dbd.R.sub.4 .dbd.H.dbd.R.sub.5 .dbd.R.sub.6 .dbd.R.sub.7 .dbd.CH.sub.3 O The composition is used as an ophthalmic solution in a method for treating glaucoma by administering a therapeutic dose of 2 to 3 drops two to four times daily to a host such as a warm-blooded animal having glaucoma.

BACKGROUND OF THE INVENTION 
The invention concerns a composition and a method for treating glaucoma in 
a host having this condition. 
It is known that the most used preparations in the treatment of glaucoma 
are pylocarpine, epinephrine and timolol. However along with their good 
therapeutic effect these preparations exhibit many side effects. For 
example pylocaprine provokes myosis, spasm of muscles around the eye, 
hyperemia of conjunctivate, and allergic reactions in the eye. (Okeda, A. 
et al -Duodecim, 95, 1979, p. 11-15, and Schiffer, H. -Merck Sharp Dohme 
Intern., 1978, p. 49-52) Epinephrine has a slight and momentary effect on 
the intraocular pressure and provokes tachicardia, midriasis, hyperemia. 
(Katz, I. -Ann. Phthalmol., 10 m 1978, p. 847-850, and Leydhecker, W. 
-Klin. Monatsblatt der Augenheilkunde, 171, 1977, p. 538-547) Timolol in 
local administration causes several side effects including bradicardia, 
hypotension and bronchospasm, in particular, in the case of persons 
suffering from asthma and bronchitis, central nervous system depression 
and sedation. (Arrata, M. -Ocular pharmacology of timolol drops, London 
Acad. Press 1980; Katz, I. -Invest. Ophthalmol. Vis. Sci., 15, 1976, p. 
489-492; Kosman, M. -JAMA, 241, 1979, p. 2301-2303, and Zimmermann, T. 
-Ophthalmol. Vis. Sci., 16, 1977, p. 687-688) These side effects limit its 
use in medicine. 
OBJECT OF THE INVENTION 
An object of this invention is to provide an antiglaucoma composition which 
does not change significantly the arterial pressure and the chronotropic 
heart function in normotensive animals and does not exhibit an irritating 
effect and allergic reaction when it is adminstered locally in the eye. 
Another object is to provide a method for treating glaucoma. 
These objects are attained by using a physiologically tolerable salts of 
hexahydrodibenzo (a,f) quinolizines in racemate or optically active forms 
having the general formula I below: 
##STR2## 
where R.sub.1 and R.sub.2 are H, CH.sub.3, CH.sub.3 CO; R.sub.3 and 
R.sub.4 are H,OH;R.sub.5,R.sub.6 and R.sub.7 are OH,H,CH.sub.3 O and X is 
Cl. 
DISCLOSURE OF PREFERRED MODE 
It is known that some hexahydrodibenzo (a,f) quinolizines of synthetic or 
plant origin cause a momentary hypotensive action (Shimamoto, K. -Nippon 
Iakugaku Zasshi, 53, 1957, p. 75-80) anticholinesterase activity 
(Berezhinskaja, V., E. Aleshinskaja, -Pharmacol. i toxicol., 31, 1968, p. 
1) and a depressive effect on the central nervous system. (Jamahara, J., 
T. Konoshima -Chem. Pharm. Bull., 24 (8), 1976, p. 1902-1912) Besides some 
of them manifest biliary antibacterial (Amin, A., T. Subbajah -Can. J. 
Microbio., 15 (9), 1969, p. 1067-1076) antiinflammatory and antiulceric 
action. (Ikram, L. -Planta Med., 28 (4), 1975, p. 353-358) However, the 
antiglaucoma activity of hexadydrodibenzo (a,f) quinolizines was not known 
previously. The highest antiglaucoma activity in this salt series is 
manifested by 
s-/-/-2,3-dihydroxy-9,10,11-trimethoxy-5,8,13,13a-tetrahydro-bH-dibenzo 
(a,f) quinolizine hydrochloride - Ia, the method of preparation and the 
physio-chemical properties of which are described in Bulgarian inventor's 
certificate No. 32353. (Ivanov, C., N. Ivanova et al., Inventor's 
certificate BG 32353) 
The advantages of the compounds with general formula I according to the 
invention are as follows: 
they do not provoke bronchospasm and bradicardia in systematic local 
administering by comparison with timolol; 
they cause only a slightly expressed and momentary hypotensive effect; 
they do not irritate the eye when given locally (in the eye); 
they do not cause myosis, hyperemia or allergic reactions when locally and 
systematically given in the eye. 
The compounds of general formula I can be used in the treatment of glaucoma 
in the form of ophthalmologic solutions (collyres) being aqueous solutions 
of the active component and supplementary pharmaceutical substances. The 
ophthalmic solutions according to the invention contain from 0.25 to 0.5% 
of the compound Ia which has exhibited the highest activity. The 
ophthalmic solutions are sterile and can contain antimicrobial agents such 
as benzalkonic chloride, phenylmercury, nitrate, timerosal. Thiourea, 
thioglycerine, ascorbinic acid or sodium metabisulphite can be used as 
antioxidants. The ophthalmic solutions are prepared by using known 
methods. 
The ophthalmologic solutions according to the invention are administered in 
therapeutic doses from 2 to 3 drops--two to four times a day. They are 
particularly effective with warm-blooded animals. 
The invention is better illustrated in non-limiting fashion by the 
following examples:

EXAMPLE 1 
To prepare an opthalmologic solution the following are mixed: 
______________________________________ 
s-/-/-2,3-dihydroxy-9,10,11-trimetoxy- 
50 g 
5,8,13,13a-tetrahydro-6H-dibenzo (a,f) 
quinolizine hydrochloride (Ia) 
4 g 
Sodium metabisulphite 
Disodium salt of EDTA 2 g 
Benzalkonic chloride 1 g 
Glycerine 470 g 
Water for injections up to 10 l 
______________________________________ 
The freshly distilled water for injections is boiled for 20 to 30 min. and 
then it is saturated by bubbling in it pure nitrogen and cooled to 
40.degree.-50.degree. C. In approximately 8 1 of thus saturated water are 
dissolved consecutively: sodium metabisulphite, disodium salt of EDTA, the 
compound Ia, glycerine and benzalkonic chloride while continuously 
saturating with nitrogen. The ready solution is filtered through a 
Minipore type filter with a 0.22.mu. membrane. The ampoule filling is 
performed with double nitrogen gasing. 
EXAMPLE 2 
Study of Ophthalmotonus 
The studies are carried out on the ophthalmotonus of not narcotized and 
normotensive rabbits. In one series of experiments the introcular pressure 
was measured by means of the tonometer of Schiotz and it is calculated in 
mm Hg after the Leydhecker scale while in another series it was measured 
by means of the tonometer Maklakov. The comparative experiments carried 
out with compound Ia and timolol administered locally in the eye in the 
form of 0.5% aqueous solution indicate that compound Ia decreases in a 
statistically significant manner and with a maximum at the 60 to 120 
minutes-the intraocular pressure that is measured by means of the Schiotz 
tonometer whereby there is no significant difference of its effect 
compared with that of timolol (see FIG. 1). 
The compound Ia is tested in the form of an ophthalmic solution 
(collyre)--0.5% aqueous solution. Administered in this therapeutic form it 
also decreases the intraocular pressure measured by the tonometer of 
Maklakov (FIG. 2). The comparative tests performed on not narcotized rats 
of the "Vistar" line show that the compound Ia by contrast to timolol does 
not cause statistically significant changes in arterial pressure and 
cardiac frequency (Table 1), when administered locally. 
EXAMPLE 3 
Influence on the heart-blood vessel system 
The compound Ia when administered in doses 0.1 or 0.5 or 1 or 2 or 3 or 5 
mg/kg intravenously reduces arterial pressure of narcotized cats and 
rabbits. Its hypotensive effect in particular in low doses is lightly 
expressed and momentary. In case of a dose 0.25 mg/kg it is 22% during 10 
min (see Table 2): 
TABLE 1 
__________________________________________________________________________ 
Comperative effects of compound Ia and timolol on arterial pressure 
and cardiac frequency in local administering on rats of "Wistar" line 
Initial 20 min. 60 min. 
Arterial pressure Arterial pressure Arterial pressure 
SUB- mm, Hg cardiac 
mm, Hg cardiac 
mm, Hg cardiac 
STANCE systolic 
diastolic 
frequency 
systol. 
diastol. 
frequency 
systol. 
diastol. 
frequency 
__________________________________________________________________________ 
Ia - 182 .+-. 
144 .+-. 
384 .+-. 
164 .+-. 
124 .+-. 
388 .+-. 
131 .+-. 
96 .+-. 
362 .+-. 
0.5% collyze 
21.9 19.7 24.2 18.7 17.8 22.2 11.2 12.9 15.3 
(p &gt; 0.05) 
(p &gt; 0.05) 
(p &gt; 0.05) 
(p &gt; 0.05) 
(p &gt; 0.05) 
(p &gt; 0.05) 
.dwnarw.9.9% 
.dwnarw.13.9% 
.dwnarw.28% 
.dwnarw.33.3% 
.dwnarw.5.7% 
Timolol - 
198 .+-. 
168 .+-. 
405 .+-. 
184 .+-. 
155 .+-. 
339 .+-. 
162 .+-. 
135 .+-. 
314 .+-. 
0.5% collyze 
7.3 7.0 17.9 8.4 8.0 20.2* 8.8* 9.0* 9.7** 
(p &gt; 0.05) 
(p &gt; 0.05) 
(p &lt; 0.05) 
(p &lt; 0.05) 
(p &lt; 0.05) 
(p &lt; 0.01) 
.dwnarw.7% 
.dwnarw.7.7% 
.dwnarw.16% 
.dwnarw.18% 
.dwnarw.20% 
.dwnarw.22% 
__________________________________________________________________________ 
* p &lt; 0.05 .vertline.n = 12 
** p &lt; 0.01 
TABLE 2 
______________________________________ 
Influence of compound Ia on the arterial pressure of cats 
Dose Hypotensive effect 
Duration 
mg/kg % min. 
______________________________________ 
0.1 18 8 
0.25 22 10 
0.5 25 24 
1 33 30 
2 38 45 
3 42 over 60 
5 52 over 60 
______________________________________ 
The pharmacological analysis with several mediators and other test 
substances proves that with compound Ia (dose of 3 mg/kg) the effects of 
dopamine and isoprenaline with respect to arterial pressure are reduced as 
well as the pressure effect from the occlusion of aa. carotes communis 
while the pressure effect of nor-adrenaline is increased. This is related 
probably to the stimulation of presinaptic beta-receptors which 
facilitates the liberation of the mediator nor-adrenaline (Table 3). The 
hypotensive effect of compound Ia is considerably suppressed with 
propranolol--1.5 mg/kg administered intravenously. 
The pharmacological investigations carried out on not narcotized rabbits 
show that compound Ia exhibits a considerably slighter expressed and a 
shorter positive chronotropic effect by comparison with isoprenaline while 
it does not provoke statistically significant changes in the chronotropism 
of the heart (FIG. 3). By contrast with the timolol the compound Ia does 
not change in a statistically significant manner the chronotropic function 
of the heart (FIG. 4). 
FIGURE 3 
______________________________________ 
Interaction of compound Ia with some mediators and other 
test substances with respect to arterial pressure of cats 
Changes in arterial 
Ia pressure, in % 
Test substances mg/kg before after 
______________________________________ 
Dopamine-20 .mu.g/kg 
2 -16.6 -8.3 
Dopamine-40 .mu.g/kg 
2 -23.0 -4.2 
Isoprenaline-1.5 .mu.g/kg 
3 -30.5 -8.8 
Noradrenaline-3 .mu.g .multidot. kg 
1.5 +21.0 +46.0 
Noradrenaline-3 .mu.g .multidot. kg 
3.0 +17.0 +33.0 
Histamine-5 .mu.g/kg 
5 -52.0 -23.0 
Occulsion of aa .multidot. carotes 
2 -40.0 
communis 5 -53.0 
Propranolol-1.5 mg/kg 
2 -42.0 -24.0 
______________________________________ 
EXAMPLE 4 
Study of local tolerance 
The local tolerance of compound Ia in the form of a collyre (0.5% aqueous 
solution) was tested by two methods: 
(a) Method of Marzuli and Simon, verified and implemented by Marzuli and 
Ruglas. In this experiment there were tested 12 white rabbits of both 
sexes with body weight 3200 to 4000 g distributed in two groups of 6 each. 
The first group was treated with the collyre while the second was treated 
only with the vehiculum of the collyre. In the conjunctival socket of one 
eye is applied 0.1 ml of the sample while the other eye serves as control. 
The local ocular reaction is determined at the first hour, 24th, 48th, 
72nd hour and on the 7th day after the treatment. The standard system 
assumed by the cited authors is applied; namely from 0 to 4 for the 
cornea, from 0 to 2 for the iris hyperemia. In recording the dynamics of 
both groups local irritation was not observed and in all three parameters 
followed up: cornea, iris and conjunctive. The results thus obtained 
indicate that compound Ia is well-tolerated, its application in the 
medical practice brings no risk of causing irritative blepharitis, 
conjunctivitis, toxic damage of cornea or of the entire eye. 
(b) Method of Mac Donald, the tests were carried out on 12 white rabbits in 
an equal number of males and females with an average weight of 3700 g 
distributed in two groups of six. The first group was treated with the 
collyre while the second only with its carrier. In the conjunctival socket 
of one eye is added dropwise 0.05 ml of the studied sample three times a 
day for 5 days. The local ocular reaction is noted every day prior to the 
respective treatment of cornea, iris and conjunctive and then it is 
compared with the control, non-treated, eye of each rabbit. In the case of 
threefold recording during the five days of treatment changes in the three 
parameters studied were not observed. 
CROSS REFERENCED LITERATURE 
Okeda, A. et al--Duodecim, 95, 1979, p. 11-15; 
Schiffer, H.--Merck Sharp Dohme Intern., 1978, p. 49-52; 
Katz, I.--Ann. Phthalmol., 10 m 1978, p. 847-850; 
Leydhecker, W.--Klin. Monatsblatt der Augenheilkunde, 171, 1977, p. 
538-547; 
Arrata, M.--Ocular pharmacology of timolol drops, London Acad. Press 1980; 
Katz, I.--Invest. Ophthalmol. Vis. Sci., 15, 1976, p. 489-492; 
Kosman, M.--JAMA, 241, 1979, p. 2301-2303; 
Zimmermann, T.--Ophthalmol. Vis. Sci., 16, 1977, p. 687-688; 
Shimamoto, K.--Nippon Iakugaku Zasshi, 53, 1957, p. 75-80; 
Berezhinskaja, V., E. Aleshinskaja,--Pharmacol. i toxicol., 31, 1968, p. 1; 
Jamahara, J., T. Konoshima--Chem. Pharm. Bull., 24 (8), 1976, p. 1902-1912; 
Amin, A., T. Subbajah--Can. J. Microbio., 15 (9), 1969, p. 1067-1076; 
Ikram, L.--Planta Med., 28 (4), 1975, p. 353-358 
Ivanov, C., N. Ivanova et al., Inventor's certificate BG 32353 
Velludo et al.--Lucrarile present. Conf. Natl. Farm., Bucharest, 1958, p. 
351-354