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Hyperadrenocorticism in four cats

W. F. G. A. Immink ª e , A.J. van Toor , J. H. Vos C , J. S. van der Linde-Sipman C & A. A. M. E. Lubberink ª

a Practice for companion animals , Surinamestraat 50, Den Haag, 2585 GK, The Netherlands

b Practice for companion animals , Thorbeckelaan 358, Den Haag, 2564 BZ, The Netherlands

Department of Veterinary Pathology , State University Utrecht , The Netherlands

d Hospital for comapanion animals ‘De Wagenrenk’ , Keijenbergseweg 18, Wageningen, 6705 BN, The Netherlands

e Surinamestraat 50, Den Haag, 2585 GK, The Netherlands Published online: 01 Nov 2011.

To cite this article: W. F. G. A. Immink , A.J. van Toor , J. H. Vos , J. S. van der Linde-Sipman & A. A. M. E. Lubberink (1992) Hyperadrenocorticism in four cats, Veterinary Quarterly, 14:3, 81-85, DOI: 10.1080/01652176.1992.9694337

To link to this article: http:/dx.doi. org/10.1080/01652176.1992. 9694337

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ORIGINAL PAPERS HYPERADRENOCORTICISM IN FOUR CATS

W. F. G. A. Immink1, A.J. van Toor2, J. H. Vos3, J. S. van der Linde-Sipman3, and A. A. M. E. Lubberink4

Veterinary Quarterly 1992; 15: 81-5

SUMMARY

This paper describes four cats with hyperadrenocorticism. Cat 1 showed polydipsia and polyphagia. Diabetes mellitus was initially diagnosed. As the animal appeared to be insulin resistant, pituitary and adrenocortical function tests were perfor- med and the diagnosis of hyperadrenocoricism was made. Resistance to the high-dose dexamethasone suppression test was noticed in this cat. Pathological examination revealed a pituitary chromophobe adenoma.

Cat 2 presented with diabetes mellitus, which was treated with insulin. The animal had a pendulous abdomen and its coat was in a poor condition. The low-dose dexamenthasone suppression test demonstrated hyperadrenocorticism. Necropsy findings of pit- uitary tumour and hyperplasia of the adrenal cortex confirmed the diagnosis.

Cat 3 showed clinical abnormalities indicative of hyperadreno- corticism, for instance, muscle weakness, alopecia, multiple abcesses. The diagnosis of hyperadrenocorticism was confirmed by the results of the lowe-dose dexamethasone suppression test. Pathological examination revealed an adrenocortical carci- noma.

Cat 4 presented with polydipsia. The cause of this symptom was not found initially. One and a half years later additional symptoms, such as nephritis and polyphagia developed. Hypera- drenocorticism was diagnosed because of a palpable mass cranial to the left kidney. The diagnosis was confirmed by the results of the lowe-dose dexamethasone suppression test and the necropsy findings.

INTRODUCTION

Hyperadrenocorticism (Cushing’s Syndrome) is a rare disorder in cats, and only a few well-documented cases have been reported (2,6,12,17,21,25).

This endocrinopathy is, as in dogs and man, caused by functional neoplasms of the adrenal cortex (6,12,17) or by bilateral adrenal gland hyperplasia due to overproduction of adrenocorticotrophic hormone (ATCH) by neoplasia or hyper- plasia of the pituitary gland (2,6,17,21,25).

Hyperadrenocorticism can also be induced by coricosteroid overdosage, although cats are far more resistant than dogs to the development of clinical signs induced by exogenous glucocorti- coids (23).

In this paper clinical and pathomorphological data are presented of four cats with hyperadrenocorticism.

Address for correspondence and about reprints from the manuscript: Surinamestraat 50, 2585 GK Den Haag, The Netherlands.

1 Practice for companion animals, Surinamestraat 50, 2585 GK Den Haag, The Netherlands.

2 Practice for companion animals, Thorbeckelaan 358, 2564 BZ Den Haag, The Netherlands.

3 Department of Veterinary Pathology, State University Utrecht, The Netherlands.

4 Hospital for comapanion animals ‘De Wagenrenk’, Keijenbergseweg 18, 6705 BN Wageningen, The Netherlands.

METHODS AND MATERIALS

Pituitary and adrenal function was investigated with the low- dose dexamethasone suppression test. Plasma cortisol values were assessed before and 8 hours after i.v. administration of 0,01 mg/kg dexamethasone. Plasma cortisol levels higher than 27 nmol/l after dexamethasone are considered indicative of hyperadrenocorticism (6).

Two additional function tests were performed in one cat, namely:

1. The high-dose dexamethasone suppression test wereby plasma cortisol levels were measured 3 hours after i.v. admini- stration of 0,1 mg/kg dexamethasone !.

2. The combined high-dose dexamethasone suppression-/ ACTH stimulation test. Plasma cortisol levels were measured before and 3 hours after dexamethasone (0,5 mg/kg i.v.) and subsequently 1,5 hours after 0,25 mg synthetic ACTH 2, which was administrated just after the second blood sample had been collected.

For histopathological examination, tissue samples were fixed in 10% buffered-formalin, embedded in paraffin, cut into 6-um slices and stained with haematoxylin and eosin, periodic acid - Schiff reaction (PAS) and alkaline Congo red.

CLINICAL DATA CAT 1

An 8-year-old sterilised female domestic shorthair cat presented with polydipsia, polyphagia and wasting for 4 weeks.

At clinical examination the coat appeared to be dull and a slight atrophy of the muscles of the back and hindlegs was noticed. Further physical examination did not reveal abnormalities. Semiquantitatively assessed blood levels of urea 3 and glucose 4 were 5 mmol/1 and 22 mmol/1, respectively. Diabetes mellitus was diagnosed. Insulin 5 therapy with doses from 3 I.U. up to 20 I.U. did not decrease blood glucose concentration below 13 mmol/1, indicating an insulin-resistant hyperglycemia. The results of the blood analysis are presented in Table 1. The insulin resistance suggested that the cat suffered from hyperadrenocorti- cism. The results of the low-dose dexamethasone suppression test (Table 1) supported this diagnosis. The plasma cortisol level was 120 nmol/ after administration of the low-dose of dexamethasone and decreased from 190 to 120 nmol/l after the combined high-dose dexamethasone suppression -/ACTH sti- mulation test and subsequently increased to 170 nmol/l.

Cortisol concentrations were the same irrespective of the dose of dexamethasone given. Moreover, a high dose of dexamethasone only partially suppressed cortisol production, and subsequent administration of synthetic ACTH induced a moderate increase in cortisol concentrations.

! Dexadreson, Intervet, Boxmeer, The Netherlands

2 Cortrosyn, Organon, Boxmeer, The Netherlands

3 Merkognost 11001, Merck, Darmstadt, Germany.

4 Haemo-Glukostest 1-44R, Boehringer, Mannheim, Germany.

$ Insuline Novo Lente, Novo Industri, Amsterdam, The Netherlands.

These findings are indicative of an adrenal tumour (12,13), and therefore a laparotomy was performed. However no abnormali- ties of the adrenal glands were observed. In view of the apparent absence of an adrenal tumour and the progressive deterioration of the animal’s condition, which was noted before surgery, the animal was put down and sent for necropsy.

CLINICAL DATA CAT 2

A 6-year-old sterilised female domestic Persian cat presented with diabetes mellitus. The owner complained about urinary incontinence and a continuing polydipsia and polyphagia in spite of treatment with an increasing dose of insulin, from 5 to 1 1 IU during the last month. The owner also mentioned that the abdomen had become larger during the preceding year. At physical examination the cat appeared to have a pendulous abdomen and a unkempt coat in poor condition. The results of blood examination (Table 1) revealed anaemia and liver failure. The blood glucose level was normal, probably as a result of the

insulin treatment. Patient history, physical abnormalities and the diabetes mellitus indicated hyperadrenocorticism. The results of the low-dose dexamethasone suppression test (Table 1) suppor- ted the diagnosis.

The cat became more incontinent and also began to lose control of its bowels. The owner requested that the animal be put down.

NECROPSY FINDINGS IN CAT 1 AND CAT 2

At necropsy, the cats appeared to be in good physical conditon, with pronounced fat deposition in the abdominal region. The liver was slightly enlarged. Both adrenal glands showed mode- rate enlargement of the cortical region. The pituitary gland also appeared to be slightly enlarged. The pancreas and all other organs did not show macroscopical abnormalities.

Samples of tissue from the brain, the pituitary gland, the liver, the adrenal glands, the kidneys and the pancreas were collected. At microscopical examination, the islet cells and the epithelial cells of the small ducts of the pancreas showed vacuolation. In cat 1, there were fewer endocrine cells in many of the islets and these cells were replaced by amorphous eosinophilic material

Table 1. Laboratory results of four cats with hyperadrenocoricism1.

BLOOD	Cat 1	Cat 2	Cat 3	Cat 4	Normal value
Haematocrit	34	28	18	38	33-46%
Haemoglobin	7.4	5.1	3.9	7.7	6.9-9.6 mmol/1
White blood cells	17.0	9.5	55.5	16.1	5.7-16.3 109/1
Neutrophils	15.1	6.7	27.8	14.9	2.5-12.5 109/1
Band cells	0	0	13.2	0	0-0.3 109/1
Eosinophils	0	0	1.1	0	0-1.5 109/1
Lymphocytes	1.36	2.3	5.0	0.7	1.5-7 109/1
Monocytes	0.51	0.23	4.4	0.3	0-0.85 109/1
Metamyelocytes	0	0	3.9	0	0 109/1
Thrombocytes	385	334	14	279	300-800 109/1
Red blood cells	-	5.2	3.89	7.5	6.5-10 1012/1
Normablasts	-	0	30	0	0 per 100 white blood cells
MCV	-	52.8	46.9	50.8	38.2-48.0 fl
MCH	-	0.98	1.0	1.04	0.81-1.04 fmol
anisocytosis	+	-	++	-	negative
BUN	-	4.8	8	13.4	5.9-12.5 mmol/l
Creatinine	80	71	42	159	71-108 Mmol/1
Na	-	157	149	165	146-158 mmol/1
K	-	4.0	4.2	4.0	3.4-5.2 mmol/1
Ca	2.48	2.41	2.06	3.00	2.3-2.6 mmol/1
Phosphorus	-	-	1.32	-	1.1-1.6 mmol/1
ALAT	22	126	90	90	27-54 IU/1
Gamma GT	-	2	2	1	0-6 IU/1
Total bilirubine	-	1.9	12	12	<3.0 umol/1
Alkaline phosphatase	59	60	34	50	26-107 IU/1
Total protein	80	73	60	102	56-85 g/l
T4	34	30	-	24	19.3-46.3 nmol/1
LOW-DOSE SUPPRESSION TEST
Cortisol before	-	108	321	88	27-121 nmol/1
and after dexamethasone	110	58	287	41	< 27 nmol/l

URINE
Specific gravity	1030
Strip2 pH	5-6
Glucose	not present
Proteins	++
Bilirubine	+++
Sediment	some red blood cells some white blood cells bacteria crystals of bilirubine

! The blood of cat 4 was examined after the start of insulin therapy

2 Multistix TM, Ames, Slough, Great Britain.

which showed green birefringence on staining with Congo red. In both cats the heparocytes showed slight vacuolation and PAS-positive granulation of the cytoplasm. In the adrenal glands compression of the zona glomerulosa was noticed, which was probably caused by hyperplasia of zona fasciculata cells in particular but also of zona reticularis cells. In cat 1 local calcification was observed.

Both cats had a small chromophobic adenoma of the pituitary gland. The kidneys of cat 1 showed a moderate mesangioprolife- rative glomerulopathy and a small number of tubuli contained proteinaceous casts. The brains of both cats did not show histological abnormalities.

CLINICAL DATA CAT 3

A 12-year-old sterilised female cat presented with polyphagia, general depression and retarded hair growth at the site of mammary gland surgery performed one year before. The cat showed poor locomotion.

On physical examination, the animal showed weight loss and had a pot-bellied appearance. Multiple abscesses and fistulae were present on the right front leg. The body temperature was 40° C. Atrophy of the skin and alopecia of the ventral parts of the body, extending to the flanks, was noticed. Abdominal palpation revealed hepatomegaly together with a swelling in the dorsal epigastrium, which was probably due to the enlargement of the right kidney. A preliminary diagnosis of Cushing’s syndrome was made.

The patient was hospitalised for further clinical evaluation and initial therapy. Blood and urine samples were taken for analysis. Blood glucose concentration, semiquantitatively assessed as described above, was 11 mmol/l. The results of the laboratory blood examination are presented in Table 1.

The cat was injected every 2 days with clamoxyl L.A.1. The animal had a good appetite and the abscesses disappeared. Locomotion, however, remained weak. A low-dose dexametha- sone suppression test was then performed.

The cat was sent home while the test results were awaited.

One week later the abcesses had returned on both forelegs and the left hindleg showed oedema. The owner requested that the animal be put down. With the owner’s persmission several organs were sampled for pathological examination. The results of the low-dose dexamethasone suppression test (Table 1) indicated hyperadrenocorticism.

NECROPSY FINDINGS

The right adrenal gland, the right kidney, the heart, the lungs and tissue samples of the skin, the liver and the pancreas were submitted for pathological examination.

On macroscopical examination, the right adrenal gland was irregular and enlarged (4x3x3cm), with the cut surface having a lobulated yellow appearance with many haemorrhages and necrosis. The kidney showed no macroscopical abnormalities. The heart was enlarged due to dilatation of the left atrium and excentric hypertrophy of the left ventricle.

The lungs were edematous. On microscopical examination, the adrenal gland consisted entirely of a cortical carcinoma, which had infiltrated into the surrounding fat tissue, causing necrosis, haemorrhage and thrombosis of vessels. The kidney was normal. The heart showed diffuse fibrosis and severe focal degeneration of cardiac muscle fibres with accumulation of fat.

1 Clamoxyl L.A., SmithKline Beecham, Zoetermeer.

Many heart failure cells were present in the lung, together with proliferation of alveolar cells and hyaline membranes. The skin showed hyperkeratosis and atrophy of the hair follicles.

The liver revealed focal centrolobular necrosis, and many iron- loaded macrophages were present. The hepatocytes were slightly vacuolated and PAS-positive material was present. The pancreas was chronically inflamed.

The islets of Langerhans were normal. The surrounding fat tissue was necrotic and showed signs of an inflammatory reaction.

CLINICAL DATA CAT 4

An 11-year-old sterilised female domestic shorthair cat presen- ted with polydipsia. Physical abnormalities could not be found. Blood concentrations of glucose, urea, creatinine and liver enzymes were normal. The cause of the polydipsia could not be determined. One and a half years later the cat presented with depression. The body temperature was 39.9º C, the left kidney was enlarged and there was haematuria. Nehpritis had been diagnosed and treated with ampicilline. The cat recovered. Two months later the cat developed polyphagia. A more-or-less distinct mass cranial to the left kidney could be palpated. The results of blood examination (Table 1) indicated neutrophylia, lymphopaenia, hyperglycemia and failure of the kidneys and liver. On the basis of the patient’s history, physical and laboratory examinations, the cat was suspected of suffering from hyperadrenocorticism. The results of the low-dose dexametha- sone suppression test (Table 1) supported the tentative diagnosis. Ten days after the function test, the cat developed a rapidly worsening dyspnoea. A radiograph of the thorax showed a large density in the lung, suggesteive of a tumour. Owing to he poor prognosis the animal was put down.

NECROPSY FINDINGS

Only the enlarged left adrenal gland (5x3x21/2 cm) and the lungs were submitted for necropsy. Microscopical examination of the adrenal gland showed that normal tissue had been almost entirely replaced by a cortical tumour that did not appear to be malignant. Local pneumonia was found in the lungs and in addition a localised adenocracinoma, most probably originating from the bronchial glands.

DISCUSSION

The definite diagnosis of hyeradrenocorticism was based on the results of the function tests. The diagnosis was confirmed by autopsy findings in the first and second cats, i.e., bilateral cortical hyperplasia of the adrenal glands associated with a pituitary adenoma, and in the third and fourth cats, i.e. an adrenocortical tumour.

Hyperadrenocorticism is apparently a slowly developing disease. The second, third and fourth cats suffered from poor fur growth, polydipsia and an enlarged abdomen, respectively, during the year before hyperadrenocorticism was diagnosed. At the moment that hyperadrenocorticism was diagnosed in the animals, all were polyphagous but had different dominating secondary problems, i.e., insulin-resistant diabetes mellitus with eventual mental deterioration in cat 1, uncleanliness in cat 2, hepatitis and recurring skin abcesses in cat 3, nephritis in cat 4. Thus hyperadrenocorticism in cats is probably not always recognised because of the predominant secundary problems, and this may be the reason why feline hyperadrenocorticism is not frequently described.

Hyperadrenocorticism in cat 1 was diagnosed on the grounds of the insulin-resistant diabetes mellitus, as has been described in

other cases of hyperadrenocorticism (17,21). Another cause of insulin-resistant diabetes mellitus is an excessive production of growth hormone by a tumour of the pituitary gland (3, 16). Recurrent diabetes mellitus, however, as the result of a pituitary tumour has been reported in cats as well (14).

The high-dose dexamethasone suppression test is used to determine the cause of hyperadrenocorticism, i.e. to establish the adrenal or pituitary dependence of the disorder (6). The adrenal function of cat 1 was hardly be suppressed by high doses of dexamethasone and was slightly stimulated by synthetic ACTH in comparison with data for healty cats (24). This suggests an autonomous hyperadrenocorticism, which is indicative of the presence of an adrenal tumour (12,13,17). However other studies have demonstrated that dexamethasone resistance, as found in this cat, can also be caused by a dysfunctioning pituitary gland (2, 21). It should be noted that cortisol level in this cat 1.5 hours after ACTH administration had probably passed its peak value, because the maximal cortisol concentra- tion is already reached after 30 minutes in healthy cats (24). Plasma ACTH levels can be used to differentiate between adrenal tumour-induced and pituitary-dependant hyperadreno- corticism (6). In dogs with functional cortical adrenal tumour, ACTH concentrations are below 40 pg/ml. Higher values are indicative of pituitary-dependant hyperadrenocorticism (4). A study has reported that an ACTH concetration below 20 pg/ml was measured in a cat with an adrenal tumour, whereas three cats with pituitary-dependant hyperadrenocorticism had an ACTH concentration above 90 pg/ml (6). It is therefore recommended that ACTH concentrations are measured in cats when hyperadrenocorticism is thought to be caused by an adrenal tumour.

Unfortunately, it could not be assessed whethe the tumour present in cat 1 originated in the adenohypophysis or in the pars intermedia, which is present in the cat (15), as tumours of the pars intermedia are known to be resistant to dexamethasone suppression, at least in dogs (10,22) and horses (19). Since these tumours are associated with elevated basal plasma a-MSH concentrations (17), it would be worthwhile assessing the a- MSH concentration in the plasma of cats with dexamethasone suppression resistance.

The corticotroph character of pituitary gland tumours can be demonstrated by immunocytochemical staining for ACTH, B- lipo trophin, ß-endorphin or a-MSH (9,20). Although immu- nocytochemical staining was not performed, the chromophobic character of the tumour cells, the clinical data and the presence of bilateral gland hyperplasia in cat 1 are strongly indicative of the corticotroph character of the pituitary adenoma: However, the coincidental presence of a non-functional pituitary adenoma cannot be excluded unequivocally, as in dogs idiopathic bilarteral adrenocortical hyperplasia is known to induce hypera- drenocorticism (1).

Morphologically, diabetes mellitus is related to pancreatic lesions with destruction of the islets or degenerative lesions of islets cells, charecterized by vacuolation of these cells (1,9) and of the epithelial cells of smaller ducts (9), as result of glycogen accumulation. In cats this vacuolar degeneration appears to develop as a response to long-term overstimulation because of insulin resistance (1). Thus the vacuolation observed in cat 1 is most probably due to exhaustion of the islets cells as result of the glucocorticosteroid-induced insulin resistance. The exclusive intra-islet presence of amyloid with the absence of amyloid in other tissues is well known in diabetic cats (8).

Additional pathomorphological feature of diabetes mellitus are

mesangial thickening in glomeruli and hepatic lipidosis (1,9). Thus the glomerular lesions of cat 1 could be related to its diabetes, but the hepatocytes only showed slight vacuolation and PAS-positive cytoplasmic granulation, which is indicative of the presence of glycogen. However, the absence of hepatic lipidosis in diabetic cats has also been reported (7,11,18). Hyperadrenocorticism in dogs is also known to cause hepatic lesions, i.e., glucocortocoid-induced hepatopathy (1). In cats with hyperadrenocorticism (17,20,25) or with symptoms re- sembling those of this disease (7,23), hepatic lesions are apparently not always present.

The muscle weakness of cat 3 was pronounced. This may be due to muscular atrophy, possibly induction of protein catabolism by cortisol. Muscular atrophy means a low protein mass, which could explain the low plasma creatinine concentration in this cat. Another cause of the muscular weakness might be a decreased cardiac performance, as indicated by the histological findings in the heart and the lungs. Serum calcium was also decreased in cat 3, probably because cortisol stimulates urinary excretion and reduces the intestinal absorption of calcium by inhibiting the action of vitamin D. (5). Bilirubinaemia, regenera- tive anaemia and leucocytosis with a left shift could indicate autoimmune haemolytic anaemia of diffuse intravascular co- agulation - both may develop in the course of tumour disease or in the course of septicaemia originating from the skin abscesses. The centrolobular hepatic necrosis observed in cat 3 could be due to the anaemia and/or cardiac dysfunction as a result of the pathological changes in the heart.

In conclusion, two suggestions for diagnostic evaluation are given. First, when a cat with polyphagia shows insulin resistance or has a pot-bellied appearance with or without symmetric alopecia with or without bacterial dermatitis, the animal should be screened for hyperadrenocorticism. If, in the case of insulin resistance, screening excludes this disease, the possibility of an excessive secretion of growth hormone should be investigated. Second, when a cat with hyperadrenocorticism shows resistance to dexamethasone suppression, the basal plasma concentration of a-MSH should be measured.

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3. Eigenmann JE, Wortman JA, and Haskins ME. Elevated Growth Hormone Levels and Diabetes Mellitus in a Cat with Acromagalic Features. J Am An Hosp Assoc 1984; 747-52.

4. Feldman EC. Distinguishing dogs with functioning adrenocortical tumors from dogs with pituitary-dependent hyperadrenocorticism. J Am Vet Med Assoc 1983; 183: 195-200.

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7. Fox JG, and Beatty JO. A Case Report of Complicated Diabetes Mellitus in a Cat. J Am Anim Hosp Ass 1975; 11: 129-34.

8. Johnson KH, Hayden DW, O’Brien TD and Westermark P. Spontaneous diabetes mellitus-islet amyloid complex in adult cats. Am J Pathol 1986; 125: 416-9.

9. Jubb KVF, Kennedy PC, and Palmer N. Pathology of Domestic Animals 3rd edit. Orlando: Academic Press Inc., 3, 1985; 238-303 and 2. 1985; 314- 29.

10. Kemppainen RJ, and Zenoble RD. Non-dexamethasone-suppressible, pituitary dependent hyperadrenocorticism in a dog. J Am Vet Med Assoc 1985; 187: 276-8.

11. Loppnow H, and Gembardt C. Zur Pathogenese des spontanen Diabetes mellitus der Katze. I. Mitteilung: Diabetes mellitus durch primare Inselver- anderungen in 10 Fallen. Berl Münch Tierärztl Wschr 1976; 89: 79-83.

12. Meyer JC, Lubberink AAME, and Gruys E. Cushing’s syndrome due to adrenolitical adenoma in a cat. Tijdschr Diergeneesk

13. Meyer JC, Lubberink AAME, Rijnberk A, and Croughs RJM. Adrenoliti- cal function test in dogs with hyperfunctioning adrenocortical tumors. J of Endocr 1979; 80: 315-19.

14. Middleton DJ, Culvenor JA, Vasak E and Mintohadi K. Growth Hormone- producing Pituitary Adenoma, Elevated Serum Somatomedin Concentra- tion and Diabetes Mellitus in a cat. Can Vet J 1985; 26: 169-71.

15. Mol JA, and Rijnberk A. Pituitary Function. In: Kaneko JJ, ed. Clinical Biochemistry of Domestic Animals. San Diego: Academic Press Inc 1989; 576-609.

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18. O’Brien TD, Hayden DW, Johnson KH, and Stevens JB. High Dose Intravenous Glucose Tolerance Test and Serum Insulin and Glucagon Levels in Diabetic and Nondiabetic Cats: Relationships to Insular Amylo- idosis. Vet Pathol 1985; 22: 250-61.

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TRANSDERMAL DELIVERY AND INTRAMUSCULAR INJECTION OF TRIMETHOPRIM/SULPHADIAZINE IN SUCKING PIGLETS

T. Sekido, E. Kokue, M. Shimoda, and T. Hayama1 Veterinary Quarterly 1992; 15: 85-7

SUMMARY

The pharmacokinetics of a combination of trimethoprim (TMP) and sulphadiazine (SDZ) after topical application to sucking piglets was compared with the pharmacokinetics after intramus- cular injection. A long-lasting and fairly constant SDZ/TMP concentration ratio in plasma was obtained after topical application. The mean plasma concentration of TMP ranged from 0.091 to 0.17 µg/ml and that of SDZ from 0.72 to 1.1 µg/ ml for at least 24 h. TMP and SDZ had different half-lives after intramuscular injection. Transdermal delivery of a combined preparation of TMP/SDZ may be usable for colibacillosis of sucking piglets, although the bioavailability of the drugs is poor.

INTRODUCTION

Sucking piglets on pig breeding farms are usually medicated with antibacterial agents by intramuscular injection or forced oral dosing to prevent infectious diseases such as colibacillosis (4). This communication describes the transdermal drug deli- very of a combination of trimethoprim (TMP)/sulphadiazine (SDZ) to sucking piglets for the treatment of colibacillosis. The pharmacokinetic profile of the drugs after topical application was compared with that after intramuscular injection.

MATERIALS AND METHODS

Animals

Commercially raised 14-day-old (n=16) and 35-day-old (n=4) piglets (Canadian Yorkshire x Irish Yorkshire x Duroc) were used.

The sixteen 14-day-old piglets were divided into two groups; one group (n=8) received a single topical application of the

IDepartment of Veterinary Medicine, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183, Japan

combined preparation and the other group (n=8) received a single intramuscular injection. The four 35-day-old piglets received a single topical application.

Drugs

Transdermal delivery. The solvent for the TMP/SDZ formula- tion was a mixture of dimethyl sulfoxide (DMSO) to enhance absorption, propylene glycol (PG) to raise the viscosity of the solvent, and N-methyl-2-pyrrolidinone (NMP, Aldrich Chemi- cal Company Inc., USA) to raise the solubility of the active ingredients (2,17).

TMP (5%) and SDZ (10%) were finally dissolved in a mixture of DMSO, PG and NMP (4.5 : 4.5 : 1, v/v/v). After clipping the trunk of eight 14-day-old piglets and the four 35-day-old piglets with a 0.5 mm clipper blade, 1 ml of the formulation/kg (50 mg TMP/kg and 100 mg SDZ/kg) was dripped from an autopi- pette and spread over the clipped area of each piglet by hand (gloves worn).

Intramuscular injection.

TMP (5%) was dissolved in a 50:1 mixture of glycerol formal (Fluka Chemica, Switzerland) and diethanolamine (Wako Chemicals, Tokyo, Japan). SDZ (10%) was dissolved in a dilute NaOH solution (pH 10). The TMP and SDZ solutions, 0.2 ml/ kg of each (10 mg TMP/kg and 20 mg SDZ/kg), were injected intramusculary to each of eight 14-day-old piglets.

Blood samples, approximately 2 ml each, were taken from the anterior vena cava under light halothane anaesthesia 3, 6, 12, 15, 18, 21 and 24 h after topical application and 1, 2, 4, 6, 8 and 10 h after intramuscular injection. The blood samples were treated with EDTA and centrifuged at 2,000 x g for 10 min to