Effects of cimetidine and ranitidine on basal gastric pH, free and total acid content in pigs

The effects of intramuscular administration of multiple doses of cimetidine and ranitidine on basal gastric pH, free and total acid content from young adult pigs were studied. Cimetidine (4.5 mg kg-1, four times a day, intramuscularly, for three days) significantly (P less than 0.05) raised the basal gastric pH above 3.5 with a simultaneous reduction in free acid content at two, three and 26 hours after the administration of the eighth dose. Ranitidine (0.75 mg kg-1, four times a day, intramuscularly, for three days) significantly (P less than 0.05) raised the basal gastric pH above 3.5 with a concomitant reduction in free acid content at three and 38 hours after the administration of the eight dose. Neither cimetidine nor ranitidine had any significant effects on total acid content. These results confirm that the pig is a basal acid secretor and that the pharmacodynamics and pharmacokinetics of cimetidine and ranitidine in pigs might be different from those in humans.     

Effects of misoprostol and omeprazole on basal gastric pH and free acid content in horses

The basal gastric pH and free acid contents from five young adult healthy horses were determined at one hour intervals for eight hours. The basal gastric pH and free acid contents varied from 1.63 +/- 0.06 to 1.97 +/- 0.11 and 26.42 +/- 4.14 to 17.92 +/- 5.28 mmol litre-1, respectively. Misoprostol, a methylester analogue of prostaglandin (5 micrograms kg-1, orally) produced a time-dependent increase in the basal gastric pH to above 3.5 (P less than 0.05) at three, four and five hours after administration with a concomitant reduction of 80 to 90 per cent in the basal gastric free acid contents throughout the eight hour period monitored. Omeprazole, a benzimidazole derivative (0.5 mg kg-1, intravenously) increased the basal gastric pH to above 3.5 at two and three hours after administration with a concomitant reduction of 65 to 90 per cent in the basal gastric free acid contents for seven of the eight hour periods monitored. These results confirm that the horse is a basal acid secretor, and both misoprostol and omeprazole are effective inhibitors of the basal gastric acid secretion, thus establishing that both prostaglandins and H+/K+-ATPase play an important role in controlling parietal cell function of the equine gastric mucosa.     

Effect of cimetidine on abomasal pH and Haemonchus and Ostertagia species in sheep

Cimetidine, a histamine H2-receptor blocking agent which reduces gastric acid flow in simple stomach animals was administered directly into the abomasum of sheep at 100 mg kg-1 twice daily for five consecutive days and again on the eighth day. The drug caused a significant increase in the pH values of the abomasal contents and was highly effective in reducing the adult population of Haemonchus contortus (100 per cent) and Ostertagia circumcincta (70 per cent) in the abomasum of sheep. The possibility of using cimetidine as a method of treating abomasal nematode parasitism is discussed.     

Pharmacokinetic studies of cimetidine hydrochloride in adult horses

Histamine type II (H2) antagonists inhibit gastric acid secretion and are useful in treating gastric and duodenal ulcer disease. To provide some information on the pharmacokinetics of the H2 antagonist cimetidine, adult horses were given 3.3 mg/kg cimetidine intravenously (iv) or 3.3 and 10 mg/kg orally. Plasma cimetidine concentrations after 3.3 mg/kg orally were too low to measure. Following 3.3 mg/kg iv, cimetidine displayed two-compartment characteristics with a t1/2 of 0.083 +/- 0.039 h and t1/2 of 2.23 +/- 0.64 h. The total body clearance was 0.443 +/- 0.160 litre/h/kg and the mean residence time was 2.74 +/- 1.11 h. This clearance and t1/2 are similar to that in man. The volume of distribution (Vss) and volume of the central compartment (Vc) were 1.138 +/- 0.230 and 0.276 +/- 0.102 litre/kg, respectively. After a single oral dose of 10 mg/kg as crushed tablets, peak plasma concentration of 1.81 +/- 0.82 micrograms/ml occurred at approximately 1.4 h. Oral absorption of cimetidine appeared variable and slow with an extent of absorption of 0.296 +/- 0.183 and a mean residence time for absorption of 1.99 +/- 0.79 h. This was less than in man. Based on a desired average steady state plasma concentration of 1.0 microgram/ml, 11.0 mg/kg/day iv and 48 mg/kg/day orally can be recommended in adult horses.     

Effect of ranitidine on gastric acid secretion in young male horses

Gastric cannulas were placed surgically in 5 young male horses. After a 2-week recovery period, horses were studied once a week. Horses were fasted for 24 hours, and gastric fluid output was collected for 5 continuous hours. Volumes were recorded every 15 minutes, and pH and hydrogen ion concentration were determined in an aliquot from each period. In 10 basal experiments, using 5 horses, volume, pH, and hydrogen ion concentration were continuously variable. Mean acid output was 45.1 +/- 2.02 microEq/15 min/kg (mean +/- SEM). In 6 experiments, using 3 horses, 0.5 mg of ranitidine/kg of body weight, given as an IV bolus after a 1-hour basal collection, significantly (P less than 0.02) inhibited hourly total acid output for 4 hours, but did not significantly change pH. The cannulation technique was done without complications, and horses tolerated the cannula for several months. Seemingly, the horse has a continuously variable gastric acid secretion, and histamine type-2 receptors have a role in this process.     

Effects of allopurinol on endotoxin-induced increase in serum xanthine oxidase in the horse

Using a modified bovine milk enzyme kinetic assay, xanthine oxidase activity of serum collected from 34 adult, healthy horses of both sexes was determined. Enzyme activity varied from 0 to 126 mU litre-1 with a mean of 44.95 +/- 21.05 mU litre-1. The optimal pH and temperature for maximal activity were 7.8 and 28 degrees C, respectively. Freezing the serum for four days at -70 degrees C did not destroy the enzyme activity. Various doses (25, 50 and 75 micrograms kg-1, intraperitoneally) of endotoxin (lipopolysaccharide D1 Escherichia coli O26:B6) previously known to have caused moderate to severe systemic clinical signs of endotoxaemia in horses produced a significant dose related increase in serum xanthine oxidase activity. Pretreatment (12 hours) with allopurinol (5 and 50 mg kg-1, intravenously [corrected]) significantly reduced the rise in xanthine oxidase activity in endotoxin (50 micrograms kg-1, intraperitoneally) treated horses. The results of this study suggest that xanthine oxidase catalysed production of superoxide radicals may play a role in the pathogenesis of endotoxaemia and that allopurinol, an alternate substrate, should be further evaluated for its therapeutic potential in endotoxin related systemic diseases in horses.     

Effect of orally administered cimetidine and ranitidine on abomasal luminal pH in clinically normal milk-fed calves

OBJECTIVE: To characterize the change of pH in the abomasal lumen throughout a 24-hour period, to determine whether pH of the abomasal body differs from pH of the pyloric antrum, and to determine whether oral administration of cimetidine and ranitidine alters pH of the abomasal lumen in milk-fed calves. ANIMALS: 5 male dairy calves (4 Holsteins-Friesian, 1 Ayrshire), 5 to 15 days old. PROCEDURE: Cannulas were surgically positioned in the abomasal body and pyloric antrum of each calf. Calves received the following treatments in a randomized crossover design: milk replacer (60 ml/kg of body weight, q 12 h [untreated control calves]), milk replacer and cimetidine (50 or 100 mg/kg, q 8 h), or milk replacer and ranitidine (10 or 50 mg/kg, q 8 h). The pH of the abomasal body and pyloric antrum was measured for 24 hours, using miniature glass pH electrodes. RESULTS: Suckling of milk replacer immediately increased abomasal luminal pH from 1.4 to 6.0, followed by a gradual decrease to preprandial values by 6 hours. Preprandial and postprandial pH values were not significantly different between the abomasal body and pyloric antrum, indicating lack of pH compartmentalization in the abomasum of milk-fed calves. Administration of cimetidine and ranitidine caused a significant dose-dependent increase in mean 24-hour abomasal luminal pH. CONCLUSIONS AND CLINICAL RELEVANCE: Abomasal acid secretion in milk-fed calves is mediated in part by histamine type-2 receptors. Cimetidine and ranitidine may be efficacious in the treatment of abomasal ulcers in milk-fed calves.     

Pharmacokinetics of single doses of cefoperazone given by the intravenous and intramuscular routes to unweaned calves

Cefoperazone pharmacokinetics were studied in unweaned calves. The antibiotic was administered to 10 calves intravenously, to eight calves intramuscularly at 20 mg kg-1 and to 10 calves intramuscularly at 20 mg kg-1 together with probenecid at 40 mg kg-1. Serum concentration versus time data were analysed by non-compartmental methods based on the statistical moment theory. The intravenous data were also fitted by a linear, open two-compartment model. The terminal halflife of cefoperazone was 127.9 +/- 28.2 min (mean +/- SD) after intravenous and 136.9 +/- 19.6 min after intramuscular administration. The t1/2 was increased to 257.3 +/- 127.3 min by the co-administration of probenecid. The total body clearance was 8.16 +/- 1.60 ml min-1 kg-1 and the volume of distribution at steady state was 0.713 +/- 0.167 litre kg-1. The mean residence time values were 87.2 +/- 10.6 min after intravenous and 140.3 +/- 20.6 min after intramuscular injection and were increased to 264.5 +/- 99.8 min by the co-administration of probenecid. The estimated mean absorption time was 53.1 min and the estimated bioavailability after intramuscular administration was 76.3 per cent. The minimal inhibitory concentration (MIC90) values of cefoperazone ranged from 0.5 to 2 micrograms ml-1 for Escherichia coli, salmonella groups C, D and E and Pasteurella multocida isolates. Salmonella group B strains appeared to be highly resistant to cefoperazone with MIC90 greater than 32 micrograms ml-1. There were no significant differences between the pharmacokinetic variables calculated by statistical moment theory or compartmental analysis indicating central compartment output of cefoperazone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Elevated bile acids in the plasma of laying hens fed rapeseed meal

A simple procedure was developed for the estimation of bile acid taurine conjugates in fowl plasma. Laying hens fed a diet containing rapeseed meal (RSM) (400 g kg-1) for 12 weeks had higher bile acid levels (154 mumol litre-1) than hens fed a control soyabean diet (116 mumol litre-1) (P less than 0.01). The incidence of liver haemorrhages was higher (34.8 per cent) in RSM-fed hens than in controls (21 per cent), but the severity of the lesions did not correlate with the bile acid concentration in affected birds. Histological examination of sections from livers of RSM-fed birds did not reveal significant hepatocyte degeneration outside the immediate vicinity of the haemorrhage. Canalicular bile plugs were never seen. The incidence of liver haemorrhages (13 per cent) and plasma bile acids (85 mumol litre-1) were lower in hens fed a diet containing beta-aminopropionitrile (0.5 g kg-1), a known lathyrogen. Acute treatment of hens with the hepatotoxin alpha-naphthyl isothiocyanate over four days induced necrosis of hepatocytes and resulted in elevated bile acid concentrations (262 mumol litre-1) compared with controls (73 mumol litre-1) given arachis oil. It was concluded that laying hens fed high levels of RSM develop cholestasis but the toxic principle is not known.     

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.     

Comparative study of ampicillin and amoxycillin after intravenous, intramuscular and oral administration in homing pigeons (Columba livia)

Pharmacokinetics of ampicillin and amoxycillin after intravenous, intramuscular and oral administration was investigated in homing pigeons. The pharmacokinetic parameters in a cross-over study after intravenous administration of the sodium salts were comparable. The only significant difference was found for the distribution phase. The bioavailability after intramuscular injection of the sodium salts was especially low for ampicillin (26 per cent, as against 57 per cent for amoxycillin). The mean peak blood levels at 0.5 hours were 13.65 and 28.80 mg litre-1 for ampicillin and amoxycillin, respectively. After oral administration of trihydrate solutions (8 mg ml-1) the bioavailability was 20 and 35 per cent, respectively, and the mean peak blood levels were 8.46 and 16.98 mg litre-1, found at 1.04 and 1.26 hours. The recovery from the droppings, which include in birds the urine fraction as well, was unexpectedly low. Based on controls for recovery of added penicillin from the droppings and uric acid suspensions, indications were found that the pigeon enzymically inactivates penicillins. The in vitro activity of ampicillin against 266 strains of bacteria isolated from birds was determined. The minimum inhibitory concentration (MIC) for 65.4 per cent of the Escherichia coli was lower than 4 mg litre-1, for 91.1 per cent of the Salmonella species was lower than 2 mg litre-1 and for 100 per cent of the Yersinia pseudotuberculosis was lower than 0.25 mg litre-1. Based on these data and a literature study dosage regimens were calculated for MIC values of 0.5 and 2.5 mg litre-1.     

Identification of the phenolic substances in bovine urine associated with oak leaf poisoning

Six phenolic substances in bovine urine associated with oak leaf poisoning were identified by means of the ferric chloride reaction, paper chromatography and gas-liquid chromatography. The results indicate that these are neither oak tannin nor tannic acid but small molecular weight phenolic compounds. The concentration of free volatile phenols in the urine of cattle affected by oak leaves (n = 9, 26.57 +/- 11.20 mg litre-1) was significantly higher than in normal cattle (n = 9, 2.59 +/- 0.03 mg litre-1).     

Effects of intravenously administrated omeprazole on gastric juice pH and gastric ulcer scores in adult horses

The study was performed to evaluate the efficacy of omeprazole powder in sterile water, administered intravenously, on gastric juice pH in adult horses with naturally occurring gastric ulcers. Omeprazole (0.5 mg/kg, IV) was administered once daily for 5 days to 6 adult horses with gastric ulcers. Gastric juice was aspirated through the biopsy channel of an endoscope and pH was measured before and 1 hour after administration of omeprazole on day 1, and then before and after administration of omeprazole on day 5. Gastric ulcer scores were recorded on day 1 before administration of omeprazole and on day 5, 23 hours after the 4th daily dose. Gastric juice pH and ulcer scores were compared between the times. When compared with the pre-injection value (2.01 +/- 0.42), mean +/- SD gastric juice pH was significantly higher when measured 1 hour after administration of the initial dose (4.35 +/- 2.31), and before (5.27 +/- 1.74) and 1 hour after (7.00 +/- 0.25) administration of omeprazole on day 5. Nonglandular gastric ulcer number score significantly decreased from a mean +/- SD of 3.2 +/- 0.80 to 2.0 +/- 1.1, but nonglandular gastric ulcer severity score remained the same. Few glandular ulcers were seen in the study, and scores did not change. Because of its potent and long duration of action on gastric juice pH, this intravenous formulation of omeprazole may show promise for treatment of equine gastric ulcer syndrome (EGUS) in horses with dysphagia, gastric reflux, or other conditions that restrict oral intake of omeprazole paste. Aspiration of gastric juice and measurement of pH can be of use to determine whether the desired pH > 4.0 has been reached after omeprazole treatment.     

Bromsulphthalein and indocyanine green elimination from plasma, and urinary bromsulphthalein excretion, in normal cats

The elimination of bromsulphthalein (BSP) and indocyanine green (ICG) from plasma and urinary excretion of BSP were investigated in healthy cats. At 5 mg kg-1, BSP elimination fitted a two-compartment open model, with mean t1/2 beta of 7.1 (SD 2.5) minutes. A tendency for slower elimination of BSP at 10 mg kg-1 suggested saturation of excretory mechanisms, while at 2 mg kg-1 accurate dosing and assay of low BSP concentrations were difficult. Urinary recovery of BSP at 5 mg kg-1 was 0.01 to 0.13 per cent of the total dose. Plasma ICG (0.5 mg kg-1) data fitted a one-compartment open model, with mean t1/2 2.7 (SD 1.0) minutes. In cats, retention tests are more attractive than clearance tests because fewer blood collections are necessary. Proposed reference values are under 3.6 per cent retention of BSP (5 mg kg-1) at 30 minutes and under 17.5 per cent retention of ICG (0.5 mg kg-1) at 15 minutes. At present economic and technical factors favour BSP over ICG.     

Disposition kinetics and dosage regimen of ceftriaxone in crossbred calves (short communication).

Disposition kinetics and urinary excretion of ceftriaxone were investigated in healthy crossbred calves after its single intravenous administration (10 mg kg-1). Based on kinetic parameters, an appropriate dosage regimen of ceftriaxone in calves was calculated. The peak plasma level of ceftriaxone at 1 min was 84.0 +/- 1.55 micrograms ml-1 which declined to 0.43 +/- 0.05 microgram ml-1 at 8 h. The value of elimination half-life (t1/2 beta), volume of distribution Vd (area) and total body clearance (ClB) were 4.39 +/- 0.63 h, 1.91 +/- 0.19 L kg-1 and 0.31 +/- 0.01 L kg-1 h-1, respectively. Approximately 41 per cent of total administered drug was recovered in the urine within 24 h of its administration. The plasma protein binding of ceftriaxone was found to be concentration dependent with an overall mean of 38.55 per cent. The binding capacity of ceftriaxone to plasma proteins and the dissociation rate constant of protein-drug complex were 20.1 x 10(-8) +/- 18.4 x 10(-8) mole g-1 and 1.07 x 10(-6) +/- 0.52 x 10(-6) mole, respectively. An appropriate intravenous dosage regimen of ceftriaxone in cattle would be 12 mg kg-1 repeated at 24 h.     

Effects of orally administered enteric-coated omeprazole on gastric acid secretion in horses.

OBJECTIVES: To determine the effects of orally administered omeprazole, as enteric-coated capsules, on baseline and stimulated gastric acid secretion in horses. ANIMALS: 5 healthy 8-year-old mixed-breed horses fitted with gastric cannulas. PROCEDURE: Enteric-coated granules of omeprazole were mixed with corn syrup and administered orally once daily for 5 consecutive days. On days 1 and 5 beginning 5 hours after omeprazole administration, 4 gastric fluid samples were collected, each for 15 minutes, via the gastric cannula (baseline samples). Pentagastrin was administered IV as a constant infusion for the subsequent 2 hours, and 15-minute gastric fluid samples were again collected (stimulated samples). Fluid volume, acidity (mmol H-/L), and pH and gastric acid production (mmol H+) were determined for all baseline samples and for stimulated samples collected during the second hour of pentagastrin infusion. Control experiments were done in a similar manner after giving corn syrup alone to the same horses. RESULTS: Compared with values obtained during control experiments, baseline and stimulated gastric fluid acidity and gastric acid production significantly decreased, and the mean pH of gastric fluid samples significantly increased, after horses were given 5 daily doses of omeprazole. CONCLUSIONS AND CLINICAL RELEVANCE: Enteric-coated omeprazole (1.0 mg/kg of body weight; PO) administered once daily for 5 days significantly inhibited unstimulated and pentagastrin-stimulated gastric acid secretion in horses. This commercially available formulation of omeprazole may be efficacious in the treatment of gastroduodenal ulcers in horses.     

Disposition of the anti‐ulcer medications ranitidine,cimetidine, and omeprazole following administration of multiple doses to exercised Thoroughbred horses

The use of anti‐ulcer medications, such as cimetidine, ranitidine, and omeprazole, is common in performance horses. The use of these drugs is regulated in performance horses, and as such a withdrawal time is necessary prior to competition to avoid a medication violation. To the authors' knowledge, there are no reports in the literature describing repeated oral administrations of these drugs in the horse to determine a regulatory threshold and related withdrawal time recommendations. Therefore, the objective of the current study was to describe the disposition and elimination pharmacokinetics of these anti‐ulcer medications following oral administration to provide data upon which appropriate regulatory recommendations can be established. Nine exercised Thoroughbred horses were administered 20 mg/kg BID of cimetidine or 8 mg/kg BID of ranitidine, both for seven doses or 2.28 g of omeprazole SID for four doses. Blood samples were collected, serum drug concentrations were determined, and elimination pharmacokinetic parameters were calculated. The serum elimination half‐life was 7.05 ± 1.02, 7.43 ± 0.851 and 3.94 ± 1.04 h for cimetidine, ranitidine, and omeprazole, respectively. Serum cimetidine and ranitidine concentrations were above the LOQ and omeprazole and omeprazole sulfide below the LOQ in all horses studied upon termination of sample collection.     

Pharmacokinetics of ceftazidime in sheep and its penetration into tissue and peritoneal fluids

Serum, tissue and peritoneal fluid concentrations of ceftazidime were studied in ewes after intravenous, intramuscular and subcutaneous administration at 50 mg kg-1 bodyweight. Tissue and peritoneal cages were implanted in the animals studied. After intravenous bolus administration, the mean serum concentration versus time profile was best described by a two-compartment open model. The distribution rate constant (alpha) was 3.5 +/- 1.1 h-1 and the half-life (t 1/2 alpha) 0.22 +/- 0.09 hour. The elimination rate constant (beta) was 0.43 +/- 0.04 h-1 and half-life (t 1/2 beta) 1.6 +/- 0.2 hours. The area under the curve was 275.7 +/- 84.0 micrograms.ml-1 h. The volume of distribution as steady state was 356.1 +/- 208.0 ml kg-1. The penetration ratio into tissue fluid was 62.6 +/- 15.1 per cent and into peritoneal fluid 61.1 +/- 16.5 per cent. After intramuscular injection, the elimination half-life was 1.7 +/- 0.2 hours, the area under the curve was 228.7 +/- 43.3 micrograms.ml-1 h. and the elimination rate constant was 0.42 +/- 0.05 h-1. The penetration ratio into tissue fluid was 68.5 +/- 37.3 per cent and into peritoneal fluid 73.3 +/- 34.4 per cent. After subcutaneous injection, the elimination half-life was 1.8 +/- 0.5 hours, the area under the curve was 231.8 +/- 65.6 micrograms.ml-1 h. and the elimination constant was 0.41 +/- 0.10 h-1. The penetration ratio into tissue fluid was 47.2 +/- 3.5 per cent and into peritoneal fluid 58.1 +/- 15.6 per cent.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bioavailability of albendazole sulphoxide after netobimin administration in sheep: effects of fenbendazole coadministration.

After oral co-administration of two dosages of netobimin (7.5 and 20 mg kg-1 with fenbendazole (1.1 mg kg-1) to Merino sheep, the AUC0-infinity of albendazole sulphoxide at the lower dosage of netobimin, was significantly increased (75.5 per cent) from control value (34.43 +/- 7.91 versus 60.33 +/- 11.93 microg h ml-1). The pharmacokinetic parameters MRT and T1/2 were also increased: 18.96 +/- 2.54 vs 26.44 +/- 4.69 h and 10.31 +/- 1.72 vs 22.28 +/- 6.75 h respectively. No data corresponding to the higher dosage of netobimin (20 mg kg-1) were statistically different from control values. It is concluded that fenbendazole increases the bioavailability of albendazole sulphoxide in sheep at the 7.5 mg kg-1 dosage, and this may produce a potentiated anthelmintic action.     

Efficacy of epsiprantel against Echinococcus granulosus infections in dogs

Dogs with 41-day-old experimental infections of Echinococcus granulosus were treated orally with epsiprantel. Single doses of 2.5 mg kg-1, 5.0 mg kg-1 or 7.5 mg kg-1 were effective in removing more than 99 per cent of these parasites, but total clearances of worms only occurred in dogs given the highest dose.