Ocular penetration of intravenously administered enrofloxacin in the horse.

REASON FOR PERFORMING STUDY: Information on antibiotic concentrations in the equine eye following systemic therapy is limited. Reports that Leptospira spp. are frequently present in the eyes of horses with recurrent uveitis, emphasises a need for studies on ocular concentrations of specific antibiotics. HYPOTHESES: 1) Enrofloxacin, administered i.v. at 7.5 mg/kg bwt q. 24 h, results in aqueous humour concentrations greater than the reported minimum inhibitory concentration (MIC) for Leptospira pomona. 2) Aqueous humour paracentesis sufficiently disrupts the blood-aqueous humour barrier (BAB) to cause an increase in aqueous humour protein and enrofloxacin concentrations. METHODS: Aqueous humour enrofloxacin and total protein concentrations were determined in 6 healthy, mature horses after i.v. administration of enrofloxacin. Paracentesis was performed on the left eye on Days 3 and 4, 1 h following enrofloxacin administration, to determine enrofloxacin concentrations in healthy eyes and in eyes with mechanical disruption of the BAB. Paracentesis was also performed on the right eye 23 h after enrofloxacin administration. Blood samples were collected from the horses at identical times to determine enrofloxacin aqueous humour:plasma ratios. RESULTS: Mean +/- s.d. enrofloxacin concentration in the aqueous humour 1 h post administration on Day 3 was 0.32 +/- 0.10 mg/l (range 0.18-0.47); and aqueous humour enrofloxacin, total protein and aqueous humour:plasma enrofloxacin ratios were higher on Day 4 than Day 3. CONCLUSIONS AND POTENTIAL RELEVANCE: Following disruption of the BAB, enrofloxacin concentrations were above the reported MIC for Leptospira pomona.

CYP1A1 and CYP1B1, two hydrocarbon-inducible cytochromes P450, are constitutively expressed in neonate and adult goat liver, lung and kidney.

The ontogeny of cytochrome P-450 isozymes (P450) in goat liver, lung and kidney was studied using anion exchange HPLC separation of solublized microsomal proteins and Western immunoblotting. Comparison of the overall HPLC profile of goat P450 isozymes between liver, lung and kidney showed that while the P450's of goat liver were equally separated into five peaks of isozyme(s), only two peaks constitute the majority of P450 isozyme(s) in lung and kidney, thus demonstrating the tissue specific differences in P450 isozyme distribution in goats. Immunoblotting analysis using polyclonal antibodies against rat CYP1B1, and mouse CYP1B1, polyaromatic hydrocarbon-regulated P450's, revealed that goat orthologs of CYP1A1 and CYP1B1 are expressed constitutively in goats. The CYP1A1 was expressed in goat liver and lung as early as 1st day of age, and the levels of its expression in adult lung and liver were, respectively, 1.3 and 5.5 pmol per mg microsomal proteins. CYP1B1 was expressed in goat livers in substantial levels as of 1 week of age and increased thereafter to reach approximately 4.5 pmol per mg microsomal proteins in adult livers, while low level was detectable only in adult but not neonate lung tissues. Furthermore, polyclonal antibodies against rat CYP1A2 detected very high levels of CYP1A2 in livers of adult and 6 week old goats. The Ah receptor which controls the expression of CYP1A1/1A2 and CYP1B1, was detected in cytosolic fractions from these tissues as a 104 kDa and a minor level of the 106 kDa form. These are potentially very important findings in light of the role of CYP1A1/1A2 and CYP1B1 in activation of polyaromatic hydrocarbons, heterocyclic amines and nitroaromatic hydrocarbons to genotoxic metabolites, and the health consequences of these metabolites on humans, as consumers of goat milk and meat. Using polyclonal antibodies against rat hepatic CYP2B1 and CYP3A1, the goat CYP2B and CYP3A forms were not detectable in livers of goats at any age, but lungs of adult and 6 week old goats expressed these two CYPs in levels equivalent to the livers of phenobarbital-induced rats. On the other hand, anti-rat CYP2C6 antibodies specifically detected two goat ortholog forms which were expressed in all three tissues and exhibited age-dependent changes. In conclusion, results from both immunoblot and HPLC analyses confirmed that, as in other species, the expression of P450 isozymes in goat is under both developmental- and tissue-specific regulatory factors.

Pharmacokinetic variables of mivacurium chloride after intravenous administration in dogs.

OBJECTIVE: To determine pharmacokinetic variables of mivacurium chloride after IV administration in dogs. ANIMALS: 5 healthy Labrador Retrievers. PROCEDURE: Anesthesia was induced with thiopental and maintained with halothane in oxygen. Dogs were ventilated mechanically to an end-tidal P(CO)2 value between 35 and 40 mm Hg. Heart rate, direct blood pressure, and arterial pH were recorded throughout the experiment. Core temperature, end-tidal P(CO)2, and halothane concentration were kept constant throughout the experiment. Paired blood samples for determination of plasma cholinesterase activity were collected prior to administration of a bolus of mivacurium (0.05 mg/kg of body weight), which was administered IV during a 2-second period. Arterial blood samples were obtained for determination of plasma mivacurium concentration 0, 1, 3, 5, 10, 30, 60, 120, 150, and 180 minutes after administration of mivacurium. Blood was collected into tubes containing EDTA and 0.25% echothiophate. Mivacurium concentration was determined, using reversed-phase high-performance liquid chromatography. RESULTS: For the trans-trans isomer, mean +/- SEM volume of distribution was 0.18+/-0.024 L/kg, median half-life was 34.9 minutes (range, 26.7 to 53.5 minutes), and clearance was 12+/-2 ml/min/kg. For the cis-trans isomer, values were 0.31+/-0.05 L/kg, 43.4 minutes (range, 31.5 to 69.3 minutes), and 15+/-2 ml/min/kg, respectively. Values for the cis-cis isomer were not calculated, because it was not detectable in plasma 60 minutes after mivacurium administration in all 5 dogs. CONCLUSIONS AND CLINICAL RELEVANCE: The transtrans and cis-trans isomers of mivacurium have a long half-life and slow clearance in healthy dogs anesthetized with halothane.

Therapeutic serum drug concentrations in epileptic dogs treated with potassium bromide alone or in combination with other anticonvulsants: 122 cases (1992-1996).

OBJECTIVE: To determine therapeutic serum drug concentrations in epileptic dogs treated with potassium bromide. DESIGN: Retrospective study. ANIMALS: 122 dogs with major motor epilepsy. PROCEDURE: Medical histories were collected for epileptic dogs treated with potassium bromide with or without phenobarbital sodium or primidone, from which serum was submitted for bromide analysis from May 1992 to May 1996 to the Therapeutic Drug Monitoring Program at Cornell University's College of Veterinary Medicine. A therapeutic response (improved seizure control) was defined as a > or = 50% reduction in seizure frequency following initiation of bromide treatment. Serum bromide and phenobarbital concentrations and therapeutic outcome were determined for all dogs. RESULTS: 72% of epileptic dogs had a > or = 50% reduction in seizure frequency following initiation of treatment with potassium bromide. Discontinuation of barbiturate treatment was possible in 19% of those dogs originally treated with phenobarbital or primidone. Of those dogs continued on bromide and phenobarbital, 45% maintained seizure control with serum phenobarbital concentrations < 20 micrograms/ml. Significantly higher serum bromide concentrations were required when dogs were initially or eventually treated with bromide alone (mean bromide concentration, 1,906 micrograms/ml) compared with dogs treated with potassium bromide along with a barbiturate (mean bromide concentration, 1,621 micrograms/ml). CLINICAL IMPLICATIONS: When dogs are treated with bromide and phenobarbital, a reasonable therapeutic range for serum bromide concentrations is 810 to 2,400 micrograms/ml, and for bromide treatment alone, the range is 880 to 3,000 micrograms/ml. When phenobarbital is used in combination with bromide, a reasonable therapeutic range for serum phenobarbital concentrations is 9 to 36 micrograms/ml, although in some dogs treated with bromide, phenobarbital can eventually be discontinued.

Corneal concentrations and preliminary toxicological evaluation of an itraconazole/dimethyl sulphoxide ophthalmic ointment.

The objectives of this study were to determine the concentration of itraconazole achieved in corneal tissue and aqueous humour after topical application of a 1% itraconazole ointment: to determine the effect of including dimethyl sulphoxide (DMSO) in the ointment on achievable ocular tissue itraconazole concentrations; and to assess if any gross or histopathologic ocular toxicity results from the topical application of 1% itraconazole with or without the addition of DMSO. The experimental trial consisted of 6 horses considered to have normal eyes. Each horse had one eye treated with 0.3 mL of 1% ultra-micronized itraconazole ointment and the fellow eye with 0.3 mL of 1% itraconazole/ 30% DMSO ointment. The ointment was applied every 6 h for a total of 28 treatments. Both ointments were well tolerated and no gross or histopathologic abnormalities developed during the trial. Corneal tissue and aqueous humour concentrations of itraconazole were determined using high performance liquid chromatography. Corneal tissue concentration averaged 1.1 (+/- 0.4) micrograms/g in horses treated with the 1% ultramicronized itraconazole ointment and 7.9 (+/- 3.3) micrograms/g for those treated with the 1% itraconazole/30% DMSO ointment: there was a statistically significant difference between ointments (P = 0.005) No itraconazole could be detected in the aqueous humour in either treatment group.

Measurements of blood flow and xanthine oxidase activity during postischemic reperfusion of the large colon of ponies.

To assess right colic artery blood flow and relevance of xanthine dehydrogenase/xanthine oxidase after experimentally induced strangulation obstruction and reperfusion of the colon, 5 ponies were subjected to 2.5 hours of complete ischemia of the left dorsal and ventral colons, allowed to recover from surgery, and monitored during a 48-hour reperfusion period. Five ponies were subjected to sham surgery and served as controls. All ponies had a Doppler ultrasound blood flow monitor implanted on the right colic artery near the pelvic flexure 10 to 14 days prior to the ischemic period. Colic artery blood flow was monitored prior to, during, and for 4 hours after surgery. Blood samples from the right colic artery and vein distal to the obstruction site were collected during surgery (prior to ischemia, after 1 and 2 hours of ischemia, and after 10 and 60 minutes of reperfusion) for determination of arterial and venous blood gas tensions and electrolytes. Prior to surgery, blood selenium and plasma vitamin E (alpha-tocopherol) concentrations and blood glutathione peroxidase (GPX) activity were determined to assess the status of endogenous antioxidants. Combined xanthine dehydrogenase (XDH) plus xanthine oxidase (XO) activity, and XO activity alone (nanomoles per minute per gram of tissue) were determined, using a dual-spectrophotometric technique. Xanthine dehydrogenase and oxidase activities were determined prior to ischemia, after 1 and 2 hours of ischemia, and at 1 and 48 hours after reperfusion. Median blood flow in the experimental and control groups (156 ml/min and 110 ml/min, respectively) was not statistically different before surgery, and was significantly (P < 0.02) lower in the experimental (4 ml/min) vs the control group (72.5 ml/min) during the ischemic period. Experimental ponies had significantly (P < 0.03) lower right colic artery blood flow during the 4 hours immediately after recovery from anesthesia. Significant difference was not observed in right colonic venous bicarbonate concentration between groups at any time. Median right colonic venous PCO2, pH, and standard base excess were different (P < 0.001) between groups during the ischemic period only. Median venous oxygen saturation and median venous PO2 were significantly (P < 0.001) lower in the experimental ponies at the end of 2 hours of ischemia, but were significantly (P < 0.05) increased during the reperfusion phase. Median venous potassium concentration was significantly (P < 0.01) higher in experimental ponies during the ischemic and reperfusion phases. Vitamin E and GPX values were within normal limits for all ponies.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of age on phenylbutazone pharmacokinetics, metabolism and plasma protein binding in goats.

Phenylbutazone (PBZ) was administered intravenously as a single dose (10 mg/kg) to adult male and 1-day-, 10-day-, 4-week- and 6 week-old male goats. The plasma concentration of PBZ and its major metabolites oxyphenbutazone (OPBZ) and gamma-hydroxyphenbutazone (gamma-OHPBZ) was measured over time. The elimination half-life (t 1/2 beta) of PBZ decreased from 120 h in the 1-day-old to 16 h in the adult goats. Although the volume of distribution (Vd) did not change significantly during maturation, the total body clearance (Cl B) increased from 2 ml.h-1.kg-1 in 1-day-old to 13 ml.h-1.kg-1 in the adult goats; the increase was 2-fold in the first 10 days of life. Oxyphenbutazone was detectable in the plasma of adult and 6-week-old goats as early as 15 min after PBZ administration. Its peak concentration occurred at 1.5 h (1.6 micrograms/ml) in adults and at 6 h (0.95 micrograms/ml) and 12 h (0.36 micrograms/ml) in 6- and 4-week-old goats respectively. The highest plasma concentration of gamma-OHPBZ was achieved in 4-week-old followed by 6-week-old and adult animals.

The postnatal development of drug-metabolizing enzymes in hepatic, pulmonary and renal tissues of the goat.

It is important to study the development of drug biotransformation enzymes, because from a pharmacological and therapeutic point of view these enzymes are responsible for eliminating most drugs. Their concentration at each age is critical when deciding the dose regimen, particularly in the neonates who are deficient or have very low levels of these enzymes. From a toxicological perspective, the role of these enzymes varies, with some of them being directly responsible for activation of certain chemicals to reactive intermediates with deleterious consequences to the animal. The time course of appearance of these enzymes throughout the life of the animal could be depicted from the study of their ontogeny and therefore the prediction of when the animal would be at risk should be possible. Experiments were designed to measure in vitro, the activity of drug-metabolizing enzymes in liver, lung and kidney of newborn, 1-week-, 4-week and 6-week-old and adult goats. The microsomal monoxygenase activities were measured utilizing substrates designed to characterize the development of the cytochrome P450 (P450). For phase II enzymes, the activity of UDP-glucuronyltransferase towards 1-naphthol and p-nitrophenol was measured in addition to the cytosolic glutathione S-transferase activity towards, 1,2-dichloro 3-nitrobenzene. The results indicated that the newborn goat tissues exhibited very low activity of drug-metabolizing capacity in all pathways studied. These activities increased to the adult values by 6 weeks of age. In general, the development of the mono-oxygenase activities followed the same pattern as the overall P450. The UDP-glucuronyltransferase activity towards both substrates was deficient at birth and surged to above adult values by the first week of age. The toxicologic and pharmacologic implication of the development of these enzyme activities are discussed.

Studies on the ontogeny of goat hepatic cytochrome P-450-associated O-dealkylase activities using monoclonal antibodies: comparison to adult lung activity.

The P-450-associated O-dealkylase activity towards ethoxyresorufin (EROD) and pentoxyresorufin (PROD) was measured in liver microsomes from 1-day-, 1-week-, 4-week-, 6-week-old and adult goats in order to characterize the ontogeny of cytochrome P-450 in this species. The inhibition of these enzyme activities by monoclonal antibodies raised against 3-methyl-cholanthrene-induced (MAb 1-7-1) and phenobarbital-induced (MAb 2-66-3) rat hepatic cytochrome P-450 was used to measure the contribution of the MAb-defined, epitope-specific P-450 to the total activities during these ages of goat development. EROD activity was undetectable until the 1st week of life and increased more than 25-fold by 4 weeks of age. The inhibition of EROD by MAb 1-7-1 increased from 20% in 1-week-old to 70% in adult goats. PROD activity, however, was detectable in the 1-day-old and reached adult levels by 6 weeks of age. The maximal inhibition (40%) of PROD activity by MAb 2-66-3 was demonstrated in 1-day-old goats. The measurement of these enzyme activities and their inhibition by the monoclonal antibodies demonstrated major differences in the ontogeny of these P-450 isozymes in goats. On the other hand, adult goat lung lacked detectable PROD activity, while it expressed approximately one tenth of the EROD activity exhibited by the liver. Over 70% of this activity was inhibitable by MAb 1-7-1.

Analysis and pharmacokinetics of cimaterol in growing Holstein steers.

Pharmacokinetic parameters for the beta 2-adrenergic agonist, cimaterol (CIM), were determined in growing Holstein steers. Compartmental analysis was used after measurement of CIM in body fluids by affinity chromatography and HPLC using UV detection. Recoveries from spiked plasma and urine standards were 70 +/- 1.2% and 68 +/- 1.1%, respectively. The minimum detection level in plasma was 1 ng/mL and the average CV was 5.1% for concentrations that ranged from 1 to 30 ng/mL. Four steers (276 +/- 24 kg) received 15 mg of CIM by bolus intravenous injection. Plasma CIM levels declined in a biphasic manner with half-lives of 2.5 min for the distribution phase and 54 min for the elimination phase. A two-compartment open model was used to describe the disappearance of CIM and the following pharmacokinetic parameters were obtained: central compartment volume (Vc) = .76 L/kg, apparent volume of distribution (Vd) = 4.1 L/kg, and transfer rate constants from the central to peripheral compartment (k12) = .177/min, from the peripheral to central compartment (k21) = .054/min and elimination from the central compartment (kel) = .074/min. After 8 h, total urinary CIM accounted for only 18.3% of the administered dose. Results suggest that circulating concentrations of CIM in growing steers are influenced by its accumulation in an unidentified peripheral pool and its conversion into unknown metabolite(s) before elimination.

Factors that affect drug disposition in food-producing animals during maturation.

Drugs administered to neonatal food-producing animals (cattle, sheep, goats, swine) may exhibit significantly different pharmacokinetic/disposition characteristics than they do in adult animals of the same species. Undesirable consequences such as suboptimum therapeutic concentrations, toxic effects, and violative tissue residues may result if adult dosage regimens are employed in young animals. Using selected drugs as examples, this paper reviews factors that contribute to differences in drug disposition in newborn vs adult animals. Immaturity of mechanisms involved in drug absorption, especially from gastrointestinal and parenteral sites of administration, and of drug distribution to sites such as plasma proteins, adipose tissue, and fluid compartments are considered. The role of developmental changes in drug biotransformation in the liver and other tissues and the maturation of excretory mechanisms, primarily from the kidney, in the increased rate of drug clearance during maturation is described. Pharmacokinetic studies with specific drugs in the target species are an important approach to establishing rational drug use in immature food-producing animals.

Effects of fluoroquinolone antimicrobials alone and in conjunction with theophylline on seizures in amygdaloid kindled rats. Mechanistic and pharmacokinetic study.

The influence of three fluoroquinolone (FQ) antimicrobial drugs (ciprofloxacin (CP), norfloxacin (NF), enrofloxacin (EF)) on seizure parameters in amygdaloid kindled rats was investigated. CP and NF (100 mg/kg i.p.) did not modify seizure parameters while EF induced a decrease in seizure activity. Since clinical data indicate a seizure enhancing interaction between FQ and theophylline (THEO) we studied the influence of concurrent FQ-THEO administration in kindled rats. CP and NF, but not EF given concurrently with a non-seizure modulating dose of THEO (10 mg/kg i.p.) caused increases in seizure activity and aggressiveness in the animals. The CP-THEO induced seizure enhancement was antagonized by 2-chloroadenosine and diazepam. Pharmacokinetic studies demonstrated that THEO serum levels and elimination were not altered by concurrent CP administration. We conclude that coadministration of FQ-THEO can aggravate amygdala kindled seizures and that this aggravation may involve centrally mediated mechanisms.

Pharmacologic considerations in the management of peripartum conditions in the cow.

As is true with the use of drugs in veterinary medicine in general, there are many controversial issues in the management of peripartum conditions in the cow. For example, the use of PG versus antibacterial drugs in the management of postpartum uterine infections has advocates for the use of either approach. Intrauterine versus systemic administration of antibacterial drugs for the prophylaxis or treatment of postpartum metritis is another area of debate. Clearly, more research is needed in this area. Equally clearly, however, the research results that are available are being disregarded on a daily basis. In considering this discussion of the use of drugs in the peripartum period, one is struck by the frequency that optimum drug therapy of a condition relies on the extralabel use of nonapproved preparations. What guidelines are available to the practitioner in this regard? One example is lack of availability of appropriate dosage regimens or withdrawal times for food derived from treated animals. Unfortunately, pharmacokinetic and residue studies that would aid in establishing guidelines generally are not available and, in most instances, are not forthcoming. Extrapolation of data from other species to the ruminant or extrapolation of information from one drug to a related compound (such as prediction of residue and withdrawal data from an approved aminoglycoside, dihydrostreptomycin, to another unapproved drug, gentamicin) is fraught with difficulties. The need for research in this area is obvious, and lack of such information is one of the major dilemmas in trying to establish rational drug therapy in the food-producing animal. Recent developments in drug therapy have led to innovative approaches for the management of peripartum and other diseases in cattle. The use of PG in the treatment of reproductive disorders, so commonplace and widely accepted in contemporary veterinary practice, is a relatively recent approach that continues to be refined with the development of new, more potent, more specific PG analogs. What will be the role of ceftiofur, a potent, third-generation cephalosporin that currently is approved only for the treatment of respiratory infections in cattle, in the management of reproductive tract infections? The fluoroquinolones, which represent a novel approach to the control of infectious diseases, are being increasingly used in veterinary and human medicine, and one may predict that these powerful antimicrobial drugs will find application in bovine practice, including for the treatment of peripartum infections. Pharmacologic manipulation of immune and defense mechanisms also is an approach with some promise.(ABSTRACT TRUNCATED AT 400 WORDS)

The fluoroquinolone antimicrobials: structure, antimicrobial activity, pharmacokinetics, clinical use in domestic animals and toxicity.

Fluoroquinolones form a promising family of new bactericidal antimicrobials. Enrofloxacin (Baytril) is the first antibacterial of this family to be available to veterinary medicine. They share a wide spectrum of antimicrobial activity, a large volume of distribution and are active at very low concentrations. Their target site for bactericidal action is the type II topoisomerase (E.C. 5.99.1.3.). The gastrointestinal absorption in mammals is rapid and substantial, the duration of action is long and the excretion mainly through the kidney. Their adverse effects are not severe when compared to the beneficial features fluoroquinolones exhibit. The target tissues for adverse effects are: the juvenile cartilage, central nervous system, urinary tract and digestive tract. In the USA, approved use is thus far limited to dogs; approval for use in food-animals is currently being sought for several fluoroquinolones. Published clinical trials as well as unpublished data from the author's laboratories are reviewed for dogs, cats, pigs, cattle and poultry.

Effect of experimental synovitis on disposition of penicillin and oxytetracycline in neonatal calves.

The effect of experimental synovitis on the distribution of antibacterial drugs into the joint space was studied in 7-day-old calves. Intrasynovial sodium urate was used to induce inflammation in the tibio-tarsal joint of calves and oxytetracycline (OTC) (11 mg/kg) or sodium penicillin G (PEN) (13.2 mg/kg) was administered intravenously 3 hours after synovitis was induced. Oxytetracycline and PEN concentrations were measured in serum and synovial fluid and pharmacokinetic parameters were calculated. The data indicate that synovitis neither enhanced nor impaired the levels of antibiotics achieved in the joint fluid. Mean peak concentrations (micrograms/ml) of the drugs in control and inflamed joints were, respectively, 8.04 and 8.79 for OTC and 9.35 and 8.92 for PEN. Rates of elimination of OTC and PEN were similar in joint fluid and serum; t1/2 beta ranged from 11.83-19.81 h for OTC and 0.980-1.125 h for PEN. The distribution and elimination of OTC and PEN from serum was described by a two-compartment model whereas elimination from joint fluid was described using a single-exponential model.

Pharmacokinetics of sulfadiazine/trimethoprim in neonatal male calves: effect of age and penetration into cerebrospinal fluid.

Sulfadiazine (SDZ)/trimethoprim (TMP; 30 mg of SDZ/TMP/kg of body weight) was given IV to the same 6 male calves at 1, 7, and 42 days of age and to 2 additional calves at 7 days of age. Serum concentrations of SDZ and TMP were best represented by a 2-compartment open model, but in 42-day-old calves, CSF concentrations of both drugs were best represented by a 1-compartment open model with first-order input. Between 1 and 42 days of age, the elimination half-life (t1/2(beta)) of SDZ decreased from 5.7 to 3.6 hours, and total body clearance (CLtot) increased from 1.43 to 1.88 ml/min/kg; the area under the curve (AUC0----infinity) decreased from 291.5 to 225.4 mg/L.h. The distribution coefficient (Vd(area)/kg of body weight) decreased with age, changing from 0.72 to 0.59 L/kg, between 1 and 42 days of age. Therapeutic concentrations of SDZ in serum (greater than 2 micrograms/ml) were maintained for 24 hours in 1-day-old calves and for about 15 hours in 7- and 42-day-old calves. The elimination rate of TMP increased about 9-fold; t1/2(beta) was 8.4, 2.1, and 0.9 hours, respectively, at 1, 7, and 42 days of age. Other values also reflected an increase in TMP elimination rate with age: CLtot increased from 2.8 to 12 to 28.9 ml/min/kg, k13 increased from 0.336 to 0.654 to 1.664/h and AUC0----infinity decreased from 32.8 to 7.9 to 3.1 mg/L.h, respectively. Therapeutic concentrations (greater than 0.1 microgram/ml) were maintained for 15 hours, 8 hours, and about 6 hours in 1-, 7-, and 42-day-old calves, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological studies with a GABA uptake inhibitor in rats with kindled seizures in the amygdala.

The anticonvulsant effects of the inhibitor of the uptake of GABA, SKF 89976-A (N-[4,4-diphenyl-3-butenyl]-nipecotic acid), were investigated using the amygdala kindling seizure model in rats. The time course of activity of the racemic mixture, given orally, and the relative potencies of its d- and l-isomers, when given intraperitoneally, were tested. The drug SKF 89976-A was active, when given orally with anticonvulsant effects lasting 2-4 hr when given at 15 mg/kg, and 4-6 hr when given at 30 mg/kg. Peak inhibition of severity of seizures occurred at 1 hr after administration with an ED50 of 17.8 mg/kg. The d-isomer of SKF 89976-A was significantly more potent than the l-isomer and inhibited various parameters of kindled seizure activity in a dose-dependent manner. The l-isomer had significant effects on kindled seizures only at the largest dose (20 mg/kg). The ED50 of the d-isomer for inhibition of severity of seizures measured 0.5 hr after intraperitoneal injection, was 11.2 mg/kg and the antiseizure effects of the d-isomer lasted for 2-3 hr. Side effects of SKF 89976-A, such as sedation, abdominal muscle relaxation, rear limb splaying and ataxia, were seen at 30 mg/kg; there was a marked suppression of seizure activity with no side effects at smaller doses. The characterization of a biphasic kindled seizure allows for speculation regarding the role of GABAergic mechanisms in its pathogenesis and of the mechanism of action of SKF 89976-A.

An efficient method for time course studies of antiepileptic drugs using the kindled rat seizure model.

A new method of testing the time course of anticonvulsant drugs in the kindled rat seizure model was investigated. To determine whether there are inhibitory effects of a kindled seizure on subsequent seizures, groups of 10 rats were made to convulse three times consecutively with interstimulation intervals of 0.5, 1, and 1.5 hr. Only with an interstimulus interval of 0.5 hr was there evidence of potential inhibitory effects lasting long enough to affect subsequent seizures. The time course of the anticonvulsant activity of diazepam was determined using two protocols: one in which groups of kindled rats were stimulated once and a second protocol in which animals were stimulated two times (at least 1.5 hr apart) following diazepam administration. The time courses of diazepam's inhibitory effect on kindled seizures obtained with each protocol were not significantly different. The data indicate that multiple stimulation episodes can be utilized in kindled rats to determine the time course following single administration of antiepileptic drugs.

The effect of age and diet on sulfadiazine/trimethoprim disposition following oral and subcutaneous administration to calves.

Thirty milligrams per kilogram of sulfadiazine/trimethoprim (SDZ/TMP, Tribrissen) was given orally and subcutaneously (s.c.) to two groups of male, Holstein calves. One group was fed milk-replacer throughout the 13-week period of the study while the second group was weaned onto a chopped grain-fiber mixture when 5 weeks old. Serum and urine were assayed for concentrations of unchanged drug. Trimethoprim bioavailability, following oral administration at 1, 6 and 12 weeks of age, is higher in milk-fed calves (non-ruminants) than in grain-fiber-fed calves (ruminants); bioavailability decreases with increasing age in both groups of calves. Serum concentrations above 0.1 micrograms/ml (the level of sensitivity of the assay) could not be obtained in ruminating calves. The rate of SDZ absorption following oral administration, as determined by the Wagner-Nelson method, was very slow in all the calves in this study with average half-life values ranging from 8.2-12.67 h; absorption was slightly faster in ruminating calves. Absorption of SDZ is rate-limiting and determines the biological half-life of the drug; SDZ serum concentrations above 2 micrograms/ml were maintained in all calves for at least 24 h. Following s.c. administration of Tribrissen to 7-and 13-week-old calves, urinary excretion patterns indicated that TMP was slowly released from the injection site; serum concentrations were below 0.1 micrograms/ml. In contrast, absorption of SDZ was very rapid; values for tmax were 1.5-1.8 h. The pharmacokinetic parameters for SDZ were calculated according to a one-compartment open model; neither diet nor age had a significant effect on SDZ disposition following s.c. injection. Subcutaneous administration of 30 mg/kg Tribrissen, b.i.d., may be the best therapeutic regimen; even though measureable concentrations of TMP cannot be achieved in the serum following a single s.c. dose, TMP concentrations should accumulate and, because of its sustained release, provide almost continual potentiation of SDZ.

The development of hepatic drug-metabolizing enzyme activity in the neonatal calf and its effect on drug disposition.

Mixed function oxidase and UDP-glucuronyltransferase activity was measured in liver microsomal preparations from 1-, 7-, and 42-day-old, male, Holstein calves. Liver samples were obtained by a surgical biopsy procedure that allowed for multiple samples to be taken from a single individual. Microsomal protein content doubled between 7 and 42 days of age and reached adult levels during this time. Cytochrome P-450 content increased 2-fold during the first week and remained constant thereafter. NADPH-cytochrome c reductase activity doubled during the first week, but then returned to its initial level by 42 days of age. UDP-glucuronyltransferase activity was well developed at 1 day of age and reached adult levels by 7 days of age. Mixed function oxidase activity was less well developed; activities at 1 day of age were only 17-50% of those at 42 days of age for O-deethylation, O- and N-demethylation, and aryl hydrocarbon hydroxylation. Development of hepatic drug-metabolizing activity was discussed in relation to the age-related increase in the rate of elimination of the antibacterial compound trimethoprim.