[Examinations on the pharmacokinetics and compatibility of enalapril in racing pigeons]. / Untersuchungen zur Pharmakokinetik und Verträglichkeit von Enalapril bei Brieftauben.

OBJECTIVE: It was the aim of this study to examine the compatibility and the pharmacokinetics of the angiotensin converting enzyme inhibitor enalapril after oral application in racing pigeons and Amazons, and to contribute to a safe dosage regime of this drug in birds. MATERIAL AND METHODS: For the examination of drug compatibility, three groups of pigeons (n = 8 each) received enalapril into the crop at a dose of 5 or 10 mg/kg body weight, or placebo, respectively. Health status, and water and food consumption were monitored regularly, and clinical, hematological and blood-chemical parameters were determined. To determine a suitable starting dosage, birds were treated with enalapril at a dose of 2.5 mg/kg (first trial) and 1.25 mg/kg (second trial), and blood samples were collected at defined time points. Using high performance liquid chromatography (HPLC), the enalapril concentration in the plasma samples was determined. RESULTS: Drug application did not cause any significant drug-related difference between the groups. Nearly all measured parameters were found to be within normal physiological ranges. Only for hematocrit was a slight but significant increase found for the group treated with 5 mg/kg enalapril. In pigeons, after application of 2.5 mg/kg enalapril, the maximum plasma concentration was found in the first sample taken (388.2 ± 174.1 mg/kg). The application of 1.25 mg/kg resulted in a maximum concentration of 116.1 ± 70.2 ng/ml after 30 minutes in pigeons. In the Amazon birds, the maximum value was found after 1 hour (first sampling) of 43.3 ±6.0 ng/ml. In all examinations, the enalapril concentration was <15 ng/ml after 8 hours. The terminal half-life was 2.68 hours for pigeons and 2.36 hours for Amazons. CONCLUSION: The results underline the good compatibility of enalapril after oral administration in healthy pigeons. A starting dosage of 1.25 mg/kg enalapril given twice daily can be recommended. CLINICAL RELEVANCE: The study provides basic data (compatibility and pharmacokinetics) for the application of enalapril in birds such as the racing pigeon.

Influence of topical dexamethasone applications on insulin, glucose, thyroid hormone and cortisol levels in dogs.

The influence of two topical dexamethasone applications (dermal and ototopical) on plasma insulin, glucose, thyroid hormone and cortisol levels was investigated in beagle dogs. Both treatments significantly decreased basal cortisol values, associated with exaggerated rise in insulin (approximately 50%), together with unchanged serum glucose levels. Dermal dexamethasone quickly decreased plasma thyroxin (T4) levels; whereas dexamethasone in ear drops gradually inhibited time-dependently T4 release (18-50%). Both formulations blunted plasma triiodothyronine (T3) levels but the response induced by dermal dexamethasone was stronger than by dexamethasone ear drops. Upon drug withdrawal, insulin secretion returned to baseline a week after treatment cessation, while cortisol, T4 and T3 levels did not reach baseline values. These results suggest that topical glucocorticoids unexpectedly trigger secondary hypothyroidism with concomitant suppression of hypothalamic-pituitary-adrenal axis but sensitize the endocrine pancreas, thus, their application needs careful evaluation for surprisingly different effects on endocrine stress axis activity.

Reflection paper on MRSA in food-producing and companion animals: epidemiology and control options for human and animal health.

The scope of this reflection paper was to review the latest research on the risk of MRSA infection and colonization in animals. Attention focused on occurrence, risk factors for colonization and infection, and human contact hazard for livestock, horses, and companion animals. Whereas the clonal relationship between MRSA strains of CC398 is straightforward in livestock this is less obvious in horses. Small companion animals typically share MRSA strains that seem to exchange with a human reservoir. Management and therapeutic options have been suggested for livestock, horses, companion animals, as well as instructions on safety measures for persons in contact with animals. Conclusions were drawn with emphasis on future research activities, especially to confirm the apparent evolution of the organism and to demonstrate efficiency of control strategies.

Effects of dermal dexamethasone application on ACTH and both basal and ACTH-stimulated cortisol concentration in normal horses.

There are no data available regarding the systemic (adverse) effects which might be induced by topical/dermal glucocorticoids (GCs) application in the horse. Besides their widespread use for the treatment of a variety of peripheral inflammatory disorders such as atopic dermatitis, eczemas or arthritis in the horse, their surreptitious application has become a concern in doping cases in competition/performance horses. Assessing both basal and ACTH-stimulated plasma cortisol as well as basal ACTH concentrations following application of dexamethsone-containing dermal ointment is necessary to determine influences on hypothalamus-pituitary-adrenal (HPA) axis. Ten clinically healthy adult standardbred horses (6 mares, 4 geldings) were rubbed twice daily each with 50 g dexamethasone-containing ointment on a defined skin area (30 x 50 cm) for 10 days. RIA and chemiluminescent enzyme immuno-metric assay were used to determine resting and ACTH-stimulated plasma cortisol and basal ACTH concentrations, respectively. HPA feedback sensitivity and adrenal function were measured by a standard ACTH stimulation test. Dermal dexamethasone suppressed significantly the resting plasma cortisol level (to 75-98%) below baseline (P < 0.001) within the first 2 days and decreased further until day 10. ACTH stimulation test showed a markedly reduced rise in plasma cortisol concentrations (P < 0.001 vs. baseline). Plasma ACTH level decreased also during topical dexamethasone application. The number of total lymphocytes and eosinophil granulocytes was reduced, whereas the number of neutrophils increased. No significant change of serum biochemical parameters was noted. Dermal dexamethasone application has the potential to cause an almost complete and transient HPA axis suppression and altered leukocyte distribution in normal horses. The effects on HPA axis function should be considered in relation to the inability of animals to resist stress situations. The data further implicate that percutaneously absorbed dexamethasone (GCs) may cause systemic effects relevant to 'doping'.

Effect of hydroxyethyl starch solution in normal horses and horses with colic or acute colitis.

Hydroxyethyl starch (HES) solution is an effective colloidal infusion solution in humans for treatment of hypovolaemic shock, but it has not been compared with fluids currently available for use in horses. On the basis of plasma-expanding effect of HES in normal horses, a 10% medium-molecular 200/0.5 solution of HES was subsequently tested in hypovolaemic horses. Six normal horses were given five protocols of a single infusion of HES at varying dosage rates (5, 10, 15 ml HES/kg), as well as isotonic saline (15 ml/kg) and hypertonic saline (4 ml/kg b.w.). Dehydrated horses suffering from acute colitis or those which had been treated surgically for ileus of the small or large intestine were given an i.v. infusion of 10 ml HES/kg in combination with 10 ml saline/kg. Clinical data and blood samples for testing were taken before the infusion, and then 10 min, 1 h, 2, 4, 6, 8, 10, 12 and 24 h after infusion (a.i.). A significant decrease in haematocrit was observed in protocol 1-5 for a period of up to 4, 4, 10 h, 10 min and up to 10 min; in group of colitis, during the entire 24-h testing period, and in groups of ileus of small intestine and of large intestine, up to 4 and 10 h a.i. HES decreases better and longer-lasting haematocrit and total protein than either isotonic or hypertonic saline. Half-life of HES increases due to higher dosage (5.83, 7.63 and 11.48 h) and distribution is exclusively intravascular. In normal horses of protocol 1-3 using HES aPTT, sodium and potassium were within the physiological range. Serum amylase activity is increased in horses using HES. On the basis of this clinical study, the decreasing effect of urea and creatinine in colic patients after surgery and fewer instances of postoperative ileus a dosage of 10 ml HES/kg could be recommended.

Equine recurrent airway obstruction does not alter airway muscarinic acetylcholine receptor expression and subtype distribution.

In recurrent airway obstruction (RAO) or heaves, bronchospasm has been attributed to enhanced cholinergic activity. However, the expression and function of muscarinic acetylcholine receptors (mAChR) and their signaling components are not yet known. Thus, we examined the expression, subtype distribution and postreceptor signaling pathways of mAChR in the peripheral lung, bronchial and tracheal epithelia with the underlying smooth muscle from nine horses with RAO and 11 healthy control horses. In RAO horses, no significant segment-dependent alteration in mAChR density and subtype distribution (assessed by [N-methyl-3H]-scopolamine binding; ([3H]-NMS)), was found, except a trend in receptor down-regulation in some peripheral parts of the lung. The total number of high mAChR binding sites (assessed by carbachol-displacement experiments in the presence or absence of guanosine 5'-triphosphate) was not changed in RAO, suggesting that the functional coupling of mAChR to the corresponding G-proteins is intact. The M2-mediated inhibition of adenylate cyclase (AC) as well as the M3-receptor-G(q/11)-phospholipase C (PLC) activity was not different between RAO and control airway tissues. In conclusion, in equine RAO airways, mAChR expression and function were not altered, and thus appear not to account for the enhanced cholinergic activity in RAO.

Plasma concentrations of voriconazole in falcons.

Doses of 12.5 mg voriconazole/kg bodyweight administered every 12 hours by crop gavage to six falcons for 14 days provided peak plasma concentrations of more than 1 microg/ml, but the trough concentrations were lower and sometimes undetectable. Administering the same doses incorporated into meat that was fed to one falcon for seven days and to three falcons for up to 91 days provided similar plasma concentrations.

Segment-dependent expression of muscarinic acetylcholine receptors and G-protein coupling in the equine respiratory tract.

Muscarinic receptors are considered to be of comparable clinical importance in chronic obstructive pulmonary disease (COPD) in equines and in humans. At present, data are scarce on the expression and distribution of probable subtypes of these receptors and their signalling pathways in airway segments, including lung parenchyma and bronchial and tracheal epithelium with the underlying smooth muscle in horses. Specific [N-methyl-3H]scopolamine chloride ([3H]NMS) binding to all three tissues was saturable and of high affinity, with KD values ranging between 1.6+/-0.7 and 1.9+/-0.3 nmol/L. [3H]NMS binding identified a higher density of total muscarinic receptors (fmol/mg protein) in the trachea (720+/-59 nmol/L) than in bronchi (438+/-48 nmol/L) or lung (22 +/- 3 nmol/L). Competitive binding studies using [3H]NMS and the unlabelled subtype-selective antagonists pirenzepine and telenzepine (M1), methoctramine and himbacine (M2), 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) (M3), tropicamide (M4) and mamba toxin (MT-3) (M4) indicated the presence of at least three muscarinic receptor subtypes in peripheral lung tissue (50:40:24-28%: M2>M3>M1), whereas in bronchus and trachea M2 subtypes (87-90%) predominated over M3 (14-22%), and M1 subtypes were lacking. No differences were found between tissues in high-affinity binding sites for carbachol in the absence (31-36%) or presence of guanosine 5'-triphosphate (GTP) (approximately 100%). Western blotting for G-protein alpha-subunits showed a much more robust expression of G(alphai1/2) in the trachea (with highest receptor density) than in the lung or bronchi, whereas G(alphas)-protein was dominantly expressed in bronchus. Concomitantly, carbachol inhibited isoproterenol- and GTP-stimulated adenylyl cyclase activity with increasing muscarinic receptor expression (trachea > bronchi > lung). We conclude that the expression and signalling pathways of muscarinic receptors in the equine respiratory tract are segment-dependent. These receptors might contribute to the pathogenesis of COPD in the horse and could provide potential drug targets for the therapeutic use of anticholinergics in this species.

Alpha1-and beta2-adrenoceptors in the human liver with mass-forming intrahepatic cholangiocarcinoma: density and coupling to adenylate cyclase and phospholipase C.

Besides the regulation of hepatic metabolic pathways in which adrenoceptors are mainly involved, their effect on the second messenger cAMP is thought to be related to the growth and differentiation of neoplastic cells. However, few studies have been done on the status of these structures in the human liver affected by cholangiocarcinoma (CC). Thus, in this study, changes in densities of alpha1- and beta2-adrenoceptors (alpha1-and beta2-ARs) were investigated in membranes of human liver with cholangiocarcinoma, and for comparison, in membranes of non-adjacent non-tumour liver using the potent antagonists [3H]-prazosin and [1I]-iodocyanopindolol (ICYP) respectively. In addition, the activity of membrane-bound phospholipase C (PLC) and adenylate cyclase (AC) was also studied. In CC liver, the density of alpha1-and beta2-ARs was significantly reduced, compared with non-tumour liver tissues (alpha1-ARs: 23.38+/-4.69 vs 80.35+/-10.52, P=0.0002 beta2-ARs: 14.27+/-2.93 vs 33.22+/-4.32 fmol/mg protein, P=0.03), whereas the ligand affinities (KD) remained unchanged. The beta2-selective antagonist ICI 118,551 was about 100 times more potent in inhibiting ICYP binding than the beta1-selective antagonist CGP 20712A; thus, more than 98% of the beta-ARs were of the beta2-subtypes. The AC activity upon stimulants acting on beta-AR (isoprenaline), G-protein (GTP, NaF) and AC (forskolin) was decreased in CC liver. Similarly, noradrenaline-stimulated PLC activity was significantly reduced in tumour tissues. In conclusion, in CC liver the alpha1- and beta2-ARs density was down-regulated and the neoplastic invasion blunted AC and PLC activity. These quantitative changes may help to elucidate not fully understood pathogenetic mechanisms of disturbed hepatic metabolic processes, such as hypoglycemia during cancer in human liver.

Possible role of dexamethasone in sensitizing the beta-2-adrenergic receptor system in vivo in calves during concomitant treatment with clenbuterol.

Beta(2)-Agonists blunt the function of the beta-adrenoceptor G-protein adenylate cyclase-signalling system, whereas glucocorticoids reverse the agonist-mediated diminished beta-adrenergic responses; however, these effects have not been reported in vivo in calf lymphocytes. In this study, we first investigated the presence of the beta(2)-adrenergic receptors on calf lymphocytes, and second we tested the effects of either clenbuterol alone or in combination with dexamethasone on receptor expression and function (isoproterenol-induced intracellular adenosine 3',5'-cyclic monophosphate (cAMP) formation) in vivo. (-)-[(125)I]-Iodocyanopindolol (ICYP) binding to intact calf lymphocytes was rapid, saturable (maximal number of binding sites 987 +/- 89 ICYP-binding sites/cell, n = 4) and of high affinity (K(D) value 17.23 +/- 2.8 pmol/l, n = 4). These binding sites were of the beta(2)-subtypes of adrenoceptors as indicated by the fact that beta-agonists inhibited ICYP binding with an order of potency: (-)-isoproterenol > (-)-adrenaline > (-)-noradrenaline. Furthermore, the selective beta(2)-adrenoceptor antagonist ICI 118.551 was about >1,500 times more potent in inhibiting ICYP binding than was the beta(1)-selective adrenoceptor antagonist CGP 20712A. Consequently, calves were treated with clenbuterol (1.0 microg/kg b.i.d., i.v.) for 9 days alone or simultaneously with dexamethasone (0.1 mg/kg, i.v., once a day for 4 days). Clenbuterol decreased the number of lymphocyte beta(2)-adrenergic receptors by about 40-50% after only 48 h of drug administration. This was accompanied by a decrement in isoproterenol-induced lymphocyte cAMP formation. Upon application of both drugs, dexamethasone restored the clenbuterol-mediated decrease in beta(2)-adrenoceptors and cAMP production. Dexamethasone elevated the number of beta(2)-adrenoceptors and cAMP almost 1.5- to 2-fold at 24 h of drug administration, an effect that persisted for up to 24 h following drug withdrawal. Neither clenbuterol nor the combination with dexamethasone had an influence on the affinity of the receptor for the ligand. The present results demonstrate that dexamethasone in vivo upregulates the number and function of calf lymphocyte beta(2)-adrenoceptors, and thus enhances the sensitivity of the beta(2)-adrenoceptor signal-transduction pathway for clenbuterol during concomitant treatment with both drugs.

Dexamethasone-induced increase in lymphocyte beta-adrenergic receptor density and cAMP formation in vivo.

The influence of dexamethasone on the density of beta(2)-adrenergic receptors (beta(2)-adrenergic receptors (beta(2)AR) and on the intracellular adenosine 3',5'-cyclic monophosphate (cAMP) response was studied in equine lymphocytes in vivo. Dexamethasone (0.1 mg/kg/day, 1-5 days) raised the number of beta(2)AR - B(max) as assessed by (-)-[(125)I]iodocyanopindolol binding (ICYP) - to 2.5- to 3.5-fold as compared with control values. The increase in beta(2)AR number was fast (342 +/- 49 vs. 960 +/- 103 binding sites/lymphocyte after 24 h), reaching a maximum between 48 and 96 h (342 +/- 49 vs. 1,289 +/- 150 and 1,106 +/- 68 binding sites/lymphocyte, respectively). The isoprenaline-induced cAMP accumulation (measured by a [(3)H]-cAMP radioimmunoassay system) was concomitantly enhanced by dexamethasone (1.5- to 2.4-fold). Both parameters were reversible to a similar rate at dexamethasone withdrawal. The changes in the functional responsiveness of lymphocytes were not reflected by changes in the binding affinity for ICYP of beta(2)AR. These results demonstrate the in vivo glucocorticoid-mediated regulation of beta(2)AR in equine lymphocytes which has already been suggested on the basis of in vitro observations in other tissues.

Regulation of equine lymphocyte beta-adrenoceptors under the influence of clenbuterol and dexamethasone.

In 12 healthy horses, the effects of the beta2-agonist clenbuterol and the glucocorticoid dexamethasone on the lymphocyte beta2-adrenoceptor density and affinity (determined by (-)-[125I]-iodocyanopindolol binding) as well as its responsiveness (assessed by lymphocyte cyclic AMP [cAMP] responses to 10 micromol/l (-)-isoprenaline) were studied. Clenbuterol treatment, 2 x 0.8 microg/kg/day i.v. for 12 days, decreased significantly ICYP binding sites by approximately 30-40%; concomitantly, lymphocyte cAMP response to (-)-isoprenaline was reduced. After withdrawal of clenbuterol, beta2-adrenoceptor density and responsiveness gradually increased, reaching predrug levels after 4 days. The effects of dexamethasone on clenbuterol-induced desensitisation were further investigated. Administration of dexamethasone (1 x 0.1 mg/kg/day, i.v. for 5 days) immediately after clenbuterol withdrawal accelerated beta2-adrenoceptor recovery: only 24 h after administration dexamethasone restored the number of binding sites and cAMP response to (-)-isoprenaline to levels statistically indistinguishable from values before clenbuterol treatment. Three days after dexamethasone administration, lymphocyte beta2-adrenoceptors were further increased about 2-fold the pretreatment values, and this increase declined gradually after dexamethasone withdrawal, reaching baseline values after 4 days. Furthermore, in groups exposed simultaneously to both drugs, dexamethasone completely prevented clenbuterol-induced decrease in lymphocyte beta2-adrenergic receptor density and responsiveness. No significant change was observed in the dissociation constant for ICYP in any of the situations. We conclude that dexamethasone (glucocorticoids) can reverse and prevent Clenbuterol-induced desensitisation (down-regulation) of the lymphocyte beta2-adrenoceptors and therefore, a combined therapy with clenbuterol and dexamethasone may be potentially beneficial in horses suffering from chronic obstructive pulmonary disease (COPD).

Study of the plasma pharmacokinetics and faecal excretion of the prodrug olsalazine and its metabolites after oral administration to horses.

Olsalazine sodium (Dipentum*) has been used therapeutically against inflammatory bowel disease in human medicine as an alternative to sulphasalazine over the past 20 years. Bacteria in the colon split this prodrug into two molecules of the locally effective 5-aminosalicylic acid (5-ASA). Considering the potential therapeutic use in equine colitis, the pharmacokinetics of olsalazine (OLZ) after single oral administration to six horses at a dosage of 30 mg/kg was investigated. Plasma concentrations of OLZ, 5-ASA, and its main metabolite N-acetyl-5-aminosalicylic acid (Ac-5-ASA) were analysed by high-performance liquid chromatography methods. Evaluation of the plasma pharmacokinetics revealed a rapid, but low extent of absorption of OLZ (peak concentrations around 1 microg/mL at 0.5-1.5 h), and a delayed minimal absorption of 5-ASA (concentrations < 0.2 microg/mL, at 11-35 h), which is immediately metabolized to Ac-5-ASA. As indicators of the local availability in the colon, high faecal water concentrations of 5-ASA and Ac-5-ASA (mean C(max) about 300 and 130 microg/mL, respectively), but only traces of OLZ were found in faeces excreted 18-50 h after dosing. Of the administered OLZ dose 26% could be recovered from faeces, almost completely as 5-ASA and Ac-5-ASA. Routine clinical examination of the horses and assay of standard haematological and serum chemistry parameters before and after OLZ administration confirmed that a single dosage of 30 mg/kg was well tolerated. To estimate the systemic availability of 5-ASA liberated from OLZ, 5-ASA was administered i.v. at a dosage of 1.5 mg/kg to four horses and plasma concentrations of 5-ASA and Ac-5-ASA were determined. The pharmacokinetic evaluation showed a very low bioavailability of 2.4% for 5-ASA, released from orally administered OLZ. Furthermore, in an in vitro experiment, the metabolic transformation of 5-ASA to Ac-5-ASA mediated by bacteria in the caecal content of horses was determined at 38 degrees C for 31 h and compared with the metabolism data of the in vivo study. The markedly lower degree of acetylation in vitro supports the assumption that biotransformation of 5-ASA in vivo occurs not only by colonic bacteria, but also at other sites.

Identification and characterisation of beta-adrenoceptors on intact equine peripheral blood lymphocytes with the radioligand (-)-[125I]-iodocyanopindolol.

In this study, beta-adrenoceptors of intact equine lymphocytes were identified and subclassified by (-)-[125I]-iodocyanopindolol (ICYP) binding. ICYP binding to intact equine lymphocytes was rapid, saturable (maximal number of binding sites 320 +/- 20 ICYP binding sites/cell, n = 12) and of high affinity (KD value for ICYP 14.4 +/- 1.7 pmol/l, n = 12). Binding was stereospecific as shown by the 10 times greater potency of (-)-propranolol to inhibit binding than its (+)-isomer. Beta-adrenoceptor agonists inhibited ICYP binding with an order of potency: (-)-isoprenaline >(-)-adrenaline >(-)-noradrenaline; the same order of potency was obtained for agonist-induced stimulation of lymphocyte cyclic AMP content. The selective beta2-adrenoceptor antagonist ICI 118,551 was about 1000 times more potent in inhibiting ICYP binding than was the beta1-selective adrenoceptor antagonist CGP 20712A. It is, therefore, concluded that in intact equine lymphocytes, ICYP labels a class of functional beta-adrenoceptors that belong predominantly (>90%) to the beta2-adrenoceptor subtype; a small (<10%) beta1-adrenoceptor component, however, cannot be ruled out completely. ICYP binding to equine lymphocytes might be a suitable model to study function and regulation of the beta-adrenoceptor system in the horse in vivo. The aim of this study was to characterise the beta-adrenoreceptor subtypes present on equine lymphocytes.

Evidence for a trigger function of valproic acid in xenobiotic-induced hepatotoxicity.

The influence of the antiepileptic drug, valproic acid (2-n-propylpentanoic acid), on the hepatocellular capacity, to cope with an extrinsic oxidative stress was investigated. Freshly isolated rat hepatocytes exposed to therapeutic concentrations of valproic acid (0.25-1.0 mmol/l) were less resistant than controls, as evidenced by a significant cytotoxic response after challenge of the cells with a non-toxic dose of allyl alcohol (2-propen-1-ol). Valproic acid alone was not toxic to hepatocytes even at ten times higher concentrations (10 mmol/l), suggesting that cell damage was not a mere additive effect. Incubation with valproic acid plus allyl alcohol induced an irreversible depletion of hepatocellular glutathione, in contrast to allyl alcohol alone which induced a transient loss. Hepatocytes treated with valproic acid plus allyl alcohol were protected by N-acetylcysteine, a precursor of glutathione. These findings indicate that valproic acid affects hepatocellular defence mechanisms and suggest that a predisposition of hepatocytes to oxidative stress may play a role in the fatal hepatotoxicity of valproic acid in epileptic patients.

A contribution to safety assessment of veterinary drug residues: in vitro/ex vivo studies on the intestinal toxicity and transport of covalently bound residues.

1. The gastrointestinal fate of protein-bound residues of the model compound furazolidone (FZD) was investigated in vitro and ex vivo. Protein-bound residues were generated in rat liver microsomes, isolated by solvent extraction and digested with 0.5% hydrochloric acid and Pronase E. 2. During digestion, 3-amino-2-oxazolidinone (AOZ), the side chain of furazolidone, was partly released from bound residues. 3. The absorption of free AOZ and digested protein-bound residues was tested in isolated perfused rat gut segments (IPGS) and in the intestinal cell line Caco-2. Free AOZ was transfered both in the IPGS model and in Caco-2 monolayer cultures, while no indications for passage of bound residues were obtained. 4. No acute toxicity of AOZ or digested food residues respectively was observed in gut segments and Caco-2 cells at concentrations that were substantially above maximum residue levels to be expected in food of animal origin after administration of therapeutic doses. 5. The results demonstrate that digestive processes can alter the chemical nature of drug residues and yield degradation products that may be bioavailable for the consumer. Thus, the covalent binding of xenobiotics to macromolecular tissue constituents cannot necessarily be regarded as an irreversible endpoint of residue bioavailability and toxicity.

[Legal determinations concerning narcotics which are important for the veterinarian]. / Für den Tierarzt wichtige betäubungsmittelrechtliche Bestimmungen.

In January 1998 the German legislation of narcotic drugs was subject of important changes also concerning the use of narcotic drugs in veterinary practice. The annexes I-III of the law of narcotic drugs (BtMG) containing all substances classified as narcotics were reorganized. Furthermore, the directive on the prescription of narcotic drugs (BtMVV) was changed with the aim to facilitate the prescription as well as the supply of narcotic drugs by veterinarians in their home dispensary. The directive on inland trade of narcotics (BtMBinHV) regulating the distribution of narcotic drugs from wholesalers to veterinarians remained unchanged. The following regulations of prescription or distribution of narcotic drugs by veterinarians for treated animals are described in detail: notification of participation on supply of narcotic drugs, general principles of the use of narcotic drugs, safety measurements, inactivation of narcotics, prescription for patients or for use in veterinary practice/clinics, details of prescription, supply to animal owners by the veterinarian home-dispensary, book-keeping, purchase of narcotic drugs.