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Introduction
Levamisole is an optic isomer of the
phenyl-imidothiazole salt of tetramisole
(MULCAHY and QUINN, 1986). It is wide-
ly used as an anthelmintic (COLES et al.,
1989; BOURDOISEAU et al., 1994; TA-
RELLO, 2002) and immunomodulatory
agent (LOWE, 1980; TREUTNIER-DON-
KER et al., 1987; MOJZISOUA et al.,
1997) in domestic animals and humans.
Levamisole has a broad spectrum of ac-
tivity against larval and adult forms of gut
nematodes (SAYLES and JACOBSON,
1983; COLES et al., 1989), lung (NEIGER
et al., 1994), and heart worms (BARRIGA
and ANDUJAR, 1988). The beneficial ef-
fects of the immunostimulatory action of
levamisole have been observed in calves,
dogs, cats, and human patients with im-
munodeficiencies (CHABANNE et al.,
1995), bacterial, viral, and fungal infec-
tions (LOWE, 1980; HADDEN, 1987), in-
flammatory disease (FLESH et al., 1982),
and some malignancies (TREUTNIER-
DONKER et al., 1987; DELORENZO and
STEWART, 1990). Furthermore, it has
also been used successfully to prevent
mastitis, foetal death, and endometritis in
cattle (FLESH et al., 1982).
Levamisole is a short and fast-acting drug
that is rapidly absorbed from the gastro-
intestinal tract or from the injection site
(GUERRERO, 1980). Distinct toxicity is
not a problem with levamisole at the re-
commended dosage, but it does not
show the extremely wide safety margin of
the benzimidazoles. Therefore, at higher
doses it produces cholinergic effects in
mammals that are manifested by saliva-
tion, hypermotility of the alimentary tract,
frequent defaecation, broncho constric-
tion, bradycardia, muscle tremors, excita-
tion, vomiting, increased salivation, colic,
convulsions and exophthalmia. Death
may occur following acute collapse, due
to asphyxia as a result of acute respira-
tory failure (CARLISLE, et al., 1984; AB-
DELSALAM, 1986; MONTGOMERY and
PIDGEON, 1986; WATSON et al., 1988;
CHAWLEY et al., 1993; BULUGAHAPI-
TIYA, 1997).
Levamisole represents an important the-
rapeutic tool for practitioners. Although
much is known about beneficial effects of
levamisole, many aspects of practical im-
portance remain to be investigated in ve-
terinary medicine. The establisment of
dose ranges, dose delivery system and
the recognition of patients and diseases
in which the use of immunomodulation
would be indicated are some of the im-
portant aspects that require elucidation.
Many undesirable side effects of levami-
sole have been reported in several dome-
sticated animals (CARLISLE et al., 1984;
MONTGOMERY and PIDGEON, 1986;
WATSON et al., 1988; CHAWLEY et al.,
1993) and man (DELORENZO and STE-
WART, 1990; BULUGAHAPITIYA, 1997).
However, its side effects are not well-de-
fined in dogs. Therefore, the aim of the
study is to investigate the side effects of
high doses of levamisole in dogs.
Dtsch. tierärztl. Wschr. 111, 49–88, Heft 2, Februar 2004
81
Originale/Originals
The effects of levamisole poisoning on the haemato-
logical and biochemical parameters in dogs
GOKCE, H. I.
1
, GUNES, V
1
., ERDOGAN, H. M
1
., CITIL, M.
1
, AKCA, A
2
., YUKSEK, N
3
.
1
Department of Internal Medicine, Faculty of Veterinary Medicine, The University of
Kafkas, Kars/Turkey
2
Department of Parasitology, Faculty of Veterinary Medicine, The University of Kafkas,
Kars/Turkey
3
Department of Internal Medicine, Faculty of Veterinary Medicine, The University of
Yuzuncu Yil, Van/Turkey
GOKCE, H. I., GUNES, V., ERDOGAN, H. M., CITIL, M., AKCA, A., YUKSEK, N. (2004):
The effects of levamisole poisoning on the haematological and biochemical
parameters in dogs.
Dtsch. tierärztl. Wschr. 111, 81–85
Summary
This study was designed to evaluate possible organ and system disorders associated
with experimentally induced levamisole poisoning in dogs. For this purpose, twelve cli-
nically healthy dogs of different ages, sexes and breeds were used. They were divided
into two equal groups (Group A and Group B) and given levamisole orally at a dose of
25 mg/kg of body weight daily for three days. The dogs in Group B were also injected
with atropin sulphate (0.04 mg/kg of body weight) subcutaneously (sc) 1 hour after each
administration of levamisole. Routine clinical examinations were made and some hae-
matological, biochemical and blood gas parameters were established at various times
after administration of levamisole. The dogs in Group A developed severe neurological
signs, gastric haemorrhage, bloody vomiting, colic, anaemia and four dogs died. In
Group B these signs were mild and only one dog died. Levamisole poisoning was
characterised by a significant reduction in the total number of red blood cells (RBCs),
concentration of haemoglobin (Hb) and packed cell volume (PCV), and by anaemia.
Peripheral blood pH, actual bicarbonate of plasma (HCO
3
), actual base excess (BE),
partial pressure of oxygen (pO
2
) and saturated oxygen (O
2
SAT) increased in both
groups of animals and these dogs developed metabolic alkalosis 48 hours
after the first administration of levamisole. The results of the study also show that
levamisole poisoning in dogs causes a significant increase in the activity of serum
alanine aminotransferase (ALT) and of alkaline phosphatase (AP) and in the concentra-
tion of urea in both Group A and Group B. In the study, atropin sulphate reduced the
severity of the clinical signs and the number of deaths, but it was not alone sufficient to
remedy levamisole poisoning in dogs.
Key words: Dog, levamisole, poisoning, haematology, clinical chemistry, blood
gases
GOKCE, H. I., GUNES, V., ERDOGAN, H. M., CITIL, M., AKCA, A., YUKSEK, N. (2004):
Auswirkungen einer Levamisolvergiftung auf hämatologische und biochemische
Parameter bei Hunden.
Dtsch. tierärztl. Wschr. 111, 81–85
Zusammenfassung
Diese Studie diente der Erfassung von Organ- und Systemstörungen bei Hunden nach
einer experimentellen Levamisolvergiftung. Zu diesem Zweck wurde 12 Hunden unter-
schiedlichen Alters, Rasse und Geschlechts (je 6 Tiere in Gruppen A und B) Levamisol
in einer Dosierung von 25 mg/kg Körpergewicht ein Mal täglich über drei Tage oral ap-
pliziert. Die Hunde der Gruppe B erhielten zusätzlich 1 Stunde nach jeder Levamisol-
gabe Atropinsulfat (0,04 mg/kg Körpergewicht) subkutan (sc) injiziert. Levamisol führte
bei den Hunden der Gruppe A zu schweren neurologischen Symptomen, zu
Magenblutungen, blutigem Erbrechen, Kolik, Anämie und zum Tod von 4 Tieren. In der
Gruppe B waren diese Symptome schwächer; hier kam es nur zu einem Todesfall. Die
Levamisolvergiftung wurde von einer signifikanten Verminderung der Gesamtzahl der
roten Blutzellen (RBC), der Konzentration des Hämoglobins (HB) und des Hämatokrit-
wertes (PCV) sowie von einer Anämie begleitet. Im peripheren Blut waren die pH-Wer-
te, aktuelles Plasma-Bicarbonat (HCO
3
-), aktueller Basenexcess (BE), partieller Druck
des Sauerstoffes (pO
2
), und der gesättigte Sauerstoff (O
2
SAT) in beiden Gruppen er-
höht. Eine metabolische Alkalose trat 48 Stunden nach der ersten bzw. 24 Stunden
nach der zweiten Levamisolgabe auf. Weitere Veränderungen betrafen die Serumwer-
te der Alanin-Aminotransferase (ALT), der alkkalischen Phosphatase (AP) und die Se-
rumkonzentration von Harnstoff. Atropin verringerte den Schweregrad der klinischen
Vergiftungssymptome und die Zahl der Todesfälle, jedoch erfordert die Levamisolver-
giftung darüber hinaus gehende Therapiemaßnahmen.
Schlüsselworte: Hund, Levamisol, Vergiftung, Hämatologie, Klinische Chemie, Blut-
gas
Materials and Methods
Dogs
Twelve clinically healthy dogs of different
ages, breeds, sexes and body weight
were used in the study. They were ran-
domly divided into two equal groups
(Group A and Group B) and kept indoors
for 2 weeks. The average of body weight
of dogs in Group A and Group B was
17.25 ± 1.35 kg and 19.33 ± 1.97 kg, res-
pectively. The average weight for all 12
dogs was 18.25 ± 1.22 kg). In addition,
the average of age for dogs in group A
and in Group B was 3.83 ± 0.40 years and
4.16 ± 0.47 years respectively. The aver-
age age for 12 dogs was 3.91 ± 0.28
years. Both groups were comprising 4
male and 2 female dogs. Food and water
were provided ad libitum.
Experimental design
The dogs in both groups A were given le-
vamisole (Citarin-L; Bayer, Istanbul, Tur-
key) orally at a dose of 25mg/kg of body
weight daily for three consecutive days.
The dogs in Group B were also injected
with atropin sulphate (0.04 mg/kg of body
weight; Vetas, Istanbul, Turkey) subcu-
taneously (sc) 1 hour after each adminis-
tration of levamisole.
Clinical examination
Routine clinical examinations were car-
ried out every morning daily for 3 days be-
fore the administration of levamisole and
then at 1, 3, 6, 24, 25, 27, 30, 48, 49, 51,
54 and 72 hours after administration of le-
vamisole. Rectal temperature, heart and
respiration rates were also recorded.
Haematology
Peripheral blood samples were collected
in dipotassium ethylenediamine tetra ace-
tic acid (EDTA)-coated evacuated tubes
daily for 3 days before administration of
levamisole and then daily for a further 3
days after administration. These blood
samples were used to establish total
white blood cell (WBCs) and total red
blood cell (RBCs) counts, packed cell
volume (PCV) and haemoglobin concen-
tration (Hb) (WILLARD, et al., 1989).
Serum samples were collected from each
dog daily for 3 days before the adminis-
tration of levamisole and then at 3, 6, 24,
30, 48, and 54 hours after administration.
These samples were used to establish the
concentrations of total protein, urea,
creatinine, glucose and the activity of
alkaline phosphatase (AP) and alanine
aminotransferase (ALT). Standard com-
mercial kits (Diasis Diagnostic Systems,
Istanbul, Turkey) were used to estimate all
the above biochemical parameters using
a Boehringer photometer 5010 autoanaly-
ser (Mannheim, Germany).
Three millilitres of peripheral blood were
also withdrawn from the jugular vein into
a syringe from each animal at 0, 6, 24, 30,
48 and 54 hours after each administration
of levamisole. These blood samples were
immediately analysed on a blood gas
analyser (Chiron diagnostics, Rapid Lab
248, Cambridge, UK) for pH, partial pres-
sure of carbon dioxide (pCO
2
), partial
pressure of oxygen (pO
2
), saturated oxy-
gen (O
2
SAT), actual bicarbonate of plas-
ma (HCO
3
-) and actual base excess (BE).
Statistical analysis
Paired t-test was used to analyse the sig-
nificance of the deviations from the pre-
treatment values (hour 0-hour x) within
each group. Student’s t-test was then
used to compare the significance of the
differences between groups. The levels
of significance accepted were P < 0.05,
P < 0.01, P < 0.001, as stated below.
Results
Clinical findings
There were no significant differences bet-
ween the rectal temperatures obtained
before and at various times after adminis-
tration of levamisole in both Group A and
82
Dtsch. tierärztl. Wschr. 111, 49–88, Heft 2, Februar 2004
Originale/Originals
Table 1. Clinical findings in dogs given levamisole (Group A) or levamisole + Atropin (Group B).
Group B (n = 6)
Clinically healthy; as with group A plus Atropin
Anorexia, dullness, increased salivation, vomiting, strai-
ning, frequent urination and defaecation, tremor , inco-
ordination
Reduced appetite, dullness, increased salivation, vomit-
ing, straining, frequent urination and defaecation,. mild
neurological signs such as incoordination, excitation,
hyperaesthesia with irritability and clonic convulsion (in
only 1 dog).
Reduced appetite, dullness, increased salivation, vomit-
ing, straining, frequent urination and defaecation
Clinically healthy; as with group A plus Atropin
Reduced appetite, dullness, increased salivation, vomit-
ing, straining, frequent urination and defecation, incoor-
dination
Reduced appetite, dullness, increased salivation, vomit-
ing, straining, frequent urination and defaecation, inco-
ordination. One dog had blood in gastric content, abdo-
minal tension and colic.
Reduced appetite, dullness, increased salivation, vomit-
ing, straining, frequent urination and defecation, inco-
ordination in all dogs. One dog had blood in gastric
content, pale mucosa, abdominal tension, colic, recum-
bency and collapse,and died at 32nd hours of the admi-
nistration.
Reduced appetite, dullness; 3
rd
levamisol dose plus
Atropin
Reduced appetite, dullness, increased salivation, vomit-
ing, straining, frequent urination and defaecation, inco-
ordination
Reduced appetite, dullness, increased salivation, vomit-
ing, straining, frequent urination and defaecation, inco-
ordination
Reduced appetite, dullness, increased salivation, vomit-
ing, straining, frequent urination and defecation, incoor-
dination
Reduced appetite, dullness
Time Group A (n = 6)
(Hours)
0 Clinically healthy; application of the first dose of levamisol
1 Anorexia, dullness, weakness, increased salivation, vomiting, straining, frequent
urination and defaecation, muscle tremor , incoordination in movement especi-
ally on hindlegs.
3 Anorexia, restlessness, increased salivation, vomiting, straining, frequent urina-
tion and defaecation, rapid and shallow respiration, exophthalmia, excitation, hy-
peraesthesia with irritability, clonic convulsion, ataxia, epilepsy-like seizures and
frothy mouth.
6 Reduced appetite, dullness, increased salivation, vomiting, straining, frequent
urination and defaecation
24 Clinically healthy; application of the 2
nd
dose of levamisol
25 Anorexia, dullness, weakness, increased salivation, vomiting, straining, frequent
urination and defaecation, tremor , head shaking, abdominal tension, colic,
bloody gastric content (in 2 dogs), anxiety and delirium.
27 Anorexia, restlessness, increased salivation, vomiting, straining, frequent urina-
tion and defaecation, tremors, rapid and shallow respiration, abdominal tension,
colic, bloody gastric content (in 3 dogs; 1 more dog had blood gastric content),
exophthalmia, clonic convulsion, ataxia, epilepsy-like seizures and frothy mouth,
prostration and collapse (in 2 dogs).
30 Reduced appetite, weakness, polydipsia, incoordination, tremor, random move-
ment, abdominal tension, colic, twitching on eyelids and forelegs. Pale mucosa
in three dogs two of which them died at 32
nd
hours of the administration.
48 Reduced appetite, dullness, pale mucosa, abdominal tension, colic; 3
rd
levami-
sole dose
49 Anorexia, restlessness, anxiety, straining, frequent urination and defaecation, in-
creased salivation, vomiting, tremors, abdominal tension, colic, random move-
ment, pale mucosa (in 1 dog). Blood in gastric content (in 1 dog).
51 Anorexia, restlessness, frequent urination and defaecation, increased salivation,
vomiting, rapid and shallow respiration, tremors, abdominal tension, colic,
exophthalmia, excitation, hyperaesthesia with irritability, clonic convulsion, epi-
lepsy-like seizures and frothy mouth, pale mucosa (in 1 dog). Blood in gastric
content (in 1 dog).
54 Anorexia, dullness, weakness, anxiety, rapid and shallow respiration, incoordi-
nation, abdominal tension, colic, recumbency and pale mucosa. Two dogs died
at 54
th
and 56
th
hours of the administration.
72 In the remaining two dogs: anorexia, dullness, weakness, abdominal tension and
colic
Group B (Table 2). In both groups heart
and respiration rate were significantly in-
creased 1 hour after each administration
of levamisole, but returned to pre-treat-
ment rates 3 hours after the administra-
tion and remained nomal up to the end of
the study (Table 2).
Clinical signs usually developed within
15 to 30 minutes, reached peak intensity
within 60 to 120 minutes and gradually
decreased 6 hours after each administra-
tion of levamisole in both Group A and
Group B.
In Group A, anorexia, dullness, weakness,
increased salivation, vomiting, straining,
frequent urination and defaecation, mus-
cle tremor and incoordination were ob-
served one hour after each administration
of levamisole and these signs gradually
decreased up to 6 hours after each admi-
nistration of the drug. Three hours after
each administration of levamisole ano-
rexia, restlessness, increased salivation,
vomiting, straining, frequent urination and
defaecation, rapid and shallow respira-
tion, exophthalmia, excitation, hypera-
esthesia with irritability, clonic convulsion,
ataxia, epilepsy-like seizures and frothy
mouth were observed. However in this
period severe neurological signs were do-
minant. Bloody gastric content, abdomi-
nal tension and colic were first observed
25 (2 dogs) and 27 (1 dog) hours after the
first administration of the drug which cor-
responds to 1 and 3 hours after the 2
nd
ad-
ministration. Pale mucosa also devel-
oped in these dogs 30 hours after
admi-nistration of levamisole. Vomiting
bloody gastric content and pale mucosa
were observed until the three dogs died.
Two dogs died at 32, 1 at 54 and 1 at 56
hours after the first administration of leva-
misole. Anorexia, dullness, weakness,
moderate abdominal tension and colic
were still present at the end of the study in
the suviving dogs (Table 1).
In Group B, all the dogs developed clini-
cal signs similar to those observed in
Group A 1 hour after each administration
of the drug. In this group, reduced appe-
tite, dullness, increased salivation, vomit-
ing, straining, frequent urination and defe-
cation were observed after each ad-
ministration of levamisole and atropin
sulphate for up to 6 hours after adminis-
tration of the former. Reduced appetite
and dull-ness were observed throughout
the study. On the other hand, only one
dog had mild neurological signs such as
incoordination, excitation, hyperaesthe-
sia with irritability and clonic convulsion 3
hours after administration of levamisole,
and these gradually disappeared within 3
hours. Additionally, one dog had bloody
vomiting, abdominal tension and colic 27
hours after administration of levamisole.
This dog developed pale mucosa in the
30
th
hour of the study and died 32 hours
after administration of levamisole (Table
1). In summary, in Group B, neurological
signs disappeared after administration of
atropin sulfate, clinical signs were mild
and only one dog died.
Haematology
The number of total RBCs and the con-
centrations of Hb were significantly re-
duced 48 hours after administration of le-
vamisole in both Group A and Group B
compared to pre-treatment values (Table
3). A significant decrease in the PCV was
first recorded 24 hours after administra-
tion of levamisole and remained high until
the end of the study in both groups of ani-
mals. There were no significant differ-
ences, compared to pre-treatment val-
ues, in the number of total WBCs of both
Group A and Group B throughout the
study (Table 3).
Blood gases
In Group B, peripheral blood pH, plasma
HCO
3
-, BE, pO
2
and O
2
SAT were signifi-
cantly higher then the pre-treatment val-
ues. These values were also high in the
dogs of Group A, but they were not statis-
tically significant. There were no signifi-
cant changes in pCO2 in either group
compared to pre-treatment values (Table
5).
Biochemical analysis
In both groups of animals the concentra-
tion of serum urea increased significanly 6
hours after administration of levamisole
and remained high 54 hours after admini-
stration (Table 6). The serum activity of AP
and ALT significantly increased 30 hours
after administration of levamisole in both
groups and remained high 54 hours after
administration (Table 7). There were no
significant differences in the serum con-
centrations of total protein, creatinine and
glucose in either group throughout the
study (Table 6 and 7).
Necropsi
Postmortem examination of dogs that
died from levamisole poisoning revealed
macroscopic lesions mostly localised on
Dtsch. tierärztl. Wschr. 111, 49–88, Heft 2, Februar 2004
83
Originale/Originals
Table 2: Temperature, heart and respiration rates of dogs in Group A and Group B. Data are
expressed as mean and standard error of the mean (mean ± SEM).
Group A (n = 6) Group B (n = 6)
Time Temperature Heart rate Respiration rate Temperature Heart rate Respiration rate
(Hours) (°C) (beats/min) (breath/min) (°C) (beats/min) (breath/min)
0 39.28 ± 0.16 98.0 ± 3.5 30.7 ± 3.2 39.11 ± 0.04 90.7 ± 9.3 28.0 ± 1.8
1 39.2 ± 0.17 117.6 ± 7.6** 51.2 ± 8.3** 39.08 ± 0.1 112.0 ± 3.4* 37.0 ± 1.3**
3 38.76 ± 0.17 99.3 ± 4.3 28.8 ± 4.6 38.7 ± 0.07 113.7 ± 4.7* 26.7 ± 1.7
6 38.88 ± 0.18 108.7 ± 7.3 27.3 ± 2.8 38.63 ± 0.1 114.7 ± 5.7* 34.7 ± 6.2
24 38.75 ± 0.15 100.7 ± 6.0 28.7 ± 1.9 38.82 ± 0.12 93.3 ± 6.4 29.3 ± 3.2
27 38.78 ± 0.17 100.3 ± 6.5 40.7 ± 8.2 38.68 ± 0.12 98.0 ± 6.8 32.0 ± 1.9
30 38.55 ± 0.16 99.7 ± 8.9 47.3 ± 10.5 38.55 ± 0.08 98.7 ± 10.8 36.0 ± 6.7
48 39.07 ± 0.17 113.5 ± 5.4* 45.0 ± 9.1 38.76 ± 0.15 121.6 ± 9.4* 34.3 ± 3.2
51 38.9 ± 0.11 116.5 ± 7.8* 43.8 ± 8.4 38.46 ± 0.05 114.4 ± 6.8* 29.2 ± 1.8
54 39.02 ± 0.17 102.0 ± 6.2 35.8 ± 7.8 38.61 ± 0.06 112.8 ± 7.6* 29.6 ± 2.7
Significant differences between pre-treatment values and post-treatment values (Hour 0-Hour x) within groups
are indicated by: * = p < 0.05, ** = p < 0.01
Table 3: Haematological parameters of dogs in Group A and Group B. Data are expressed as
mean and standard error of the mean (mean ± SEM).
Group A (n = 6) Group B (n = 6)
Time RBC Hb PCV RBC Hb PCV
(Hours) (x10
6
/(l) (g/dl) (%) (x10
6
/(l) (g/dl) (%)
0 6.554 ± 619.3 13.44 ± 0.5 42 ± 1.7 5.874 ± 297.9 12.75 ± 0.8 39.7 ± 2.1
24 6.494 ± 397.4 12.52 ± 0.8 52.8 ± 4.1** 5.997 ± 526.4 11.57 ± 0.97 48 ± 3.7*
48 4.447 ± 519.1** 8.44 ± 0.5** 58.3 ± 2.2** 4.427 ± 464.7** 9.62 ± 0.56* 49.7 ± 3.1**
b
54 4.712 ± 445.2* 9.70 ± 0.8** 60.5 ± 1.7** 4.293 ± 449.1** 9.55 ± 0.57* 51.4 ± 2.3**
b
Significant differences between pre-treatment values and post-treatment values (Hour 0-Hour x) within groups
are indicated by: * = p < 0.05, ** = p < 0.01
Significant differences in the values between Group A and Group B are indicated by: b = p < 0.01
Table 4: Effects of levamisole on the peripheral blood pH, actual bicarbonate of plasma
(HCO
3
–
) and actual base excess (BE) of dogs in Group A and Group B. Data are ex-
pressed as mean and standard error of the mean (mean ± SEM).
Group A (n = 6) Group B (n = 6)
Time pH HCO
3
–
BE pH HCO
3
–
BE
(Hours) (mmol/l) (mmol/l) (mmol/l) (mmol/l)
54 39.02 ± 0.17 102.0 ± 6.2 35.8 ± 7.8 38.61 ± 0.06 112.8 ± 7.6* 29.6 ± 2.7
0 7.33 ± 0.01 20.57 ± 1.1 -4.36 ± 0.97 7.32 ± 0.01 19.72 ± 0.9 -4.85 ± 0.76
6 7.33 ± 0.02 19.50 ± 0.8 -4.8 ± 0.71 7.35 ± 0.02 20.12 ± 0.8 -4.45 ± 0.77
24 7.34 ± 0.01 19.50 ± 1.2 -4.85 ± 1.28 7.34 ± 0.02 20.18 ± 0.6 -5.06 ± 0.65
30 7.35 ± 0.01* 18.10 ± 1.8 -6.83 ± 1.76 7.38 ± 0.01**
b
20.43 ± 0.9 -3.33 ± 0.72
48 7.36 ± 0.02* 18.58 ± 0.4 -5.53 ± 0.74 7.41 ± 0.02**
b
24.34 ± 0.8** -1.42 ± 0.74***
c
54 7.36 ± 0.01* 19.9 ± 0.7 -4.6 ± 0.93 7.37 ± 0.02** 23.6 ± 0.89* -1.86 ± 1.07**
Significant differences between pre-treatment values and post-treatment values (Hour 0-Hour x) within groups
are indicated by: * = p < 0.05, ** = p < 0.01, *** = p < 0.001
Significant differences in the values between Group A and Group B are indicated by:
b
= p < 0.01,
c
= p < 0.001.
the liver, kidney, lung, and stomach. Hy-
peraemia and haemorrhage were observ-
ed in the liver. There was acute hepatic
degeneration and necrosis of 0.5 cm to
3,5 cm in size. Dilation of the bile ducts
and gallbladder was also observed. The
kidneys were oedematose, there was
severe congestion of the cortex and cor-
tico-medullar area and haemorrhage was
observed on the pelvis renalis. The kid-
neys were enlarged. Sero-haemorrhagic
exudation was observed on the cutting
edge of the cranial lobes of lung. Conges-
tion, ecchymotic and petechial haemor-
rhage and foam were also detected in the
trachea and bronchus. There was mas-
sive haemorrhage and congestion on the
cardia, fundus and corpus of the sto-
mach.
Discussion
Levamisole is a short and fast-acting drug
that is rapidly absorbed from the gastro-
intestinal tract or from the injection site.
The liver and the kidney are the main or-
gans involved in the metabolism and
excretion of levamisole (GUERRERO,
1980; ABDELSALAM, 1986). Normal
anthelmintic and immunomodulator do-
ses of levamisole in dogs are 10-11 mg/
kg of the body weight and
1
/
3
of the
anthelmintic dose respectively (ABDEL-
SALAM and NOURELHUDA, 1988;
URQUHART et al., 1998). However, when
levamisole is used at higher doses or
when its usage is prolonged, it causes
many undesirable side effects in animals
(CARLISLE et al., 1984; MONTGOMERY
and PIDGEON, 1986; ABDELSALAM and
NOURELHUDA, 1988; WATSON et al.,
1988; CHAWLEY et al., 1993) and hu-
mans (DELORENZO and STEWART,
1990; BULUGAHAPITIYA, 1997). It pro-
duces a reversible ganglion-stimulating
effect on both para-sympathetic and
sympathetic sites of mammalian tissues.
It has also been suggested that it has a
hypertensive effect in dogs and cats as
the result of the release of catechola-
mines from adrenergic nerve endings and
the adrenal medulla. Furthermore, levami-
sole is strongly suspected of inhibiting
cholinesterases, particularly at high
doses, leading to manifestation of the
nicotinic and muscarinic action of
acetylcholine such as muscle tremors,
salivation, broncho-constriction and hy-
permotility of the alimentary tract (AB-
DELSALAM, 1986). Therefore, some of its
toxic effects can be antigonized by cho-
linergic blocking agents such as atropine
and mecamylamine (HSU, 1980; ABDEL-
SALAM, 1986).
In the present study, dogs poisoned with
levamisole developed severe neurological
signs such as incoordination, excitation,
hyperaesthesia with irritability, clonic
convulsion, ataxia, epilepsy-like seizures
and frothy mouth. These clinical signs
suggest that the canine nervous sysytem
is seriously affected by levamisole. Ani-
mals developed haemorrhagic gastritis
most probably resulting from the irritant
effects of the drug on gastric mucosa.
Therefore, the poisoning was also cha-
racterised by gastric haemorrhage with
bloody vomiting, colic, abdominal ten-
sion, asphyxia and death, resulting from
the inhibition of cholinesterases. Animals
treated with levamisole also developed
more severe clinical signs and a higher
number of deaths occurred in this group
compared to dogs given levamisole and
atropin sulphate. Injection of atropin sul-
phate, a cholinergic blocking agent, re-
duced the number of deaths and severity
of the clinical signs, especially neurologi-
cal signs. However, still deaths and some
neurological signs occurred in this group,
suggesting that atropin sulphate although
may antagonizing some nicotinic and
muscarinic action of acetylcholine, itself
is not sufficient to remedy levamisole poi-
soning completely. Other studies have re-
vealed, too, that atropin sulphate, a com-
bination of atropin sulphate and me-
camylamine (HSU, 1980; GOKCE, 1996),
and phenoxybenzamine, dexamethasone
and nilamide (SHAH et al., 1986) may
have beneficial effects in the treatment of
levamisole poisoning in animals.
Several studies have indicated that leva-
misole poisoning causes acute hepatic
degeneration with marked subcapsular
haemorrhage, massive hepatic necrosis
and renal degeneration (HSU, 1980; AB-
DELSALAM, 1986). This equals to our
macroscopic findings in the dogs which
died from levamisole poisoning
In the study, there was a significant re-
duction in the number of total RBCs, in
the concentration of haemoglobin and in
PCV in both groups of dogs. The reduc-
tion in the number of RBCs and concen-
tration of Hb and the presence of diffuse
gastric haemorrhages, bloody vomiting
and pale mucosa indicate the develop-
ment of anaemia in dogs poisoned by le-
vamisole. The reduction in the PCV pos-
84
Dtsch. tierärztl. Wschr. 111, 49–88, Heft 2, Februar 2004
Originale/Originals
Table 5: Effects of levamisole on the peripheral blood partial pressure of carbon dioxide
(pCO
2
), partial pressure of oxygen (pO
2
) and saturated oxygen (O
2
SAT) of dogs in
Group A and Group B. Data are expressed as mean and standard error of the mean
(mean ± SEM).
Group A (n = 6) Group B (n = 6)
Time pO
2
pCO
2
O
2
SAT pO
2
pCO
2
O
2
SAT
(Hours) (mmHg) (mmHg) (%) (mmHg) (mmHg) (%)
0 38.68 ± 2.90 41.78 ± 2.97 61.37 ± 7.98 38.17 ± 2.98 38.6 ± 1.89 60.53 ± 5.42
6 42.49 ± 2.80 37.21 ± 1.52 76.07 ± 6.43 44.03 ± 4.11 37.22 ± 1.99 70.1 ± 5.95
24 41.57 ± 2.72 36.90 ± 1.72 70.03 ± 3.89 42.37 ± 2.78 41.46 ± 1.81 64.89 ± 3.60
30 45.33 ± 3.69 37.03 ± 3.40 72.53 ± 6.67 41.36 ± 3.67 35.73 ± 1.89 69.22 ± 5.47
48 45.60 ± 3.24 36.0 ± 1.86 72.88 ± 6.40 47.40 ± 2.52** 40.02 ± 1.46 80.5 ± 1.56**
a
54 41.51 ± 2.52 37.93 ± 1.33 68.25 ± 1.52 46.78 ± 2.74** 37.93 ± 1.95 78.68 ± 2.38**
a
Significant differences between pre-inoculation values and post-inoculation values
(Hour 0-Hour x) within groups are indicated by: ** = p < 0.01
Significant differences in the values between Group A and Group B are indicated by:
a
= p < 0.05
Table 6: Effects of levamisole on the concentrations of total protein, urea and creatinine in
the peripheral blood of dogs in Group A and Group B. Data are expressed as mean
and standard error of the mean (mean ± SEM).
Group A (n = 6) Group B (n = 6)
Time Total protein Urea Creatinine T. protein Urea Creatinine
(Hours) (x10
6
/(l) (g/dl) (%) (x10
6
/(l) (g/dl) (%)
G/dl mg/dl mg/dl g/dl mg/dl mg/dl
0 5.95 ± 0.48 16.8 ± 1.2 1.36 ± 0.08 5.94 ± 0.84 18.6 ± 1.2 1.33 ± 0.02
6 6.28 ± 0.38 21.6 ± 2.2* 1.51 ± 0.11 6.04 ± 0.70 23.4 ± 1.5* 1.35 ± 0.07
24 6.12 ± 0.66 20.5 ± 1.3* 1.56 ± 0.12 5.4 ± 0.45 26.4 ± 2.2**a 1.36 ± 0.13
30 6.75 ± 0.39 22.5 ± 1.9** 1.39 ± 0.07 6.16 ± 0.6 30.2 ± 3.5**a 1.40 ± 0.03
48 6.98 ± 0.34 23.8 ± 1.8** 1.44 ± 0.08 6.08 ± 0.5 37.4 ± 4.5**b 1.45 ± 0.14
54 6.85 ± 0.36 29.0 ± 3.6** 1.41 ± 0.10 6.96 ± 0.54 38.0 ± 3.4*** 1.59 ± 0.09**
Significant differences between pre-treatment values and post-treatment values (Hour 0-Hour x) within groups
are indicated by:*= p < 0.05, **= p < 0.01, ***= p < 0.001
Significant differences in the values between Group A and Group B are indicated by: a= p < 0.05, b= p < 0.01
Table 7: Effects of levamisole on the concentrations of glucose, alanine aminotransferase
(ALT) and alkaline phosphatase (AP) in the peripheral blood of dogs in Group A and
Group B. Data are expressed as mean and standard error of the mean (mean ±
SEM).
Group A (n = 6) Group B (n = 6)
Time Glucose ALT AP Glucose ALT AP
(Hours) mg/dl U/l U/l mg/dl U/l AP U/l
0 77.8 ± 7.2 33.5 ± 12.1 60.3 ± 3.1 74.6 ± 6.2 29.0 ± 0.9 62.4 ± 7.4
6 83.8 ± 9.5 39.8 ± 10.1 74.8 ± 8.2 64.6 ± 3.8 28.4 ± 1.7 72.8 ± 5.6
24 76.5 ± 10.2 31.8 ± 8.2 69.0 ± 6.1 59.8 ± 7.9 31.2 ± 3.7 75.8 ± 3.1
30 85.0 ± 8.7 56.8 ± 3.2* 82.5 ± 9.3** 68.8 ± 12.3 49.8 ± 8.6* 92.6 ± 9.1**
48 86.1 ± 3.9 60.67 ± 6.2* 127.2 ± 26.4** 64.2 ± 6.8 46.4 ± 7.4* 132.8 ± 22.1**
54 73.8 ± 3.9 58.6 ± 5.5* 167.5 ± 32.4** 76.6 ± 15.1 50.8 ± 6.7** 135.0 ± 22.8**
Significant differences between pre-treatment values and post-treatment values (Hour 0-Hour x) within groups
are indicated by:*= p < 0.05, **= p < 0.01
sibly developed due to reduced food and
water in-take and in the presence of se-
vere vomiting, frequent urination and
defaecation. Studies have revealed that
levamisole causes haematologic side
effects such as agranulocytosis, leukope-
nia and thrombocytopenia in animals and
humans (MCANULTY and RUDD, 1985;
MULCAHY and QUINN, 1986; ABDELSA-
LAM and NOURELHUDA, 1988; QUINN,
1990; BULUGAHAPITIYA, 1997). Haemo-
lytic anaemia was also observed in two of
six dogs after repeated doses of levami-
sole for an extended period (HSU, 1980).
Peripheral blood pH, plasma HCO
3
-, BE,
pO
2
, and O
2
SAT increased in both groups
of animals, but the increases in Group A
were not statistically significant. The in-
crease in these values indicates the de-
vel-opment of metabolic alkalosis 48
hours after administration of levamisole.
There was severe vomiting in these ani-
mals which may explain the presence of
metabolic alkalosis in the dogs. Meta-
bolic alkalosis was also reported by
UNSUREN et al. (1995) in dogs after re-
peated administration of tetramisole of
high doses.
In the present study, significant increases
in the concentration of blood urea and the
serum activities of ALT and AP were ob-
tained in both Group A and Group B. The
increase in these values and the presence
of macroscopic lesions on the liver and
kidneys were consistent with several
studies which suggest that levamisole
causes both liver and kidney damage and
affects their function in dogs and humans
(BULUGAHAPITIYA, 1997). On the other
hand, changes in blood transaminases
were found to be minimal in sheep (AB-
DELSALAM, 1986) and were not corre-
lated with the clinical signs caused by va-
rious doses, but a significant increase in
the plasma creatinine phosphokinase and
alkaline phosphatase activity have been
observed in levamisole toxicosis in ani-
mals (HSU, 1980) and in humans (ABDEL-
SALAM, 1986; BULUGAHAPITIYA, 1997).
In conclusion, there were severe nervous
signs, gastric haemorrhage, bloody
vomiting, colic, anaemia and death in
Group A. Atropin sulphate reduced the
severity of the clinical signs, especially
neurological and muscular signs, and the
number of deaths suggesting the presen-
ce of beneficial effects of atropin sulpha-
te in the treatment of levamisole poison-
ing. However it is not alone sufficient to
remedy levamisole poisoning. We there-
fore recommended that in addition to
atropin sulphate to eliminate severe neu-
rological signs, fluid therapy for dehydra-
tion and metabolic alkalosis and suppor-
tive therapy for haemaorrhage and
anaemia should be taken into considera-
tion for the treatment of levamisole poiso-
ning in dogs.
Acknowledgements
The authors wish to thank Mrs Catherine
Akca for proof reading the manuscript.
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Address for correspondence:
Dr. H. I. GOKCE, Department of Internal
Medicine, Faculty of Veterinary Medicine,
The University of Kafkas, KARS-36040/
TURKEY
Tel: +90 474 2426889
Fax: +90 474 2426853
E-Mail: devrek@hotmail.com
Dtsch. tierärztl. Wschr. 111, 49–88, Heft 2, Februar 2004
85
Originale/Originals
Fallbericht
Diphallus bei einem Deutschen Holsteinkalb
BÄHR, C., DISTL, O.
Institut für Tierzucht und Vererbungsforschung, Tierärztliche Hochschule Hannover
BÄHR, C., DISTL, O. (2004):
Fallbericht – Diphallus bei einem Deutschen Holstein-
kalb.
Dtsch. tierärztl. Wschr. 111, 85–86
Zusammenfassung
Bei einem Kalb der Rasse Deutsche Holsteins trat ein Diphallus auf. Bei der klinischen
Untersuchung konnten eine Verdopplung der Glans penis, des Corpus penis und der
Urethra, aber keine weiteren Missbildungen festgestellt werden. Eine chromosomale
Anomalie könnte als Ursache für diese kongenitale Anomalie in Frage kommen.
Schlüsselworte: Rind, Deutsche Holsteins, kongenitale Anomalie, Diphallus
BÄHR, C., DISTL, O. (2004):
Case report – Diphallus in a German Holstein calf.
Dtsch. tierärztl. Wschr. 111, 85–86
Summary
A diphallus was found in a German Holstein calf. Clinical examination revealed a dupli-
cation of glans penis, corpus penis and urethra, but no further anomalies were ob-
served. Possibly, this congenital anomaly is caused by a chromosomal aberration.
Key words: Cattle, Deutsche Holsteins, congenital anomaly, diphallus
