[Broad interpretation 'mortal danger'].
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Animals↗
Biomedical subjects
A S van Miert
Publications and source records attributed to A S van Miert.
Pharmacological and pathophysiological modulation of food intake and forestomach motility in small ruminants.
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Animals↗
Effects of pentoxifylline and polymyxin B on the acute-phase-response to Escherichia coli endotoxin in dwarf goats.
The purpose of this study was to assess whether polymyxin B together with pentoxifylline, had beneficial effects on the acute-phase-response to E. coli endotoxin in the dwarf goat (n = 6). Polymyxin B partly neutralizes E. coli endotoxin by forming inactive polymyxin B-lipopolysaccharide (LPS) complexes; pentoxifylline has been reported to suppress the LPS-induced production of tumour necrosis factor (TNF-alpha). E. coli LPS (0.0067 microgram/kg/min over 30 min) induced fever, tachycardia, inhibition of rumen motility, a decline in WBC, lymphopenia, and decreases in plasma zinc and iron concentrations. Most of the haematological, blood biochemical and clinical effects of E. coli LPS were significantly reduced by polymyxin B pretreatment (0.1 mg/kg/min over 30 min, i.v.). Pentoxifylline (0.3 mg/kg/min over 30 min, i.v.) did not reduce the clinical and blood biochemical effects of E. coli LPS, however, it modulated the number of circulating neutrophils. No synergistic effects were observed after i.v. infusion of polymyxin B with pentoxifylline. The lack of synergy may be due to the production and release of pro-inflammatory cytokines other than TNF-alpha.
Acute-Phase Reaction↗
Differential effect of pentoxifylline on lipopolysaccharide-induced downregulation of cytochrome P450.
It is now established that inflammatory stimuli such as lipopolysaccharides (LPS) and polyinosinic acid:polycytidylic (polyIC) suppress hepatic expression of cytochrome P450 (P450) genes in rat liver. Previous studies have suggested that LPS- or polyIC-induced downregulation of P450 was due to endogenously released inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1, interleukin-6, and interferons (IFNs). To improve our understanding of the role of inflammatory cytokines in mediating P450 depression, we investigated the possibility of preventing P450 downregulation with pentoxifylline. Pentoxifylline has been shown to inhibit LPS-induced TNF-alpha production by suppression of TNF-alpha gene expression. The present study shows that in uninduced male rats pentoxifylline selectively prevents the downregulation of microsomal P4501A2 and P4502B caused by LPS. No protective effect of pentoxifylline on the downregulation of P4502E1 and P4503A1/2 was observed. PolyIC-induced downregulation of P4501A2, P4502B, P4502E1, and P4503A1/2 was not affected by pentoxifylline. These results suggest that the LPS-induced downregulation of P4501A2 and P4502B is mediated to a large extent by TNF-alpha. Other cytokines might be involved in the suppression of P4502E1 and P4503A1/2. The fact that polyIC-induced downregulation is not protected by pentoxifylline is further evidence that this agent acts via a selective induction of IFNs.
Animals↗
Side effects of oral antimicrobial agents in the horse: a comparison of pivampicillin and trimethoprim/sulphadiazine.
To evaluate the side effects of oral pivampicillin and trimethoprim/ sulphadiazine, 200 horses receiving these antimicrobial agents were studied. The horses received either trimethoprim/ sulphadiazine (30 mg/kg twice daily) or pivampicillin (25 mg/kg twice daily) for three or more days. No adverse effects other than loose faeces and diarrhoea were detected. The risk of diarrhoea was significantly less after the oral administration of pivampicillin (3 per cent) than after trimethoprim/ sulphadiazine (7 per cent). Horses whose appetite was reduced appeared to be predisposed to develop diarrhoea after the administration of either oral antimicrobial agent.
Administration, Oral↗
Primary bovine hepatocytes in the study of cytokine induced acute-phase protein secretion in vitro.
To investigate the utility of primary cultures of bovine hepatocytes for compartmentalized acute phase protein studies the secretion of serum amyloid-A (SAA) and haptoglobin (Hp) was measured after stimulation by pro-inflammatory cytokines (recombinant human IL-6 (rhIL-6) and recombinant human tumour necrosis factor-alpha (rhTNF-alpha)). During the incubation period of the experiment, the SAA and Hp secretion into the culture medium increased (P < 0.05). SAA concentrations showed an additional increase following treatment with each of the cytokines (P < 0.01). Hp concentrations remained unchanged, whereas incubation with a combination of both resulted in a significant increase of the medium concentration of both SAA (P < 0.01) and Hp (P < 0.05). From these findings it is concluded that primary bovine hepatocytes can be used for in vitro studies on acute-phase protein secretion.
Acute-Phase Proteins↗
A survey of horses with acute diarrhoea: diagnosis, assessment of the prognosis, and comparison of two antibiotic therapies.
Twenty horses, ponies, and foals referred with acute diarrhoea were divided at random into two treatment groups. One group was treated intravenously with trimethoprim/ sulfadiazine and the other group with ampicillin/gentamicin. Both groups were given the same standardized symptomatic therapy. All animals were evaluated clinically and 5 variables (general impression, heart rate, rectal temperature, appetite, and consistency of the faeces) were estimated on a five point scale (0-4). Jugular blood samples were taken at admittance and at regular intervals for routine screening. Three blood variables (packed cell volume, white blood cell count, and base excess) were also classified in a 5-point scale. The 'diarrhoea prognosis index' was the total sum of the eight variables scaled. Faecal samples were cultured aerobically and examined for worm eggs and larvae. A definite diagnosis was only reached in 11 horses (55%). Salmonellosis and parasitic infections were the most common causes of the diarrhoea. Seven horses (35%), three from the ampicillin/gentamicin group and four from the trimethoprim/sulfadiazine group, died or were euthanized because of a poor prognosis. Only the packed cell volume differed significantly between horses that died and horses that survived. No single clinical or haematological/biochemical variable did forecast the prognosis for the individual patient reliably, nor did the 'diarrhoea prognosis index'. The only reliable indication for the outcome of an individual horse appeared to be the clinical response to treatment within 4 days. The clinical outcome of both treatment groups did not differ significantly. In conclusion, it was difficult to reach a specific diagnosis in these horses with diarrhoea. It was not possible to forecast the prognosis of an individual patient by a single variable or by a combination of variables. No significant differences were found between the two antibiotic treatment groups.
Acute Disease↗
Cytochrome P4502E in vivo and in vitro in the dwarf goat: effects of enzyme induction and the applicability of chlorzoxazone as marker substrate.
Cytochrome P4502E activities, inducibility and the applicability of chlorzoxazone as a marker substrate for this enzyme were investigated in female dwarf goats. Goats were treated with either isoniazid or beta-naphthoflavone. Treatment with isoniazid resulted in a 1.4 fold increase of the chlorzoxazone hydroxylation rate in hepatic microsomes. Aniline- and p-nitrophenol hydroxylation rates were increased by roughly the same extent (1.6 and 1.25 fold resp.) and increased levels of cytochrome P4502E apoproteins were found by Western blotting. Treatment with the cytochrome P4501A inducer beta-naphthoflavone resulted in a 2.5 fold induction of the in vitro chlorzoxazone hydroxylation rate, whereas the hydroxylation rates of aniline and p-nitrophenol were not induced. After treatment with isoniazid, chlorzoxazone plasma clearance was increased from 5.0 mL/min/kg to 11.0 mL/min/kg. Chlorzoxazone was almost completely excreted in the urine as conjugated hydroxy metabolites. These results do not support the hypothesis that cytochrome P4502E is of particular importance in goats, as has been suggested earlier. Furthermore, chlorzoxazone has limited value as a marker substrate for this enzyme, since cytochrome P4501A enzymes appear to play an important role in its biotransformation.
Aniline Compounds↗
In vitro and in vivo binding of trimethoprim and sulphachlorpyridazine to equine food and digesta and their stability in caecal contents.
Binding of antibiotics to food has received little attention in equine medicine, although such binding could potentially reduce the bioavailability and clinical efficacy. In the present study, binding of trimethoprim (TMP) and sulphachlorpyridazine (SCP) to hay, grass silage and concentrate was investigated in vitro in buffer at pH 6.8 at different concentrations. The binding of TMP and SCP to caecal contents was also studied. In addition, the degradation of TMP and SCP by the caecal microflora was investigated by incubating sterilized and non-sterilized caecal contents for 3 h at 37 degrees C under anaerobic conditions and comparing the TMP and SCP contents. Further, a TMP/SCP powder formulation was adminstered orally with concentrate at a dose rate of 5 mg/kg TMP and 25 mg/kg SCP to three ponies with a caecum fistula; the animals were deprived of food for 8 h before administration. Blood samples, caecal contents samples and faecal samples were collected and analysed for TMP and SCP concentrations by means of high performance liquid chromatography (HPLC). Three non-fistulated ponies, acting as control animals, were fed the same dose of TMP/SCP with concentrate after 8 h of food deprivation and blood samples were taken. The percentage of in vitro binding of TMP as well as SCP to hay, grass silage and concentrate at concentrations of 4 micrograms/mL to 10 micrograms/mL was high (60-90%). TMP and SCP were also extensively bound to caecal contents (50-70%). At spiking concentrations above 10 micrograms/mL the percentage of binding decreased. There was no evidence of biodegradation of TMP or SCP in caecal contents. In vivo, both drugs could be detected in the caecal contents and in the faeces of three fistulated ponies. However, the fistulated ponies differed from the control ponies in that their TMP and SCP plasma concentrations were higher, and two fistulated ponies did not show double peaks in their plasma concentration-time curves. Therefore, the fistulated ponies did not provide an optimal model for in vivo binding studies. Despite this limitation, it can be concluded that binding of TMP and SCP to food is a major cause of the limited bioavailability of these drugs in the horse. It is hypothesized that the binding is reversible, and that a second absorption phase occurs in the large intestine, but part of the administered dose remains bound as both drugs were found in the faeces.
Administration, Oral↗
Cytochrome P-450 complex formation in rat liver by the antibiotic tiamulin.
Tiamulin is a semisynthetic diterpene antibiotic frequently used in farm animals. The drug has been shown to produce clinically important--often lethal--interactions with other compounds. It has been suggested that this is caused by a selective inhibition of oxidative drug metabolism via the formation of a cytochrome P-450 metabolic intermediate complex. In the present study, rats were treated orally for 6 days with tiamulin at two different doses: 40 and 226 mg/kg of body weight. For comparison, another group received 300 mg of triacetyloleandomycin (TAO) per kg, which is equivalent to the 226-mg/kg tiamulin group. Subsequently, microsomal P-450 contents, P-450 enzyme activities, metabolic intermediate complex spectra, and P-450 apoprotein concentrations were assessed. In addition, effects on individual microsomal P-450 activities were studied in control microsomes at different tiamulin and substrate concentrations. In the rats treated with tiamulin, a dose-dependent complex formation as evidenced by its absorption spectrum and an increase in cytochrome P-4503A1/2 contents as assessed by Western blotting (immunoblotting) were found. The effects were comparable to those of TAO. Tiamulin induced microsomal P-450 content, testosterone 6 beta-hydroxylation rate, erythromycin N-demethylation rate, and the ethoxyresorufin O-deethylation activity. Other activities were not affected or decreased. When tiamulin was added to microsomes of control rats, the testosterone 6 beta-hydroxylation rate and the erythromycin N-demethylation were strongly inhibited. It is concluded that tiamulin is a potent and selective inducer-inhibitor of cytochrome P-450. Though not belonging to the macrolides, the compound produces an effect on P-450 similar to those of TAO and related compounds.
Animals↗
In vitro and in vivo oxidative biotransformation in the West-African dwarf goat (Caprus hircus aegagrus): substrate activities and effects of inducers.
1. Cytochrome P450 activities in vivo and in vitro and enzyme induction by phenobarbital, beta-naphthoflavone, isoniazid and triacetyloleandomycin were investigated in the female dwarf goat. In vivo kinetics of antipyrine, sulphadimidine and caffeine were studied separately and as a combination ("cocktail'). After establishing a lack of interaction between these compounds the effects of the inducing agents were investigated. In vitro, hepatic microsomal enzyme activities and apoprotein levels were determined. 2. In the beta-naphthoflavone treated goat, the microsomal ethoxy-resorufin-O-deethylation rate was markedly increased. beta-naphthoflavone also induced caffeine plasma clearance but did not affect microsomal caffeine 1- and 3-demethylation rates. After phenobarbital treatment, caffeine plasma clearance was also increased. In contrast with beta-naphthoflavone treatment, phenobarbital treatment resulted in an increase of microsomal caffeine 1- and 3-demethylation rates. 3. Goat liver microsomes were able to hydroxylate tolbutamide, predominantly a CYP2C9 activity in man, and debrisoquine, a CYP2D activity in different species. These activities were not affected by either beta-naphthoflavone or phenobarbital. Sulphaphenazole was found to be a more potent inhibitor of tolbutamide hydroxylation than sulphadimethoxine. Quinine was a more potent inhibitor of debrisoquine hydroxylation than was quinidine. 4. As expected, the microsomal aniline-4-hydroxylation rate (CYP2E) was increased after isoniazid treatment. 5. The microsomal testosterone 6 beta-hydroxylation rate (CYP3A) was increased after phenobarbital and triacetyloleandomycin treatment. Antipyrine plasma clearance was also increased after phenobarbital treatment. 6. As cytochrome P450 activities and inducibility in the dwarf goat show many resemblances to those in man, they may be of value as a model for human biotransformation research.
Animals↗
Oral bioavailability and in vitro stability of pivampicillin, bacampicillin, talampicillin, and ampicillin in horses.
OBJECTIVES: To determine the oral bioavailabilities of 3 ampicillin esters (pivampicillin, bacampicillin, and talampicillin) and ampicillin sodium, and to determine in vitro stability of the ampicillin esters in ileal contents (pH 8.3 to 8.5). DESIGN: A crossover design to administer the 4 drugs orally, and ampicillin i.v. to all horses in the study. ANIMALS: 4 healthy adult horses. PROCEDURE: The drugs were administered intragastrically to the horses at a dosage equimolar to 15 mg of ampicillin/kg of body weight. Also, ampicillin sodium was administered i.v. at the same dosage. Blood samples were taken up to 12 hours after drug administration, and ampicillin concentrations in plasma were determined. For the in vitro study, the ampicillin esters were incubated at 37 C in ileal contents obtained from ponies with cecal fistulas. After incubation, the remaining intact ester and the formed ampicillin were measured. RESULTS: Absolute oral bioavailability was 31, 39, 23, and 2% for pivampicillin, bacampicillin, talampicillin, and ampicillin sodium, respectively. In the in vitro study, 90% decomposition of the ester took place in 30, 60, and 5 minutes, for pivampicillin, bacampicillin, and talampicillin, respectively. CONCLUSIONS: Pivampicillin and bacampicillin are promising candidates for oral antibiotic treatment of horses. The rapid decomposition of ampicillin esters is caused by chemical hydrolysis at the high pH of equine ileal contents.
Administration, Oral↗
Pharmacokinetics and therapeutic potential for repeated oral doses of trimethoprim/sulphachlorpyridazine in horses.
The pharmacokinetic parameters of a powder formulation of trimethoprim/sulphachlorpyridazine were studied in eight healthy horses which received 5 mg/kg trimethoprim and 25 mg/kg sulphachlorpyridazine 12-hourly with concentrate for five days. The intake of the medicated concentrate by the horses was variable during the first two days, but after they became accustomed to the taste the intake by all the horses during the last three days was good. Faecal samples taken before and on the last day of the drug administrations were negative when cultured for salmonella. Compared with the results of a previous single-dose experiment, higher plasma concentrations and a higher area under the curve for both the drugs were observed. The repeated doses provided plasma concentrations above the minimal inhibitory concentration for Streptococcus zooepidemicus, S equi, Actinobacillus equuli and Rhodococcus equi isolated from the respiratory tract of horses. Synergism between the two drugs occurred at different drug concentration ratios with different bacterial species.
Administration, Oral↗
[Off-label use of lincomycin hydrochloride in 2 horses. Dysbacteriosis and fatal complications due to inadequate symptomatic therapy].
A lawyer inquired about the possible harmful effects of 'off-label use' of lincomycin in two trotting horses. From information in the relevant dossier it could be concluded that there was no direct indication to use antibiotics. In addition, mistakes were made in the medicinal treatment of horses, namely, the off-label use of lincomycin without prior consultation with the manufacturer, fluid and electrolyte replacement therapy not continued for long enough, and incorrect use of antipyretic analgesics. The intravenous administration of gentamicin to dehydrated patients is permissible only in combination with adequate administration of fluids and electrolytes.
Animals↗
In vitro susceptibility to antimicrobial drugs of 62 Salmonella strains isolated from horses in The Netherlands.
The in vitro activity of 17 antimicrobial drugs against strains of Salmonella typhimurium (n = 52), Salmonella thompson (n = 2), Salmonella heidelberg (n = 3), Salmonella hadar (n = 2), Salmonella enteritidis (n = 1), Salmonella infantis (n = 1) and Salmonella derby (n = 1) was tested using the agar dilution method. The strains were isolated from horses admitted to the Large Animal Clinics of Utrecht University. The majority of strains were susceptible to gentamicin, amikacin, kanamycin, enrofloxacin, ciprofloxacin, flumequine, colistine, furazolidone and ceftiofur. However, all strains of Salmonella typhimurium phage type 200 (n = 14), were multiresistant i.e. were resistant to ampicillin amoxycillin, amoxycillin in combination with clavulanic acid, chloramphenicol, nitrofurantoin, trimethoprim, aditoprim and baquiloprim. Two of these strains were also resistant to gentamicin. Based on the susceptibility data found in the present study in combination with pharmacokinetic data available in the literature a rationale for antimicrobial therapy in equine salmonellosis is given. As first choice, gentamicin at a dosage of 3 mg/kg combined with ampicillin at a dosage of 20 mg/kg given with a 8-12 hour dosing interval by intravenous route is advised. As an alternative, the intravenous administration of trimethoprim/sulfonamide combinations given twice daily at a combined dose of 30 mg/kg is suggested.
Animals↗
Pro-inflammatory cytokines in a ruminant model: pathophysiological, pharmacological, and therapeutic aspects.
Infection evokes complex changes which are thought to be caused by production and release of pro-inflammatory cytokines such as tumour necrosis factor (TNF-alpha), interferons (INFs), and interleukins (ILs). They regulate local inflammatory reactions, but may also gain access to the circulation and induce systemic effects collectively known as the Acute Phase Response. To improve our understanding of the pathophysiology of pro-inflammatory cytokines in ruminants, studies have been performed with TNF-alpha, IL1-alpha/beta, and IFN-alpha/ gamma as well as with cytokine-inducers in dwarf goats. In relation to therapy, the following aspects may be of interest: a) Cytokine therapy given before or just after microbial challenge induces in vivo antimicrobial activity. Moreover, cytokines potentiate in vivo the antimicrobial activity of antibiotics, b) Cytokines may act as biological response modifiers for enhancing specific immunity to vaccines, and c) Cytokines may affect drug absorption, disposition, and metabolite formation in disease states. Although studies of the actions of corticosteroids, nonsteroidal anti-inflammatory and antipyretic agents, antibodies to endotoxin, TNF-alpha, or IL-1, synthetic E. coli lipid A precursors, hydrazine, isoniazid, chloroquine, polymyxin B, bicyclic imidazoles, hydroxamates, and tyrosine kinase inhibitors in endotoxaemic animals have shed further light on inflammatory processes, clinical studies in this field are urgently required to evaluate their beneficial effect.
Animals↗
Oral bioavailability of sulphonamides in ruminants: a comparison between sulphamethoxazole, sulphatroxazole, and sulphamerazine, using the dwarf goat as animal model.
The various sulphonamides show marked differences in disposition characteristics after administration to ruminants. For use in combination with a diaminopyrimidine derivative such as trimethoprim or baquiloprim, it is essential that a sulphonamide has similar pharmacokinetic properties in order to obtain optimal synergy. In the present study the pharmacokinetics of sulphamethoxazole, sulphatroxazole, and sulphamerazine were investigated in dwarf goats (n = 6) after IV and intraruminal administration at a dose of 30 mg/kg bodyweight. In addition, the in vitro binding of sulphamerazine to ruminal contents was studied as a possible explanation for a reduced absorption rate. Sulphamethoxazole showed the most rapid absorption after intraruminal administration (mean tmax +/- SD : 0.8 +/- 0.2h). However, the drug was rapidly eliminated from the plasma (t1/2 beta : 2.4 +/- 1.5 h) and the bioavailability was only 12.4 +/- 4.7%, most likely due to an extensive 'first-pass' effect. The bioavailability of orally administered sulphamerazine and sulphatroxazole was much higher (67.6 +/- 13.5% and 70.2 +/- 32.3%, respectively). After intraruminal administration, sulphatroxazole showed the highest plasma peak concentration (26.1 +/- 6.3 mg/l) and the longest plasma half-life (4.7 +/- 1.8h) and mean residence time (13.9 +/- 4.5 h). Sulphamerazine showed considerable binding to rumen contents in vitro. Based on its pharmacokinetic properties sulphatroxazole appears to be a suitable candidate to be used in combination with the more recently developed diaminopyrimidines such as baquiloprim.
Administration, Oral↗
Pharmacokinetics of trimethoprim/sulphachlorpyridazine in horses after oral, nasogastric and intravenous administration.
In the present study, the pharmacokinetic parameters of a trimethoprim/sulphachlorpyridazine preparation following intravenous administration, administration by nasogastric tube and administration with concentrate were determined in the horse. Eight adult horses were dosed at 1 week intervals in a sequentially designed study at a dose of 5 mg/kg trimethoprim (TMP) and 25 mg/kg sulphachlorpyridazine (SCP) on all occasions. Plasma concentrations of both drugs were measured serially for 48 h. Pharmacokinetic parameters of clinical importance (distribution and elimination half-lives, clearance, bioavailability, volume of distribution) were determined both for TMP and SCP. Following intravenous administration, the volume of distribution at steady-state (Vd(ss)) was significantly larger for TMP (1.51 +/- 0.25 L/kg than for SCP (0.26 +/- 0.05 L/kg. The clearance was 7.73 +/- 2.26 mL/min.kg for TMP and 2.64 +/- 0.48 mL/min.kg for SCP. For both TMP and SCP, mean peak plasma concentrations (Cmax) and the bioavailabilities (F) were reduced significantly when the drugs were mixed with concentrate (ct) as compared with those after nasogastric administration (ngt) (Fct = 44.3 +/- 10.7% vs. Fngt = 68.3 +/- 12.5% for TMP; Fct = 46.3 +/- 8.9% vs. Fngt = 67.3 +/- 13.7% for SCP). Following the administration of TMP and SCP mixed with concentrate, the plasma concentration-time curves showed a biphasic absorption pattern in all horses. The first peak occurred 1-2 h and the second peak 8-10 h after administration of the combination preparation.(ABSTRACT TRUNCATED AT 250 WORDS)
Absorption↗