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

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

Endotoxin-induced fever and associated haematological and blood biochemical changes in the goat: the effect of repeated administration and the influence of flurbiprofen

Flurbiprofen, a potent non-steroidal anti-inflammatory and antipyretic agent, was given as an intravenous infusion (2 mg/kg) followed by a bolus injection of 1 mg/kg six hours later. After drug administration body temperature and rumen contractions were slightly depressed, whereas urea values gradually increased; serum sorbitol dehydrogenase (SDH) activity, plasma iron concentration and the number of circulating lymphocytes were significantly lower. Intravenous injection of endotoxin from Escherichia coli O111B4 (0.1 microgram/kg) caused shivering, fever, inhibition of rumen contractions, changes in heart rate, lymphopenia, neutropenia followed by neutrophylic leucocytosis, changes in urea values, hypoferraemia, hypozincaemia and a decline in serum alkaline phosphatase (ALP) activity, whereas gamma-glutamyltranspeptidase, glutamic oxalacetic transaminase, lactic dehydrogenase and SDH values were not significantly altered. Pretreatment with flurbiprofen completely abolished the febrile reactions to endotoxin. The endotoxin-induced inhibition of rumen contractions was only delayed. The drug blocked the initial tachycardia to endotoxin but did not prevent the secondary biphasic increase in heart rate. Flurbiprofen failed to modify the endotoxin-induced decrease in both plasma zinc and serum ALP activity whereas the decline in plasma iron concentration was delayed. After drug pretreatment the changes in circulating white blood cells were more pronounced. These data demonstrate that most of the haematological, blood biochemical and clinical effects of endotoxin cannot be blocked by flurbiprofen, and that these effects are not due to the increase in body temperature alone. Tolerance induced by repetitive daily intravenous administration of endotoxin resulted in an almost complete abolition of all the effects. However, the plasma iron values from tolerant goats were significantly lower than those from non-tolerant animals, which demonstrates that the development of a refractory state can result in modification of this biochemical parameter.     

Antimicrobial drug use in veterinary medicine

Recognizing the importance of antimicrobial resistance and the need for veterinarians to aid in efforts for maintaining the usefulness of antimicrobial drugs in animals and humans, the Board of Regents of the American College of Veterinary Internal Medicine charged a special committee with responsibility for drafting this position statement regarding antimicrobial drug use in veterinary medicine. The Committee believes that veterinarians are obligated to balance the well-being of animals under their care with the protection of other animals and public health. Therefore, if an animal's medical condition can be reasonably expected to improve as a result of treatment with antimicrobial drugs, and the animal is under a veterinarian's care with an appropriate veterinarian-client-patient relationship, veterinarians have an obligation to offer antimicrobial treatment as a therapeutic option. Veterinarians also have an obligation to actively promote disease prevention efforts, to treat as conservatively as possible, and to explain the potential consequences associated with antimicrobial treatment to animal owners and managers, including the possibility of promoting selection of resistant bacteria. However, the consequences of losing usefulness of an antimicrobial drug that is used as a last resort in humans or animals with resistant bacterial infections might be unacceptable from a public or population health perspective. Veterinarians could therefore face the difficult choice of treating animals with a drug that is less likely to be successful, possibly resulting in prolonged or exacerbated morbidity, to protect the good of society. The Committee recommends that voluntary actions be taken by the veterinary profession to promote conservative use of antimicrobial drugs to minimize the potential adverse effects on animal or human health. The veterinary profession must work to educate all veterinarians about issues related to conservative antimicrobial drug use and antimicrobial resistance so that each individual is better able to balance ethical obligations regarding the perceived benefit to their patients versus the perceived risk to public health. Specific means by which the veterinary profession can promote stewardship of this valuable resource are presented and discussed in this document.     

Drugs and renal function

This article considers the interactions between drugs and renal function, first, the adverse effects of nephrotoxic drugs and the changes in drug response associated with renal failure. It then discusses drugs intended to alter urinary sodium excretion (diuretics) and urinary pH as well as drugs which alter renal concentrating and diluting capacity. In each case emphasis is placed on the relationship between the drug effects and normal renal mechanisms. Reasons for the special vulnerability of the kidney to the toxic effects of drugs (e.g. antibiotics) are discussed and the practical problems of adjustment of drug dosage according to renal function are indicated. Finally, consideration is given to drugs, notably oral sorbents, which can partially substitute for renal function and might therefore eventually prove ideal for the management of advanced renal failure in small animals.     

Treatment of heartwater: potential adverse effects of furosemide administration on certain homeostatic parameters in normal sheep

Diuretics, in particular furosemide, are generally recommended as a supportive treatment in the advanced stages of heartwater in ruminants. However, after what appeared to be possible adverse effects accompanying its use in field cases of heartwater, the effects of this drug on certain blood and urine parameters were investigated in normal sheep at the same dose rates. Diuresis with concomitant natriuresis was significant after furosemide administration, as was the expected plasma volume decrease. Other significant changes included metabolic alkalosis, hypokalaemia and reduced blood ionised calcium. The difference in duration of the diuretic effect and the duration of the changes in blood parameters from c. 3 h and c. 6 h respectively make it difficult to determine a time interval between successive treatments with furosemide. It appears that the probable cause of death of sheep with heartwater is a drastic reduction in blood volume and decreased cardiac output that leads to general circulatory failure. A therapeutic approach that involves further loss of plasma volume due to diuresis appears contradictory. The added effects of potentiating respiratory alkalosis and the terminal drop in blood ionised calcium seen in heartwater-affected animals indicate that the use of furosemide in supportive treatment of this disease is not warranted.     

Advances in topical glaucoma therapy

Significant advances have recently been achieved in the development of topical glaucoma medications. The primary advantage of a topical preparation is the reduced incidence of adverse systemic effects attributable to a given drug compared to its systemically administered counterpart. However, the strong protective barrier of the eye forces topical ophthalmic preparations to be highly concentrated and in some cases, they have the potential to produce unwanted systemic effects, particularly in smaller animals. Oral carbonic anhydrase inhibitors are commonly associated with adverse effects in both humans and animals. Two recently developed topical carbonic anhydrase inhibitors, dorzolamide and brinzolamide, have shown promise in reducing intraocular pressure in animals and systemic side effects are apparently limited with their use. The topical alpha2-agonist apraclonidine, on the other hand, effectively reduces intraocular pressure in cats and dogs, but in its currently available form is likely to induce unwanted systemic effects. Latanoprost is a topical prostaglandin F2alpha analog that has proven effective in reducing intraocular pressure in dogs and horses, but while systemic side effects have not yet been reported, this topical preparation may exacerbate pre-existing or concurrent ocular inflammatory disease.     

The short-term clinical efficacy of amitriptyline in the management of idiopathic feline lower urinary tract disease: a controlled clinical study

In a controlled study, the effects of amitriptyline compared with that of a placebo in cats suffering from idiopathic Feline Lower Urinary Tract Disease (FLUTD) have been investigated. Thirty-six animals were selected by veterinary practitioners and treated with a placebo or 10mg amitriptyline once daily. All animals received concomitant antibiotic treatment. A total of 24 cats were included in the final assessment of the results. The severity of symptoms before and after treatment were compared between groups and showed no significant difference. Results indicated that the 7-day course of 10mg amitriptyline was not effective in the treatment of idiopathic FLUTD. Thus, it is considered not to be beneficial as a short-term therapy where the therapeutic results depend on peripheral effects of the drug. Long-term effects may be expected 4 or more weeks after the start of therapy and need to be further investigated.     

The effect of dexamethasone and promethazine in combination with buparvaquone in the management of East Coast fever

The effects of dexamethasone and promethazine on the amelioration of pulmonary oedema in East Coast fever were investigated. The clinical effects of these drugs were further investigated when used in conjunction with the antitheilerial drug, buparvaquone. In the first experiment, 15 crossbred (Friesian x Zebu) steers were divided into four groups. With the exception of the animals in group IV, that served as a control group all the others were infected with Theileria parva sporozoites. On the second day of the febrile reaction, the steers in groups I and II were treated with dexamethasone (0.1 mg/kg) and promethazine (1 mg/kg), respectively. Group III steers served as the infected untreated controls. On the fifth day of the febrile reaction the animals in groups I, II and III were infused intravenously with tattoo ink suspension and 1 h later sacrificed for post-mortem examination and tissue sampling. The clinical picture indicated that both drugs significantly mitigated dyspnoea and the post mortem examination revealed a significant reduction in morphological changes. Tattoo ink particle count reflected a significant (P< 0.01) reduction in vascular leakage in the treated animals, with promethazine being significantly (P < 0.05) more effective than dexamethasone in this respect. In the second experiment, 18 steers were infected with T. parva sporozoites, and then were randomly allotted into three groups each of which contained six animals. After the onset of ECF clinical signs, the animals in the first two groups were treated with buparvaquone in combination with either dexamethasone (group I) or promethazine (group II), and the third group was treated with buparvaquone alone. The results indicated that all the animals in groups I, II and III recovered well and no significant differences were observed in clinical disposition between the groups. Two months later, serum samples were collected from the refractory animals and demonstrated the presence of antibodies against T. parva. When the animals were subsequently artificially challenged with T. parva, none of them succumbed to clinical disease. The same T. parva stabilate stock was used in both experiments and it proved to be infective in a separate batch of steers.     

Effect of composition and quality of diet and feeding time on the kinetics and efficacy of some anthelmintic drugs: a mini-review

This article reviews the literature dealing with the effects of composition and quality of diet and feeding time on the pharmacokinetics and efficacy of some anthelmintic drugs in ruminants. Studies have suggested that greater availability, and therefore improved anthelmintic activity, is possible through temporary feed restriction. It is also recommended that anthelmintic drugs should not be given to animals whilst they are maintained on large feed intakes, particularly of lush pasture that promotes rapid gastric transit, as this may reduce drug availability and anthelmintic efficacy. Generally, feeding animals low-quality fibrous diets reduces the passage rate of digesta and allows more time for absorption of several anthelmintic drugs and their metabolites from the gut. Some kinetic data of drugs given to animals on such diets may be slightly different, but this does not necessarily indicate alteration of the dosages of the anthelmintic drug. Nonetheless, due consideration should be given to anthelmintic dosages under various dietary regimes if optimum efficacy is to be achieved at all times.     

Controversial issues in drug treatment during cardiopulmonary resuscitation.

The goal of advanced life support in CPR must be to restore and maintain respiratory and hemodynamic effectiveness, and to correct the underlying dysrhythmia. Optimal basic life-support techniques must be continued to meet these goals. Many drugs have been suggested in the treatment of cardiac arrest, but unfortunately, drug effects are inconsistent and resuscitation rates remain low. Epinephrine, atropine, lidocaine, bretylium, and naloxone remain important drugs for consideration in CPR in most animals with cardiac arrest. The best chance of survival remains in early recognition of animals susceptible to arrest and in treatment of the underlying cause.     

Bovine coccidiosis: protective effects of low-level infection and coccidiostat treatments in calves

Twenty coccidia-free Holstein bull calves were allotted to groups to study effects of treatment with lasalocid and decoquinate on subsequent resistance to coccidiosis (Eimeria spp infections). Calves fed medicated rations of either drug at dosages of 50 mg/kg of feed (approx 1.2 mg/kg of body weight) had significantly fewer oocysts (P less than 0.01) than did nontreated controls regardless of other procedures used. Treated calves premunized with 2,000 oocysts/day for 5 days and later challenge inoculated with 200,000 oocysts did not develop diarrhea, unless the drugs were withdrawn from feed. Animals premunized (2,000 oocysts/day for 5 days) in absence of drug were no more resistant to the challenge inoculation than nonpremunized animals. These results indicated that lasalocid and decoquinate were efficacious coccidiostats and protected calves as long as they were administered. Cessation of drug treatment usually resulted in appearance of oocysts in feces and diarrhea. Premunization alone cannot be expected to prevent coccidiosis when animals are exposed to large numbers of oocysts.     

乌鲁木齐地区不同健康状态和饲养环境中宠物源沙门菌耐药特征分析

为探究不同健康状态和不同饲养环境下沙门菌对临床常用抗菌药物的耐药情况及耐药基因携带情况,采用琼脂稀释法对健康与患病、家养与流浪宠物粪样中分离出的99株沙门菌进行临床常用12种抗菌药物的耐药性检测;用PCR方法对获得的耐药菌株进行相关耐药基因的检测。结果:分离出的宠物源沙门菌对所有被检的抗菌药物耐药率均未超过10.0%,对头孢噻呋、安普霉素、阿米卡星、卡那霉素和硫酸庆大霉素100%敏感;患病动物源沙门菌对被检抗菌药物的耐药率高于健康动物源沙门菌,家养动物源沙门菌对被检抗菌药物的耐药率高于流浪动物源沙门菌(P<0.05)。耐药基因检测结果显示:floR的检出率为3.0%;ant(3″)-Ia、tetA、tetB检出率均为2.0%;blaTEM、oqxA、aac(6′)-Ib-cr基因检出率均为1.0%,未检出其他被检基因。结果表明,新疆乌鲁木齐市不同健康状态和不同饲养环境下宠物源沙门菌对被检抗菌药物的耐药率及耐药基因携带率低,仅有2株沙门菌存在ant(3″)-Ia+tetA+tetB 3种耐药基因共存情况。根据试验结果发现检出的耐药表型与耐药基因之间存在相关性,可根据药敏试验结果合理选用抗菌药物进行临床细菌病的治疗。     

The effect of water deprivation on the pharmacokinetics of antipyrine and sulphadimidine following intravenous administration in Nubian goats

The effect of water deprivation on the pharmacokinetic parameters of antipyrine and sulphadimidine in the Nubian goat was studied. Water deprivation, to a level of dehydration at which the animals lost an average of 7.5% body weight, resulted in a significant reduction in antipyrine clearance (p<0.05), and a consequently increased AUC value (p<0.05). No effect was observed on the distribution parameters of the drug. In dehydrated animals which had lost an average of 10% or 12.5% of their body weight owing to water deprivation, significant changes were found in the distribution and elimination pharmacokinetic parameters of antipyrine and sulphadimidine. The volume of distribution was significantly decreased, resulting in elevated plasma levels for the two drugs compared to normally watered animals. Significant decreases in clearance and subsequent prolongation of the elimination half-lives were observed during these periods of water deprivation. These changes in the disposition kinetics of the two drugs may be attributed to the loss of total body water and extracellular fluids and changes in the liver and kidney functions taking place during dehydration.     

Isometamidium in pigs: disposition kinetics, tissue residues and adverse reactions

The disposition and adverse effects of the anti-trypanosomal drug isometamidium in pigs were evaluated. Following intramuscular administration of the drug at doses of 0.5, 15 and 35 mg kg-1, the drug was rapidly absorbed within 15 to 30 minutes to reach maximum plasma concentrations of 12 to 477 (n = 6), 302 to 655 (n = 4) and 1620 (n = 1) ng ml-1, respectively. No drug was detectable in plasma (less than 5 ng ml-1) 24 hours after drug administration at the three doses used. The half-lives of disappearance of the drug from plasma during the terminal phase were 7.12 h for the pigs given a dose of 15 mg kg-1, and 7.20 h for the pig which received a dose of 35 mg kg-1. At all the intramuscular injection sites, high drug concentrations were found six weeks after administration. The most dramatic adverse reactions observed were: one death after intramuscular administration at a dose of 35 mg kg-1 to two animals, and two deaths after intravenous administration at a dose of 2 mg kg-1 to two animals. For all these cases, the immediate cause of death was acute cardiovascular collapse. Biochemical analyses and gross and histological examinations showed that the animals that tolerated the high doses of 15 and 35 mg kg-1 given intramuscularly had extensive and severe tissue damage at the injection sites. Significant increases in plasma gamma-glutamyltransferase and alanine aminotransferase following drug administration suggested a degree of hepatobiliary damage.     

Pharmacokinetics in immature animals: a review.

Differences in drug pharmacokinetics between newborn and adult mammals are reviewed. The pharmacokinetic alterations during the maturation process are related to changes in the pattern of absorption, distribution, metabolism, and renal excretion. The most pronounced feature in neonates vs adults is the prolonged elimination half-life of drugs. The main factors causing delayed elimination are under-developed renal clearance and immature metabolism of drugs. Special attention has to be paid to central nervous system depressants and to drugs that are extensively metabolized because they will accumulate with repeated dosing of newborn animals.     

Effects of fluprostenol administration in mares during late pregnancy

The effectiveness of the prostaglandin F analogue fluprostenol in inducing labour in the mare was examined by giving sequential injections over the last 50 days of gestation. The behavioural and endocrine changes elicited by the drug in pregnant and non-pregnant animals and in foals were also studied. Fluprostenol (250 or 500 micrograms intramuscularly) failed to induce labour before 320 days gestation; thereafter its effect was capricious. Twelve mares foaled 1 to 36 h after the last test; eight delivered normal, viable, apparently 'term' foals and four produced stillborn/premature animals. Eight of the deliveries (five term and three pre-term foals) could be ascribed to the action of fluprostenol because they occurred 1 to 6 h after its administration, at a time when spontaneous foaling would have been unlikely. The other four mares foaled between 12 and 36 h after the fluprostenol injection and it is therefore doubtful whether there was a causal relationship between the two events. In the mares which delivered viable foals the pre-partum milk samples were characteristic of full term samples with respect to calcium, sodium and potassium. Those which delivered premature/stillborn foals had low calcium and a high sodium/potassium ratio in the pre-partum milk. Behavioural changes (sweating, increased respiration, defaecation etc), which varied in intensity between tests and individuals, were seen in all three groups of animals following the administration of fluprostenol. These changes were accompanied by rises in plasma cortisol and adrenocorticotrophic hormone concentration during the 2 h sampling period, suggesting a centrally mediated response to the drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

Typing of Mycobacterium bovis isolates from cattle and other animals in the same locality

The effects of high doses of the beta-2 agonists iso-prenaline, salbutamol and fenoterol on the myocardium were studied experimentally in sheep. Each drug was given intravenously in progressively increasing doses to four sedated animals and four controls. The experiments were repeated during hypoxaemia and animals were necropsied 3 days later.     

Simulation of Pastoral Management in Mongolia: An Integrated System Dynamics Model

High grazing density has given rise to concerns about grassland degradation in periurban areas in Mongolia. Moreover, whether livestock can increase without harming the vegetation in these areas in Mongolia and what types of policy measures should be implemented is not documented. As such, this study develops an integrated simulation model of grassland biomass, animal growth, and livestock management for a forest-steppe area in northern Mongolia and conducts a simulation on long-term changes. The simulations show that, under current conditions, the number of animals will continue to increase, while the grassland biomass will decrease. Cooperative grassland management would lead to an increase in grassland biomass and higher incomes for herders. Furthermore, herders’ population changes would have a significant impact on animal density adjustments, while the effects of conventional economic measures, such as a tax on animals, would be limited if all other conditions remain constant. Consequently, the synergistic effects of herder population changes and cooperative management can contribute toward maintaining the herders’ income while preserving the grassland ecosystem.     

Prolonged depression of thermoregulation after xylazine administration to cats

Xylazine administered subcutaneously (s.c.; 1–4 mg/kg) or intravenously (i.v.; 0.5-2 mg/kg) to cats consistently caused dose-related decreases in body temperature which were maximal 3–4 h after injection and lasted for at least 12 h. Otherwise the animals appeared to have recovered fully from the central nervous system effects of the drug within 1.5–3.5 h. Xylazine-induced hypothermia developed more rapidly in cats placed in a 4°C environment and, in contrast, was replaced by a hyperthermic response in cats placed in a 32°C environment. These changes in body temperature were not opposed by compensatory thermoregulatory effector activity such as shivering or tachypnea. This pattern of responses at varied environmental temperatures is indicative of a general depression of the thermo-regulation. Thus, animals given xylazine should not be exposed to extreme heat or cold for several hours to avoid development of hyper- or hypothermia.     

Antifungal activity of ketoconazole with emphasis on zoophilic fungal pathogens

The antifungal activity of ketoconazole was studied against fungal pathogens associated with various mycotic infections in animals. A concentration of 10 micrograms of ketoconazole/ml of medium proved fungicidal to Trichophyton verrucosum. The same concentration acted as a strong fungistat against the majority of the tested dermatophytes. Yeasts were generally more sensitive than yeast-like pathogens. Ketoconazole also proved fungicidal against Pityrosporon canis and strongly inhibitory on Cryptococcus neoformans and Torulopsis famata at the lowest used concentration. Candida albicans, Candida tropicalis, and Aspergillus fumigatus required a higher concentration in order for the drug to demonstrate some gross changes. However, variable serious microscopic effects were detected. The most marked effect of ketoconazole was in connection with the dimorphic fungi. The action was fungicidal or strongly inhibitory on both the mycelial form and the tissue phase, respectively. The effect of the drug involved both gross morphologic and microscopic changes of the fungi. The mechanism of action of the drug is described in detail. The results are promising and encouraging for the use of ketoconazole in veterinary medicine.