nephrotoxic effects of kanamycin: a preliminary report
TRANSCRIPT
![Page 1: NEPHROTOXIC EFFECTS OF KANAMYCIN: A PRELIMINARY REPORT](https://reader031.vdocument.in/reader031/viewer/2022020407/5750814c1a28abf34f8ea025/html5/thumbnails/1.jpg)
NEPHROTOXIC EFFECTS OF KANAMYCIN: A PRELIMINARY REPORT
B y Mark Winfield and George 0. Crisp Medical Service, Veterans Administration Center, Los Angeles, C d y .
Morton H . Maxwell University of California at Los Angeles Medical Cmter, Los Angeles, Calg.
Charles R. Kleeman Metabolic Service, Veterans Administration Center and University of California at Los Angeles
Medical Center, Los Angeles, Ca-lif.
Introduction Kanamycin is a bactericidal antibiotic that apparently has a wide spectrum
including Micrococcus pyogenes, Mycobacterium tuberculosis, and Gram-negative bacilli. Therapeutic failures are frequently seen in infections caused by Diplococcus pneumoniae and Toxic effects in humans have not as yet been clearly evaluated. The present study was undertaken to investi- gate the nephrotoxicity of large intramuscular doses of kanamycin adminis- tered over relatively long periods of time.
Materials and Methods Twenty patients were studied before, during, and after kanamycin therapy.
Studies have been completed on sixteen, and incomplete data have been assembled on four. All the patients except one were being treated for various infections. The common denominator was that the patient was receiving kanamycin. All serum creatinine levels prior to administration of the drug were within normal limits (0.8 to 1.3 mg. per cent). The duration of therapy ranged from 6 to 31 days with a mean of 20.2 days. Total dosage ranged from 18.5 to 108 gm. with a mean of 46.5 gm. Nine patients were treated with SO mg./kg. and 10 received 25 mg./kg. One man received a combination of both dosages. Although it was originally planned to treat all patients for at least 30 consecutive days, in more than 50 per cent of the patients it was necessary to discontinue the drug sooner because of auditory toxicity. Renal function was evaluated by the following tests: inulin, creatinine, and para-amino hippurate (PAI-I) clearances, serum creatinine, PSP excretion, and urinalysis. The clearance tests were performed by methods previously described from this laboratory.h* These studies were undertaken in the postabsorptive state with patients in the supine position. Urine collections during the clearance periods were obtained by spontaneous voiding and by bladder catheterization when necessary. Examinations of qualitative proteinuria and urine sediments were performed on morning urine specimens examined within one half hour after voiding. Maximum urinary concentration was determined after over- night dehydration, and a 4-hour intravenous infusion of 240 cc. of 5 per cent glucose and water containing 4 milliunits of aqueous pitressin per ml. Maxi- mum urinary dilution was determined by measuring specific gravity and osmo-
140
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R. B
. D
urat
ions
Dos
e?
w. P.
Dur
atio
n
Dos
e
T. M
. D
urat
ion
Dos
e
L. R.
Dur
atio
n
Dos
e
c. s.
D
urat
ion
Dos
e
__.__
lear
ance
cc./m
rn.
121.7
109.7
91.25
154.83
-
-
-
28
50
29
50
25
25
16
50
28
50
-
-
Inul
in
clea
ranc
e
__
_~
cc
./min
.
100.6
94.6
59.2
131.9
Bef
ore
Dur
ing
Aft
er
Bef
ore
Dur
ing
Aft
er
Bef
ore
Dur
ing
Aft
er
Bef
ore
Dur
ing
Aft
er
Bef
ore
Dur
ing
Aft
er
PAH
le
arau
ce
cc./m
in.
637.5
453.63
436.7
569.1
720.2
579.13
624.0
772.4
485.5
537.5
562.9
-
726.67
-
179.
0
* Dur
atio
n m
easu
red
in
t Dos
e m
easu
red
in m
g.,
$ Ur
maF
osm
olal
ity in
Seru
m
crea
tini
ne
-~
mg.
per
cn
t
1.0
0.9-1.6
2.6-1.4
0.8
0.8-1.3
0.85
1.0
0.85-1.3
1.35
1.0
1.0-1.5
1.35-2.0
1.1
0.83-1.3
1.0-
1.2
138.7
199.1
177.9
147.5
-
91.67
166.3
-
TAB
LE 1
CUM
ULA
TIV
E DA
TA
130.3
122.6
105.7:
128.0
-
94.0
180.0
-
Spec
ific
grav
ity
Max
imal
co
ncen
trat
ion
1020 -
1013
1014 -
1024 (598)
1027 (760)
1020 (536)
1024 (690)
1027 (768)
1027 (747)
-
-
-
1027
(79
8)
Max
imal
di
luti
on
1004 -
1005
1008 (82)’
-
1010
1004 -
1004 (78)
1018 (495
1015 (379
1005
(79)
-
-
1004 (
120
PSP
5
min
2
hour
n c
en,
20.4
64.9
3.8
35.5
10.7
39.2
39.0
60.0
-
-
19.2
92.2
41.0
87.0
35.0
87 .O
15.6
80.0
38.0
71 .O
44.0
70.5
-
-
-
__
_
_
Qua
li,ut
iye
prot
elou
rla
0 1+
0 1+
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ace
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ace
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Tra
ce
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ce
Uri
nary
sed
imen
t
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y W
BC
Man
y W
BC
7-10 W
BC
5’
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3
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cc
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; 5-7
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cr. g
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z Y
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TA
BL
E 1-C
ontin
ued
c. c.
D
urat
ion
Dos
e
A. L
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urat
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M. S
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urat
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- -_
_
~~
-_ 29
25
31
25
28
50 6 50
13
25
-
-
Bef
ore
Dur
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Bef
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Dur
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Aft
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Bef
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Dur
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Bef
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Dur
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Bef
ore
Dur
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Aft
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.___
__
_ -
Cre
- ai
iuiil
c le
aran
ce
cc./
min
.
148.
3
106.
7
131 .
O
133.
5
108.
7
54.3
189.
0
180.
0 14
3.0
381.
0
-
212.
0
66.7
-
43.5
__
_
_
~ __
_
Inul
in
eara
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c./
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n.
154.
7
130.
3
140.
0
152.
7
82.7
54.0
174.
0
132.
0 12
4.0
115.
0
-
77.0
90.5
39.6
-
~-
~
PAH
le
aran
ce
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tin.
529.
0
665.
3
548.
7
723.
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0
309.
0
729.
0
694.
0 62
6.0
368.
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-
340.
0
396.
0
-
195.
0
__
_
_
Seru
m
crea
tlnin
e
'g
pev
cent
1.3
1.3-
1.7
1.8-
1.5
1.2
1.2-
2.1
2.0-
1.7
1.2
1.0-
1.5
1.2-
1.3
1.4-
1.5
1.4
1 .5
-t .
6
1.3-
1.5
1.3-
1.4
1.2-
1.4
.___
Spec
ific g
ravi
ty
Max
ima!
co
ncen
trat
ion
1023
(70
3)
-
1020
(63
0)
1021
(644)
-
1020
1028
(86
2)
-
1022
(76
5)
1025
(79
5)
I
1021
(66
3)
1032
(99
1)
1014
(47
8)
-
Max
imal
di
lutio
n
1006
(13
7
1006
(16
1
1003
(17
6
-
-
1003
(10
7
1007
(12
0)
-
1007
(11
6
1005
(11
0
-
1006
(15
0
lo05
(13
4
1002
(95
) -
__
_
_
PSp
5 m
,n
! ho
ur
__
er
ces
i
19.0
61.0
22.2
43
.4
22.0
43
.0
-
-
16.0
54
.0
50.0
91
.0
34.0
81
.O
7.3
17.4
23.0
42
.O
19.2
61
.5
25.0
46
.5
-
-
-
__
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Qua
lita t
iye
pror
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ia
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__
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Occ
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C
0
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ed
with
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; 2
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cked
R
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; 0-
pack
ed
Num
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BC
: fe
w R
BC
W
BC
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; num
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BC
s 2
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BC
; oc
c. R
BC
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BC
; 10
-20
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$ z
3&40
W
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KB
C
Num
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C
34
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C
5-10
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; O
CC
. R
BC
![Page 6: NEPHROTOXIC EFFECTS OF KANAMYCIN: A PRELIMINARY REPORT](https://reader031.vdocument.in/reader031/viewer/2022020407/5750814c1a28abf34f8ea025/html5/thumbnails/6.jpg)
N. P.
Dur
atio
n
Dos
e
J. A
T D
urat
ion
Dos
e
T. B
. D
urat
ion
Dos
e
R. H
. D
urat
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Dos
e
J. B
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urat
ion
Dos
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rv. T
. D
urat
ion
Dos
e
17
50
12
25
19
25 6 50
15
50
18
25
-
- B
efor
e
Dur
ing
Afte
r
Bef
ore
Dur
ing
Afte
r
Bef
ore
Dur
ing
Afte
r
Bef
ore
Dur
ing
Afte
r
Bef
ore
Dur
ing
Aft
er
Bef
ore
Dur
ing
Aft
er
~ __
108.
6
97.4
90
.8
123.
8
-
82.2
93.1
-
85.7
83.7
-
71.0
155.
0
196.
0 -
100.
0
101.
7 -
__
_
_
__
_
__
103.
1
97.8
86
.6
88.0
-
36.8
92.2
-
75.7
71.3
-
52.0
144.
0
183.
0
75.9
.
-
-
-
__
_
_
__
_
~
738.
2
417.
0 37
0.5
467.
5
259.
2
640.
4
-
-
374.
5
356.
0
-
316.
0
591 .
O
688.
0 -
279.
1
-
311.
4
__
_
_
1.4
1 .3-
1.8
1.0
1.4-
1.8
1.5-
1.7
1.8-
1.1
1.1-
1.3
1 M.
3
1.1
1.97
1.8-
2 .O
1.
65
1.1
1.
2 1.
0
0.85
1.1-
1.4
1.2
__
~
1027
(65
6)
1032
(71
4)
1024
1021
(62
4)
1015
(46
0)
1032
(74
6)
1020
-
-
1015
1020
-
1037
10
26
1027
(96
0)
1023
(65
9)
1021
(64
6)
-
1013
(16
1:
1009
(73
) 10
19 (
497:
1002
(70
)
-
1006
(16
4:
1008
(12
01
101 1
-
1001
(73
)
-
1007
(73
)
1020
1002
(63
)
1011
(28
0:
1003
(14
9:
-
-
__
_
_
34.0
61
.0
11.0
59
.0
66.0
79
.0
39.0
65
.0
32 .O
52
.0
30.0
60
.O
14.2
64
.9
21.0
56
.7
-
-
-
-
-
-
5.2
53.2
29.5
54
.5
8.0
41 .O
I
__
_
_
Tra
ce
Trac
e-1 +
Tra
ce
0-1 +
0-1 +
Tra
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+
0-1+
0-1 + 0 0 T
race
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2+
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Occ
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7-10
W
BC
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CC.
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cr. g
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ast
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BC
50-6
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BC
20-3
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BC
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um.
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144
____-
Patient
0. u.
M. S.
N. P.
J. M.
T. B.
R. H.
J. B.
W. T.
C. L.
x. n.
w. F.
T. M.
1,. R.
C. s.
___I_
Annals New York Academy of Sciences TABLE 2
Clearance
Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Iriulin PAH Ser. creat. Creat. Inulin P.4H Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat. Creat. Inulin PAH Ser. creat.
_______
RENAL HEMC _____
Before ( 1 )
381 115 368
1.2-1.5 66.7 90.5
396.0 1.3-1.5 108.6 103.1 738.2 1.4
123.8 88.0
467.5 1.4-1.8
93.1 92.2
640.4
83.7 71.3
356.0
1.1-1.3
1.97
1 .1 100.0 75.9
279.1 0.85
148.3 154.7 525.7
1.0-1.7 121.7 100.7 637.5
1 .o 154.83 131.9 569.1 0.8
138.7 130.3
1 .o 147.5 128.0 485.5
1 .o 166.3 180.0 726.67 1.1
629. a
CNAMICS
During (2)
- - - 1.4 __ - -
1.3-1.4 97.4 97.8
417 1.3-1.8 - - -
1.5-1.7 - - -
1.2-1.3 - - -
1.8-2.0 - - -
1.2 - - -
1.1-1.4 106.7 130.3 665.3 .84-1.1 109.7 94.6
453.63
142.15 157.5, 720.2
199.1 122.6 562.9
0.9-1.6
0.8-1.3
0.85-1.3
.-
- 1 . o-1 .5
0.83-1.3 _____-
After (3)
212 77
340 1.5-1.6 43.5 39.6
195.4
90.8 86.6
370.5 1 .o 82.2 36.8
259.2
85.7 75.7
374.5 1 .o 71 .O 52.0
316.0 1.65
196.0 183.0 688.0 1 .o
101.7
311.4 1.2
131.0 140.0 581.5 1.7 91.25 59.20
436.70
123.17 131.77 579.13 0.85
177.9 105.75 772.4 1.35 91.67 94.0
537.5 1.35-2 . O 122.5 152 .O 779.0 1.0-1.2
1.2-1.4
-
2.6-1.4
____
Percentage difference from control (1-3)
-44.3 -33.0 -7.6
-35.0 -56.0 -51.0
-16.0 -16.0 -50.0
-33.6 -58.1 -44.5
-7.9 -17.8 -44.6
-15.1 -27.0 -14.0
+26.4 +27.0 4-16.4
0
+11.5
-11.6 -9.5 +10.6
-
-25.0 -41 .O -31.4
-20.0 0
-2.0
+28.2
+22.7 -18.87
-38.0 -26.5 +11.0
-26.0 -15.5 +7.0
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Patient
c. c.
A. L.
A. B.
Winfield et ul. : Nephrotoxic Effects
Clearance
Creat. Inulin PAH Ser. creat. Creat. Inalin PAH Ser. creat. Creat. Inulin PAH Ser. creat.
___ .- -___ ___
TABLE 2-Continued
Before (1)
148.3 154.7 529.0
1.3 133.5 152.7 725.0 1.2
189.0 174.0 729.0 1.2
145
During (2)
106.7 130.3 665.3
108.7 82.7
480.0 1.2-2.1 180.0 132.0 694.0 1 .o-1.5
1.3-1.7
,_
After (3)
131.0 140.0 548.7 1.8-1.5 54.3 54.0
309.0
143.0 124.0 626.0
2 .O-1.7
1.2-1.3
Percentage difference from control (1-3)
-11.67 -9.5 +3.7
-59.3 -64.6 -57.27
-24.3 -28.7 -14.1
lality of the most dilute hourly urine specimen obtained during a 5-hour period following the oral ingestion of 1500 cc.
Results and Conclusions The results are listed in TABLE 1 for the 16 patients on whom complete data
were obtained. It is readily apparent from these data and those of subsequent tables that parallel qualitative and quantitative changes were not observed for each major renal function that was measured.
On the basis of possible errors inherent in experimen- tal techniques and chemical analyses as well as physiological variability, a change in renal function was not considered significant unless it exceeded 20 per cent of the control value (TABLE 2). Of 17 patients in whom clearances were obtained before and after treatment with kanamycin, creatinine clearance was significantly decreased in 9 (52.9 per cent), inulin clearance in 8 (47 per cent), and PAH clearance in 6 (35.2 per cent). Arbitrarily selecting an incre- ment of 0.4 mg. per cent serum creatinine as significant, 7 of 20 patients (35 per cent) had a significant increase during treatment, 2 (10 per cent) remained elevated after cessation of therapy, and 5 returned to the pretreatment range within 6 weeks. This indicates that long-term follow-up is necessary to deter- mine the reversibility of renal toxicity.
Of 16 patients, 6 (37.5 per cent) exhibited a reduction in maximal specific gravity exceeding 0.004 (TABLE 3). Three patients (18.7 per cent) were unable to dilute their urine to within 0.004 of the control value. The pattern of change in urinary osmolality confirms these changes in concen- trating and diluting ability.
Pre- and posttreatment PSP tests were done in 13 patients, and 3 (23 per cent) showed more than 20 per cent loss of function.
Urinalysis. Proteinuria of significance appeared in only 2 (10 per cent) of the 20 patients and persisted in 1 (5 per cent), TABLE 4. Microscopic hema- turia was noted in 6 (30 per cent), but only 4 (20 per cent) of these could be definitely attributed to the drug.
Renal hcmodynamics.
Tubular function.
Significant cylindruria was not observed.
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Pati
ent
R. B
.
w. F
.
T. M
.
L. R
.
c. s.
c. c
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1 I I I 1 I
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![Page 10: NEPHROTOXIC EFFECTS OF KANAMYCIN: A PRELIMINARY REPORT](https://reader031.vdocument.in/reader031/viewer/2022020407/5750814c1a28abf34f8ea025/html5/thumbnails/10.jpg)
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![Page 11: NEPHROTOXIC EFFECTS OF KANAMYCIN: A PRELIMINARY REPORT](https://reader031.vdocument.in/reader031/viewer/2022020407/5750814c1a28abf34f8ea025/html5/thumbnails/11.jpg)
148 Ten (50 per cent) of the 20 patients sustained hearing loss of mild to severe
degree, with 2 (10 per cent) losing acuity in the conversational range. All of the patients who had auditory loss demonstrated renal toxicity as well. Seven of these 10 subjects received doses of 50 mg./kg. and 3 received 25 mg./kg., showing a positive correlation between dosage and auditory toxicity.
Although all patients showed some evidence of nephrotoxicity (significant decrease in a t least 1 parameter of renal function), of the 10 with the most severe damage, 7 were receiving 50 mg./kg. and 3 received 25 mg./kg. This demonstrates a correlation between dosage and renal toxicity as well. Neither auditory nor renal toxicity seemed to be related to duration of therapy or total dosage.
Annals New York Academy of Sciences
Summary Renal impairment of varying magnitude was noted during or after treatment
with kanamycin, a new antibiotic, in 100 per cent of 20 men who received the drug. Toxicity occurred in the hemodynamic and tubular functions, but did not necessarily involve all aspects in a given case. Auditory loss occurred in 10 (50 per cent) of the patients, all of whom had concurrent renal damage. Less toxicity was seen with the lower dosage of the drug (25 mg./kg.) than with 50 mg./kg. The duration and reversibility of this renal toxicity have not been fully evaluated.
References 1. UMEZAWA, H., M. UEDA, K. MAEDA, K. YAGASHITA, S. KONDO, Y. OKAMI, R. UTAHARA,
Y . OSATO, K. NITTA & T. TAKEUCHI. Production and isolation of a new anti- biotic, kanamycin.
2. GOIJREVITCII, I\., G. A. HUNT & J. LEIN. 1958. Antibacterial activity of kanamycin. Antibiotics & Chemotherapy. 8: 149.
3. DICKISON, H. L. & D. E. TISCH. A preliminary report upon the pharmacology of kanamycin. Trans. 17th Conf. Chemotherapy of Tuberculosis. : 391.
4. CRON, M. J., D. L. JOIINSON, F. M. PALERMITI, Y . PERRON, H. D. TAYLOR, I>. F. WHITE- HEAD & T. R. HOOI’ER. 19.58. Kanamycin. I. Characterization and acid hydrolysis studies.
5 . KI.EEMAN, C. R., M. H. MAXWELL & R. KOCKNEY 1957. Production of hypertonic urine in humans in the probable absence of antidiuretic hormone (ADH). Proc. SOC.
19.57. J. Antibiotics Japan. Ser. A. 10: 181.
1958.
(Communication to the editor.) J. Am. Chem. SOC. 80: 752.
Exptl. Biol. Metl. 96: 189.
thyrotoxicosis with hypercalcemia. 6 . KLEEMAN, C. R., S. TUTTLF. & S. H. BASC~TT. 19.58. Metabolic observations in a case of
J. Clin. Endocrinol. Metabolism. 18: 477.