A Clinical Appraisal of Pentapyrrolidinium
(M&B 2050) in Hypertensive Patients

By Epwarp D. Freis, M.D., Epwarp A. Parrenopr, M.D., Lawrence 8. Liienrretp, M.D.,
AND Joun C. Ross, M.D.

The new ganglionic blocking agent, pentapyrrolidinium or M&B 2050, appears to have several
distinct advantages over hexamethonium in the treatment of severe hypertension. These advantages
include longer duration of action, greater potency, less tolerance, less interference with intestinal
motility, and, most important, a more uniform response from day to day on oral administration.
However, critical adjustment of dosage is necessary and side effects are not infrequent, the most
disturbing being postural faintness and impotence.

HE advantages as well as the deficiencies

of hexamethonium in the treatment. of

hypertensive patients! have stimulated
interest in the development of ganglionic
blocking agents which will retain the desirable
effects of hexamethonium and eliminate its
undesirable qualitics. By the very nature of its
action it can be expected that any drug which
acts by inhibiting transmission through au-
tonomic ganglia will exhibit many of the side
effects of such blockade. However, it seems
possible that there may be differences in the
predilection of various compounds for certain
ganglia as compared with others; and also that
other advantages might be gained, such as
longer duration of action, lessened tolerance,
greater and more predictable absorption from
the gastrointestinal tract, which would decrease

 

From The Cardiovascular Research Laboratory,
Georgetown University Hospital, the Department of
Medicine, Georgetown University School of Medicine,
and the Veterans Administration Hospital, Wash
ington, D.C.

Supported in part by research grants from the
National Heart Institute of the National Institutes
of Health, Public Health Service (Grant H-720), and
the Squibb Institute for Medical Research, New
Brunswick, N. J.

Pentapyrrolidinium bitartrate was supplied by
May & Baker Ltd., England and by Wyeth Labora-
tories, Philadelphia, Pa.

Sponsored (in part) by the Veterans Adminis-
tration and published with the approval of the Chief
Medical Director. The statements and conclusions
published by the authors are a result of their own
study and do not necessarily reflect the opinion or
policy of the Veterans Administration.

540

the hazards and inconveniences attendant upon
hexamethonium administration.

Recently, a new ganglionic blocking agent,
pentamethylene 1:5-bis-(1-methyl-pyrrolidin-
ium bitartrate) (pentapyrrolidinium or M&B
2050) has been synthesized by Libman, Pain
and Slack.?

Detailed pharmacologie studies in animals
have been carried out by Wein and Mason.
Preliminary clinical trials by Campbell and
Maxwell suggested that the new drug was more
potent, longer-acting, and produced a more
predictable response on oral administration
than hexamethonium.® Smirk found that
pentapyrrolidinium administered orally was
more effective and better tolerated by hyper-
tensive patients than was hexamethonium.®
The purpose of the present report is to describe
the experiences in this clinic with this new
agent in hypertensive patients. For the sake of
clarity all dosage of both hexamethonium and
M&B 2050 will be referred to in terms of the
amount of ion. Hexamethonium was admin-
istered in the form of the chloride and M&B
2050 as the bitartrate salt.

Potency AnD Duration or Action or M&B
2050 as ComMpaRED witH HEXAMETHONIUM

Four hospitalized hypertensive patients were
given hexamethonium intravenously in an
amount sufficient to produce a significant re-
duction of arterial pressure. Several days later
pentapyrrolidinium was injected slowly intra-
venously until the fall of blood pressure was
similar to that produced by the hexameth-

Circulation, Volume IX, April, 1954
FREIS, PARTENOPE, LILIENFIELD AND ROSE

541

TaBLeE 1.—Comparison of Single Intravenous Dosages of Hecamethonium (C6) and Pentapyrrolidinium (U&B 2050)
in Previously Untreated Hypertensive Patients

 

 

 

Blood Reduction of Blood Pressure Change in Heart | Dose, Duration of Effect
Pressure mm. Hg Rate Beats Min. mg. of Ion In Hours
Patient __ _ . noe coe _—_ __ ae
ee SS — _—— -|- —
C.B. 195/120 28/22 48/35 0 —4 18 4 6 10
R. C. 220/145 65/30 72/38 +16 +18 50 7 6 10
A. 5S. 215/115 68/27 92/28 —4 —4 20 4 6 11
P.D. 185/135 60/20 50/30 +18 +16 12 3 5 9

onium. These patients had received no prior
therapy with either agent.

On the basis of these acute comparative
studies M&B 2050 was approximately five
(range four to seven) times more potent than
hexamethonium (table 1). The average dura-
tion of action of M&B 2050 also was 42 per
cent (range 40 to 46 per cent) longer than that
of hexamethonium.

During an intravenous titration with hexa-
methonium the blood pressure falls rapidly
when the effective dose has been reached.
When M&B 2050 is administered intrave-
nously, however, the reduction in the blood
pressure proceeds more gradually over a period
of 10 minutes or more following an effective
dose. Thus, intravenous titration with M&B
2050 is more difficult than with hexameth-
onium since the effective dose may be exceeded.
This could be avoided in some measure by
injecting the drug quite slowly with the patient
sitting on the side of the bed, since postural
hypotension appears before supine hypoten-
sion.

RELATION BETWEEN EFFECTIVE PARENTERAL
AND OraAL Dosages or M&B 2050

Following intravenous titration 10 hyper-
tensive patients were treated with M&B 2050
subcutaneously twice daily either in the hos-
pital or, occasionally, in the home. If treatment
was on an ambulatory basis, the blood pressure
was recorded five times daily in the home. At
the end of one week parenteral therapy was
discontinued and the drug administered orally
every eight hours. The dosages were increased
every other day until the average daily blood
pressure approximated that achieved during
parenteral therapy.

The mean effective parenteral dose of M&B
2050 was 15 mg. per day, whereas the mean
daily oral dose was 280 mg. Thus, the effective
oral dose was approximately 20 times as great
as the effective parenteral dose. This relation-
ship between oral and parenteral dosage is
similar to that previously observed with
hexamethonium.’ It also agrees in general with
urinary recoveries of M&B 2050 in animals,
which indicated that less than 20 per cent of
an orally administered dose is absorbed.’

Pentapyrrolidinium given orally differed
from hexamethonium administered orally in
one important respect. The onset of action was
far more predictable than with hexamethonium,
beginning approximately one hour after an ef-
fective dose. There also was less variation
from day to day in the response to a given dose
of M&B 2050 than had previously been ex-
perienced with the response to hexamethonium.?
However, as will be discussed later, many ex-
traneous factors influenced the response to
M&B 2050 so that the extent of blood pressure
reduction was not completely uniform from
one day to another. The improvement in pre-
dictability of response after M&B 2050 as
compared with hexamethonium was one of de-
gree, therefore, rather than being an absolute
qualitative difference.

ToLERANCE TO M&B 2050

During one week of therapy with M &B 2050,
administered subcutaneously twice daily to 10
hypertensive patients, there was no evidence
of development of tolerance. In five of these
listed in table 2 at the end of the week the
mean effective dose of M&B 2050 was 0.5 times
less (range — 1.8 to +1.6 times) than the initial
titrating dose. Five of these patients previously
542 PENTAPYRROLIDINIUM IN HYPERTENSION

had been under continuous therapy with
hexamethonium for periods of 6 to 19 months.
Review of their records showed that at the end
of the first week of therapy with hexameth-
onium given subcutaneously, dosages had been
raised progressively to a mean dose which was
1.9 times (range 1.5 to 2.5 times) the initial
titrating dose. Thus, during this short period
of observation the degree of tolerance induced
by M&B 2050 administered subcutaneously
was far less than that experienced previously
with hexamethonium.

If oral administration was begun without
any preceding period of parenteral therapy,
there frequently was a transient hypotensive
response lasting one to several days and occur-
ring at a level considerably below the final
effective maintenance dose. Following this, the
increase in tolerance to the drug was very slight.
For example, in 15 patients treated with oral
M&B 2050 alone for periods varying from
three to six weeks, the mean effective dose at
the beginning of therapy was 232 mg. (range
45 to 518 mg.) per day of the ion; while at the
end of the above period the average effective
dosage was 275 mg. (range 135 to 562 mg.) per
day.

Cross ToLERANCE BETWEEN M&B 2050
AND HEXAMETHONIUM

The degree of cross tolerance existing be-
tween M&B 2050 and hexamethonium seemed
to be very small. This was estimated in five
patients who had been treated continuously
with hexamethonium, subcutaneously admin-

TaBle 2.—Effect of Hexamethonium and Pentapyr
rolidinium in the Same Patients Showing Develop
ment of Tolerance to Each and Degree of Cross
Tolerance

 

 

Pentapyrrolidinium

Hexamethonium Ion, Effective Ton, Effective Dose

 

 

 

 

Dose (mg.) (mg.)
Patient
After 6 to
wy Aft va Af
Initial 4 wk 18 mos. of | Initial i we
ALS. 8 | 12 20 2 1.5
H. B. 30 75 100 ll 10
C.P. 2 4 | 75 1.8 3
O. A. 30 45 90 1 11
J.C. 50 100 120 20 i

istered for periods of six months to two years
(table 2). When comparison is made between
the initial effective dose of hexamethonium
obtained by intravenous titration (prior to any
previous therapy with ganglionic blocking
agents) and the initial effective titrating dose
of M&B 2050 (after prolonged therapy with
hexamethonium) the data indicate that M&B
2050 was approximately 2.5 times more active
(range 0 to 4 times) than hexamethonium.
Thus, in these hexamethonium-treated pa-
tients, the relative potency of M&B 2050 was
only half as great as in patients previously un-
treated with ganglionic blocking agents.

However, when comparison was made in
these same patients between the initial titra-
tion dose of M&B 2050 and the dosage of
hexamethonium required after prolonged ther-
apy with the latter drug, the mean relative
potency of M&B 2050 was 13.5 times (range
5 to 35 times) that of hexamethonium. It
would appear, therefore, that the degree of
cross tolerance between the two drugs is so
slight that for practical clinical purposes one
may consider that tolerance to hexamethonium
does not induce significant tolerance to M&B
2050.

Factors PorENTIATING THE HyYPpoTEeNSIVE
Response to M&B 2050

Since the majority of the patients under
treatment with M&B 2050 recorded their
blood pressures at home, it was possible to
study in some detail the various extraneous
factors which influenced the blood pressure.
These were as follows:

Postural Effects. (1) When the patient was
up and about a smaller dosage usually was
necessary to lower the blood pressure than
when he was supine. Henee, a larger dose
usually was required at bedtime. (2) Severe
postural hypotension with faintness occurred
more frequently after the morning dose than
at other times. (3) Some of the patients noticed
increased nocturia accompanied by decreased
urinary frequency during the day.

Additive K'ffects of Other Vasodilating Influ-
ences. (1) The ingestion of aleohol frequently
was followed by marked potentiation of the
hypotensive action of M&B 2050. The amount
FREIS, PARTENOPE, LILIENFIELD AND ROSE 043

of alcohol need not be large since one or two
“cocktails” was sufficient to induce significant
additional reductions of blood pressure. (2) The
ingestion of a large meal at times acted as a
potentiating factor. (3) Vigorous exercise such
as pushing a lawn mower was followed at
times by an additional fall of blood pressure.
This was in contrast to the untreated individual
whose blood pressure usually increases with
exercise. (4) During the hot summer weather
the dosage of M&B 2050 frequently had to be
reduced because of marked hypotension. The
incidence of postural faintness or frank syncopal
attacks increased at the onset of a period of
unusually hot weather.

Salt Depletion. (1) When patients were placed
on diets rigidly restricted in sodium the hypo-
tensive effect of M&B 2030 was exaggerated.
Such individuals became unusually susceptible
to postural hypotension, while the margin
widened between the level of blood pressure in
the erect position as compared with the supine
position. For this reason it seemed advan-
tageous to permit a moderate salt intake in
all of the noncardiac patients. In this way
dosages could be raised to the point of influ-
encing the supine pressure without inducing
postural syncope. (2) Mercurial diuretics were
administered at times to the cardiac patients
in order to control the signs of congestive heart
failure although the necessity for using them
usually decreased greatly after the institution
of hypotensive therapy. It was noted that as the
edema accumulated the dosages of M&B 2050
became progressively less effective. However,
immediately following the mercurial-induced
diuresis marked reductions of blood pressure
occurred. For this reason it. was necessary in
some instances to reduce the dosage of M&B
2050 for a day or two following the mercurial
injection. (8) The potentiating action of hot
weather described above may have been due in
part to excessive salt loss.

THERAPEUTIC RESULTS

Twenty-seven patients were treated with
M&B 2050 orally as the sole medication for
periods varying from two to six months. All
could be classified as having severe, “fixed”
hypertension. Twelve had grade LV hyperten-

sion with papilledema or had shown evidence
of papilledema in the recent past (21 of the
total group had received previous therapy with
other drugs), nine had grade III and six had
grade II hypertension.°

Dosages of the drug were administered as
close to every eight hours as possible, the
first dose being taken immediately after arising
in the morning. Because of its long duration of
action, the dosages of M&B 2050 should be
widely spaced in order to avoid the additive
effect. of one dose overlapping on another.‘
Following the initial period of adjustment the
mean daily effective dose was 300 mg. (range
135 to 630 mg.) of the ion. This was divided
as follows: the average morning requirement
was 95 mg., the afternoon dose 86 mg., and
the mean bedtime dose was 122 mg. The larger
dosage at night was well tolerated and usually
was required to lower the blood pressure while
the patient was in the supine position.

The results are based on the means of many
home and clinic readings taken with the pa-
tient in the sitting position (table 3). Record-
ings taken with the patient in the supine
position were somewhat higher, and those
taken in the erect position were somewhat
lower. The control value in each case was the
level of blood pressure taken prior to any
therapy after 48 hours or more of rest in bed
in the hospital.

The average pretreatment blood pressure
for the entire group was 230/135 (range 180/110
to 260/160) mm. Hg; the mean post-treatment

TaBLe 3.—Mean Reduction of Blood Pressure in
27% Hypertensive Patients Treated with Pentapyr-
rolidinium. Basis of Comparison Is Hospital Control
Blood Pressure Prior to Any Form of Drug Therapy

 

 

 

 

 

 

 

 

 

Reduction of Blood Pressure No. %
Systolic
60 mm. Hg or more......... 15 55
40 mm. Hg or more......... 22 $1
20 mm. Hg or more......... 26 96
Less than 20 mm. Hg....... 1 4
Diastolic
30 mm. Hg or more......... 14 52
20 mm. Hg or more......... 23 85
15 mm. Hg or more......... 24 89
Less than 15 mm. Hg....... 3 11

 
544 PENTAPYRROLIDINIUM IN HYPERTENSION

blood pressure was 170/110 (range 130/95 to
210/130) mm. Hg. Slightly more than 50 per
cent of the patients exhibited a reduction of
60 mm. Hg or more in systolic pressure and of
30 mm. Hg or more in the diastolic pressure.
Twenty-two, or 81 per cent, showed systolic
reductions of 40 mm. Hg or more and 23, or
85 per cent exhibited diastolic reductions of
20 mm. Hg or more.

The hypotensive response to M&B 2050
was somewhat more predictable than the
response to hexamcthonium and once a main-
tenance dosage level had been established, the
necessity for constantly modifying it was not
nearly as great. Nevertheless, variability pro-
duced by the extraneous additive factors pre-
viously discussed or by unknown causes was
sufficient to be an ever-present potential
source of inconvenience and even hazard to
many patients.

For example, patient C. P., a 42 year old,
white, male teacher with ‘malignant’? hyper-
tension in therapeutic remission was taking 3
doses per day of 100, 150 and 350 mg. of M&B
2050 in the morning, afternoon and at bedtime,
respectively. On arising in the morning his
blood pressure usually was 190/110 mm. Hg;
this fell after the morning dose to 140/95 mm.
Hg. It then rose gradually to 190/120 mm. Hg
at 2 p.m. but fell again after the 2 p.m. dose
to 160/110 mm. Hg. During the evening the
blood pressure rose gradually to 190/120 mm.
Hg. Two hours after his morning dose on a hot
July day he walked up a steep hill to the hos-
pital for his regular office visit. When he ap-
peared in the clinic he was pale and on the

TaBle 4.—Incidence of Side Effects Produced by
Pentapyrrolidinitum in 27 Hypertensive Patients

 

 

Side Effect No Y

Impaired visual accommoda-
tion. 2. eee 14 52
Dry mouth.......00..0........ 12 40
Constipation of any degree... 11 40

Not controlled by neostyg-
mine. ................0.0. 4 15
Isnemas required............ 0 0
Postural faintness. ........... 8 30
Postural syncope............. 1 4
Impotence.................... 8 30

 

verge of syncope. His blood pressure sitting
in a chair was 90/75 mm. Hg. Immediately
after lying down the pressure rose to 165/115
mm. Hg, and after resting supine for an hour
the patient was able to go about his usual
day’s activities,

SIDE EFFECTS

The so-called side effects of M&B 2050 were
similar to those experienced with hexameth-
onium; all could be accounted for on the basis
of ganglionic blockade. The most prominent
of these were postural faintness, dry mouth
and loss of visual accommodation (table 4).
These side effects were most pronounced when
the blood pressure was the lowest. Many of the
patients required reading glasses with positive
lenses for occupations requiring accommoda-
tion for near vision and tinted glasses to wear
in bright sunlight because of the failure of
pupillary constriction.

In contrast to the lack of constipation in
patients treated with parenteral M&B 2050,
oral ingestion of the drug was accompanied by
some degree of constipation in many instances
(table 4). It was not as severe as that observed
in patients taking hexamethonium and in most
instances responded to oral neostigmine in
doses of 15 to 45 mg. In a few instances irritant
cathartics also were necessary. Paralytic ileus
and severe obstipation did not occur. One of the
patients who suffered severe bouts of acute
gastric dilatation when taking parenteral
hexamethonium suffered a similar attack on
oral M&B 2050.

Impotence was a frequent and troublesome
side cffect in the male. In general the middle
aged and elderly patients suffered complete
impotence during the entire period of treat-
ment whereas most of the younger patients
were only partially incapacitated. The urethane
of @-methylcholine (Urecholine), 10 mg. under
the tongue every hour for threc hours preceding
sexual intercourse, seemed to benefit some of
the patients, but it is impossible to say whether
the effect of Urecholine was real or psychogenic.

A few patients complained of chilly sensa-
tions in a cold environment probably due to
failure of reflex vasoconstriction in the skin.
This required that they dress warmly during
FREIS, PARTENOPE, LILIENFIELD AND ROSE 545

cooler weather in order to conserve body heat.
None of the patients taking M&B 2050 suf-
fered from inability to empty the urinary blad-
der; one of these patients had been unable to
take hexamethonium because of this side ef-
fect.

Certain side reactions, particularly dryness
of the mouth and frequent postural faintness,
were most prominent during the early stages
of treatment but tended to diminish as treat-
ment progressed, whereas other side effects
such as impotence remained unchanged during
the entire period of treatment.

Discussion

The purposes of this study were twofold:
to determine, first, whether M&B 2050 pos-
sessed therapeutic advantages over hexameth-
onium and, second, whether it could be given
safely and effectively by the oral route of ad-
ministration. Our findings in general are in
agreement with those of Smirk.® In regard to
the first question M&B 2030 appeared to be
superior to hexamethonium in several re-
spects:

1. The degree of tolerance induced by M&B
2050 definitely was less than that observed
with hexamethonium. The negligible degree of
cross tolerance was of theoretic as well as of
practical importance. The reason for the de-
velopment of “tolerance” to the hypotensive
effects of hexamcthonium has not been clear.
It was unknown whether this represented a
true drug tolerance or whether, despite con-
tinued ganglionic blockade, some other hyper-
tensive mechanism operating humorally, or in
some other way not dependent upon transmis-
sion of impulses through automatic ganglia,
had been activated to restore the hypertension.
The fact that after the development of tolerance
to hexamethonium the patients remained sensi-
tive to relatively small doses of M&B 2050
suggests strongly that the resistance to
hexamethonium represented true drug. toler-
ance, From the practical point of view the
lesser degree of tolerance experienced with
M&B 2050 permitted management of the pa-
tient with less frequent need for dosage read-
justment,

2. When compared with hexamethonium,

the duration of action of pentapyrrolidinium
was longer than that of hexamethonium and
permitted less frequent administration.

3. The response following oral administration
of M&B 2050 was more predictable than that
observed after hexamcthonium. The effective
dosage range was not as wide and the variations
of blood pressure response on a given dose from
day to day not as great. The greater pre-
dictability of response may have been related
at least in part to the lesser effect of M&B 2050
on intestinal motility than that produced by
hexamethonium. The degree of constipation
and stasis in the gastrointestinal tract produced
by oral M&B 2050 could be controlled usually
by simple measures such as the administration
of oral neostygmine. As a result accumulation
of the drug in the gut seldom occurred. In the
case of oral hexamethonium such accumulation
of the drug may be followed by absorption of
large dosages over a long period of time leading
to severe and persistent hypotensive reactions.
Although syncopal attacks occurred after M&B
2050, the prolonged collapse reactions often
accompanied by ileus were not seen as they had
been with hexamethonium.

Nevertheless, oral therapy with M&B 2050
left much to be desired. Some of the patients
were controlled, with minimal side effects, but
in the majority critical dosage adjustment was
required, slight excesses producing hypotensive
reactions and slight under-dosage failing to
induce a significant hypotensive response. In
addition, in order to lower the blood pressure,
it usually was necessary to elevate dosage to a
point where side effects were frequent par-
ticularly during the early weeks of adjustment.

During the treatment period it was observed
frequently that vasodilator influences such as
heat, alcohol, exercise and food, which ordi-
narily would have no effect on blood pressure,
produced a significant hypotensive effect in the
patient treated with M &B 2050. Under normal
conditions such vasodilator influences are
opposed immediately by homeostatic vaso-
constrictor responses mediated over the sym-
pathetic nervous system. These reflexes produce
vasoconstriction in other vascular arcas thereby
preventing any appreciable fall in total
peripheral vascular resistance. However, M&B
046 PENTAPYRROLIDINICUM IN HYPERTENSION

2050, by producing ganglionic blockade, pre-
vents these homeostatic adjustments. There-
fore vasodilation in one vascular area will be
unopposed by vasoconstriction in other regions,
and, if the dilated areca is large, the systemic
blood pressure will fall. These considerations
provide a rational basis for combining the
ganglionic blocking agents with other vaso-
dilating drugs. The effects of combining penta-
pytrolidinium with other hypotensive agents
will be discussed in a succeeding paper.!°

SUMMARY AND CONCLUSIONS

1. Comparisons were made between the ef-
fects of hexamethonium and pentapyrrolidin-
ium (M&B 2050) in hypertensive patients.
The following differences were noted: (a) M&B
2050 was approximately five times more potent
than hexamethonium. (b) The duration of the
hypotensive effect was 40 per cent longer. (c)
Less tolerance occurred after M&B 2050. Cross
tolerance between this drug and hexameth-
onium was very slight. (d) Less constipation
was produced by M&B 2050 and there was no
interference with emptying of the urinary
bladder. The constipation could be controlled
with oral neostygmine and/or irritant cathar-
ties. (e) On oral administration a more pre-
dictable hypotensive response was obtained.

2. The other side effects of ganglionic block-
ade were similar to those observed with
hexamethonium.

3. Various extrancous factors such as pos-
tural changes, ingestion of alcohol or a heavy
meal, exercise, hot weather and salt depletion
intensified the hypotensive effect of M&B
2050.

4. Unlike hexamethonium it was possible to
lower the blood pressure significantly in the
majority of patients with oral administration
of M&B 2050 without producing prolonged
collapse reactions or paralytic ileus. However,
critical adjustment of dosage was necessary
and side effects were not infrequent, the most
disturbing being postural faintness and im-

potence. For these reasons M&B 2050 seems to
be of greatest value in those cases of severe
hypertension which cannot be controlled by
simpler measures.

SuMARIO EspaNou

El nuevo agente bloqueador ganglionar,
pentapyrrolidintum o M&B 2050 aparenta
tener ciertas ventajas distinctivas sobre el
hexamethonium en el tratamiento de Ja hiper-
tensién severa. Estas ventajas incluyen una
accién mas prolongada, mayor potencia, menor
tolerancia, menos interferencia con la movili-
dad intestinal y mas importante atin, una
respuesta) mas uniforme de dia en dia a la
administracién oral. Sinembargo, un ajuste
critico de la posologia fué necesario y los efectos
no deseables no fueron infrequentes, el mas
alarmante siendo el desfallecimiento postural y
la impotencia.

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4 Wien, R., anp Mason, D. F. J.: Pharmacology of
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5 Maxweut, R. D. H., anp Camppeti, A. J. M.:
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6 Smirk, F. H.: Action of a new methonium com-
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7Mitne, G. D., anp Onersxy, 8.: Absorption of
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8Wirn, R.: Personal communication to the
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9Keira, N. M., Wagener, H. P., anp Barker,
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0 Preis, 1. D., Livrenrisyp, L. 5., Parrenors, E.
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