Europ.J.clin.Pharmacol. 8, 131-134 (1975) © by Springer-Verlag 1975
Persistent Parotid Pain Due to Guanacline M. Le Moine Parker Queen Victoria Memorial Hospital, Melbourne, Australia Received: June 25, 1973, accepted: August
13, 1974
S~a~.
Details are given of 17 patients who developed parotid pain during treatment with guanacline and which persisted after cessation of guanaeline for upto five and a half years. These patients are compared with 17 patients who received similar treatment with guanacline and who did not develop parotid pain. There was no significant difference between patients who experienced parotid pain and those who did not with respect to sex, age, clinical diagnosis, blood urea, previous hypotensive therapy or other drugs given concurrently with guanacline. There was a slightly greater association of parotid pain with other side effects and with a larger daily dose of guanacline. It is suggested that persistent parotid pain after guanacline therapy is due to prolonged or permanent selective sympathetic nerve damage in the region of the cervical sympathetic nerve supply to the salivary glands.
Key words: Guanacline, persistent parotid pain.
Introduction
Patients and Methods
The effective therapy of hypertension necessitates the use of compounds with powerful pharmacological actions which exert at a number of sites and result in a number of physiological changes in addition to that of lowering blood pressure. Moreover, most patients require treatment with more than one drug at a time. The incidence of complications and unwanted side effects is thus relatively high. Fortunately in most instances side effects are reversed or resolved by alterations in drug dose or the method of administration or by ceasing therapy with that particular drug. In some cases, however, side effects may persist long after the drug has been stopped and can no longer be exerting any direct, chemical effect. Such is the case with parotid pain and postural hypotension induced by the adrenergic neurone inhibitor guanacline. In 1969 Parker et al. (1) reported the results of a clinical trial of guanacline in which half the patients developed parotid pain I. Some patients experienced very severe pains which necessitated cessation of therapy with guanacline. In the majority, parotid pains persisted for many months after treatment was stopped and in some the symptom appears to be a permanent feature. This paper is an attempt to further document these patients in the light of a follow - up evaluation exceeding 5 years.
Between November 1966 and December 1967, 34 patients were treated for hypertension with guanacline. All patients were women and their ages ranged from 18 to 68 years, mean age was 39.5 years and the median was 37 years. Ten patients received guanacline alone, 18 patients received a thiazide diuretic, 4 received methyldopa and a thiazide, I received reserpine and a thiazide, I received frusemide and methyldopa. Prior hypotensive treatment had been given to 27 patients, of whom 24 were taking a diuretic and 19 were taking methyldopa. Guanacline was started initially in a dose of 15 mg twice daily and increased by 15 to 30 mg daily at intervals of not less than 3 days until blood pressure control was satisfactory or unwanted side effects developed.
lln Germany the first cases of persistent parotid pain were reported by Bock et al
Results Results are given in terms of the development of parotid pain, postural hypotension and significant other side effects. Patients who developed these complications are compared with those who did not in an attempt to determine possible associations between the development of parotid pain and contributing factors (Table I). The symptom picture was identical in all patients with parotid pain. Pain came on acutely with the first few bites, particularly of acid or bitter foods. It was felt in the region of the parotid, was often lancinating in character, tended to wear off quite rapidly as mastication proceeded but with
132 a tendency to recurr if another 'sharp' food was a close fitting blunt metal cannula connected by a taken. saline filled polyethylene tube to a transducer Of the 17 patients who developed parotid pain which was in turn attached to a Beckmann R.P. Dynograph. In each instance the resting intraduct presthe average duration of t~eatment before the onset of pain was 10.1 weeks with a range from 2 to 20 sure was determined and then salivation was induced by a stimulus of bitter lemon juice. The pressure weeks and the median was 8 weeks. In most patients increase was recorded for a number of repeated stimguanacline was stopped within 4 weeks of the onset uli and the symptom of pain was noted. of symptoms. After cessation of guanacline parotid After a return to basal level, a similar prespain persisted for a month or longer in all but 3 sure or a greater pressure in the parotid duct was patients whose symptoms resolved in from I to 3 obtained by injection of normal saline. Again the weeks. The mean duration of symptoms from the time pressure achieved was correlated with the onset of of stopping treatment was 21.7 months with a range pain - if it occurred. The results obtained are from 1 week to 5 and a half years. Three patients given in Table 4. show no evidence of losing their pain with time, The response to stimulation in terms of volume and 1 patient has symptoms which appear to be inor composition of saliva was not determined. creasing in severity and frequency. It will be seen that there was a fair uniformity In those patients who developed parotid pain in of resting parotid duct pressure in all patients less than 8 weeks treatment with guanacline the and the control. average daily dose was 60 mg compared with 85.5 mg The occurrence of parotid pain by physiological per day in patients who developed pain after treatstimulation was associated with high intraduct presment for 8 weeks or longer. Patients whose symptoms sures in 2 patients and in one of these saline inpersisted less than 14 and a half months had rejection caused a similar degree of pain at a simiceived an average daily dose of 67.5 mg guanacline lar duct pressure to that with physiological stimwhereas those with symptoms persisting for 14 and ulation. In patient 3 there were technical diffia half months or longer had received an average culties and the investigation was incomplete. The daily dose of 82 mg of guanacline. control patient had a low duct pressure with physioThe relationship ton parotid pain and other symplogical stimulation and was able to withstand a toms is given in Table 2. Of the 5 patients with duct pressure of 250 cm of water without experiencpostural hypotension, the most severe disturbance ing pain. In patients I and 2 there was no alterwas in the patient who did not have parotid pain. The 4 patients with postural hypotension and parotid atiQn of duct pressures achieved or the pain experienced following physiological stimulation after pain had only transient mild postural hypotension parasympathetic blockade by atropine. Patients 2 which did not persist off guanacline whereas they and 3 had a sialogram which showed a radiologically had parotid pain from 30 months to indefinite durnormal parotid duct system. ation. After cessation of guanacline in the group of parotid pain patients, 8 had therapy continued with guanethidine and chlorothiazide, 5 had methylOiscussion dopa and a chlorothiazide, 2 had chlorothiazide alone, ! had reserpine and chlorothiazide and ! Guanacline (Cyclazenin, Leron) is chemically N-2patient had guanethidine methyldopa and chloroguanidoethyl)-4-methyl- I, 2, 5, 6, - tetrahydrothiazide. The duration of symptoms in relationship pyridine suphate. Pharmacological action results to subsequent drug therapy is given in Table 3. in adrenergic neurone blockade with marked catecholThe patients who did not develop the symptom of amine depletion in the postganglionic sympathetic parotid pain had a mean duration of treatment with nerve fibres. Ganglion blocking effect is relatively guanacline of 25 weeks and 9 patients had treatlimited. Complications of therap~ with guanacline ment for less than 20 weeks which is the maximum were relatively common and in particular parotid period of treatment before the onset of parotid pain and postural hypotension were prominent in a pain in any patient in this series. In each case number of trials (1,2,3). Postural hypotension was often severe and in some patients persisted indeguanacline was stopped because of side effects or finitely after cessation of guanacline therapy. poor blood pressure control. For this reason it is possible the incidence of parotid pain may have Dawborn and others (4) have postulated that been higher had this group of 9 continued longer guanacline causes irreversible depletion of noradrenaline stores in adrenergic nerve terminals on treatment. in some patients and have shown that these patients have a persistently reduced urinary excretion of catecholamines. Supersensitivity of salivary glands Parotid Duct Pressures due to prolonged administration of guanethidine and As parotid pain due to guanacline was very similar bretylium in cats was demonstrated by Emmelin and Engstrom (5) and shown to be similar in effect to in nature to that which occurs in patients with that resulting from excision of the superior cervisalivary calculi and partial occlusion of the salical ganglion. More recently Burnstock and others vary duct, four patients and one control were in(6) have shown that in rats treated with guanacline vestigated to determine pressure rises in the parotid duct and the possible relationship between for 18 weeks there was persistent hypotension after intraductal pressure and symptoms of pain. cessation of guanacline and that this was associated The method was to canulate the parotic duct with with degenerative changes in sympathetic ganglion
133 Table I. Patient characteristics and parotid pain Parotid Pain
Table 4. Parotid duct pressure study (intraduct pressures in cent]metres of water)
No Parotid Pain
o
o O
Patients
17
I7
Essential Hypertension
13
1t
O
Chronic Renal Disease
4
6
Previous Hypotensives
13
13
8
11
13
10
Previous Methyldopa Previous Thiazide Previous other Drugs
6
4
Guanacline alone
4
6
11
10
3
1
Guanacline + Thiazide Guanacline + Methyldopa
24-56 39.2 36 18-68 39.6 37
Blood Urea mg/100 ml
15-60 28.4 28 19-54 33.5 30
Daily Dose Guanacline mg
30-120
54 45
Table 2. Parotid pain and other side effects Parotid Pain
No Parotid Pain
Patients
17
17
Other Side Effects (Patients)
11
7
Postural Hypotension
4
I
Head and Neck Pains
3
2
Myalgia
2
1
Other
2
3
Table 3. Parotid pain related to subsequent treatment Treatment of Guanacline
Pain Pain Pain 14.5 months 24-60 months>60 months
Ismelin + Thiazide
5
2
2
Methyldopa + Thiazide
2
2
I
Other
3
1
O
• O ~'~
~ 50
r-q U • ~ ~) ~ u~ . ~ ¢ ~
1
4
75
+
2
0.5
87.5
++
3
1
12.5
0
-
4
2
9
0
26
0.5
5
0
250
Control
Age. Years
75 60 15-105
+ .~ ~
-~4 4 O ¢~ ¢ ~
I ~
120 87
~ O
+
.~
50 -~4 ¢0 ~ O ¢~ ~ Z
0 ++ ++ 0
cells. These changes consisted of a strong yellow autofluorescence shown by electron microscopy to consist of a massive deposition of lipoprotein granules comparable to aging pigment. Changes of this severity and type were not produced by similar exposure to guanethidine although this did cause some cell damage which resolved after the drug was discontinued. It seems very probable that guanacline can produce similar prolonged or permanent damage to sympathetic nerves supplying the salivary glands and consequent symptoms of parotid pain. From analysis of the patients in this series it is apparent that there was no significant difference between patients who experienced parotid pain and those who did not when considered in respect of sex, age, clinical diagnosis or blood urea nor were there any differences in regard to previous hypotensive treatment or to other drugs given concurrently with guanacline. There was a slightly greater incidence of other associated side effects in patients with parotid pain but this does not reach statistical significance with these numbers. The mean daily dose of guanacline was higher in the group who had parotid pain - 75 mg a day as compared with 54 mg a day - but the range was very similar. In addition there was a trend to a dose symptom relationship with respect to: a) Duration of symptoms after withdrawal of guanacline in that those patients whose total duration of symptoms was below the median of 14.5 months had received a mean daily dose of 67.5 mg whereas those patients with symptoms persisting longer than 14.5 months had received a mean daily dose of 85.5 mg. b) Patients treated for less than the median of 8 weeks before the onset of symptoms had received a mean daily dose of 60.0 mg guanacline whereas those treateG for longer than 8 weeks before symptoms had received a mean daily dose of 85.5 mg. It is possible that this latter effect is only an apparent dose symptom relationship and merely represents the fact that there is a tendency for an increasing dose of drug to maintain or achieve a satisfactory hypotensive response as the duration of treatment increases. Duration of symptoms after withdrawal of guanac-
134 line may represent the degree of damage caused by guanacline alone but it may also represent an effect which was perpetuated by the action of subsequent drugs. In this respect it may not have been wise to follow guanacline with guanethidine in 9 of the 17 patients as guanethidine has been known to cause parotid pain (albeit very rarely) and produces ultrastructural changes in sympathetic ganglion cells (6). However, there is no significant difference in relation to duration of symptoms in those patients who were given guanethidine compared with those who received methyldopa or a thiazide alone or a thiazide plus reserpine after guanacline was withdrawn.
References I. Parker, M. Le Moine, Bullen, M.: Guanacline, a new hypotensive drug. Med. J. Aust. 2, 159
(1969) 2. Jerums, G., Ebringer, A., Doyle, A.E.: A comparison of guanacline with methyldopa in the treatment of hypertension. Med. J. Aust. 2, 466 (1968)
3. Hall, G.V., Michell, G.: Clinical experience with guanacline, a new hypotensive agent. Med. J. Aust. 2, 1047 (1968) 4. Dawborn, J.K., Doyle, A.E., Ebringer, A., Howqua, J., Jerums, G., Johnston, C.I., Mashford, M.K., Parkin, J.D.: Persistent postural hypotension due to guanacline. Pharmaeologia Clinica
2, 1 (1969) 5. Ermnelin, N., Engstr~m, J.: Supersensitivity of salivary glands following treatment with bretylium or guanethidine. Brit. J. Pharmaeol.16,
315 (1961) 6. Burnstock, G., Doyle, A.E., Gannon, B.J., Gerken, J.F., lwayama, T., Mashford, M.L.: Prolonged hypotension and ultrastructural changes in sympathetic neurones following guanacline treatment. Europ. J. Pharmacol. 13, 175 (1971)
Nr. M, Le Moine Parker Queen Victoria Memorial Hospital Melbourne 3000 Victoria Australia
Persistent Parotid Pain Due to Guanacline M. Le Moine Parker Queen Victoria Memorial Hospital, Melbourne, Australia Received: June 25, 1973, accepted: August
13, 1974
S~a~.
Details are given of 17 patients who developed parotid pain during treatment with guanacline and which persisted after cessation of guanaeline for upto five and a half years. These patients are compared with 17 patients who received similar treatment with guanacline and who did not develop parotid pain. There was no significant difference between patients who experienced parotid pain and those who did not with respect to sex, age, clinical diagnosis, blood urea, previous hypotensive therapy or other drugs given concurrently with guanacline. There was a slightly greater association of parotid pain with other side effects and with a larger daily dose of guanacline. It is suggested that persistent parotid pain after guanacline therapy is due to prolonged or permanent selective sympathetic nerve damage in the region of the cervical sympathetic nerve supply to the salivary glands.
Key words: Guanacline, persistent parotid pain.
Introduction
Patients and Methods
The effective therapy of hypertension necessitates the use of compounds with powerful pharmacological actions which exert at a number of sites and result in a number of physiological changes in addition to that of lowering blood pressure. Moreover, most patients require treatment with more than one drug at a time. The incidence of complications and unwanted side effects is thus relatively high. Fortunately in most instances side effects are reversed or resolved by alterations in drug dose or the method of administration or by ceasing therapy with that particular drug. In some cases, however, side effects may persist long after the drug has been stopped and can no longer be exerting any direct, chemical effect. Such is the case with parotid pain and postural hypotension induced by the adrenergic neurone inhibitor guanacline. In 1969 Parker et al. (1) reported the results of a clinical trial of guanacline in which half the patients developed parotid pain I. Some patients experienced very severe pains which necessitated cessation of therapy with guanacline. In the majority, parotid pains persisted for many months after treatment was stopped and in some the symptom appears to be a permanent feature. This paper is an attempt to further document these patients in the light of a follow - up evaluation exceeding 5 years.
Between November 1966 and December 1967, 34 patients were treated for hypertension with guanacline. All patients were women and their ages ranged from 18 to 68 years, mean age was 39.5 years and the median was 37 years. Ten patients received guanacline alone, 18 patients received a thiazide diuretic, 4 received methyldopa and a thiazide, I received reserpine and a thiazide, I received frusemide and methyldopa. Prior hypotensive treatment had been given to 27 patients, of whom 24 were taking a diuretic and 19 were taking methyldopa. Guanacline was started initially in a dose of 15 mg twice daily and increased by 15 to 30 mg daily at intervals of not less than 3 days until blood pressure control was satisfactory or unwanted side effects developed.
lln Germany the first cases of persistent parotid pain were reported by Bock et al
Results Results are given in terms of the development of parotid pain, postural hypotension and significant other side effects. Patients who developed these complications are compared with those who did not in an attempt to determine possible associations between the development of parotid pain and contributing factors (Table I). The symptom picture was identical in all patients with parotid pain. Pain came on acutely with the first few bites, particularly of acid or bitter foods. It was felt in the region of the parotid, was often lancinating in character, tended to wear off quite rapidly as mastication proceeded but with
132 a tendency to recurr if another 'sharp' food was a close fitting blunt metal cannula connected by a taken. saline filled polyethylene tube to a transducer Of the 17 patients who developed parotid pain which was in turn attached to a Beckmann R.P. Dynograph. In each instance the resting intraduct presthe average duration of t~eatment before the onset of pain was 10.1 weeks with a range from 2 to 20 sure was determined and then salivation was induced by a stimulus of bitter lemon juice. The pressure weeks and the median was 8 weeks. In most patients increase was recorded for a number of repeated stimguanacline was stopped within 4 weeks of the onset uli and the symptom of pain was noted. of symptoms. After cessation of guanacline parotid After a return to basal level, a similar prespain persisted for a month or longer in all but 3 sure or a greater pressure in the parotid duct was patients whose symptoms resolved in from I to 3 obtained by injection of normal saline. Again the weeks. The mean duration of symptoms from the time pressure achieved was correlated with the onset of of stopping treatment was 21.7 months with a range pain - if it occurred. The results obtained are from 1 week to 5 and a half years. Three patients given in Table 4. show no evidence of losing their pain with time, The response to stimulation in terms of volume and 1 patient has symptoms which appear to be inor composition of saliva was not determined. creasing in severity and frequency. It will be seen that there was a fair uniformity In those patients who developed parotid pain in of resting parotid duct pressure in all patients less than 8 weeks treatment with guanacline the and the control. average daily dose was 60 mg compared with 85.5 mg The occurrence of parotid pain by physiological per day in patients who developed pain after treatstimulation was associated with high intraduct presment for 8 weeks or longer. Patients whose symptoms sures in 2 patients and in one of these saline inpersisted less than 14 and a half months had rejection caused a similar degree of pain at a simiceived an average daily dose of 67.5 mg guanacline lar duct pressure to that with physiological stimwhereas those with symptoms persisting for 14 and ulation. In patient 3 there were technical diffia half months or longer had received an average culties and the investigation was incomplete. The daily dose of 82 mg of guanacline. control patient had a low duct pressure with physioThe relationship ton parotid pain and other symplogical stimulation and was able to withstand a toms is given in Table 2. Of the 5 patients with duct pressure of 250 cm of water without experiencpostural hypotension, the most severe disturbance ing pain. In patients I and 2 there was no alterwas in the patient who did not have parotid pain. The 4 patients with postural hypotension and parotid atiQn of duct pressures achieved or the pain experienced following physiological stimulation after pain had only transient mild postural hypotension parasympathetic blockade by atropine. Patients 2 which did not persist off guanacline whereas they and 3 had a sialogram which showed a radiologically had parotid pain from 30 months to indefinite durnormal parotid duct system. ation. After cessation of guanacline in the group of parotid pain patients, 8 had therapy continued with guanethidine and chlorothiazide, 5 had methylOiscussion dopa and a chlorothiazide, 2 had chlorothiazide alone, ! had reserpine and chlorothiazide and ! Guanacline (Cyclazenin, Leron) is chemically N-2patient had guanethidine methyldopa and chloroguanidoethyl)-4-methyl- I, 2, 5, 6, - tetrahydrothiazide. The duration of symptoms in relationship pyridine suphate. Pharmacological action results to subsequent drug therapy is given in Table 3. in adrenergic neurone blockade with marked catecholThe patients who did not develop the symptom of amine depletion in the postganglionic sympathetic parotid pain had a mean duration of treatment with nerve fibres. Ganglion blocking effect is relatively guanacline of 25 weeks and 9 patients had treatlimited. Complications of therap~ with guanacline ment for less than 20 weeks which is the maximum were relatively common and in particular parotid period of treatment before the onset of parotid pain and postural hypotension were prominent in a pain in any patient in this series. In each case number of trials (1,2,3). Postural hypotension was often severe and in some patients persisted indeguanacline was stopped because of side effects or finitely after cessation of guanacline therapy. poor blood pressure control. For this reason it is possible the incidence of parotid pain may have Dawborn and others (4) have postulated that been higher had this group of 9 continued longer guanacline causes irreversible depletion of noradrenaline stores in adrenergic nerve terminals on treatment. in some patients and have shown that these patients have a persistently reduced urinary excretion of catecholamines. Supersensitivity of salivary glands Parotid Duct Pressures due to prolonged administration of guanethidine and As parotid pain due to guanacline was very similar bretylium in cats was demonstrated by Emmelin and Engstrom (5) and shown to be similar in effect to in nature to that which occurs in patients with that resulting from excision of the superior cervisalivary calculi and partial occlusion of the salical ganglion. More recently Burnstock and others vary duct, four patients and one control were in(6) have shown that in rats treated with guanacline vestigated to determine pressure rises in the parotid duct and the possible relationship between for 18 weeks there was persistent hypotension after intraductal pressure and symptoms of pain. cessation of guanacline and that this was associated The method was to canulate the parotic duct with with degenerative changes in sympathetic ganglion
133 Table I. Patient characteristics and parotid pain Parotid Pain
Table 4. Parotid duct pressure study (intraduct pressures in cent]metres of water)
No Parotid Pain
o
o O
Patients
17
I7
Essential Hypertension
13
1t
O
Chronic Renal Disease
4
6
Previous Hypotensives
13
13
8
11
13
10
Previous Methyldopa Previous Thiazide Previous other Drugs
6
4
Guanacline alone
4
6
11
10
3
1
Guanacline + Thiazide Guanacline + Methyldopa
24-56 39.2 36 18-68 39.6 37
Blood Urea mg/100 ml
15-60 28.4 28 19-54 33.5 30
Daily Dose Guanacline mg
30-120
54 45
Table 2. Parotid pain and other side effects Parotid Pain
No Parotid Pain
Patients
17
17
Other Side Effects (Patients)
11
7
Postural Hypotension
4
I
Head and Neck Pains
3
2
Myalgia
2
1
Other
2
3
Table 3. Parotid pain related to subsequent treatment Treatment of Guanacline
Pain Pain Pain 14.5 months 24-60 months>60 months
Ismelin + Thiazide
5
2
2
Methyldopa + Thiazide
2
2
I
Other
3
1
O
• O ~'~
~ 50
r-q U • ~ ~) ~ u~ . ~ ¢ ~
1
4
75
+
2
0.5
87.5
++
3
1
12.5
0
-
4
2
9
0
26
0.5
5
0
250
Control
Age. Years
75 60 15-105
+ .~ ~
-~4 4 O ¢~ ¢ ~
I ~
120 87
~ O
+
.~
50 -~4 ¢0 ~ O ¢~ ~ Z
0 ++ ++ 0
cells. These changes consisted of a strong yellow autofluorescence shown by electron microscopy to consist of a massive deposition of lipoprotein granules comparable to aging pigment. Changes of this severity and type were not produced by similar exposure to guanethidine although this did cause some cell damage which resolved after the drug was discontinued. It seems very probable that guanacline can produce similar prolonged or permanent damage to sympathetic nerves supplying the salivary glands and consequent symptoms of parotid pain. From analysis of the patients in this series it is apparent that there was no significant difference between patients who experienced parotid pain and those who did not when considered in respect of sex, age, clinical diagnosis or blood urea nor were there any differences in regard to previous hypotensive treatment or to other drugs given concurrently with guanacline. There was a slightly greater incidence of other associated side effects in patients with parotid pain but this does not reach statistical significance with these numbers. The mean daily dose of guanacline was higher in the group who had parotid pain - 75 mg a day as compared with 54 mg a day - but the range was very similar. In addition there was a trend to a dose symptom relationship with respect to: a) Duration of symptoms after withdrawal of guanacline in that those patients whose total duration of symptoms was below the median of 14.5 months had received a mean daily dose of 67.5 mg whereas those patients with symptoms persisting longer than 14.5 months had received a mean daily dose of 85.5 mg. b) Patients treated for less than the median of 8 weeks before the onset of symptoms had received a mean daily dose of 60.0 mg guanacline whereas those treateG for longer than 8 weeks before symptoms had received a mean daily dose of 85.5 mg. It is possible that this latter effect is only an apparent dose symptom relationship and merely represents the fact that there is a tendency for an increasing dose of drug to maintain or achieve a satisfactory hypotensive response as the duration of treatment increases. Duration of symptoms after withdrawal of guanac-
134 line may represent the degree of damage caused by guanacline alone but it may also represent an effect which was perpetuated by the action of subsequent drugs. In this respect it may not have been wise to follow guanacline with guanethidine in 9 of the 17 patients as guanethidine has been known to cause parotid pain (albeit very rarely) and produces ultrastructural changes in sympathetic ganglion cells (6). However, there is no significant difference in relation to duration of symptoms in those patients who were given guanethidine compared with those who received methyldopa or a thiazide alone or a thiazide plus reserpine after guanacline was withdrawn.
References I. Parker, M. Le Moine, Bullen, M.: Guanacline, a new hypotensive drug. Med. J. Aust. 2, 159
(1969) 2. Jerums, G., Ebringer, A., Doyle, A.E.: A comparison of guanacline with methyldopa in the treatment of hypertension. Med. J. Aust. 2, 466 (1968)
3. Hall, G.V., Michell, G.: Clinical experience with guanacline, a new hypotensive agent. Med. J. Aust. 2, 1047 (1968) 4. Dawborn, J.K., Doyle, A.E., Ebringer, A., Howqua, J., Jerums, G., Johnston, C.I., Mashford, M.K., Parkin, J.D.: Persistent postural hypotension due to guanacline. Pharmaeologia Clinica
2, 1 (1969) 5. Ermnelin, N., Engstr~m, J.: Supersensitivity of salivary glands following treatment with bretylium or guanethidine. Brit. J. Pharmaeol.16,
315 (1961) 6. Burnstock, G., Doyle, A.E., Gannon, B.J., Gerken, J.F., lwayama, T., Mashford, M.L.: Prolonged hypotension and ultrastructural changes in sympathetic neurones following guanacline treatment. Europ. J. Pharmacol. 13, 175 (1971)
Nr. M, Le Moine Parker Queen Victoria Memorial Hospital Melbourne 3000 Victoria Australia
