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British Journal of Ophthalmology, 1979, 63, 45-
Piloplex, a new long-acting pilocarpine polymer salt.
A: Long-term study
URIEL TICHO,1 MICHAEL^ BLUMENTHAL,2 SHLOMO^ ZONIS,'^ ALON^ GAL,
IZHAK BLANK,4 AND^ ZEEV^ W.^ MAZOR
From the 'Department of Ophthalmology, Hadassah^ Hospital, Jerusalem,^ the^ 2Department^ of^ Ophthalmology, Sheba Hospital, Tel-Hashomer, the 3Department of Ophthalmology, Rambam Hospital, Haifa, and
4Hydrophilics Laboratories, Haifa, Israel
SUMMARY Thirty eyes of 15 patients with open-angle glaucoma were followed up for a period of up
to 1 year while being treated with Piloplex eye drops containing a new long-acting pilocarpine
polymer salt.^ Average^ morning^ intraocular^ pressure^ (IOP)^ values^ during^ treatment^ with^ pilocarpine
hydrochloride administered^ 4 times^ daily^ was^ 20 5^ mmHg. Average morning IOP^ values^ during
Piloplex medication administered^ only^ twice^ daily^ were^ 19-8^ to^ 18-2 mmHg^ (range^ of^ averages on^14
sessions). These^ findings indicate^ the lower^ average^ pressure^ during Piloplex^ medication^ and show
its prolonged hypotensive^ effect.^ Both^ medications^ contained^ an^ equivalent^ total^ daily^ amount^ of
pilocarpine. Throughout the^ 1-year study period^ no^ adverse side^ effects^ were^ reported,^ and^ only^1
patient complained of^ local^ sensitivity reaction.^ Visual disturbances^ characteristic of^ pilocarpine
eye drops were reduced^ from^3 times^ a^ day on^ pilocarpine hydrochloride 4 times^ daily to^ once^ a
day on Piloplex twice daily.
One of the major problems in the treatment of
glaucoma is the limited therapeutic effect (6 to 8
hours) of pilocarpine eye drops. Consequently many
attempts have been made to prolong the hypotensive
effect of pilocarpine. Increase in concentration of
pilocarpine above 4 % has failed to show a significant increase or prolongation of therapeutic effect (Harris
and Galin, 1970; Drance and Nash, 1971). Also,
increased viscosity of the ophthalmic solution
administered only twice daily did not give adequate
control for clinical usefulness (Quigley and Pollack,
A prolongation of therapeutic effect, however, can be achieved by sustained release of pilocarpine to the ocular tissues. This is possible only when release of the drug from its vehicle is rate-limiting (Sieg and
Robinson, 1977).
Piloplex emulsion, which contains a new pilo- carpine polymer salt, has been designed to give sustained release of pilocarpine. This characteristic of Piloplex has been demonstrated in vitro by comparing the release patterns of pilocarpine hydro- chloride with Piloplex. The results, summarised in Fig. 1, indicated that the release time of 80% of the
Address for reprints: Dr U. Ticho, Department of Ophthal- mology, Hadassah Hospital, Jerusalem, Israel
100
-; 80
vv a(A 60
.C_^ c a^40
a-2. 20
0
- l (^) #....----~~~~~~~~~~.......
o Pilocarpine hydrochloride 1291. in aqueous
. Pilocarpine hydrochloride 12-9a/. (pilocarpine 11"I.)
i n hyd roxyethyl ce Iulo se solut ion,
viscosity 3800 cp (pilocarpine 11'/.)
- (^) Piloplex 11, viscosity 600cp( pilocarpine 11/.) l (^0 ) Time (hours)
8 12 16 20
Fig. 1^ In vitro release ofpilocarpine from Piloplex and
pilocarpine hydrochloride solutions from a dialysis bag. The medium^ was an^ agitated isotonic^ saline solution (pH 7 1)^ maintained^ at^ 37°C.^ Active^ ingredient^ was determined spectrophotometrically (Ticho et al., 1978)
active ingredient from Piloplex is 6 hours, against (^1) hour for the corresponding pilocarpine hydro- chloride solutions.
Preliminary clinical^ trials^ on^68 patients^ with
glaucoma treated with Piloplex confirmed its 45
Uriel Ticho, Michael Blumenthal, Shlomo Zonis, Alon Gal, Izhak Blank, and ZEtv W. Mazor
prolonged hypotensive effect (Ticho et al., 1978;
Blumenthal et^ al., 1979). In^ these studies^ Piloplex administered twice daily induced^ a^ lower^ average diurnal intraocular pressure (IOP) level with fewer IOP fluctuations than pilocarpine hydrochloride
administered 4 times daily (Fig. 2). The^ total^ daily
amount of pilocarpine applied in^ the^ two^ different
medications was equal. The^ present paper reports on the therapeutic effect and safety of long-term Piloplex medication.
Patients and methods
The study was carried out at 3 different glaucoma
units. At the Hadassah, Sheba, and Rambam
hospitals in Israel 30 eyes of 15 patients who agreed
to participate in this survey with their informed
consent were studied. All patients had bilateral open-angle glaucoma with visual field defects. All had been under our medical supervision for at least 2 years before this study. Ten of our patients were males and 5 were females. They were aged 48 to 84 except for^1 patient who^ was^18 years old. The study was divided into two^ periods:^ (1)^ Two-week period in (^) which the patients were treated with their pre- study medications. These medications consisted of pilocarpine hydrochloride (PHCI)^2 %^ or 4^ %^4 times daily, which contains 1-7 and 3-4 % pilocarpine base.
To 5 patients additional epinephrine borate (1 % of
free base) and/or acetazolamide 250 mg were administered twice a day. The detailed prestudy
24 L-
'^ cn
E 2
E
v 18
0 a a 12
F
0 0
I I
Pilocarpine hydrochloride (PHCI)2l/.q.id.
Piloplex 3*4 b.i.d.
Time of PHCI eye drop administration Time (^) of Piloplex eye drop administration Standard deviation
I
6 9 Clock time
Fig. 2 Average diurnal^ I hospitalised patients) on^ tl hydrochloride 2% 4 times third day of Piloplex 3-4 ti (Blumenthal et al., 1979)
Table 1 Patients and medication data
Patients Prestudy Study Studj'
- medicine medicine duration No. Age Sex (period A) (period B) (months)
1 65 F PHCI 2 PX 3-4^12 2 66 M PHCI 2 PX^ 3-4^8 3 78 M PHCI 2 PX 3-4 12 4 76 M PHCI 2 PX 3-4 8 5 65 M PHCI 2 PX 3 4 11 6 73 M PHCI 2, E PX 3-4, E 9 7 18 F PHCI 2, E, AC PX 3 4, E, AC 8
8 54 M PHCI 4 PX 6-8 12 9 61 M PHCI 4 PX 6-8 12 10 65 F^ PHCI 4 PX 6^8 11 49 F PHCI 4 PX 6-8 12 12 69 M PHCI 4, AC PX 6-8, AC 12 13 52 M PHCI 4, E, AC PX 6-8, E, AC 8 14 84 F PHCI 4, E, AC PX 6-8, E, AC 9 15 60 M PHCI 4, E, AC PX 6 8, E, AC 12
Abbreviations for^ medications administered^ are as^ follows:^ PHCI^ - pilocarpine hydrochloride^ given^4 times^ daily (number^ following^ PHCI indicates the percentage of PHCI).^ PX^ -Piloplex given^ twice daily (number following PX^ indicates the^ percentage of pilocarpine). E -^ epinephrine borate (I% of free base) given twice daily. AC - acetazolamide 250 mg given twice daily.
medication is listed in Table 1. (2) After the first 2
weeks of treatment PHCI 2 or 4% was replaced by
Piloplex 3-4 and 6-8 twice daily respectively. Piloplex
3-4 and 6-8 contains 3-4 and 6-8% pilocarpine.
Morning intraocular pressures were measured by
the Goldmann applanation tonometer before
medications on day 14 of period A and on days 7,
14, and 28 and every month thereafter through 8 to
12 months of period B. At each visit tolerance and
side effects were (^) recorded. Visual (^) fields were obtained every 3 months.
Results I Out of the (^30) eyes studied 26 (87 %) had an IOP of less than 24 mmHg throughout all measurements , , , over an 8- to 12-month period. None of the patients 12 15 18 21 presented progression in field loss. Average morning IOP of the 30 (^) eyes at the end of the first 2 weeks of OP curve of 21 eyes (12 PHCI^ 4 times daily (period A) was 20 5 mmHg. he third day ofpilocarpine This value was higher than those measured during
daily treatment and on^ the the 8 to 12 months of^ Piloplex^ twice^ daily^ (period^ B>
wice daily treatment (range of^ average morning IOP values:^ 19-8^ to^ 18- mmHg). The average morning IOP curve throughout
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