Mammary and renal excretion of sulphadoxine and trimethoprim in cows

DAVITIYANANDA, DANIS and FOLKE RASMUSSEN: Mammary and renal excretion of sulphadoxine and trimethoprim in cows. Acta vet. scand. 1974, 15, 340–355. — In 21 experiments on 5 healthy, nonpregnant cows are sulphadoxine and trimethoprim infused intravenously for maintenance of constant levels of the drugs through the experimental periods. The experiments show that both sulphadoxine and trimethoprim are bound to the proteins in blood plasma and milk. Further it is demonstrated that sulphadoxine (an acid) is excreted into milk in concentrations lower than in blood plasma while trimethoprim (a base) is excreted into milk in concentrations higher than in blood plasma. Both results are consistent with the theory that drugs are excreted through the mammary gland by passive diffusion.Glomerular filtration and back-diffusion are both involved in the renal handling of sulphadoxine and trimethoprim. For trimethoprim active tubular secretion is also demonstrated. Both the mammary and renal handling of sulphadoxine as well as trimethoprim are influenced by the pH of milk and urine, respectively. The experiments underline that it is the unionized, non-protein-bound fraction of the drugs which diffuses through biological membranes.sulphadoxine; trimethoprim; mammary excretion; renal excretion; cow.     

Concentrations of trimethoprim and sulphadoxine in tissues from goats and a cow.

The concentration of trimethoprim and sulphadoxine in plasma and tissue from goats and a cow have been determined after a single intravenous injection. Furthermore, the concentration of the two drugs and their metabolites in plasma and tissues have been determined after continuous intravenous infusion for 2½–3 hrs. Trimethoprim was present in all tissues but brain at higher concentrations than in plasma while the concentration of sulphadoxine in the different tissues were lower than in plasma. The highest concentration of the 2 drugs and their metabolites was found in the kidney. The distribution pattern of trimethoprim and sulphadoxine was similar in cow and goats.     

Pharmacokinetics of sulphadoxine and trimethoprim in horses. Half-life and volume of distribution of sulphadoxine and trimethoprim and cumulative excretion of [14C]-trimethoprim

A proprietary combination product containing sulphadoxine and trimethoprim was administered to horses by intravenous injection. Protein-binding of sulphadoxine was dependent on the concentration in plasma and decreased from 72% at 50 μg/ml to 14% at 450 μg/ml. Sulphadoxine is eliminated from plasma in accordance with a three compartment open model. The elimination half-life was on average 14 h while the volume of distribution was found to be 0.39 1/kg. Trimethoprim was eliminated from plasma in accordance with a two compartment open model. The elimination half-life was on an average 3 h. Experiments in which trimethoprim was administered alone showed that the elimination half-life was not dependent on the simultaneous administration of sulphadoxine. About 50% of trimethoprim was bound to plasma proteins, but in contrast to sulphadoxine there was no dependence between plasma concentration and protein binding. The protein binding of trimethoprim was independent of the presence of sulphadoxine and vice versa. Experiments with ¹⁴C-labelled trimethoprim showed that it was excreted in almost equal amounts in urine and faeces. 97% of the administered dose was recovered in urine and faeces during the course of the first 4 days after administration.     

Pharmacokinetics of sulphadoxine and trimethoprim and tissue irritation caused by two sulphadoxine-trimethoprim containing products after subcutaneous administration in pre-ruminant calves

The pharmacokinetics of sulphadoxine-trimethoprim was studied in 6 pre-ruminant calves using two different products. Product A, which contained 200 mg sulphadoxine and 40 mg trimethoprim per mL, was administered intravenously or subcutaneously at a dosage of 25 mg sulphadoxine and 5 mg trimethoprim.kg-1 bodyweight. Product B, containing 62.5 mg sulphadoxine and 12.5 mg trimethoprim per mL plus lidocaine (1 mg.mL-1), was given subcutaneously at the same dosage. After intravenous administration of product A the mean time of half-life of elimination phase (t1/2) for sulphadoxine was 12.9 h, steady-state volume of distribution (Vd(ss)) was 0.44 L.kg-1 and clearance was 0.024 L.kg-1.h-1. Respective values for trimethoprim were 1.9 h, 2.0 L.kg-1 and 0.9 L.kg-1.h-1. After subcutaneous administration, the bioavailability of sulphadoxine was 96% and 98% and the time to reach a maximum concentration was 6.3 and 8.0 h for products A and B, respectively. The Cmax for trimethoprim was higher for product A (0.49 microgram.mL-1) than for product B (0.32 microgram.mL-1) (p = 0.014). Slow absorption from the injection site appeared to delay the elimination of trimethoprim after subcutaneous administration when compared to that after intravenous administration: apparent elimination t1/2 for trimethoprim after intravenous administration of product A was 1.9 h compared to 3.9 h and 3.6 h after subcutaneous administration of products A and B, respectively. The difference between intravenous and subcutaneous administrations was statistically significant (p < 0.05). Also the mean residence time was significantly shorter (p < 0.05) after intravenous administration (2.4 h) than that after subcutaneous administration of product A (6.9 h) and B (7.1 h). The bioavailability of trimethoprim was lower than that of sulphadoxine: 76% and 74% for products A and B, respectively. All 6 calves showed pain after subcutaneous administration of product A and the injection sites were warm and showed soft oedematous reactions 5-8 cm in diameter. Three of the calves also showed some pain after subcutaneous administration of product B; the local reactions were less severe. A marked increase was seen in creatine kinase activity after subcutaneous administration of both products. Product A caused a more pronounced increase but the difference was not statistically significant. We suggest 30 mg.kg-1 at 24-h intervals or alternatively 15 mg.kg-1 at 12-h intervals as the minimum dosage of sulphadoxine-trimethoprim combination for pre-ruminant calves. Extravascular routes of administration should be avoided due to marked tissue irritation at the injection site.     

Antibacterial drugs used against mastitis in cattle by the systemic route

The veterinarian in clinical practice is often confronted with cases of mastitis that require systemic antibacterial treatment in addition to local treatment. This paper reviews the suitability of drugs available in New Zealand, taking into account their anti-staphylococcal activity, routes of administration, and their ability to attain and maintain therapeutic levels in the udder following systemic administration. The drugs considered include the more common penicillins, aminoglycosides and macrolides; oxytetracyline, chloramphenicol, trimethoprim, and several sulphonamides.

The success of systemic therapy against mastitis depends to a large extent on the concentration of antibacterial drug achieved at foci of infection. Passage of drugs across the blood-milk barrier takes place by passive diffusion, and the factors influencing this diffusion are discussed.

Whe mastitis is associated with sensitive organisms, penicillin is recommended, although, as with all other antibacterials discussed, the dose used must be higher than normal. For penicillin, doses of the order of 16,500 iu/kg are recommended.

The intramuscular injection of oxytetracycline will not produce therapeutic levels in milk but, after intravenous injection of high doses (10 mg/kg), this antibiotic is likely to maintain therapeutic levels in milk over a 24-hour period.

As a first choice for the systemic treatment of mastitis, either tylosin or erythromycin is recommended. At a dose rate of 12.5 mg/kg, either will maintain for 24 hours milk levels in excess of the average MICs for staphylococci.

Of the sulphonamides, sulphanilamide and sulphadimidine produce the highest milk levels. After intravenous administration at a dose rate of 200 mg/kg, sulphadimidine will maintain therapeutic levels in milk for 12 hours.

Although trimethoprim has a very short half-life in cattle which limits its usefulness, it readily enters the milk and a combination of trimethoprim (as a suspension) with sulphadiazine, at a dose rate of 48 mg/kg, might be expected to maintain therapeutic levels in the milk for 12 hours.

It is concluded that dihydrostreptomycin, neomycin, chloramphenicol, and the combination sulphadoxine/trimethoprim, are not suitable for the systemic treatment of bovine mastitis.     

Risk Factors for the Development of Hypokalemia in Neonatal Diarrheic Calves

Background

Neonatal diarrheic calves have a clear negative potassium balance because of intestinal losses and decreased milk intake but in the presence of acidemia, they usually show normokalemic or hyperkalemic plasma concentrations.

Objectives

To assess whether marked hypokalemia occurs in response to the correction of acidemia and dehydration and to identify factors that are associated with this condition.

Animals

Eighty‐three calves with a clinical diagnosis of neonatal diarrhea.

Methods

Prospective cohort study. Calves were treated according to a clinical protocol using an oral electrolyte solution and commercially available packages of 8.4% sodium bicarbonate, 0.9% saline and 40% dextrose infusion solutions.

Results

The proportion of hypokalemic calves after 24 hours of treatment (19.3%) was twice as great as it was on admission to the hospital. Plasma K⁺ after 24 hours of treatment was not significantly correlated to venous blood pH values at the same time but positively correlated to venous blood pH values on admission (r = 0.51, P < .001). Base excess on admission (Odds ratio [OR] = 0.81, 95% confidence interval [CI] = 0.70–0.94), duration of diarrhea (OR = 1.37, 95% CI = 1.05–1.80), milk intake during hospitalization (OR = 0.54, 95% CI = 0.37–0.79) and plasma sodium concentrations after 24 hours (OR = 1.12, 95% CI = 1.01–1.25) were identified to be independently associated (P < .05) with a hypokalemic state after 24 hours of treatment.

Conclusions and Clinical Importance

Findings of this study suggest that marked depletion of body potassium stores is evident in diarrheic calves that suffered from marked metabolic acidosis, have a low milk intake and a long history of diarrhea.     

Antimicrobial residues in milk. Comparison of different agar diffusion methods

Different agar diffusion methods were compared in order to find a sensitive method for the detection of various antimicrobial residues in milk. A total of 588 producer milk samples were analyzed using subsets of the most sensitive methods.With the IDF method, 2 positive cases (0.34 %) appeared among the producer milk samples, with the Thermocult method 13 positive cases (2.21 %) and with the Test agar pH 8 method with trimethoprim and glucose 4 positive cases (0.68 %). A combination of the IDF method and the Test agar pH 8 method resulted in 6 positive cases (1.02 %) and a combination of the Thermocult method and the Test agar pH 8 method in 17 positive cases (2.89 %). With penicillinase 41 % of the positive cases were identified as β-lactam antibiotics and with p-aminobenzoic acid 18 % of the positive cases were identified as sulphonamides. 41 % of the positive cases remained unexplained.The best combination for the detection of antimicrobial agents in milk seems to be that of the Thermocult method and the Test agar pH 8 method with trimethoprim and glucose.     

Blood and tissue concentrations of trimethoprim following its administration alone and in combination with josamycin.

Following a single oral dose of trimethoprim (10 mg/kg b. wt.) in normal fowls, the highest serum concentration achieved 4 hours post-administration with value of 0.64 microgram/ml. The absorption half-life time was 0.64 hours. The elimination half life was 4.73 hours. During repeated oral administration of 10 mg/kg b. wt., once daily for five consecutive days, trimethoprim peaked in serum, 4 h after each dose. Trimethoprim persisted in all fowl's tissues for 96 hours after stopping of drug administration. After oral administration of josamycin (18 mg/kg b. wt.) and trimethoprim (10 mg/kg b. wt.) in normal fowls, a maximum serum concentration of trimethoprim was recorded at 2 hours with half-life of absorption (t0.5(ab)) valued 0.74 hour. The elimination half-life (t0.5 beta) was 4.37 hours. During repeated oral administration of josamycin (18 mg/kg b. wt.) and trimethoprim (10 mg/kg b. wt.) once daily for five consecutive days in normal fowls, the highest plasma concentrations of trimethoprim occurred 2 hours post each dose. The daily maximum plasma concentrations during the repeated oral administration of both tested drugs were nearly constant.     

Bioavailability and Pharmacokinetics of Sulphadiazine,N<Superscript>4</Superscript>-acetylsulphadiazine and Trimethoprim following Intravenous and Intramuscular Administration of a Sulphadiazine/Trimethoprim Combination in Sheep

The combination of sulphadiazine and trimethoprim is extensively used in farm animal species; however, there are no data concerning its pharmacokinetics after intramuscular administration in sheep. Twelve rams of the Chios breed were used to study the disposition of sulphadiazine, its metabolite N⁴-acetylsulphadiazine and trimethoprim after intravenous (i.v.) and intramuscular (i.m.) administration of a sulphadiazine/trimethoprim (5:1) combination in sheep. Sulphadiazine bioavailability (±SD) was 69.00%±10.51%. The half-life of the terminal phase (4.10±0.58 h afteri. v., and 4.03±0.31 h after i.m. administration) was significantly higher than the respective value for trimethoprim (0.59±0.19 h) afteri.v. administration. The maintenance of a constant plasma concentration ratio after i.v. administration was therefore impossible. The acetylation capacity in sheep, determined by the AUC ratio between N⁴-acetylsulphadiazine and the parent compound, sulphadiazine, was very low (less than 4%). The most remarkable finding of this study was that trimethoprim was not detected in sheep plasma after i.m. injection. In conclusion, according to the findings of the present study, following i.v. administration of the sulphadiazine/trimethoprim combination, trimethoprim can be considered as the limiting factor for any possible synergistic effect, and the i.m. route cannot be recommended in sheep.     

Tilmicosin antibacterial activity and pharmacokinetics in cows

The minimal inhibitory concentration (MIC) of tilmicosin for 90% of 112 Staphylococcus aureus isolates from the bovine udder was 0.78 μg/mL and 149 of 164 (90.8%) other gram-positive udder pathogens were inhibited by tilmicosin concentrations < 3.12 μg/mL. The MIC of the drug for 19 of 22 S. aureus isolates was < 0.78 μg/mL when the test was conducted using Mueller-Hinton (MH) agar or MH agar containing 7.5% skimmed milk. Acute cardiac toxicity followed intravenous (i.v.) injection of the drug at 10 mg/kg to 3 cows, but animals appeared clinically normal within 30 min after treatment. The pharmacokinetics of i.v.-administered tilmicosin is typical for the macrolide class of antibiotics, i.e. low serum drug concentrations and a large volume of distribution (> 2.0 L/kg). The elimination half-life (t_1/2β values for 3 cows were 46.4. 56.0 and 72.8 min. The drug was administered subcutaneously (s.c.) to 5 cows at 10 mg/kg; the elimination half-life (t_1/2el) was 4.18 ± 0.55 h and the mean s.c. bioavailability was 22%. Rapid and extensive penetration of tilmicosin from blood into milk, and slow elimination from the milk were among the characteristic kinetic features of the drug after i.v. and s.c. administration. Tilmicosin was injected s.c. at 10 mg/kg once to 9 cows after the last milking of lactation; dry udder secretion samples were collected daily for 11 consecutive days and assayed microbiologically. Concentrations of drug > 0.78 μg/mL were found in the secretion for 8–9 days after dosing. Systemic side-effects were not observed after s.c. drug administration.     

Pharmacokinetics of sulphadoxine and trimethoprim in sows: Influence of lactation

A potentiated sulpha drug was administered intravenously to 12 sows on the 17th day of lactation and to 4 sows in early pregnancy to study the influence of lactation on its disposition kinetics. The dose-rate of sulphadoxine (SDX) used was 12 mg/kg b.w. while that of trimethoprim (TMP) was 2.4 mg/kg b.w. The pharmacokinetic parameters of SDX showed no significant difference between lactating and pregnant sows (V _ss, 0.24±0.04 L/kg; Cl _s , 0.25±0.05 ml/min per kg: MRT, 17.08±4.48 h). SDX did not accumulate in milk, the concentrations in milk being less than the concentrations in serum at the same time. Of the pharmacokinetic parameters for TMP, only the mean residence time was significantly different between the two groups (V _ss, 1.60±0.31 L/kg; Cl _s , 4.62±1.07 ml/min per kg: MRT_lactating, 5.43±1.26 h; MRT_pregnant, 7.74±1.72 h). TMP was excreted in milk to a considerable extent, the ratio of its concentration in milk to that in serum at the same time being over 2.2. These two substances show a completely different pharmacokinetic behaviour. Even though TMP is excreted more quickly in lactating sows, adjusting the dose of this potentiated sulpha drug does not seem to be appropriate.Abbreviations AUC area under the curve - AUMC area under the first-movement curve - terminal elimination rate constant - b.w. body weight - Cl _s clearance at steady state - D dose - MRT mean residence time - SD standard deviation - SDX sulphadoxine - TMP trimethoprim - V _ss apparent volume of distribution at steady state     

Evaluation of route and frequency of administration of three antimicrobial drugs in cattle

This study in six cows compared serum concentrations of trimethoprim and sulphadoxine (16 mg/kg body weight (BW)) after once daily and twice daily administration, and of procaine penicillin G (20,000 IU/kg BW) after subcutaneous (SQ) and intramuscular (IM) administration, and evaluated postmortem tissue concentrations of penicillin following SQ treatment. Trimethoprim and penicillin were measured microbiologically, and sulphadoxine colorimetrically. Using minimum inhibitory concentrations (MIC), trimethoprim reached serum concentrations above 0.5 μg/mL from 15 minutes to 120 minutes, and sulphadoxine exceeded 9.5 μg/mL from 10 minutes to 12 hours, after administration. At 24 hours after treatment, both had declined to below the MIC of most organisms. A second treatment at 12 hours maintained concentrations of sulphadoxine above 9.5 μg/mL for a further 24 hours. For penicillin administered IM and SQ, concentrations that peaked at 0.88 μg/mL would inhibit most common grampositive bacteria for the entire 24 hour period and fastidious gram-negative organisms from 90 minutes to 12 hours after SQ treatment, but for virtually the entire period after IM administration. Mean ± SD concentrations (μg/mL) of penicillin at euthanasia, five days after the last SQ administration, were 1.15 ± 1.27 (injection site), 1.00 ± 0.80 (liver), 0.90 ± 0.58 (renal cortex), 0,58 ± 0.17 (renal medulla), 0.13 ± 0.11 (diaphragm), 0.10 ± 0.08 (gluteal muscle), and 0.06 ± 0.04 (fat). Therefore, except for the most sensitive organisms, twice daily injection of trimethoprim/sulphadoxine (16 mg/kg BW) may be required. Penicillin G administered SQ at 20,000 IU/kg BW should provide effective serum levels for as long as IM administration against gram-positive organisms, but for only about half as long against gram-negative bacteria. The label withdrawal time of five days cannot be used when penicillin is given SQ at 20,000 IU/kg BW for three days.     

Kappa-casein in milk. An immunochemical investigation of the kappa-casein content in milk from Danish cattle breeds

The ϰ-casein content in milk from the Danish cattle breeds SDM, RDM and Jersey was investigated by means of immunoquantitation in antibody containing agarose gels. The method, which determines the total ϰ-casein complex, is suitable for routine work. The reproducibility of the method was found to be ± 4.1 %.The ϰ-casein concentration, expressed as percentage of the total protein content in milk, was significantly lower in milk from SDM (21.5%) and RDM (21.3%) than in Jersey (23.9%). The investigation showed that the ϰ-casein constitutes a greater part of the protein in milk than previously assumed.The amount of ϰ-casein was positively correlated with the protein content in milk, but there was no relation between the relative ϰ-casein content and the percentage of fat, milk yield and the time after calving.Keyword: kappa-casein, milk, cattle, immunoquantitation     

Effects of Alkalinization and Rehydration on Plasma Potassium Concentrations in Neonatal Calves with Diarrhea

Background

Increased plasma potassium concentrations (K⁺) in neonatal calves with diarrhea are associated with acidemia and severe clinical dehydration and are therefore usually corrected by intravenous administration of fluids containing sodium bicarbonate.

Objectives

To identify clinical and laboratory variables that are associated with changes of plasma K⁺ during the course of treatment and to document the plasma potassium‐lowering effect of hypertonic (8.4%) sodium bicarbonate solutions.

Animals

Seventy‐one neonatal diarrheic calves.

Methods

Prospective cohort study. Calves were treated according to a clinical protocol using an oral electrolyte solution and commercially available packages of 8.4% sodium bicarbonate (250–750 mmol), 0.9% saline (5–10 L), and 40% dextrose (0.5 L) infusion solutions.

Results

Infusions with 8.4% sodium bicarbonate solutions in an amount of 250–750 mmol had an immediate and sustained plasma potassium‐lowering effect. One hour after the end of such infusions or the start of a sodium bicarbonate containing constant drip infusion, changes of plasma K⁺ were most closely correlated to changes of venous blood pH, plasma sodium concentrations and plasma volume (r = −0.73, −0.57, −0.53; P < .001). Changes of plasma K⁺ during the subsequent 23 hours were associated with changes of venous blood pH, clinical hydration status (enophthalmos) and serum creatinine concentrations (r = −0.71, 0.63, 0.62; P < .001).

Conclusions and Clinical Importance

This study emphasizes the importance of alkalinization and the correction of dehydration in the treatment of hyperkalemia in neonatal calves with diarrhea.     

Oxytetracyclines in cattle. A comparison between a conventional and a long-acting preparation

Pharmacokinetics of oxytetracycline (OTC) were studied in 4 cows after administration of either a conventional (OTC-C) or a long-acting (OTC-LA) preparation. After intravenous administration of OTG-G the elimination half-life for OTG was found to be 6 h. Intramuscular injection of OTC-C and OTC-LA resulted in almost identical plasma concentrations of OTC with peak values after 6–8 h. For both preparations the bioavailability after i.m. administration was 100 % and about 60 % of the dose was excreted in the urine during the first week. Plasma concentrations above 0.5 μg/ml were with both preparations maintained for approximately 60 h, indicating no retard effect of OTC-LA as compared to OTC-C.Key words: Oxytetracycline, pharmacokinetics, cattle     

Mannheimia haemolytica in Feedlot Cattle: Prevalence of Recovery and Associations with Antimicrobial Use,Resistance, and Health Outcomes

Background

Mannheimia haemolytica is an important etiological agent in bovine respiratory disease.

Objectives

Explore risk factors for recovery of susceptible and resistant M. haemolytica in feedlot cattle and explore associations with health outcomes.

Animals

Cattle (n = 5,498) from 4 feedlots sampled at arrival and later in feeding period.

Methods

Susceptibility of M. haemolytica isolates tested for 21 antimicrobials. Records of antimicrobial use and health events analyzed using multivariable regression.

Results

M. haemolytica recovered from 29% of cattle (1,596/5,498), 13.1% at arrival (95% CI, 12.3–14.1%), and 19.8% at second sampling (95% CI, 18.7–20.9%). Nearly half of study cattle received antimicrobial drugs (AMDs) parenterally, mostly as metaphylactic treatment at arrival. Individual parenteral AMD exposures were associated with decreased recovery of M. haemolytica (OR, 0.2; 95% CI, 0.02–1.2), whereas exposure in penmates was associated with increased recovery (OR, 1.5; 95% CI, 1.05–2.2). Most isolates were pan‐susceptible (87.8%; 95% CI, 87.0–89.4%). AMD exposures were not associated with resistance to any single drug. Multiply‐resistant isolates were rare (5.9%; 95% CI, 5.1–6.9%), but AMD exposures in pen mates were associated with increased odds of recovering multiply‐resistant M. haemolytica (OR, 23.9; 95% CI, 8.4–68.3). Cattle positive for M. haemolytica on arrival were more likely to become ill within 10 days (OR, 1.7; 95% CI, 1.1–2.4).

Conclusions and Clinical Importance

Resistance generally was rare in M. haemolytica. Antimicrobial drug exposures in penmates increased the risk of isolating susceptible and multiply‐resistant M. haemolytica, a finding that could be explained by contagious spread.     

Detection of staphylococcal enterotoxin A, B, and C in milk by an ELISA procedure

Enterotoxigenic reference strains of Staphylococcus aureus were cultivated in sterile whole and skim milk for 18 h at 37°G. Staphylococcal enterotoxin A, B, and C were detected directly in the milk by an enzyme linked immunosorbent assay (ELISA), sensitive down to 1 ng/ml. Enterotoxins in the range of 1 ng–20 µg/ml milk were detected without any concentration or extraction. Skim and whole milk were almost identical as medium for enterotoxin production.     

A survey of the postpartum reproductive performance of dairy cows with fertility problems in southern Iceland

The purpose of this survey was to evaluate the reproductive performance of dairy cows on problem farms in southern Iceland. In all 229 cows on 6 farms were studied. The animals were examined clinically by rectal palpation, once a month. Blood samples were taken 2–5 and 7–10 weeks after calving. The blood samples were analysed for the contents of glucose, urea, inorganic phosphate, calcium and magnesium. Milk samples for progesterone profiles were taken, by the farmer, every 4th day from day 10 postpartum until first oestrus. Because of this sampling method, 128 cows had no rise in progesterone levels, when milk sampling was stopped. These 128 animals were excluded from the study. The results are based on 101 animals.There was a large variation between cows in postpartum reproductive performance. In the total material 1st ovulation occurred later than reported in many other countries. Fifty percent of the cows had ovulated 35 days after calving and 90 percent 70 days after calving.The first luteal phase was short in about 60 % of the cows. The progesterone values assayed from those short cycles were lower than the values assayed from the following cycle. First artificial insemination (ai) was on the average 77 days postpartum (pp). The conception rate to first service was 49 %. Of 100 milk samples taken at the time of ai, 20 had high progesterone value. This indicates a high frequency of luteal phase inseminations.Clinical ketosis was diagnosed in 35 cows. Of these, 31 had a low glucose value. Cows with clinical ketosis ovulated, on the average, later than other animals and 24 ovulated later than 40 days pp. The results indicated that the fertility problems of these cows studied were late ovulations, low conception rate, probably in part, due to luteal phase inseminations, and a high frequency of ketosis which could be caused by low quality feedstuff.     

Pharmacokinetics of sulphadiazine-trimethoprim in lactating dairy cows

Five Finnish Ayrshire cows in mid or end-lactation were treated with 40 mg sulphadiazine/kg and 8 mg trimethoprim/kg using intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) routes. Elimination of sulphadiazine was not affected by the route of administration (median t1/2 4.4-5.0 h) while elimination of trimethoprim was strongly limited by slow absorption from the injection site after s.c. and i.m. administration (median for apparent t1/2 21-25 h) compared to that after i.v. administration (median t1/2 1.2 h; p < 0.05). The median bioavailability of trimethoprim was also decreased, being 37% and 55% after s.c. and i.m. administration, respectively. When i.v. administration was used, trimethoprim concentration exceeded 0.1 mg/l in milk between 0.15-8 h while sulphadiazine concentrations above 2 mg/l were maintained from 0.5-2 h to 8 h. After s.c. and i.m. administration sulphadiazine in milk behaved similar to that after i.v. administration, while trimethoprim time-concentration curves were flat and trimethoprim concentrations were around 0.1 mg/l for an extended period of time (8-12 h). Median Cmax values in milk were only 0.07 mg/l and 0.10 mg/l for s.c. and i.m. administrations, respectively. After s.c. administration, 4 out of 5 cows showed signs of pain. After i.m. administration, 2 of the cows showed clear signs of pain and one had some local tenderness at the site of injection.