Preclinical Toxicology Studies with a Novel Antithyroid Medication
Rafiq R. A. Abou-Shaaban1,* Malaz AbuTarif2, David R. Taft2 and Anthony P. Simonelli2
1
Faculty of Pharmacy and Health Sciences, Ajman University of Science and Technology, Abu
Dhabi, United Arab Emirates
2
Division of Pharmaceutics, Long Island University, Brooklyn NY 11201 USA
*
Corresponding Author:
Dr. Rafiq R. A. Abou-Shaaban
Faculty of Pharmacy and Health Sciences
Ajman University of Science and Technology
Abu Dhabi Campus
PO Box 5102
Abu Dhabi, United Arab Emirates
Fax: +971-2-676-1828
Tel: +971-50-445-8952
Email: rafiq_a@hotmail.com
Running Title: Preclinical Toxicology of Abouthioline
Key Words: Abouthioline; Toxicology; Propylthiouracil; Methimazole; Preclinical
-1-
Abstract
Abouthioline (1-Cyclohexyl-3(3-quinolyl)-2-thiourea) is a novel compound with antithyroid
activity. Abouthioline was designed based on structure-activity relationships (E-state indexes)
aimed at reducing the antioxidant properties of the compound by modification of acyclic
thiourylene moiety. Antioxidant effects of currently available treatments (e.g., propylthiouracil,
methimazole) are associated with an incidence of agranulocytosis and aplastic anemia. In the
present study, the preclinical toxicology of abouthioline was determined in mice and rats and
compared to several reference compounds (e.g., propylthiouracil, methimazole).
Following
short-term administration (7 days) to mice, ABL had minimal effects of on biochemical
parameters, although significant reductions in both total protein and albumin were noted.
Chronic toxicity studies (30 days) in rats revealed significant effects of abouthioline,
propylthiouracil and methimazole on serum electrolyte and glucose levels. Abouthioline had no
detrimental effects on hematologic parameters. However, total WBC count (propylthiouracil)
and neutrophil levels (propylthiouracil and methimazole) were significantly decreased among
other treatment groups. The results of this investigation suggest that abouthioline is a promising
new antithyroid therapy with a reduced risk of hematologic toxicity that is associated with
current pharmacological treatments. Further studies are warranted to assess the safety and
efficacy of abouthioline.
-2-
Introduction
Antithyroid medications are used throughout the world in the treatment of
hyperthyroidism resulting from Graves’ disease (1,2). Antithyroid therapy is also indicated in
patients with toxic adenoma or toxic multinodular goiter prior to chemical or surgical
thyroidectomy (3). The most commonly prescribed antithyroid medications are the thionamides.
Agents in this class include methimazole (MTH) and propylthiouracil (PTU). Thionamide
medications are generally administered for long periods of time. While the incidence of adverse
effects with antithyroid therapy is low, these medications are associated with severe hematologic
toxicity including agranulocytosis and aplastic anemia (4-8).
Agranulocytosis is a severe and life-threatening complication of thionamide therapy.
Agranulocytosis is presumably an autoimmune reaction to circulating anti-neutrophil antibodies
and lymphocyte sensitization to antithyroid medications. The presence of a cyclic thioamide
group in the structure of medications such as MTM and PTU may be responsible for the
stimulation of anti-neutrophil antibodies that mediate agranulocytosis. Antibody production is
thought to result from the antioxidant effects of these compounds (9,10).
Recent efforts have been directed towards the development of new antithyroid agents
with a more favorable toxicity profile. A series of compounds have been synthesized using
structure-activity relationships.
The design of these compounds was based on atom level
electrotopological state (E-state) indexes, a measure of atom electronic accessibility that is a
useful tool in drug design of compounds with desired pharmacologic activity (11-13). E-state
indexes of the thiourylene moiety have successfully been utilized to design antithyroid
compounds with reduced antioxidant properties (14). One of these compounds is Abouthioline
(1-Cyclohexyl-3(3-quinolyl)-2-thiourea, ABL, Figure 1). A series of investigations have been
-3-
published evaluating the antithyroid and antioxidant activities of ABL.
Using the
125
I-
thiocyanate discharge technique in rats, ABL demonstrated significantly greater antithyroid
efficacy compared to PTU (15).
Additional studies of the chemiluminescence response and
phagocytic activity of polymorphonuclear lymphocytes demonstrated that ABL had reduced
antioxidant and phagocytic activity compared to PTU and MTM (16). Thus, it appears that ABL
may represent a useful antithyroid medication with a reduced risk of toxicity.
In the present investigation, the preclinical toxicology of ABL was studied in mice and
rats. The objective of these experiments was to compare the effects of ABL, PTU, MTM and
thyroxine on biochemical and hematological parameters in these species.
Methodology
All animal experiments were conducted in accordance with the Institute for Laboratory
Animal Research (ILAR) “Guide for Care and Use of Laboratory Animals” (17)
Acute toxicity assessment in mice
Equimolar doses of test and reference compounds were utilized: ABL (17mg/kg /day),
PTU (10mg/kg/day), MTM (6.7 mg/kg/day) and thyroxine (77g/kg/day). The compounds were
freshly dispersed in 1% tween-80 aqueous solution prior to oral dosing.
Thirty male mice were divided into on of five study groups: control (n=10), ABL (n=5),
PTU (n=5), MTM (n=5) and thyroxine (n=5).
The control group received 0.1ml/10g/day of
0.1% Tween-80 aqueous vehicle. Each of the treatment groups were administered 0.1ml/10g/day
of drug dispersion. Drug dosing (including control) was performed daily for seven days. At the
end of the seventh day, blood samples were collected via the tail vein. Blood biochemical
-4-
parameters were measured using an AxSym Analyzer (Abbott Laboratories, North Chicago, IL).
Parameters included the following: glucose, urea, creatinine, sodium, potassium, chloride, uric
acid, calcium, inorganic phosphorous, magnesium, iron, total bilirubin, total protein, albumin,
cholesterol, triglycerides, alkaline phosphatase, lactate dehydrogenase (LDH), alanine
aminotransferase (ALT), aspartate aminotransferase (AST), and creatine kinase.
Long term toxicity in rats
The dose of test (ABL) and reference compounds (PTU, MTM) was 20 mg/Kg/day. The
compounds were freshly dispersed in 2% Cremophor EL/Saline solution prior to oral dosing.
Twenty-five male Sprague-Dawley rats were divided into one of four study groups:
control (n=10), ABL (n=5), PTU (n=5) and MTM (n=5).
The control group received
0.1ml/10g/day of 0.1% Cremophor EL/Saline aqueous vehicle. Each of the treatment groups
were administered 0.1ml/10g/day of drug dispersion. Drug dosing (including control) was
performed daily for 30 days days. At the end of 30 days, blood samples were collected via the
tail vein. Blood biochemical parameters were measured using an AxSym Analyzer (Abbot
Laboratories, North Chicago, IL) as described previously.
Hematological parameters were
determined using a Cell-Dyne 1700 Analyzer (Abbott Laboratories). The hematologic profile
consisted of a CBC (WBC, RBC, HgB, HCT, MCV, MCH, MCHC, RDW and PLT), a three-part
WBC differential (lymphocyte, monocyte, granulocyte) and histograms of RBC, WBC and
platelets.
-5-
Statistical Analysis
The effects of ABL and reference compounds on biochemical and hematological
parameters were analyzed by one-way analysis of variance. Dunnett’s test was utilized to
identify significant differences between individual treatment groups and controls (p < 0.05).
Results
Acute Toxicity in Mice
The results of acute toxicity studies in mice are presented in Table 1.
Reported in the
table are the biochemical parameters for control studies together with the compounds tested.
Overall, there were few treatment effects on serum chemistry. Mice treated with thyroxine and
ABL had a slightly higher sodium level, although this finding appears to be clinically
insignificant.
Additionally, both compounds significantly reduced uric acid.
ABL
administration was associated with significant reductions in total protein and albumin
concentrations.
Chronic Toxicity in Rats
The effects of long term exposure (30 days) of ABL, PTU and MTM on serum
biochemistry in rats are presented in Table 2. In contrast to the acute toxicity studies (Table 1), a
number of effects were noted. Both PTU and ABL were associated with significant reductions in
serum glucose. Each compound studied produced varying degrees of electrolyte imbalance (K,
Cl, Mg). Total protein levels were significantly increased. PTU administration significantly
increased creatinine, bilirubin, ALT and AST levels.
-6-
Table 3 provides contains a summary of hematologic findings. ABL administration was
associate with changes in Hct, mean cell volume and mean cell width. No other changes in
hematology were noted with ABL. PTU caused a significant reduction in total WBC count.
Neutrophil concentrations were significantly reduced by both PTU (absolute value) and MTM
(both absolute value and %total).
Discussion
ABL is a novel antithyroid compound specifically designed to reduce the incidence of
severe hematologic toxicity that is associated with medications that are presently used in the
treatment of Graves’ disease (PTU and MTM).
pharmacologic activity of ABL (14,15).
Previous studies have demonstrated the
The goal of this investigation was to assess the
tolerability of ABL as compared to PTU and MTM. Acute toxicity studies in mice established
that ABL compared favorably with the reference compounds. Although serum protein and
albumin levels were decreased by ABL, the reason for this effect is unclear. Reduced protein
concentrations can sometimes be a manifestation of liver toxicity, although this seems unlikely
given the short duration of the study and the fact that other indices of hepatobiliary function
(e.g., ALT, AST, bilirubin, LDH) were unchanged. Furthermore, these changes did not occur
following long-term administration to rats.
ABL also appeared to perform well following chronic administration. Although the
compound appeared to cause electrolye imbalance and hypoglycemia, similar observations were
observed with PTU and MTM. The clinical significance of this observation is yet to be
evaluated, although the magnitude of this imbalance is unlikely to be dose limiting. There was
-7-
evidence of drug-induced kidney and liver damage in rats treated with PTU. These findings
were not observed with ABL and MTM.
ABL did not appear to cause any disturbances in hematological values. There was no
evidence associating ABL with the most severe side effect of present antithyroid therapy,
agranulocytosis (characterized by neutropenia). Conversely, both MTM and PTU were
associated with changes in WBC (PTU) and neutrophil concentrations (PTU and MTM).
In summary, the results of this preclinical toxicity study indicated that ABL compared
favorably with existing antithyroid medications. Serum chemistry data from mice and rats
indicated similar effects of ABL, PTU and MTM on electrolyte and glucose levels. In contrast to
the reference compounds, there were no detrimental effects of ABL on hematologic parameters
(i.e., WBC and neutrophils). These results suggest that ABL is a promising new antithyroid
therapy with a reduced risk of the blood dyscrasias (agranulocytosis and aplastic anemia) that
have been reported with commonly prescribed medications. Additional studies are warranted to
further investigate the safety and efficacy of this compound.
-8-
References
1. Chiovato L, Santini F, Pinchera A 1995 Treatment of hyperthyroidism. Thyroid Int. 2:1-22.
2. Roti E, Minelli R, Gardini E 1994 Controversies in the treatment of thyrotoxicosis. Adv.
Endocrinol. Metab. 5:429-460.
3. Klein I, Becker DV, Levey GS 1994 Treatment of hyperthyroid disease. Ann Intern Med
121:281-288.
4. Bartalena L, Bogazzi F, Martino E 1996 Adverse effects of thyroid hormone preparations
and antithyroid drugs. Drug Safety 15:53-63.
5. Tajiri J, Noguchi S, Murakami T, Murakam T 1990 Antithyroid drug–induced
agranulocytosis: the usefulness of routine white blood cell count monitoring. Arch. Intern.
Med. 150:621-624.
6. Tajiri J, Noguchi S, Okamura S, Morita M, Tamaru M, Murakami N, Niho Y 1993
Granulocyte
colony-stimulating
factor
treatment
of
antithyroid
drug-induced
granulocytopenia. Arch. Intern. Med. 153:509-514.
7. Retsagi G, Kelly JP, Kaufman DW. 1988 Risk of agranulocytosis and aplastic anemia in
relation to use of antithyroid drugs: international agranulocytosis and aplastic anemia study.
BMJ 297:262-265.
8. Biswas N, Ahn Y, Goldman JM, Schwartz JM 1991 Case report: aplastic anemia associated
with antithyroid drugs. Am. J. Med. Sci. 301:1353-1362.
9. Wall JR, Fang SL, Kurocki T, Lagbar SH , Braverman LE 1984 In vitro immunoactivity of
propylthiouracil, methimazole and carbizole in patients with Graves’ disease: a possible
cause of antithyroid drug-induced agranulocytosis. J. Clin. Endocrinol. Metab. 58:868-872.
-9-
10. Wilson R, McKillop JH, Travers M, Smith J, Smith E, Thomson JA 1990 The effect of
antithyroid drugs on intracellular mediators. Acta Endocrinol. Copenh. 122:605-609.
11. Hall LH, Mohney B, Kier LB 1991 The electrotopological state: an atom index for QSAR.
Quant. Struct. Act. Relat. 10:43-52.
12. Kier LB, Hall LH 1992 An atom description in QSAR models: development and use of an
atom level index. In: Testa B (ed) Advances in Drug Design, Academic Press Ltd, New
York, pp. 1-38.
13. Hall LH, Kier LB 1992 Binding of salicylamides: QSAR analysis with electrotopological
state indexes. Med. Chem. Res. 2:497-502.
14. Abou-Shaaban RRA, Al-Kahmees HA, Abou-Auda HS, Simonelli AP 1996 Atom level
electrotopological-state indexes in QSAR: designing and testing antithyroid agents. Pharm.
Res. 13:129-136.
15. Abou-Shaaban RRA, Al-Kahmees HA, Abou-Auda HS, Simonelli AP 1995 Development of
new antithyroid compounds with reduced antioxidant property. Saudi Pharmaceutical Journal
3:180-195.
16. Abou-Shaaban RRA, Simonelli AP Antioxidative and proliferative activity of two newly
synthesized
antithyroid
drugs,
abouthiazine
and
abouthioline,
as
compared
to
propylthiouracil and methimazole. (submitted for publication?)
17. Institute for Laboratory Animal Research. National Research Council. Guide for the Care
and Use of Laboratory Animals. Washington DC, National Academy Press, 1996.
- 10 -
Table 1. Serum Biochemistry Data Following Acute Exposure (7 days) in Micea
Serum
Parameters
(SI units)
Concentration of Parameters (Mean ± SD)
Control
PTU
MTM
Thyroxine
ABL
Glucose
8.84
7.4
9.28
7.54
8.96
(mmol/l)
(± 2.10)
(± 1.17)
(± 0.89)
(± (0.79)
(± 0.94)
Urea
10.1
10.52
8.90
9.56
9.60
(mmol/l)
(± 1.47)
(±1.61)
(± 0.47)
(± 0.58)
(± 0.93)
Creatinine
33.3
32.2
30.50
30.00
28.80
(micmol/l)
(± 3.72)
(± 3.31)
(± 1.80)
(± 3.41)
(± 3.31)
Sodium
151.8
153.6
153.00
154.60
154.40
(mmol/l)
(± 2.36)
(± 1.4)
(± 0.71)
(± 1.36)*
(± 0.49)*
Potassium
6.49
6.9
6.88
6.78
5.62
(mmol/l)
(± 0.87)
(± 0.43)
(± 0.37)
(± 0.26)
(± 0.31)
Chloride
88.0
74.0
82.00
83.20
96.00
(mmol/l)
(± 18.7)
(± 3.29)
(± 2.24)
(± 6.94)
(± 4.05)
Uric Acid
180.3
218.2
229.00
93.40
89.40
(micmol/l)
(± 97)
(± 73.9)
(± 44.43)
(± 6.62)
(± 19.32)
Calcium
2.58
2.52
2.48
2.56
2.48
(mmol/l)
(± 0.10)
(± 0.1)
(± 0.04)
(± 0.05)
(± 0.04)
Inorg.
3.35
3.44
3.33
3.72
3.28
Phosphorous
(± 0.25)
(± 0.54)
(± 0.23)
(±0.44)
(± 0.28)
(mmol/l)
Mg
0.99
1.14
0.99
1.04
0.86
(mmol/l)
(± 0.13)
(± 0.22)
(± 0.12)
(± 0.20)
(± 0.08)
Fe
46.1
49.8
61.75
32.60
42.80
(mmol/l)
(± 12.57)
(± 8.61)
(± 12.17)
(± 7.47)
(± 6.62)
Total bilirubin
2.76
2.96
3.00
2.98
2.22
(micmol/l)
(± 0.55)
(± 0.3)
(± 0.42)
(± 0.31)
(± 0.37)
Total protein
51.7
52.0
52.75
50.80
44.80
(g/l)
(± 1.9)
(± 1.4)
(± 1.48)
(± 1.60)
(± 1.72)*
Albumin
28.1
26.6
29.00
26.40
25.20
(g/l)
(± 1.45)
(± 1.02)
(± 0.00)
(± 1.50)
(± 0.98)*
Cholesterol
2.99
2.96
2.83
2.28
2.52
(mmol/l)
(± 0.37)
(± 0.34)
(± 0.18)
(± 0.32)*
(± 0.32)
Triglycerides
1.60
1.60
1.48
1.30
1.52
(mmol/l)
(± 0.28)
(± 0.27)
(± 0.11)
(± 0.22)
(± 0.27)
Alk. Phosphatase
127.6
104.2
142.25
164.40
101.20
(U/l)
(± 32.99)
(± 21.7)
(± 26.93)
(± 38.24)
(± 16.19)
LDH
963
917
813.50
995.40
728.40
(U/l)
(± 381)
(± 141.2)
(± 100.64)
(± 76.75)
(±75.76)
ALT
41.9
51.8
48.00
99.00
51.00
(U/l)
(± 7.2)
(± 9.74)
(± 9.03)
(± 45.45)*
(± 18.06)
AST
199.4
278
192.50
284.20
181.80
(U/l)
(± 68.7)
(± 49.8)
(± 29.92)
(±68.76)
(± 20.89)
Creatine Kinase
253
244.4
248.75
329.40
179.40
(U/l)
(± 127.4)
(± 140)
(± 42.16)
(±71.06)
(± 45.40)
a
data reported as Mean ( SD) for control (n = 10) and treatment groups (n = 5). The following daily doses were
studied: PTU (10mg/kg/day) , MTM (6.7 mg/kg/day), thyroxine (77g/kg/day), ABL (17mg/kg /day).
*
denotes significant difference compared to control (p < 0.05)
- 11 -
Table 2. Serum Biochemistry Data Following Chronic Exposure (30 days) in Ratsa
Serum
Parameters
(SI units)
Glucose
(mmol/l)
Urea
(mmol/l)
Creatinine
(micmol/l)
Sodium
(mmol/l)
Potassium
(mmol/l)
Chloride
(mmol/l)
Uric Acid
(micmol/l)
Calcium
(mmol/l)
Phosphorous
(mmol/l)
Mg
(mmol/l)
Fe
(mmol/l)
Total bilirubin
(micmol/l)
Total protein
(g/l)
Albumin
(g/l)
Cholesterol
(mmol/l)
Triglycerides
(mmol/l)
Alk. Phosphatase
(U/l)
LDH
(U/l)
ALT
(U/l)
AST
(U/l)
Creatine Kinase
(U/l)
Concentration of Parameters (Mean ± SD)
Control
5.44
(± 0.75)
5.90
(± 0.53)
55.20
(± 3.66)
144.60
(± 0.80)
5.16
(± 0.25)
98.00
(± 1.41)
56.60
(± 5.85)
2.55
(± 0.09)
2.50
(± 0.11)
1.09
(± 0.15)
37
(± 8.22)
2.16
(± 0.81)
68.4
(± 1.96)
31.2
(± 0.98)
1.36
(± 0.16)
0.64
(± 0.17)
150.2
(± 35.7)
636
(± 307)
45.6
(± 8)
126.2
(± 22.9)
516
(± 231.7)
PTU
1.60 *
(± 0.5)
11.2 *
(± 1.2)
75.6 *
(± 3)
143.2
(± 2.1)
3*
(± 0.5)
103 *
(± 1.9)
67.8
(± 30)
2.7
(± 0.11)
2.1
(± 0.34)
1.6 *
(± 0.1)
27.6
(± 8.2)
4.1 *
(± 0.4)
83.2 *
(± 2.2)
31
(± 1.3)
2.2 *
(± 0.38)
0.78
(± 0.1)
178.6
(± 30)
725
(± 559.8)
64 *
(± 8.5)
171 *
(± 31.7)
518.6
(± 249)
- 12 -
MTM
3.44
(±0.71)
5.56 *
(± 1.50)
55.6
(± 1.74)
143.6
(± 0.49)
3.3 *
(± 0.30)
98.2
(± 0.40)
53.2
(± 16.19)
2.72
(± 0.07)
2.36
(± 0.14)
1.6 *
(± 0.06)
25
(± 5.76)
2.42
(± 0.53)
75.4 *
(± 2.73)
32.2
(± 0.98)
2.44 *
(± 0.54)
0.92 *
(± 0.19)
158.6
(± 11.41)
353
(± 119)
38.20
(± 6.27)
96.6
(± 4.63)
648.2
(± 477)
ABL
2.32 *
(± 0.61)
7.14
(± 0.70)
54.80
(± 3.66)
144.20
(± 1.33)
2.54 *
(± 0.53)
91.0 *
(± 2.97)
78.40
(± 21.30)
2.90 *
(± 0.06)
2.60
(± 0.18)
1.66 *
(± 0.14)
24.60
(± 5.85)
2.38
(± 0.61)
76.20 *
(± 1.72)
32.40
(± 0.80)
1.90
(± 0.17)
0.82
(± 0.17)
172.20
(± 23.40)
530.60
(± 143.23)
57.20
(± 8.75)
147.40
(± 9.16)
439.80
(± 57.31)
a
data reported as Mean ( SD) for control (n = 10) and treatment groups (n = 5). The dose of each test compound
was 20 mg/Kg/day.
*
denotes significant difference compared to control (p < 0.05)
- 13 -
Table 3. Hematology Data Following Chronic Exposure (30 days) in Ratsa
Blood Parameters
(S.I. Units)
Control
Mean Parameter Values ( SD)
PTU
MTM
ABL
White blood counts
14.06
8.62
13.34
13.22
(x103 /l)
( 1.61)
( 1.70)
( 2.42)
( 2.50)
Red blood counts
7.81
6.82*
7.22
7.36
(x 106 /l)
( 0.15)
( 0.52)
( 0.67)
( 0.54)
Hemoglobin (Hg)
14.58
13.44
13.72
14.20
(g/dl)
( 0.32)
( 0.53)
( 0.92)
( 0.70)
Hematocrite
45.78
43.68
44.22
53.12*
(%)
( 1.09)
( 2.64)
( 3.08)
( 2.77)
Mean cell volume
58.64
64.22
61.40
72.54*
(fl.)
( 2.27)
( 3.98)
(2.08)
( 6.46)
Mean cell Hg
18.64
20.25
19.02
19.34
(pg.)
( 0.67)
( 0.30)
( 0.76)
( 0.66)
Mean cell Hg conc.
31.80
30.80
30.98
26.84*
(g/dl)
( 0.75)
( 1.04)
( 0.21)
( 2.01)
Red cell distribution width
15.24
16.36
15.30
22.56*
(%)
( 0.91)
( 1.26)
( 0.72)
( 2.14)
Platelets
951.40
714.20*
669.20*
953.40
(x 103/l)
( 30.05)
( 121.9)
( 88.08)
( 261.29)
Mean platelet volume
6.10
7.50*
7.12*
6.72
(fl)
( 0.26)
(0.58)
( 0.47)
( 0.42)
Neutrophils
28.20
21.00
5.60*
39.00
(%)
( 7.60)
( 12.99)
( 1.85)
( 15.13)
Lymphocytes
67.40
77.40
92.40*
59.00
(%)
( 7.68)
( 12.29)
( 2.06)
( 15.17)
Monocytes
1.80
1.00*
1.00*
0.60
(%)
( 1.17)
( 0.63)
( 0.63)
( 0.49)
Eosinophils
2.60
0.60
1.00
1.40
(%)
( 1.02)
( 0.49)
( 0.89)
( 1.85)
Basophils
0.00
0.00
0.00
0.00
(%)
( 0.00)
( 0.00)
( 0.00)
( 0.00)
Neutrophils Absolute value
4.07
1.92
0.78*
5.01
3
(x10 / l)
( 1.41)
( 1.46)
( 0.34)
( 1.96)
Lymphocyte Absolute value
9.36
6.57
12.30
7.98
(x103/ l)
( 0.54)
( 1.25)
( 2.13)
( 2.88)
Monocytes Absolute value
0.27
0.08
0.13
0.09
3
(x10 / l)
( 0.18)
( 0.06)
( 0.10)
( 0.07)
Eosinophils Absolute value
0.35
0.05*
0.13*
0.14
(x103/ l)
( 0.11)
( 0.04)
( 0.11)
( 0.16)
Basophils Absolute value
0.00
0.00
0.00
0.00
(x103/ l)
( 0.00)
( 0.00)
( 0.00)
( 0.00)
a
data reported as Mean ( SD) for control (n = 10) and treatment groups (n = 5). The dose of each test compound
was 20 mg/Kg/day.
*
denotes significant difference compared to control (p < 0.05)
- 14 -
Figure Legend
Figure 1.
Chemical structures of propylthiouracil, methimazole and abouthialine
- 15 -
H
N
S
CH3
HN
O
Propylthiouracil (PTU)
H3C
N
SH
N
Methimazole
NH
S
HN
N
Abouthialine
(1-Cyclohexyl-3(3-quinolyl)-2-thiourea)
- 16 -