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An evaluation of atropine as an antisialogogue in dentistry
ORAL MEDICINE .
.
.
.
AN EVALUATION IN
.
.
.
.
.
OF ATROPINE
.
.
.
.
.
.
.
.
.
.
AS AN ANTISIALOGOGUE
DENTISTRY
Dou.glas H. Kazen, B.S. Pharm., Department
of
Pharmacology,
and James M. Dille, Ph.D., M.D., Seccttlc, Wnsh.
School of Medicine,
Uhwsity
of
Washington
T
HE action of atropine in diminishing or abolishing salivary secretion is well known.1-3 This effect of atropine has been used in dentistry for situations in which excessive salivary flow presents difficulties. These situations usually occur in procedures involving the entire oral cavity, such as the fitting of orthodontic appliances, since local areas may be convenirntly isolated from disturbing salivary secretions by means of a properly placed dental dam and by the use of suction. The potent saliva-suppressing activities of atropine have been recorded in animals, and indeed, this effect of atropine is often demonstrated in laboratory courses in pharmacology. Quantitative studies of the salivary-secretion-suppressing effects of atropine in human subjects are generally not reported objectively ; rather, these effects are simply referred to as “dryness of the mouth.” This article presents carefully controlled quantitative data on the relationship between the dose of atropine and its antisialogogue effect and comparative studies of the rate of onset and degree of cffcct of three common dosage forms (tablet, capsule, and solution). EXPERIMENTAL
PROCEDURE
A total of sixty young adult male volunteers participated in the experiment. Careful attention was given to the principles of the double-blind technique, and all subjects as well as the dosages were randomized by accepted statistical procedures using a table of random numbers. The subjects were instructed regarding the purpose of the experiment; the antisialic effect of atropine was described along with its other pharmacologic actions, and the general principles of the double-blind study were explained. The entire procedure, which extended over a period of 4 hours beginning at 1 P.M., was carried out at one time according to a predetermined rigid routine. 919
li.\%f~:s
!)“O
\SIl
t I.5
1)11,1.1~:
0 51. 6 0 I’. \lir!l.t. I’)/>:
Measuremclrt of tho salivary ti~,\v was tl~~tc~ru~inc~cIas follows: ‘l’ht~ subjwt WAS directed to tdlear his mouth of ~;lli~;l, (~s~x~ctoratiug into a container. 11~ then chewed a ~ubc of pa~*affi~~, apl)I’(JSilrlat(~ly s/j inch, for 2 minutes, ~xl)c:ctorating on a signal every 30 strands into ii, 10 c.c. griitlUatC!d cylinder. 121;ttlr! end of 2 minutes, the total salivary production was ~lctrrmined and the value to the nearest 0.2 cc. was rccortled. Such ‘L minutt~ m(lasurements of saliva13 BOW were made at the heginlCn p of caac*h15 minute int(xrral (luring the CO~IX of the experiment. The subjects were rantlolrlly divided into six groups. Ten subjects were lost by not appearing for the stutlp a11t1 for health r(‘asons. Th(l groups rt’ceived the following medication : Groul) Group GYOU~ G~ou;l, Group Group
1 d 3 4
(9 subjects)-0.8 (8 subjects)-0.4 (9 subjects)-0.6 (9 subjects)--a placebo). 5 (6 subjects)-0.4 S (9 subjects)-0.4
mg. atropinc sulfate in a mg. atropine sulfate in a mg. atropine sulfate in a flavored solut,ion containing mg. atropine atropine
mg.
flavored solution. fla\ored solution. flavored solution. no atropinc (the
sulfate in a tablet. sulfate in a capsule.
In order that absolutely uniform conditions might be achieved, each was given all three dosage forms (the liquid, the tablet, and the capsule). no given subject nor the person conducting the experiment knew which medications contained the atropinc. For oxample, in (Iroup 1 the 0.8 mg. atropine was contained in the flavored solution, while the tablet and t,he received by the subjects in this groul) WV blank. In (+roup 4 (the group) the liquid, tablet, and capsule were all blank. The procedure, which was cnrcfully adhered to. was as follows:
subject Hence, of the dose of capsule placebo
1. Instructions were given regarding the method of measuring salivary flow. 2. I)ata sheets consisting of a table and graph were distributed, and instructions were given regarding the collrction of the data. 3. Xach subject then drank 300 C.C. of water. 4. On a signal, each subject, chewed paraffin for thr 2 minute interval as described preyiousl>-. This was the first control measurement. 5. Fifteen minutes later the stand control measurement was made. 6, Immediately following the second determination, each subject then took the three dosage forms which had been prepared beforehand and assigned to him by a registered pharmacist. ‘7. Each subject then drank 150 cc. of water. 8. At each 15 minute interval thereafter, saliva was collected as described above, and its volume was determined. No food or liquid was allowed during Salivary secretion determinations were following administration of the drug. At determinations were recorded, a tabulation
the course 01: the experiment. carried out over a period of 3 hours the end of this time, when all the of side act.ions was made on a sheet
VOl”nx Number
16 8
ATROPISE
AS
ANT181dI,OGOGUE:
921
listing nineteen symptoms. Of these, seven could be referable to pharmacologic effects of atropine; the others were inserted in order to avoid suggestibility of the subject. RESULTS
Table I shows the averages for each group at each of the 15 minute time intervals. For convenience in handling these data, each consecutive pair of 15 minute determinations was averaged t,ogether. Thus, the fourt,een determinations for each subject produced seven mean values. The first two determinations made prior to administration of the drug thereby produced one control figure for each subject. The remaining twelve determinations produced six postdrug values for each subject, with one value for ea.ch postdrug period. The control figure for each subject was then subtracted from each of the six postdrug averages. The resulting six values, then, rqrcscnt change from premedication salivation and are the values used in the various statistical analyses. These values will be termed “difference scores.” TABLE
I.
SALIVARY
~~ECRETIOA-
P~onrrcm
my
EXPERIMENTAL
GROUP NO.
NO.OF SUBJECTS
DOSAGE FORM AND TOTAL DOSEOF ATROPINE ( MG.)
AVERAGE
ATROPISE PROCEDURE
SAIdVh
CONTROL ____ MINUTES
0 1 15
UNDER
PRODKCTION EXPERIMENTAL
THE
(Ix
COKDITIO~S
C.C.) PERIOD
OF
PRODUCED
THE
DURING
MINUTES
15 j 30 1 45
I 60 j 75 1 90
/ 105 / 120 I135
1 150 1165
1180
1
9
Solution 0.8
7.42
7.79
8.19
8.52
7.66
7.23
6.36
5.77
5.28
4.97
4.99
5.13
5.28
5.17
2
8
Solution 0.4
6.41
6.95
7.12
7.66
7.15
6.62
5.52
5.08
5.15
5.40
4.79
5.06
5.21
5.30
3
9
Solution 0.6
5.38
6.13
6.40
6.48
6.21
5.47
4.82
3.87
3.76
3.56
3.51
3.64
3.69
3.72
9
Placebo
6.24
6.87
6.62
6.80
6.80
6.77
6.67
6.87
6.73. 6.31
7.04
6.53
6.41
6.20
6
Tablet 0.4
6.12
6.80
6.90
7.47
6.73
6.00
4.85
4.87
4.6i
4.40
4.97
4.9i
5.37
5.33
9
Capsule 0.4
5.19
5.22
5.78
5.76
5.76
5.82
5.09
4.47
4.49
4.07
4.40
4.13
4.24
4.49
Comparison of Dose Levels.-Three dose levels of atropine sulfate were used: 0.4 mg., 0.6 mg., and 0.8 mg. These were total d,oscs.The effect of these doses along with that of the placebo are reflected in Fig. 1, where the mean difference scores of the four groups are plotted. An analysis of variance, using difference scores of the four groups, was performed for each period separately. In periods where the resulting E’ was significant, all dose level groups were compared to each other and to the placebo group, using the t test to determine significant differences between the groups. The t's were computed, using an error term based on the within-group variance of the analysis of variance. All t’s were one-tailed, since the ranking of the effects was predicted; that is, the
0 Fig.
i.-A
comparison
II I Time
II I1 II 2 3 4 period following
II II 5 6 medication
of the effects of the three dose levels (0.4, sulfate in flavored solution on the salivary
0.6, and flow.
0.S nrg)
of atropine
largest dose was predicted to have the largest depressant effect, and the smallest dose was predicted to have the smallest depressant effect, on salivation. Fig. 1 reveals that the prcdictcd order of effects occurred in all but the first postdrug period. The stat,istica.lly significant F’s found for the periods numbered 3, 4, 5, and 6 indicate existence of genuine differences between the rffects of the various levels of drugs. as do the fourteen significant t’s of the twenty-four calculated. The fact that the first significant F to appear is that of the third postdrug period appears to indicate that reliable effects can be detected by 1.1/2 hours following drug administration in the doses used. These effects seem to remain for t,he next al/, hours, as indicated by the significant F’s for the fourth, fifth, and sixth periods. Comp&son of Doscge Porms.-The mean difference scores of t,he three different groups administered different dosage forms in the amount of 0.4 mg., along with that of the placebo group, are shown in Fig. 2. An analysis of variance using difference scores of the four groups was performed for each period separately. In periods whcrc the resulting F was significant, all dosage form groups were compared to each othrr and to t,hc placebo group using the t test to determine significant differences between the groups. The t’s were comput.&, using an error term based on the within-group variance of the analysis of variance. All t’s were one-tailed, since the ranking of effects was predicted; that is, capsules were predicted to have t,he least effect and a solution the most cff wt.
t
IO-,& 4 0-N
rr-, ;
\\ \
. * \
- IO--
placebo
\.
\ \ ‘\
‘=,. ‘o-.-•
\
I I
0 Fig.
2.-A
colnparison
I
2 Time
of the
effects
I I
I I
3 period of 0.4
\.
\.P-*’
-2o--
I 1
---d----.0.4
mg. capsule 0.4 mg. tablet -0.4mg. solution
/’ .I’
/r/
I I
I I
4 5 6 following medication
mpr;fsatropine
sulfate
administered
in
three
dosage
Fig. 2 reveals that the predicted order of effects occurred with respect, to the capsule but not consistently with respect to tablets and solutions. The significant F’s found for periods 3, 4, and 5 indicate the existence of bona fide differences between the effects of dosage forms (including placebo), as do the eleven significant t’s of the twenty-four t’s calculated. Three t’s indicate the capsule group to be significantly inferior in effect to the tablet or solution forms. Salivary Plow Immediately After Xedication.-In view of the rise in the curves of all drug groups immediately following drug administration, as shown in both Figs. 1 and 2, a t was computed, testing the mean of the placebo group against the average of all the drug subjects considered together. A t of 1.516 with 48 degrees of freedom (d.f.) does not meet the 0.05 point of significance (t = 1.69 needed), but it does meet the 0.10 point of significance (t = 1.31 needed), suggesting that a genuine rise in salivation might occur in the first period although the t obtained fails to meet the arbitrary probability of 0.05 usually considered to indicate reliable difference. Dosage and Body Weight.-An analysis of Tariance of the body weights (F < 1, d.f. 5 and 44) indicated no significant difference between any of the six treatment groups, including t,he placebo group. This finding supports t,he h)-pothesis that the various differences in effect of atropine sulfate found between the groups cannot be attributed to differences in body weight between the groups. Body weight-dosage ratios would be affected in an uncontrolled manner by body weight differences in the groups.
!)“-I-
Using double-blind techniques anal rigi(\Iy controlled esperimc~ntal conditions with human volunteer subjects, \v(’ wcr(: able to show somff significant aspects of the antisialogoguc act ion of atropinc. There was a significant difference in the suppression of salivary flow in doses differing as little as 0.2 mg. (total dose). This was possible when as few as nine subjects were used in each group. From the standpoint of the drug’s use in dentistry, a11 understanding of the time of onset of the antisialogoguc effect and its duration is of some importance. These experiments show that, the antisialogogue effcvt (*annot, be c~spected to develop for at least an hour aftt.1, administration of the mctlication. 1ts maximum effect is reached in about 2 hours. This is important if ow is to secure the masimum benefit of atropino as an antisialogogue. The dosage form for ol*al administration is also of importance in securing an early onset, of effect. In this rcspcdct atropinc sulfate in flavored solution is slightly better than in tablet form, an(l both are considerably better than t,hc capsule form. The capsule is not only significantly more slowly absorbed, hut, its degree of eEect is significantly less. The proper dose of atropine is important for its successful use. The close should be one which will depress salivary secretion sufficiently for dental procedures but small enough to have minimal side effects. It was possible in these cxpedments, knowin g the body weight of each participant, to calculate the dose on a basis of body weight (kilograms or pounds). It was found that the dose range for attsopine sulfate is, roughly, between 0.0024 mg. and 0.005 mg. per pound of body weight. For the hypothetical patient of 150 pounds, the total dose of atropine sulfate would work out to he between 0.36 and 0.75 mg. It can be generally concluded, for practical purposes, that for the average adult an effective dose of atropinc would be between 0.4 and 0.8 mg. On the basis of the body weight. diff’crential, a child of 12 or 13 years weighing 100 pounds should receive two-thirds 01’ the above total dose, and persons weighing more should receive proportionately moor to arhic1.c ihc desired salivary suppression. The use of a flavored solution of atropine sulfate has evident advantages in tailoring a dose to the body weight of the individual patient. of some interest was the finding of increased salivary flow which occurred shortl;- after oral ingestion of ttte drug. This phenomc~non was present at all dose levels and with all dosage forms ant1 \vas found to be st,atistically valid as compared to the finding with the placebo. We have 110 explanation for this. There are relatively few contraindications to t,he use of atropine in dentistry. It should not be used in patients with cardiovascular disease of any kind. This would include patients under digitalis medication as well as t,hose under medication for the relief of hypertension.
htropine is an effective salivary-secretion suppressant and, therefore, useful in dentistry. Its value depends upon a careful selection of proper dosage in order to achieve maximum antisialogogic effects with a minimum of side actions. This dose would range between 0.4 m g. and 0.X mg. of atropine sulfate (total dose) for
an average weight for on children with it the
adult. A children. under 6 dose can
proportional reduction should be made on the basis of body It should probably not be used at all for dental procedures years of age. A liquid form of the drug is preferable, since be roughly proportioned to the body weight of the patient.
REFERENCES
1. Drill,
V. A.: Pharmacology in Medicine, ed. 2, New York, 1958, McGraw-Hill Book pany, Inc., p. 411. 2. Goodman, L. S., and Gilman, Alfred: The Pharmacological Basis of Therapeutics, New York, 1955, The Macmillan Company, p. 548. 3. Krantz, J. C., and Carr, C. J.: The Pharmacologic Principles of Medical Practice, Baltimore, 1961, Williams & Wilkins Company, p. 929.
Comed. 2, I&
5,
.
.
.
AN EVALUATION IN
.
.
.
.
.
OF ATROPINE
.
.
.
.
.
.
.
.
.
.
AS AN ANTISIALOGOGUE
DENTISTRY
Dou.glas H. Kazen, B.S. Pharm., Department
of
Pharmacology,
and James M. Dille, Ph.D., M.D., Seccttlc, Wnsh.
School of Medicine,
Uhwsity
of
Washington
T
HE action of atropine in diminishing or abolishing salivary secretion is well known.1-3 This effect of atropine has been used in dentistry for situations in which excessive salivary flow presents difficulties. These situations usually occur in procedures involving the entire oral cavity, such as the fitting of orthodontic appliances, since local areas may be convenirntly isolated from disturbing salivary secretions by means of a properly placed dental dam and by the use of suction. The potent saliva-suppressing activities of atropine have been recorded in animals, and indeed, this effect of atropine is often demonstrated in laboratory courses in pharmacology. Quantitative studies of the salivary-secretion-suppressing effects of atropine in human subjects are generally not reported objectively ; rather, these effects are simply referred to as “dryness of the mouth.” This article presents carefully controlled quantitative data on the relationship between the dose of atropine and its antisialogogue effect and comparative studies of the rate of onset and degree of cffcct of three common dosage forms (tablet, capsule, and solution). EXPERIMENTAL
PROCEDURE
A total of sixty young adult male volunteers participated in the experiment. Careful attention was given to the principles of the double-blind technique, and all subjects as well as the dosages were randomized by accepted statistical procedures using a table of random numbers. The subjects were instructed regarding the purpose of the experiment; the antisialic effect of atropine was described along with its other pharmacologic actions, and the general principles of the double-blind study were explained. The entire procedure, which extended over a period of 4 hours beginning at 1 P.M., was carried out at one time according to a predetermined rigid routine. 919
li.\%f~:s
!)“O
\SIl
t I.5
1)11,1.1~:
0 51. 6 0 I’. \lir!l.t. I’)/>:
Measuremclrt of tho salivary ti~,\v was tl~~tc~ru~inc~cIas follows: ‘l’ht~ subjwt WAS directed to tdlear his mouth of ~;lli~;l, (~s~x~ctoratiug into a container. 11~ then chewed a ~ubc of pa~*affi~~, apl)I’(JSilrlat(~ly s/j inch, for 2 minutes, ~xl)c:ctorating on a signal every 30 strands into ii, 10 c.c. griitlUatC!d cylinder. 121;ttlr! end of 2 minutes, the total salivary production was ~lctrrmined and the value to the nearest 0.2 cc. was rccortled. Such ‘L minutt~ m(lasurements of saliva13 BOW were made at the heginlCn p of caac*h15 minute int(xrral (luring the CO~IX of the experiment. The subjects were rantlolrlly divided into six groups. Ten subjects were lost by not appearing for the stutlp a11t1 for health r(‘asons. Th(l groups rt’ceived the following medication : Groul) Group GYOU~ G~ou;l, Group Group
1 d 3 4
(9 subjects)-0.8 (8 subjects)-0.4 (9 subjects)-0.6 (9 subjects)--a placebo). 5 (6 subjects)-0.4 S (9 subjects)-0.4
mg. atropinc sulfate in a mg. atropine sulfate in a mg. atropine sulfate in a flavored solut,ion containing mg. atropine atropine
mg.
flavored solution. fla\ored solution. flavored solution. no atropinc (the
sulfate in a tablet. sulfate in a capsule.
In order that absolutely uniform conditions might be achieved, each was given all three dosage forms (the liquid, the tablet, and the capsule). no given subject nor the person conducting the experiment knew which medications contained the atropinc. For oxample, in (Iroup 1 the 0.8 mg. atropine was contained in the flavored solution, while the tablet and t,he received by the subjects in this groul) WV blank. In (+roup 4 (the group) the liquid, tablet, and capsule were all blank. The procedure, which was cnrcfully adhered to. was as follows:
subject Hence, of the dose of capsule placebo
1. Instructions were given regarding the method of measuring salivary flow. 2. I)ata sheets consisting of a table and graph were distributed, and instructions were given regarding the collrction of the data. 3. Xach subject then drank 300 C.C. of water. 4. On a signal, each subject, chewed paraffin for thr 2 minute interval as described preyiousl>-. This was the first control measurement. 5. Fifteen minutes later the stand control measurement was made. 6, Immediately following the second determination, each subject then took the three dosage forms which had been prepared beforehand and assigned to him by a registered pharmacist. ‘7. Each subject then drank 150 cc. of water. 8. At each 15 minute interval thereafter, saliva was collected as described above, and its volume was determined. No food or liquid was allowed during Salivary secretion determinations were following administration of the drug. At determinations were recorded, a tabulation
the course 01: the experiment. carried out over a period of 3 hours the end of this time, when all the of side act.ions was made on a sheet
VOl”nx Number
16 8
ATROPISE
AS
ANT181dI,OGOGUE:
921
listing nineteen symptoms. Of these, seven could be referable to pharmacologic effects of atropine; the others were inserted in order to avoid suggestibility of the subject. RESULTS
Table I shows the averages for each group at each of the 15 minute time intervals. For convenience in handling these data, each consecutive pair of 15 minute determinations was averaged t,ogether. Thus, the fourt,een determinations for each subject produced seven mean values. The first two determinations made prior to administration of the drug thereby produced one control figure for each subject. The remaining twelve determinations produced six postdrug values for each subject, with one value for ea.ch postdrug period. The control figure for each subject was then subtracted from each of the six postdrug averages. The resulting six values, then, rqrcscnt change from premedication salivation and are the values used in the various statistical analyses. These values will be termed “difference scores.” TABLE
I.
SALIVARY
~~ECRETIOA-
P~onrrcm
my
EXPERIMENTAL
GROUP NO.
NO.OF SUBJECTS
DOSAGE FORM AND TOTAL DOSEOF ATROPINE ( MG.)
AVERAGE
ATROPISE PROCEDURE
SAIdVh
CONTROL ____ MINUTES
0 1 15
UNDER
PRODKCTION EXPERIMENTAL
THE
(Ix
COKDITIO~S
C.C.) PERIOD
OF
PRODUCED
THE
DURING
MINUTES
15 j 30 1 45
I 60 j 75 1 90
/ 105 / 120 I135
1 150 1165
1180
1
9
Solution 0.8
7.42
7.79
8.19
8.52
7.66
7.23
6.36
5.77
5.28
4.97
4.99
5.13
5.28
5.17
2
8
Solution 0.4
6.41
6.95
7.12
7.66
7.15
6.62
5.52
5.08
5.15
5.40
4.79
5.06
5.21
5.30
3
9
Solution 0.6
5.38
6.13
6.40
6.48
6.21
5.47
4.82
3.87
3.76
3.56
3.51
3.64
3.69
3.72
9
Placebo
6.24
6.87
6.62
6.80
6.80
6.77
6.67
6.87
6.73. 6.31
7.04
6.53
6.41
6.20
6
Tablet 0.4
6.12
6.80
6.90
7.47
6.73
6.00
4.85
4.87
4.6i
4.40
4.97
4.9i
5.37
5.33
9
Capsule 0.4
5.19
5.22
5.78
5.76
5.76
5.82
5.09
4.47
4.49
4.07
4.40
4.13
4.24
4.49
Comparison of Dose Levels.-Three dose levels of atropine sulfate were used: 0.4 mg., 0.6 mg., and 0.8 mg. These were total d,oscs.The effect of these doses along with that of the placebo are reflected in Fig. 1, where the mean difference scores of the four groups are plotted. An analysis of variance, using difference scores of the four groups, was performed for each period separately. In periods where the resulting E’ was significant, all dose level groups were compared to each other and to the placebo group, using the t test to determine significant differences between the groups. The t's were computed, using an error term based on the within-group variance of the analysis of variance. All t’s were one-tailed, since the ranking of the effects was predicted; that is, the
0 Fig.
i.-A
comparison
II I Time
II I1 II 2 3 4 period following
II II 5 6 medication
of the effects of the three dose levels (0.4, sulfate in flavored solution on the salivary
0.6, and flow.
0.S nrg)
of atropine
largest dose was predicted to have the largest depressant effect, and the smallest dose was predicted to have the smallest depressant effect, on salivation. Fig. 1 reveals that the prcdictcd order of effects occurred in all but the first postdrug period. The stat,istica.lly significant F’s found for the periods numbered 3, 4, 5, and 6 indicate existence of genuine differences between the rffects of the various levels of drugs. as do the fourteen significant t’s of the twenty-four calculated. The fact that the first significant F to appear is that of the third postdrug period appears to indicate that reliable effects can be detected by 1.1/2 hours following drug administration in the doses used. These effects seem to remain for t,he next al/, hours, as indicated by the significant F’s for the fourth, fifth, and sixth periods. Comp&son of Doscge Porms.-The mean difference scores of t,he three different groups administered different dosage forms in the amount of 0.4 mg., along with that of the placebo group, are shown in Fig. 2. An analysis of variance using difference scores of the four groups was performed for each period separately. In periods whcrc the resulting F was significant, all dosage form groups were compared to each othrr and to t,hc placebo group using the t test to determine significant differences between the groups. The t’s were comput.&, using an error term based on the within-group variance of the analysis of variance. All t’s were one-tailed, since the ranking of effects was predicted; that is, capsules were predicted to have t,he least effect and a solution the most cff wt.
t
IO-,& 4 0-N
rr-, ;
\\ \
. * \
- IO--
placebo
\.
\ \ ‘\
‘=,. ‘o-.-•
\
I I
0 Fig.
2.-A
colnparison
I
2 Time
of the
effects
I I
I I
3 period of 0.4
\.
\.P-*’
-2o--
I 1
---d----.0.4
mg. capsule 0.4 mg. tablet -0.4mg. solution
/’ .I’
/r/
I I
I I
4 5 6 following medication
mpr;fsatropine
sulfate
administered
in
three
dosage
Fig. 2 reveals that the predicted order of effects occurred with respect, to the capsule but not consistently with respect to tablets and solutions. The significant F’s found for periods 3, 4, and 5 indicate the existence of bona fide differences between the effects of dosage forms (including placebo), as do the eleven significant t’s of the twenty-four t’s calculated. Three t’s indicate the capsule group to be significantly inferior in effect to the tablet or solution forms. Salivary Plow Immediately After Xedication.-In view of the rise in the curves of all drug groups immediately following drug administration, as shown in both Figs. 1 and 2, a t was computed, testing the mean of the placebo group against the average of all the drug subjects considered together. A t of 1.516 with 48 degrees of freedom (d.f.) does not meet the 0.05 point of significance (t = 1.69 needed), but it does meet the 0.10 point of significance (t = 1.31 needed), suggesting that a genuine rise in salivation might occur in the first period although the t obtained fails to meet the arbitrary probability of 0.05 usually considered to indicate reliable difference. Dosage and Body Weight.-An analysis of Tariance of the body weights (F < 1, d.f. 5 and 44) indicated no significant difference between any of the six treatment groups, including t,he placebo group. This finding supports t,he h)-pothesis that the various differences in effect of atropine sulfate found between the groups cannot be attributed to differences in body weight between the groups. Body weight-dosage ratios would be affected in an uncontrolled manner by body weight differences in the groups.
!)“-I-
Using double-blind techniques anal rigi(\Iy controlled esperimc~ntal conditions with human volunteer subjects, \v(’ wcr(: able to show somff significant aspects of the antisialogoguc act ion of atropinc. There was a significant difference in the suppression of salivary flow in doses differing as little as 0.2 mg. (total dose). This was possible when as few as nine subjects were used in each group. From the standpoint of the drug’s use in dentistry, a11 understanding of the time of onset of the antisialogoguc effect and its duration is of some importance. These experiments show that, the antisialogogue effcvt (*annot, be c~spected to develop for at least an hour aftt.1, administration of the mctlication. 1ts maximum effect is reached in about 2 hours. This is important if ow is to secure the masimum benefit of atropino as an antisialogogue. The dosage form for ol*al administration is also of importance in securing an early onset, of effect. In this rcspcdct atropinc sulfate in flavored solution is slightly better than in tablet form, an(l both are considerably better than t,hc capsule form. The capsule is not only significantly more slowly absorbed, hut, its degree of eEect is significantly less. The proper dose of atropine is important for its successful use. The close should be one which will depress salivary secretion sufficiently for dental procedures but small enough to have minimal side effects. It was possible in these cxpedments, knowin g the body weight of each participant, to calculate the dose on a basis of body weight (kilograms or pounds). It was found that the dose range for attsopine sulfate is, roughly, between 0.0024 mg. and 0.005 mg. per pound of body weight. For the hypothetical patient of 150 pounds, the total dose of atropine sulfate would work out to he between 0.36 and 0.75 mg. It can be generally concluded, for practical purposes, that for the average adult an effective dose of atropinc would be between 0.4 and 0.8 mg. On the basis of the body weight. diff’crential, a child of 12 or 13 years weighing 100 pounds should receive two-thirds 01’ the above total dose, and persons weighing more should receive proportionately moor to arhic1.c ihc desired salivary suppression. The use of a flavored solution of atropine sulfate has evident advantages in tailoring a dose to the body weight of the individual patient. of some interest was the finding of increased salivary flow which occurred shortl;- after oral ingestion of ttte drug. This phenomc~non was present at all dose levels and with all dosage forms ant1 \vas found to be st,atistically valid as compared to the finding with the placebo. We have 110 explanation for this. There are relatively few contraindications to t,he use of atropine in dentistry. It should not be used in patients with cardiovascular disease of any kind. This would include patients under digitalis medication as well as t,hose under medication for the relief of hypertension.
htropine is an effective salivary-secretion suppressant and, therefore, useful in dentistry. Its value depends upon a careful selection of proper dosage in order to achieve maximum antisialogogic effects with a minimum of side actions. This dose would range between 0.4 m g. and 0.X mg. of atropine sulfate (total dose) for
an average weight for on children with it the
adult. A children. under 6 dose can
proportional reduction should be made on the basis of body It should probably not be used at all for dental procedures years of age. A liquid form of the drug is preferable, since be roughly proportioned to the body weight of the patient.
REFERENCES
1. Drill,
V. A.: Pharmacology in Medicine, ed. 2, New York, 1958, McGraw-Hill Book pany, Inc., p. 411. 2. Goodman, L. S., and Gilman, Alfred: The Pharmacological Basis of Therapeutics, New York, 1955, The Macmillan Company, p. 548. 3. Krantz, J. C., and Carr, C. J.: The Pharmacologic Principles of Medical Practice, Baltimore, 1961, Williams & Wilkins Company, p. 929.
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