Effect of Experimental Hypothyroidism on Glomerular Filtration Rate and Plasma Creatinine Concentration in Dogs

Background: Hypothyroidism affects renal function in a manner opposite the effects of hyperthyroidism.
Objective: To evaluate the effects of experimentally induced hypothyroidism on glomerular filtration rate (GFR) and basal plasma creatinine concentration in dogs.
Animals: Sixteen anestrous, female dogs.
Methods: Hypothyroidism was induced by administration of ¹³¹I in 8 dogs, and 8 healthy euthyroid dogs acted as controls. Exogenous plasma creatinine clearance (an estimate of GFR) was measured in all dogs before (control period) and 43–50 weeks after induction of hypothyroidism (posttreatment period). Other pharmacokinetic parameters of creatinine were also determined.
Results: No significant difference was observed for basal plasma creatinine concentration and creatinine clearance between control and hypothyroid dogs in the control period. In the posttreatment period, mean ± SD creatinine clearance in the hypothyroid group (2.13 ± 0.48 mL/min/kg) was lower ( P < .001) than that of the control group (3.20 ± 0.42 mL/kg/min). Nevertheless, basal plasma creatinine concentrations were not significantly different between the hypothyroid and control groups (0.74 ± 0.18 versus 0.70 ± 0.08 mg/dL, respectively) because endogenous production of creatinine was decreased in hypothyroid dogs (22 ± 3 versus 32 ± 5 mg/kg/d, P =.001).
Conclusion and Clinical Importance: Hypothyroidism causes a substantial decrease in GFR without altering plasma creatinine concentrations, indicating that GFR evaluation is needed to identify renal dysfunction in such patients.     

Effect of silymarin and vitamin E on gentamicin-induced nephrotoxicity in dogs

Drug-induced nephrotoxicity is an important cause of renal failure in dogs. Aminoglycoside antibiotics, such as gentamicin, can produce nephrotoxicity in dogs, due to in part to an imbalance of pro- and antioxidants (oxidative stress). Silymarin (the mixture of flavonolignans extracted from Silybum marianum) has potentially beneficial antioxidant properties. A control group (saline, group 1, n = 5) was compared with dogs that were administrated gentamicin by intramuscular injection, at dosage of 20 mg/kg, once daily for 9 days (groups 2-5, n = 5 per group). The effects of vitamin E (group 3) and silymarin (group 4) alone and in combination (group 5) were compared for induced nephrotoxicity. Renal function was assessed using serum biochemical markers (creatinine and urea). Malondialdehyde (MDA) concentration were measured as a marker of lipid peroxidation. The activity of total serum antioxidants (TSAO) was assessed as a marker of antioxidant defences. Serum creatinine and urea concentrations were increased significantly and TSAO was decreased significantly in group 2 compared with group 1. Serum creatinine concentrations but not urea concentrations were significantly lower in groups 3 and 4 than in group 2 (P = 0.001). Serum MDA concentrations was significantly different between groups 2 and 3 (P = 0.01), 2 and 4 (P < 0.001) and 4 and 5 (P = 0.01). TSAO activity was significantly in group 4 (silymarin) than in group 2 (P = 0.002). Silymarin and vitamin E decreased gentamicin-induced nephrotoxicity in dogs.     

Urinary gamma-glutamyl transpeptidase activity in dogs with gentamicin-induced nephrotoxicity

Serum creatinine concentrations, 24-hour endogenous creatinine clearance, and 24-hour urinary gamma-glutamyl transpeptidase (UGGT) activity were measured daily in 6 dogs given nephrotoxic dosages of gentamicin (10 mg/kg of body weight) every 8 hours for 10 days. Mean UGGT activity was significantly increased by day 5 (P less than 0.05) and preceded significant increases in serum creatinine values (greater than 2.0 mg/dl) observed on day 9. Endogenous creatinine clearance remained within normal limits (2.98 +/- 0.96 ml/min/kg) until day 8. Urinalyses performed 8 days after initiation of gentamicin treatment indicated renal tubular damage (granular casts) in 1 of the 6 dogs, and glucosuria in 3 of the 6 dogs. Measurement of UGGT activity was a more sensitive and reliable method of assessing acute renal tubular damage induced by gentamicin than were serum creatinine concentrations or 24-hour endogenous creatinine clearance.     

Serum haptoglobin concentration as a marker of clinical signs in finishing pigs

A case-control study of 340 finishing pigs aged 10 to 25 weeks in 15 commercial Danish pig herds was carried out to investigate serum haptoglobin concentration as an objective marker of clinical signs of disease. Pigs with different clinical signs were matched to control pigs without clinical signs with respect to herd, pen, estimated weight and gender, and each pig was subjected to a standard clinical examination. In 86 of the case-control pairs, the rectal temperature was also recorded. There was a significantly higher mean haptoglobin concentration in the serum of lame pigs (P<0.0001), pigs with respiratory disease (P=0.0004), pigs with tail or ear bites (P=0.0004) and pigs with diarrhoea (P=0.02). Similarly, a higher mean rectal temperature was recorded in lame pigs (P<0.0001), pigs with respiratory disease (P=0.002) and pigs with tail or ear bites (P=0.0003). There was a significant but low correlation between rectal temperature and haptoglobin concentration in serum (P=0.003, r=0.20). The area under the receiver-operating-characteristic curve was between 0.67 and 0.78 for the different clinical signs. The maximum simultaneous levels of sensitivity (0.61 to 0.71) and specificity (0.61 to 0.77) of serum haptoglobin for the different clinical signs were obtained at a cut-off value of 1.1 mg/ml. At a cut-off value of 1.8 mg/ml, the sensitivity decreased to 0.31 to 0.60, and the specificity increased to 0.82 to 0.86. It was not possible to define a cut-off value which classified individual pigs according to their clinical signs.     

Respiratory, renal, hematologic, and serum biochemical effects of hypertonic saline solution in endotoxemic calves

The respiratory, renal, hematologic, and serum biochemical effects of hypertonic saline solution (HSS) treatment were examined in 12 endotoxic, pentobarbital-anesthetized calves (8 to 20 days old). Escherichia coli endotoxin (055:B5) was infused IV at a rate of 0.1 microgram/kg of body weight over 30 minutes. Endotoxin induced severe respiratory effects, with marked hypoxemia and increases in arterial-alveolar O2 gradient (P[A-a]O2), physiologic shunt fraction (Qs/Qt), and physiologic dead space to tidal volume ratio (Vd/Vt). Oxygen consumption was decreased, despite an increase in the systemic O2 extraction ratio. Peak effects were observed at the end of endotoxin infusion. The renal response to endotoxemia was characterized by a decrease in free-water reabsorption and osmotic clearance, as well as a decrease in sodium and phosphorus excretion. Endotoxemia induced leukopenia, thrombocytopenia, hyperphosphatemia, hypoglycemia, acidemia, and increased serum alkaline phosphatase concentrations. Calves were treated with HSS (2,400 mosm/L of NaCl, 4 ml/kg, n = 4) or an equivalent sodium load of isotonic saline solution (ISS; 300 mosm/L of NaCl, 32 ml/kg, n = 4 90 minutes after the end of endotoxin administration. Both solutions were infused over a 4- to 6-minute period. A control group (n = 4) was not treated. Infusion of HSS or ISS failed to induce a significant change in Pao2, P(A-a)O2, (Qs/Qt), (Vd/Vt), or oxygen consumption. Both solutions increased systemic oxygen delivery to above pre-endotoxin values. Hypertonic saline infusion induced significant (P less than 0.05) increases in serum Na and Cl concentrations and osmolality, whereas ISS induced a significant increase in serum Cl concentration and a significant decrease in serum phosphorus concentration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Drug disposition and dosage determination of once daily administration of gentamicin sulfate in horses after abdominal surgery.

OBJECTIVE: To evaluate pharmacokinetics of once daily i.v. administration of gentamicin sulfate to adult horses that had abdominal surgery. DESIGN: Prospective study. ANIMALS: 28 adult horses that underwent abdominal surgery for colic. PROCEDURE: 14 horses were treated with each dosage of gentamicin (i.e., 6.6 or 4 mg/kg, i.v., q 24 h) and blood samples were collected for pharmacokinetic analysis. Plasma gentamicin concentrations were measured by use of a fluorescence polarization immunoassay. Pharmacokinetic analysis measured the elimination half-life, volume of distribution, and gentamicin total systemic clearance. Treatment outcome, CBC, and serum creatinine concentrations were recorded. RESULTS: 1 horse in the high-dosage group died. All other horses successfully recovered, and did not develop bacterial infection or have evidence of drug toxicosis resulting in renal injury. Mean pharmacokinetic variables for gentamicin administration at a high or low dosage (i.e., 6.6 or 4 mg/kg, i.v., q 24 h) were half-life of 1.47 and 1.61 hours, volume of distribution of 0.17 and 0.17 L/kg, and systemic clearance of 1.27 and 1.2 ml/kg/min, respectively. Mean serum creatinine concentration was 1.74 and 1.71 for the high and low dosages, respectively, and serum creatinine concentration was not correlated with gentamicin clearance. CONCLUSIONS AND CLINICAL RELEVANCE: Gentamicin administration at a dosage of 4 mg/kg, i.v., every 24 hours, will result in plasma concentrations that are adequate against susceptible bacteria with a minimum inhibitory concentration (MIC) of < or = 2.0 micrograms/ml. Gentamicin administration at a calculated dosage of 6.8 mg/kg, i.v., every 24 hours will result in optimum plasma concentrations against susceptible bacteria with a MIC of < or = 4.0 micrograms/ml.     

Effects of benazepril hydrochloride in cats with experimentally induced or spontaneously occurring chronic renal failure

We examined effects of an angiotensin converting-enzyme inhibitor, benazepril hydrochloride (BH), on renal hypertension and chronic renal failure (CRF) in cats. For experimental CRF, healthy cats (n=5) underwent 7/8 renal ablation. After renal insufficiency and hypertension were confirmed by blood urea nitrogen (BUN), serum creatinine, creatinine clearance and telemetric recording of systemic blood pressure, BH was administered orally once daily at 0.9 to 2.0 mg/kg/day for 2 to 3 weeks. Within 2 months after renal ablation, renal failure and hypertension developed as evidenced by significant increases in BUN, serum creatinine and systemic blood pressure (p<0.01 or 0.05) and significantly decreased creatinine clearance accompanied by elevated plasma renin activity, angiotensin I and II, and aldosterone (p<0.01 or 0.05). BH administration corrected systemic hypertension (p<0.05) and significantly reduced angiotensin II and aldosterone (p<0.05). Upon discontinuation of BH, these values returned to the pre-administration levels. Studies on spontaneous CRF enrolled 11 cats with spontaneously occurring CRF. BH was administered orally to 6 cats once daily for 24 weeks at a final dose of 1.0 mg/kg/day, while 5 cats served as control. BH administration reduced serum creatinine and urinary protein concentration in every cat. Results demonstrate that in cats, loss of renal mass leads to activation of the renin-angiotensin-aldosterone system and associated renal hypertension, and indicate that BH is effective in correcting renal hypertension and may provide renal benefits to cats with CRF.     

Effects of porcine growth hormone on glucose metabolism of pigs: II. Glucose tolerance, peripheral tissue insulin sensitivity and glucose kinetics

This study was conducted to determine whether the increase in serum glucose observed in pigs treated chronically with pGH is due to an increase in hepatic glucose output or to an impairment in glucose clearance. Barrows (n = 4 per treatment) were treated with pituitary derived pGH (ppGH), recombinant pGH analog (rpGH) or vehicle. Pigs were treated for 28 d by daily i.m. injections. Insulin tolerance and glucose tolerance tests (GTT) were performed on d 19 and 21, respectively, following treatment with pGH. Glucose turnover was quantified on d 28 using [6-3H]glucose. Chronically treating pigs with pGH resulted in a significant decrease (26%; P less than .05) in glucose clearance, as determined by the GTT. Glucose clearance was affected similarly by ppGH and rpGH. Intra-arterial glucose infusion markedly increased plasma insulin concentration in pGH-treated pigs. Peak plasma insulin response was 87% and 58%, respectively, higher (P less than .05) in ppGH- and rpGH-treated than in control pigs. Insulin infusion elicited a marked hypoglycemia in pigs; however, the extent and duration of hypoglycemia were significantly less in pGH-treated pigs (ppGH or rpGH). Glucose production rates were 23% higher (P = .085) in ppGH-treated than in control pigs. These results establish that the hyperglycemia induced by pGH is the result of an increase in hepatic glucose output and a concurrent impairment in glucose clearance.     

Phenolsulfonphthalein pharmacokinetics and renal morphologic changes in adult pony mares with gentamicin-induced nephrotoxicosis

Changes in renal function, determined by pharmacokinetics of phenolsulfonphthalein (PSP), and renal morphologic features were examined in adult pony mares given 20 mg of gentamicin sulfate/kg of body weight, IV, q 8 h (group A) n = 7 or isotonic saline solution, IV, q 8 h, n = 5 (group B) for 14 days. Susceptibility of ponies to gentamicin-induced nephrotoxicosis was varied. Two group-A ponies developed acute renal failure and were euthanatized before treatment day 14, whereas 5 group-A A ponies did not develop physical or behavioral abnormalities after 14 days of gentamicin administration. All group-A ponies but none of group-B ponies developed ultrastructural abnormalities of the proximal tubular epithelium, consistent with gentamicin-induced nephrotoxicosis. Significant (P less than 0.05) differences were not detected in pharmacokinetic values of either group. Clearance of PSP was reduced in 4 group-A ponies that developed the most severe gentamicin-induced nephrotoxicosis. Changes in clearance of PSP were significantly (P less than 0.05) correlated with changes in the serum creatinine concentration.     

Disposition of gentamicin administered intravenously to horses with sepsis.

Plasma concentration of gentamicin was measured 1, 4, and 6 hours after IV administration in 35 hospitalized adult horses on days 1, 3, 5, and 10 of treatment. The mean apparent elimination rate constant beta was 0.53 +/- 0.10 h-1 on day 1 for horses with normal plasma creatinine concentration and 0.41 +/- 0.13 h-1 for horses with abnormally high plasma creatinine concentration. There was no significant difference between beta of the hospitalized horses and of 6 healthy horses treated with gentamicin, but total clearance for the hospitalized horses with normal plasma creatinine concentration was significantly greater than that of the healthy horses and the hospitalized horses with abnormally high plasma creatinine concentration. Gentamicin clearance was significantly correlated with plasma creatinine concentration for healthy horses and hospitalized horses, and beta was significantly correlated with plasma creatinine concentration for hospitalized horses. Twelve of the 35 hospitalized horses required an adjustment in gentamicin dosage. Ten required a reduction, 1 an increase, and 1 a change in dosage and interval with no net change in total daily dose. One horse of 35 (2.9%) developed signs compatible with nephrotoxicosis on day 14 of treatment, despite appropriate gentamicin concentrations on day 10.     

Alleviation of reproductive toxicity of gossypol using selenium supplementation in rams

The objective of this study was to evaluate the reproductive toxicity of gossypol and the possible counteracting effect of selenium supplementation in rams. Twenty-five mature crossbred (Barki × Rahamni) rams were randomly divided into 5 equal groups. The first group served as a control (no gossypol in diet). The second and third groups received diets containing free gossypol of 9 and 14 mg·kg(-1) BW·d(-1)(low level and high level of gossypol), respectively. The fourth and fifth groups received the same diets given to the second and third groups, respectively, with an oral administration of 1 mg selenium (as sodium selenite) daily for each animal. Results showed reductions in ejaculate volume (P = 0.028), percentage of dead sperm (P = 0.003), total functional sperm fraction (P < 0.001), and blood serum concentration of testosterone (P < 0.001) in the presence of both levels of gossypol inclusion. Furthermore, high level of gossypol reduced forward motility (P < 0.001) and semen initial fructose concentration (P = 0.002) and increased abnormal-head sperm (P = 0.003) and blood serum concentration of triiodothyronine (P = 0.006). Regardless of selenium supplementation, increasing level of free gossypol in diet resulted in a significant decrease in the percentage of forward motility (P = 0.037) and significant increases in the mean values of sperm concentration (P < 0.001), total sperm output (P = 0.002), percentage of total abnormal sperm (P = 0.058), and abnormal-head sperm (P = 0.016). On the other hand, regardless of levels of gossypol inclusion, selenium supplementation resulted in significant increases in libido (P < 0.001), mean values of ejaculate volume (P < 0.001), percentage of forward motility (P = 0.019), total sperm output (P < 0.001), total functional sperm fraction (P < 0.001), semen initial fructose concentration (P = 0.031), and blood serum concentrations of both testosterone and triiodothyronine (P < 0.001). In conclusion, free gossypol in diet induced adverse effects on semen quality in rams, but selenium supplementation successfully counteracts most of the hazardous effects of gossypol on semen characteristics.     

The effects of experimentally induced bronchopneumonia on the pharmacokinetics and tissue depletion of gentamicin in healthy and pneumonic calves

The effects of a bovine bronchopneumonia model on the pharmacokinetics and tissue residue depletion profiles of gentamicin in calves weighing 90-140 kg was explored. Two groups of heifer calves were used. The first was a normal group, while the second group had bronchopneumonia induced. A scoring system was developed to evaluate the extent of disease in the groups. A bimodal distribution of the serum pharmacokinetic parameters in the pneumonic group was caused by the effects of dehydration. When the severely dehydrated calves were omitted from the analysis, serum clearance of gentamicin was significantly higher in the pneumonic group than in the normal group (P less than 0.05). The pharmacokinetic equations used to fit the tissue concentrations varied from tissue to tissue and between groups. Because the best equation of a particular tissue's concentrations varied between groups, withdrawal periods, which are normally determined in healthy animals, may be inappropriate in diseased animals. Addition of several parameters (serum creatinine, serum urea nitrogen, albumin, fibrinogen, and total protein concentrations, white blood cell counts, central fluid volume, volume of distribution at steady state, area under the serum concentration vs time curve, serum clearance, and elimination rate constant) to these tissue-depletion models using multiple regression improved the prediction of a concentration in a given tissue.     

Plasma disappearance of creatinine as a renal function test in the dog

The serum concentration of creatinine at 120 minutes (SC120) after intravenous injection of 88 mg kg-1 of creatinine, the plasma half-life (t1/2) and the plasma clearance of creatinine (PCC) were evaluated as renal function tests in 30 healthy adult dogs and six adult dogs with known or suspected renal disease. The mean SC120 in the normal dog was 0.31 +/- 0.08 mmol litre-1 and in the clinical cases 0.71 +/- 0.19 mmol litre-1. The correlation coefficients between SC120 and renal creatinine clearance (RCC) for the normal dogs and the clinical cases were -0.76 and -0.69, respectively. At 120 minutes after injection, 95 per cent of normal dogs would be predicted to have a serum creatinine concentration below 0.46 mmol litre-1. The mean plasma t1/2 of creatinine for the normal dogs was 107.7 +/- 17.96 minutes, while the clinical cases had a wide range of values (148.8 to 620.1 minutes). Plasma t1/2 of creatinine was correlated with RCC for both the normal dogs and the clinical cases (r = -0.55, r = -0.91, respectively). The mean PCC for the normal dogs was 7.42 +/- 2.22 ml min-1 kg-1 (range 4.95 to 13.28 ml min-1 kg-1). There was a good correlation between RCC and PCC (r = 0.7). The PCC for the clinical cases ranged from 0.76 to 3.37 ml min-1 kg-1. The correlation between RCC and PCC was significant (r = 0.91). Thus SC120, t1/2 and PCC may be useful methods of assessing renal function in dogs with renal impairment insufficient to cause azotaemia.     

Determinants and Utility of the Anion Gap in Predicting Hyperlactatemia in Cattle

The objectives of this study were to investigate the determinants of the anion gap (AG) in cattle and to evaluate the utility of AG in detecting hyperlactatemia in sick neonatal calves and adult cattle. The AG was calculated as AG = ([Na+] + [K+]) - ([Cl^-] + [HCO₃]), with all values in mEq/L. The AG of healthy neonatal calves (n = 16) was 29.6 ± 6.2 mEq/L (mean ± SD), and the blood L-lactate concentration ranged from 0.5 to 1.2 mM/L. The AG was significantly (P > .05) correlated with serum phosphate (r = .66) and creatinine (r = .51) concentrations. The AG of neonatal calves with experimentally induced diarrhea (n = 16) was 28.6 ± 5.6 mEq/L, and the blood L-lactate concentration ranged from 1.1 to 2.9 mM/L. The AG was significantly correlated with blood L-lactate concentration (r = .67), serum phosphate concentration (r = .63), creatinine concentration (r = .76), and blood pH (r = -.61). The AG of adult cattle with abomasal volvulus (n = 41) was 20.5 ± 7.8 mEq/L, and the blood L-lactate concentration ranged from 0.6 to 15.6 mM/L. The AG was significantly correlated with blood L-lactate concentration (r = .60), serum phosphate concentration (r = .71), creatinine concentration (r = .65), albumin concentration (r = .47), total protein concentration (r = .54), blood pyruvate concentration (r = .67), and blood pH (r = -.41) but not plasma β-OH butyrate concentration. The results indicate that the AG in cattle is only moderately correlated with blood L-lactate concentration and is similarly correlated with serum phosphate and creatinine concentrations in neonatal calves and adult cattle, as well as with serum albumin and total protein concentrations in adult cattle. Anion gap determination is of limited usefulness in predicting blood L-lactate concentration in sick cattle, whereas the correlation between AG and serum creatinine concentration in sick cattle suggests that an increased AG should alert the clinician to the potential presence of uremic anions.     

Mannan oligosaccharide increases serum concentrations of antibodies and inflammatory mediators in weanling pigs experimentally infected with porcine reproductive and respiratory syndrome virus

Mannan-containing products are capable of modulating immune responses in animals. However, different products may have diverse immunomodulation. The experiment was conducted to examine effects of mannan oligosaccharide (Actigen; ACT) on growth performance and serum concentrations of antibodies and inflammatory mediators in weanling pigs (Sus scrofa) experimentally infected with porcine reproductive and respiratory syndrome virus (PRRSV). A total of 32 PRRSV-negative pigs (3 wk old) were randomly assigned from within blocks to 1 of 4 treatments in a 2 by 2 factorial arrangement [2 types of diet: control (0%) and ACT addition (0.04%); and with and without PRRSV] in a randomized complete block design. Pigs were blocked by initial BW within sex. Ancestry was equalized across treatments. Pigs (8/treatment) were kept individually in each pen. After 2 wk of an 8-wk period of feeding the treatments, pigs received an intranasal inoculation of PRRSV or sham medium at 5 wk of age. Infection by PRRSV decreased ADG, ADFI, and G:F throughout the experiment (P < 0.01). Actigen did not affect ADG (P = 0.450), but decreased (P = 0.047) ADFI from 28 to 42 days postinoculation (DPI). During that time, ACT improved G:F in infected pigs but not in sham controls (interaction, P = 0.009). Dietary ACT did not affect viremia in infected pigs (P > 0.05), but increased PRRSV-specific antibody titer at 35 DPI (P = 0.042). Infection with PRRSV induced the febrile responses of pigs from 3 to 10 DPI (P < 0.001) with return to normal at 14 DPI. During the experimental period, the rectal temperature of pigs was found slightly elevated by ACT (P = 0.045). Infected pigs had greater serum concentrations of IL-1β, tumor necrosis factor (TNF)-α, IL-12, interferon (IFN)-γ, IL-10, and haptoglobin (Hp) than sham controls (P < 0.001). These results indicate that PRRSV stimulated secretion of cytokines involved in innate, T-helper 1, and T-regulatory immune responses. Actigen tended to decrease the serum TNF-α concentration regardless of PRRSV (P = 0.058). The ACT × PRRSV interaction was significant for IL-1β (P = 0.016), IL-12 (P = 0.026), and Hp (P = 0.047), suggesting that infected pigs fed ACT had greater serum concentrations of these mediators than those fed the control. The increases in IL-1β and IL-12 may favorably promote innate and T-cell immune functions in infected pigs fed ACT. Feeding ACT may be useful as ACT is related to increased PRRSV antibody titers and G:F in infected pigs at certain times during infection.     

Pharmacokinetics, inhibition of lymphoblast transformation, and toxicity of cyclosporine in clinically normal pigs

Pharmacokinetic variables were calculated from time-concentration data obtained after IV (10 mg/kg of body weight; n =9) and oral (12.5 mg/kg to group A [n = 3]; 25 mg/kg to group B [n = 3]; and 50 mg/kg to group C [n = 3] pigs) cyclosporine (formerly, cyclosporine A) administration. Resulting mean (+/- SD) pharmacokinetic variables were as follows: half life of distribution, 0.96 (+/- 0.7) hours; half life of elimination, 7.71 (+/- 2.6) hours; volume of distribution at steady state, 4.47 (+/- 2.22) L/kg; volume of the central compartment, 1.71 (+/- 0.78) L/kg; and systemic clearance, 8.95 (+/- 2.7) ml/kg/min. Oral bioavailability was: overall 57 (+/- 19) %; group A, 44 (+/- 11) %; group B, 78 (+/- 15) %; group C, 48 (+/- 6) %. Time to peak concentration was 3.55 (+/- 0.88) hours. During the 22 days of daily oral cyclosporine administration, blood 24-hour trough concentrations were: group A, 224.3 (+/- 78.4) ng/ml; group B, 640.7 (+/- 174.6) ng/ml; and group C, 2,344 (+/- 1,095) ng/ml. Lymphoblast transformation stimulation index was suppressed in all pigs except 1, which had a corresponding cyclosporine concentration of 92.4 ng/ml. Minimal, although statistically significant, decreases in serum albumin and magnesium concentrations and increases in serum creatinine and urea nitrogen concentrations were evident in pigs of some treatment groups. Histologic examination of necropsy specimens revealed mild hepatic necrosis (n = 1 pig), renal tubular dilatation (n = 5), and pulmonary inflammation (n = 2). Pigs given 25 and 50 mg of cyclosporine/kg failed to gain weight.     

Urinary indices of renal function in sheep with induced aminoglycoside nephrotoxicosis

Aminoglycoside nephrotoxicosis (AGNT) was induced in ewes by daily SC administration of gentamicin. Changes in urinary indices of renal function during the development of AGNT are reported. Measurements from timed, volume-measured urine samples were made on days 0, 7, and 8 and included creatinine clearance, total excretion (TE) rates of electrolytes (Na, K, Cl, P) and urine volume. Measurements from free-catch urine samples (without volume measurement) were made daily and included fractional excretion (FE) rate of electrolytes, urine osmolality, and urine-to-serum osmolality and urine-to-serum creatinine ratios. With the onset of AGNT, FE rates of Na, K, Cl, and P- increased many fold above baseline values (200x, 4 to 5x, 6 to 9x, and 70 to 95x, respectively, on days 7 and 8), indicating decreased tubular reabsorption or increased tubular secretion. The increased FE rates were not representative of increases in total electrolyte excretion rates. The total excretion of Na (TENa) was mildly increased, TEK was decreased, TECl was unchanged, and TEP was significantly increased on days 7 and 8. Abnormal urinalysis results, glucosuria, and increased FEP preceded appreciable increase in serum creatinine concentration. Other abnormal urinary indices of renal function coincided with or followed the increase in serum creatinine concentration. Urinary indices may help characterize renal function associated with the disease state, but did not provide early indication of AGNT.     

Efficacy of dietary selenium sources on growth and carcass characteristics of growing-finishing pigs fed diets containing high endogenous selenium

A study was conducted to determine the efficacy of organic (Se-yeast, SelenoSource AF, Diamond V Mills Inc., Cedar Rapids, IA) and inorganic sources of Se on growth performance, tissue Se accretion, and carcass characteristics of growing-finishing pigs fed diets with high endogenous Se content. A total of 180 pigs at 34.4 +/- 0.06 kg of BW were allotted to 1 of 5 dietary treatments: a negative control without added Se (NC); 3 treatment diets with 0.1, 0.2, or 0.3 mg/kg of added Se from an organic source; and a diet with 0.3 mg/kg of added Se as sodium selenite. Each treatment had 6 pens, with 6 pigs per pen-replicate. Experimental diets were changed twice at 66.1 +/- 0.5 kg and 99.0 +/- 0.9 kg of BW, and were fed until the pigs reached market weight. Growth performance was measured at the end of each phase. Upon reaching 129.9 +/- 1.4 kg of BW, the pigs were transported to a local abattoir (Seaboard Foods, Guymon, OK), where carcass, loin, and liver samples were obtained. Hair and blood samples were obtained at the beginning and end of the study for Se analysis. Growth performance did not differ (P > 0.05) among treatments. Percent drip loss of the NC pigs was greater (2.41 vs. 1.75, P = 0.011) compared with pigs supplemented with Se. Pigs fed diets with added Se had greater Se concentrations in the liver (0.397 vs. 0.323 ppm, P = 0.015), loin (0.236 vs. 0.132 ppm, P < 0.001), serum (0.087 vs. 0.062 ppm, P = 0.047), and hair (0.377 vs. 0.247 ppm, P = 0.003) compared with the NC pigs. Percentage drip loss was linearly reduced [percent drip loss = 2.305 - (2.398 x Se), r2 = 0.29, P = 0.007] as dietary organic Se concentration increased. The Se concentration (ppm) in the liver [liver Se = 0.323 + (0.291 x Se), r2 = 0.33, P = 0.003], loin [loin Se = 0.122 + (0.511 x Se), r2 = 0.57, P < 0.001], serum [serum Se = 0.060 + (0.113 x Se), r2 = 0.33, P = 0.004] and hair [hair Se = 0.237 + (0.638 x Se), r2 = 0.56, P < 0.001] increased linearly as dietary organic Se concentration increased. Slope ratio analysis indicated that the relative bioavailability of organic Se for percent drip loss and loin and hair Se response was 306, 192, and 197% of that for inorganic Se, respectively. The results of the study show a potential advantage of organic Se supplementation in reducing drip loss even when the basal diet contains an endogenously high Se concentration of 0.181 ppm.     

Multiple once-daily dose pharmacokinetics and renal safety of gentamicin in dogs

In this study the pharmacokinetics and renal safety of gentamicin in healthy dogs was investigated after multiple dosing. Six adult male dogs received once-daily gentamicin (6 mg/kg) intramuscularly for 5 days. Serial blood samples were taken on days 1 and 5 of treatment, and at predose, 1 and 6 h on days 2, 3 and 4. Urinalysis, hematology and serum biochemistry evaluation were carried out before, 7 and 14 days after the first gentamicin administration. Mean value of the main pharmacokinetic parameters were: AUC (microg.h/mL), 97.4 and 100.2; terminal half-life (harmonic mean), 0.76 and 1.01 h; ClB/F (mL/min.kg), 1.24 and 1.10; VD(area)/F (L/kg), 0.084 and 0.10; MRT (h), 1.48 and 1.77; Cmax (microg/mL), 54.5 and 49.2; tmax (h), 0.40 and 0.48 for the first and last dose, respectively. Accumulation was determined as R1 = 0.97 and R2 = 1.22. Mean trough gentamicin serum concentrations were 0.06, 0.07, 0.09, 0.1 and 0.1 microg/mL for the first, second, third, fourth and fifth dose, respectively. Statistically significant increases (P < 0.05) were found for last dose MRT and fourth and fifth trough gentamicin serum concentrations. Laboratory tests detected a slight increase in serum creatinine and urea nitrogen concentrations (one dog), decreased specific urine gravity (one dog) and presence of few granular casts (two dogs). It is concluded that once-daily administration of gentamicin may provide adequate serum levels to treat most susceptible gram-negative infections with little or no nephrotoxicity in dogs.     

Effects of experimentally induced Streptococcus suis infection on the pharmacokinetics of penicillin G in pigs

The pharmacokinetics of potassium penicillin G were studied in both healthy (n = 8) and experimentally Streptococcus-suis-infected (n = 6) pigs following intramuscular administration (15,000 iu/kg). Streptococcus-suis infection was induced artificially in young cross-bred pigs by subcutaneous inoculation with 9 x 10(8) to 10(9) colony-forming units of S. suis. The rectal temperature of infected pigs was significantly increased (P less than 0.01) before penicillin G injection and this was maintained for 8 h after the drug was given. Other clinical symptoms were also present. The serum concentration-time data for penicillin were found to fit a one-compartment open model with first-order absorption in the two groups of pigs. Significant changes were not observed between healthy and diseased pigs in following parameters: A, Ka, Ke and Tmax. However, in diseased pigs, significant increases (P less than 0.01) were found in Vd and ClB, and significant decreases (P less than 0.01) in Cmax and AUC occurred. The increased body clearance (ClB) and greater apparent volume of distribution (Vd) of penicillin G could partly explain why the serum values of the drug were much lower in diseased pigs than in healthy pigs.