Effects of Ehrlichia phagocytophila infection on serum thyroid hormone concentrations and on antipyrine clearance and metabolite formation in dwarf goats.

The influence of infection with Ehrlichia phagocytophila (EP) on serum thyroid hormone concentrations and on antipyrine (25 mg/kg of body weight, IV) plasma elimination and urinary metabolite excretion was studied in castrated male dwarf goats. Mean thyroid hormone concentrations moderately decreased in EP-infected goats, with maximal decrease in total and free triiodothyronine and thyroxine serum concentrations of 56, 64, 23, and 19%, respectively. The estimated pharmacokinetic values of antipyrine (AP) in EP-infected goats were similar to those in the goats when healthy. However, glucuronidation of the AP-metabolites 3-hydroxymethyl-AP, 4,4'-dihydroxy-AP, and 4-hydroxy-AP was reduced during the febrile episode of the acute-phase response to EP infection.     

Effects of triiodothyronine treatment on pharmacokinetic properties and metabolite formation of antipyrine in dwarf goats.

The influence of triiodothyronine (5 micrograms/kg of body weight, sc, q 12 h for 7 days) on antipyrine (AP, 25 mg/kg, IV) plasma elimination and urinary metabolite excretion was studied in castrated male dwarf goats. After triiodothyronine treatment, a significant increase in AP elimination was found. However, the observed changes in clearances for production of AP metabolites (nor-AP, 3-hydroxymethyl-AP; 4-hydroxy-AP, and 4,4'-dihydroxy-AP) do not suggest a clear selectivity of triiodothyronine toward any of the metabolic pathways of AP.     

Hormonal regulation of oxidative drug metabolism in the dwarf goat. The effect of sex and hormonal treatment on plasma disposition and metabolite formation of sulphadimidine

Sulphadimidine (20 mg/kg i.v.) plasma elimination and metabolite formation were studied in intact male, castrated male, and female dwarf goats. Plasma pharmacokinetics and urinary metabolite patterns were first studied in un-treated animals. Afterwards, females and castrates were treated with a combination of testosterone-propionate (1 mg/kg) and 17P-oestradiolbenzoate(0.02 mg/kg) once every 3 days, for a period of 4 weeks. In untreated animals, males showed a considerably lower plasma clearance than females or castrates. This was accompanied by lower partial clearances for the production of two hydroxylated sulphadimidine metabolites. After hormonal treatment of females and castrates, sulphadimidine plasma clearance was significantly reduced, to values corresponding with those observed in control males. Furthermore, hydroxylation was significantly inhibited after treatment. The results indicate that sulphadimidine hydroxylation in the goat is performed by enzymes of the cytochrome P450 complex which are strongly influenced by gonadal hormones. Androgens seem to play a central role in this respect.     

Effect of trenbolone and testosterone on the plasma elimination rates of sulfamethazine, trimethoprim, and antipyrine in female dwarf goats

Plasma elimination rates of sulfamethazine (100 mg/kg of body weight, IV), trimethoprim (20 mg/kg, IV), and antipyrine (35 mg/kg, IV) were studied in adult female dwarf goats (n = 5) before and after implantation with trenbolone acetate (5 mg/kg). Pretreatment with trenbolone caused a significant decrease in the elimination rate of the drugs tested: for sulfamethazine, 5 times; for antipyrine, 3 times; and for trimethoprim, 2 times. After treatment with testosterone (1 mg/kg, SC, twice weekly for 2.5 weeks), female goats (n = 5) had a similar decrease in the elimination rate of sulfamethazine. Other induced effects included a change in social behavior, a lower voice, and the development of a typical billy goat-like odor. Plasma creatinine concentrations after androgen administration were significantly higher than those before androgen administration; changes were not observed in plasma urea values. Because of the differences observed, we believe that more attention should be paid to the effects of androgenic agents on drug kinetic properties, with particular reference to studies on clinical efficacy, side effects, and drug residues in food products.     

The effect of testosterone on the plasma disappearance rates of sulphadimidine and antipyrine in castrated dwarf goats

Plasma disappearance of sulphadimidine and antipyrine was studied in adult castrated dwarf goats before and following pretreatment with testosterone. Comparison was made with entire males before and after castration. Testosterone pretreatment caused a significant increase in the apparent elimination half-life in castrates, whilst in entire males castration caused a significant decrease.     

The effect of testosterone on the plasma disappearance rates of sulphadimidine and antipyrine in castrated dwarf goats

Summary

Plasma disappearance of sulphadimidine and antipyrine was studied in adult castrated dwarf goats before and following pretreatment with testosterone. Comparison was made with entire males before and after castration. Testosterone pretreatment caused a significant increase in the apparent‐ elimination half‐life in castrates, whilst in entire males castration caused a significant decrease.     

Effect of experimental fasciolosis on antipyrine metabolism and clearance in water buffaloes

The effect of chronic Fasciola hepatica infection on the metabolism of antipyrine, a marker of microsomal oxidative metabolism, was investigated in male water buffaloes dosed daily with 60 F. hepatica metacercariae over 20 days. The plasma elimination half-life of antipyrine was significantly elevated by 23% at 11 weeks postinfection (p.i.) but did not significantly differ from the control period at 20 weeks p.i. The systemic clearance of antipyrine decreased by 48% at 11 weeks p.i. and then returned to normal. The renal clearance for each of the main antipyrine metabolites decreased at 11 weeks p.i. (hydroxymethylantipyrine (HMA), -42%; norantipyrine (NORA), -58%; and 4-hydroxyantipyrine (OHA), -70%) and did not significantly differ from the control period at 20 weeks p.i. These findings indicate that experimental subclinical fasciolosis leads to altered antipyrine kinetics and to an inhibition of the different antipyrine metabolic pathways in water buffaloes.     

Effects of human chorionic gonadotrophin and castration on plasma gonadal steroid hormones of the dog

An intramuscular injection of 500 I.U. of human chorionic gonadotrophin resulted in an increase of plasma testosterone and progesterone concentrations in the intact male dog, but had no effect on plasma 17B-estradiol concentration. Castration caused a rapid decrease in concentration of testosterone, progesterone, and 17B-estradiol, indicating that the tests were the major organs producing these hormones in the male dog.     

The impact of acute phase response on the plasma clearance of antipyrine, theophylline, phenytoin and nifedipine in rabbits

The impact of acute phase response (APR) on the plasma clearances of antipyrine, theophylline, phenytoin and nifedipine was studied using 50 female rabbits. APR was induced by a bolus intramuscular injection of Escherichia coli lipopolysaccharide (LPS, 50 microg/kg). No abnormal findings, other than an increase in rectal body temperature and the plasma concentration of interleukin-6 (IL-6), were observed in the LPS-treated animals. Twenty-four hours after LPS injection, the pharmacokinetic parameters of the four drugs were obtained following intravenous administrations of antipyrine (7 mg/kg), theophylline (5 mg/kg), phenytoin (10 mg/kg) and nifedipine (1 mg/kg). Total body clearances of antipyrine, theophylline, phenytoin and nifedipine in LPS-treated rabbits decreased, and terminal elimination half-life and the mean residence time of these drugs increased compared with those in the control rabbits. The apparent volume of distribution for phenytoin and nifedipine increased after the LPS injection, although the binding percentage of the drugs with plasma protein did not change. These results suggested that APR appears to decrease the plasma clearances of these drugs in rabbits, which may be due to the suppression of the activity of cytochrome P450 enzymes.     

Comparative aspects and sex differentiation of plasma sulfamethazine elimination and metabolite formation in rats, rabbits, dwarf goats, and cattle.

Plasma disposition and urinary recovery of sulfamethazine (SMZ), its N4-acetylated metabolite (N4AcSMZ), and 2 of its hydroxylated metabolites--5-hydroxysulfamethazine (5OHSMZ) and 6-hydroxymethylsulfamethazine (6CH2OHSMZ)--were determined in either sex of 4 animal species: rats, dwarf goats, rabbits, and cattle. Rats, rabbits, and dwarf goats had significant (P < 0.01) sex difference in SMZ plasma clearance. Male rats had higher plasma clearance than did female rats, and excreted higher amounts of the hydroxy metabolites and lower amounts of N4AcSMZ. The N4AcSMZ metabolite was predominant in plasma and urine of rabbits. Male rabbits had higher plasma clearance than did female rabbits, but differences in metabolite profile were not apparent. With regard to plasma SMZ elimination, the situation in goats was opposite to that in rats. Male goats had considerably lower clearance than did female goats. This was associated with a lower hydroxylation rat in males. Plasma half-life of SMZ in cows was lower than that in bulls, probably because of a smaller distribution volume in cows. Compared with elimination via urine, elimination via milk was negligible in cows. Significant differences in metabolite profiles were not found between bulls and cows. Similar to those in rats and mice, hormone-dependent xenobiotic metabolic pathways may exist in other species. Depending on species and xenobiotic compound residue concentrations of xenobiotics, their metabolites, or both may differ with sex of the animal, or may be altered after treatment with anabolic hormones.     

Effect of Haemonchus contortus infection on the clearance of antipyrine, sulfobromophthalein, chloramphenicol, and sulfathiazole in lambs

A study was made to determine the effect of Haemonchus contortus parasitic infection in lambs on the clearance of several IV administered drugs. Clearance of sulfobromophthalein or sulfathiazole from the plasma of lambs was unaffected by infection with H contortus. Clearance of antipyrine was enhanced by the infection, and thiabendazole treatment did not alter this effect. Clearance of chloramphenicol (CAP), administered as the succinate ester (CAPS), was not changed by the infection, but it was increased after treatment with thiabendazole. Changes in the mean body residence time and initial plasma concentration of CAPS and CAP after treatment with thiabendazole indicate that hydrolysis of CAPS to CAP was reduced. High concentrations of CAPS apparently enhanced its own elimination directly rather than via the expected sequence involving hydrolysis, glucuronidation, and excretion of CAP-glucuronide. Enhanced clearance of antipyrine following infection of lambs with H contortus can be explained in at least 2 ways. First, it is possible that the lambs did not have mature amounts of hepatic drug metabolizing enzyme activity as reported by other investigators, which may be explained by breed differences or animal husbandry practices. Second, infection of lambs by H contortus may have triggered an inductive response in hepatic cytochrome P-450-mediated activities, which might result via a generalized enhancement in hepatic protein synthesis associated with the physiologic response to replace plasma proteins and other blood components lost through gastrointestinal hemorrhage caused by the active feeding of adult worms. Other phase-II reactions such as acetylation, glucuronidation, and glutathione-S-transferase apparently were not affected.     

Radiographic investigation of dystocia in the West African dwarf goat

Lateral and ventrodorsal radiographs were obtained from 30 West African dwarf goats with dystocia. The pelvic size was estimated from the ventrodorsal radiographs as the product of the transverse and conjugate diameters of the pelvic inlet. Radiography clearly showed the number of fetuses present, their presentation and position. The posture was clearly defined in singletons but not in twins and triplets. The commonest abnormal fetal disposition was bilateral flexion of the forelimbs with the head in the pelvic canal. The major maternal abnormality was small pelvic area. Of 19 dead fetuses, 13 showed radiographic signs of intrauterine death including free intracavity gas, tissue emphysema, abnormal fetal disposition and overlapping cranial bones. It was concluded that radiography is useful during examination of goats with dystocia especially small sized goats that cannot be manipulated easily.     

Effect of fasting on plasma metabolites and hormones in lactating dairy cows

Metabolic and pathophysiologic changes of secondary ketosis were studied. Plasma samples were obtained from a group of 8 mature, lactating dairy cows before, during, and after a 48-hour fast. These samples were analyzed for glucose, free fatty acids (FFA), lactic acid, ketone bodies, glucocorticoids, insulin, and growth hormone concentrations. In the prefasting period, metabolites and hormones remained constant. Lactic acid and glucocorticoids also remained stable during the entire experiment, except on the 1st day after termination of the fast, when glucocorticoids increased significantly (P less than 0.05). Glucose values decreased significantly (P less than 0.01) with the onset of fasting, began to rise halfway through the fast, and were elevated following termination of the fast. Plasma glucose concentration returned to normal by the end of the experiment. Plasma FFA concentrations increased during the early portions of the fast and decreased thereafter. Plasma ketone body concentration responded similarly, but the change occurred approximately 12 hours after the plasma FFA changes. A value determined as ketotic was reached during the fast (14.6 +/- 1.3 mg/dl). Insulin concentrations remained low during the fast and increased after fasting. Plasma growth hormone concentration increased to a new plateau in response to fasting and then decreased somewhate after fasting was ended.     

Effect of steroid hormones on the innate immune response induced by Staphylococcus aureus in the goat mammary gland

The objective of this study was to compare the dynamics of innate immune components after intramammary infusion of Staphylococcus aureus (SA) under conditions of high oestrogen and high progesterone in goats. In one group (“E‐group”), controlled internal drug release (CIDR) devices were inserted intravaginally from days ?11 to ?4. Prostaglandin F2α was administered immediately after removal of the CIDR device at day ?3, and then oestradiol benzoate (E) was injected intramuscularly once a day from days ?2 to 3. Heat‐inactivated SA was then administered via intramammary infusion to the left udder at day 0, whilst only saline was infused to the right udder as a control. In a second group (“P‐group”), CIDR devices were inserted intravaginally from days ?3 to 7 and SA was infused at day 0 in the same way as in the E‐group. The milk yield and the concentration of innate immune components (somatic cell count (SCC), lactoferrin (LF), S100A7 and goat ß‐defensin 1 (GBD‐1)) in the milk were measured. Milk yield decreased drastically in both SA and control udders in the E‐group, whereas the P‐group exhibited increased milk yield in both SA and control udders. SCC increased after SA infusion in both E‐ and P‐groups, although it was higher in the E‐group than in the P‐group. There was no significant change in LF concentration in the E‐group, but a decrease was observed in the P‐group. Concentrations of S100A and GBD‐1 were significantly increased after SA infusion in the E‐group but not in the P‐group. These results suggest that E enhances the innate immune response induced by SA in the goat mammary gland. This effect may be due to the reduction in milk yield and upregulation of innate immune components.     

Studies on the functional relationship between thyroid, adrenal and gonadal hormones

In order to clarify the functional relationship between thyroid, adrenal and gonadal hormones, hypothyroidism was induced by administration of thiuoracil in adult male and female rats, and the effects of hypothyroidism on the adrenal and the gonadal axes were investigated in the present study. 1. The functional relationship between thyroid and adrenal hormones: Adrenal weights and corticosterone were lowered, whereas the secretion of ACTH, corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) increased in hypothyroid rats compared to euthyroid rats. These results indicate that hypothyroidism causes adrenal dysfunction directly and results in hypersecretion of CRH and AVP from the hypothalamus. 2. The functional relationship between thyroid and gonadal hormones: The pituitary response to LHRH was lowered, whereas the testicular response to hCG was not changed in hypothyroid rats. Hypothyroidism suppressed copulatory behavior in male rats. These results suggest that hypothyroidism probably causes dysfunction in gonadal axis at the hypothalamic-pituitary level in male rats. In adult female rats, hypothyroidism inhibited the follicular development accompanied estradiol secretion, whereas plasma concentrations of progesterone and prolactin (PRL) increased in hypothyroid female rats. Hypothyroidism significantly increased the pituitary content of vasoactive intestinal peptide (VIP) though it did not affect dopamine synthesis. These results suggest that hypothyroidism increases pituitary content of VIP and this increased level of VIP likely affects PRL secretion in a paracrine or autocrine manner. In female rats, inhibition of gonadal function in hypothyroid rats mediated by hyperprolactinemia in addition to hypersecretion of endogenous CRH.     

Effect of meal feeding on plasma volume and urinary electrolyte clearance in ponies

The effect of meal size and frequency on plasma volume, plasma aldosterone concentration and urinary Na and K clearances was determined in ponies. A daily maintenance ration of hay-grain pellets was provided either as a multiple feeding regimen, ie, 12 equal portions fed at 2-hour intervals, or as single large feedings, ie, half the ration fed every 12 hours at 0800 and 2000 hours. Only the effect of the single morning feeding was studied, using the latter regimen. Serial measurements of plasma volume were made by use of an indicator-dilution technique and indocyanine green (0.15 mg/kg of body weight, IV) that allowed repeated determinations at 2-hour intervals. Ingestion of the single large meal caused a 15% decrease in plasma volume by the end of a 1-hour feeding period. Feeding hypovolemia was confirmed by a coincident increase in plasma protein concentration (12%) and, in separate experiments, by analysis of postfeeding changes in the elimination of Evans blue dye. Plasma aldosterone concentration was significantly (P less than 0.05) increased from 2 to 5 hours after feeding. Urinary Na clearance decreased in response to feeding and remained lower than the prefeeding value until 9 hours after feeding. Urinary K clearance increased from prefeeding and reached a peak value between 5 and 7 hours after feeding. Creatinine clearance was unaffected. In contrast, the aforementioned variables were unchanged during the multiple regimen. Results indicate that ingestion of a large concentrate meal by ponies causes periprandial hypovolemia, activation of the renin-angiotensin-aldosterone system, and a subsequent antinatriuresis-kaliuresis that lasts for several hours.     

Pollakisuria in a dwarf goat due to pathologic enlargement of the uterus

Pollakisuria in adult goats can be caused by diseases of the urinary tract and by distension of parts of the genital tract leading to irritation of the bladder. Hydrometra is the most common cause of uterine distension in goats and usually can be resolved by prostaglandin injections. But other pathologies of the uterus can generate a similar syndrome. A dwarf goat was presented at the clinic with a history of chronic pollakisuria and tenesm. An initial ultrasonographic examination of the abdomen led to the suspicion of hydrometra, but treatment with injections of prostaglandin were not successful. Blood samples revealed low progesterone and high oestrogen values. A laparotomy was performed and an enlarged uterus with 1.5 L of mucous content and cystic ovaries were found and partially removed. A single solid leiomyoma was diagnosed histologically in the uterine wall. Two months later the goat's condition had deteriorated and therefore she was euthanized. Necropsy and pathohistological examination revealed the presence of a metastasized adenocarcinoma of the uterus. In this case, the pollakisuria provoqued by distension of the uterus was not caused by hydrometra, but by neoplasia. The syndrome and the pathogenesis of the adenocarcinoma in consideration of the hormonal status of the patient is discussed.     

Effect of age on the pharmacokinetics of antipyrine in calves

Single doses of 15 mg kg⁻¹ antipyrine were given intravenously to 10 female calves of the black and white breed at one, two, four, six, eight and 12 weeks of age, and the concentrations of antipyrine, 4-hydroxyantipyrine (4-oha), 3-hydroxymethylantipyrine (hma) and norantipyrine (nora) were measured in plasma and urine by high performance liquid chromatography. The first three months of life were characterised by a steady decrease in the apparent volume of distribution (aV_d) and half-life (t_0.5) of antipyrine. The systemic clearance (Cl_s) of antipyrine per unit bodyweight increased significantly between one and 12 weeks of age. Age did not influence the excretion of hma and nora in urine, but the excretion of 4-oha by 12-week-old calves was significantly greater than by one-week-old calves. There was an age-related change in the partial clearances of the antipyrine metabolites when expressed per unit bodyweight.     

Effect of tiamulin on antipyrine kinetics in chickens

Tiamulin {14-deoxy-14[(2-diethylaminoethyl)-mercaptoacetoxy]-mutilin} hydrogen fuma-rate is a semisynthetic antibiotic. It is clinically effective against pathogenic mycoplasma organisms, e.g. Treponema hyodysenteriae , a large number of Gram-positive and some Gram-negative organisms (Drews et al. , 1975). Tiamulin has been shown, under controlled laboratory conditions (Laber & Schutze, 1975; Baughn et al. , 1978) and against natural infection under field conditions (Stipkovits et al. , 1977), to control respiratory tract infections effectively involving Mycoplasma galliseptkum in chickens and turkeys. It has also been demonstrated that tiamulin could be used as an aid in the control of avian coccidiosis produced by Eimeria acervulina and E. tenella in broilers chickens (Cruthers et al. , 1980).