Review of the pharmacokinetics,interactions and adverse reactions of cyclosporine in people,dogs and cats

Cyclosporine is being increasingly used in veterinary medicine. Oral formulations of the drug have found many therapeutic uses, but topical formulations have met with only limited success, probably owing to their poor penetration through the stratum corneum. The concurrent use of ketoconazole to inhibit cyclosporine metabolism has been shown to reduce the required dose and hence the cost of cyclosporine therapy. In human medicine, adverse reactions to the drug, especially nephrotoxicity, are common but in dogs given the commonly used oral dose of 5 mg/kg per day there have been few adverse reactions. However, no toxicity studies lasting longer than 12 months have been carried out in this species. This paper reviews the pharmacokinetics, drug and procedural interactions, contraindications and the adverse reactions to cyclosporine, with particular reference to its use in the treatment of dermatological conditions in dogs, cats and people.     

The ACVD task force on canine atopic dermatitis (X): is there a relationship between canine atopic dermatitis and cutaneous adverse food reactions?

In humans, allergies to foods are known to induce skin lesions in some patients with atopic dermatitis. This is particularly evident in infants with severe atopic dermatitis. Food allergy in humans is an IgE-mediated hypersensitivity in most cases, and thus has the same (or very similar) pathogenic mechanism of disease induction as environmental allergen-induced atopic dermatitis. Cutaneous adverse food reactions and atopic dermatitis in dogs are often indistinguishable from each other on historical and clinical grounds alone. Limited current evidence suggests that dogs with cutaneous adverse food reactions may be predisposed to developing atopic dermatitis. However, confirmation of any association between these two diseases in dogs awaits further elucidation of the pathogenic mechanism of cutaneous adverse food reactions, and epidemiological studies of the relative prevalence of these diseases in relation to each other and the general population.     

氟苯尼考及其制剂研究进展

本文对近年来国内外氟苯尼考药物、制剂及不良反应等报道进展进行综述。阐述了国内氟苯尼考的生产、质量、原料、制剂研发进展，氟苯尼考的毒副反应等报道进展，分析了氟苯尼考制剂引发不良反应的几种可能因素，并对氟苯尼考新制剂工艺在养殖业减抗限抗的时代背景下发挥氟苯尼考更大应用价值做出展望。文章通篇对氟苯尼考关键点综述有助于养殖场及研发人员加深对氟苯尼考的认识，并制定养殖场更合理的氟苯尼考制剂使用方案。     

Overview of suspected adverse reactions to veterinary medicinal products reported in South Africa (March 2003 - February 2004)

The Veterinary Pharmacovigilance and Medicines Information Centre is responsible for the monitoring of veterinary adverse drug reactions in South Africa. An overview of reports of suspected adverse drug reactions received by the centre during the period March 2003 to February 2004 is given. A total of 20 reports was received. This had declined from the previous year. The general apathy with regards to the reporting of adverse drug reaction has prompted the Medicines Control Council to make reporting a legal obligation on all members of the veterinary and medical profession as from August 2004. The majority of reports involved suspected adverse reactions that occurred in dogs and cats. Most of the products implicated were Stock Remedies. Veterinarians predominantly administered these products. Only two reports were received from a veterinary pharmaceutical company.     

Rabies and brucellosis immunization status and adverse reactions to rabies vaccines in veterinary students.

Rabies pre-immunization has been recommended for high risk professions, including veterinarians. Cell-cultured rabies vaccines have considerably reduced the risk of post-vaccination neurological reactions found in earlier vaccines. However, some adverse reactions have been reported with Human Diploid Cell Vaccines. 329 French veterinary students were surveyed about their rabies and brucellosis vaccination status, the occurrence of adverse reactions to rabies vaccine, and their antibody titer monitoring practices. Questions also were asked to determine if mandatory rabies pre-exposure immunization upon entry to veterinary school motivated students to maintain their rabies pre-exposure vaccination. The overall vaccination rate was 98.5% for rabies and 17% for brucellosis. 19% of the rabies vaccinated students reported some form of adverse reaction, whatever the vaccine brand used, but not experienced systemic allergic reaction. Adverse reactions were twice more frequent in female than male students and were more frequent after primary series than revaccination series (Relative Risk = 1.76). Despite the mild reactions encountered, rabies pre-exposure vaccination has been well-accepted by French veterinary students. In contrast, vaccination against brucellosis was not as well-accepted for prophylaxis.     

Adverse reactions to veterinary drugs reported in Sweden during 1991–1995

The present article gives a summary of suspected adverse reactions reported by Swedish veterinarians during the period 1991–1995. The summary shows that severe adverse drug-reactions sometimes occur in Swedish veterinary practice. In horses, several cases of acute reactions in animals treated with procaine benzylpenicillin were reported and seven horses died within a few minutes after intramuscular injections of the drug. In cattle and swine most reports referred to the use of antimicrobial agents. In dogs reactions to vaccines were the most frequently reported adverse effects. The reactions were, however, usually rather mild. In dogs there were also several reports of severe reactions related to treatments with non-steroid anti-inflammatory drugs (NSAID) and α₂-receptor agonists. Amongst the reports six deaths were observed for each of these groups of drugs. In cats, as in dogs, adverse effects to vaccines were the most frequently reported reactions.     

The use of microbiological end-points in the safety evaluation and elaboration of maximum residue limits for veterinary drugs intended for use in food producing animals

The safety evaluation of veterinary drugs intended for use in food producing animals relies heavily on the results of toxicity studies in laboratory animals, supported where possible by any data resulting from human exposure. The general approach involves the calculation of an acceptable daily intake which in turn can be used to elaborate maximum residue limits. It is an approach used in the European Union, in other countries and at the international level. In recent years, concern has been expressed over the presence of microbiologically active residues of veterinary drugs in food and their possible effects on the human gastrointestinal microflora. Methodologies for conducting microbiological safety studies have been investigated and approaches to microbiological safety assessments have been debated. The whole approach has proved to be controversial, partly because there are considerable doubts over the ability of low concentrations of antibiotic substances to produce adverse effects on the human gut flora and partly because there are no validated methods for testing for these attributes. This paper reviews the problems in some detail and discusses the regulatory consequences.     

Effects of pine processionary caterpillar Thaumetopoea pityocampa contact in dogs: 41 cases (2002-2006)

The pine processionary caterpillar, Thaumetopoea pityocampa, is considered an emerging pine pest in Mediterranean countries, with high medical relevance. In recent years, adverse reactions reports in humans following contact with T. pityocampa have been increasingly reported. Dogs living in pinewood areas are also frequently exposed to the caterpillar. This work consisted on a retrospective study of 41 cases of lepidopterism. All dogs presented drooling, dysphagia, submandibular lymphadenomegaly and clinical signs of pain. The animals were distributed in three groups, according to the time span from exposure to the caterpillar until presentation: up to 2 h (group 1), 2-5 h (group 2) and more than 5 h (group 3). All animals from groups 2 (n = 5) and 3 (n = 9), and eight dogs from group 1 (n = 27) developed lingual necrosis. Lepidopterism coursed through a predictable clinical pattern. The evolution was mainly dependent on the time span between exposure to the caterpillar and medical intervention, which should take place earlier than 2 h from exposure.     

Suspected adverse reactions to medicines during 1989

There was an increase in reports of suspected adverse reactions to veterinary medicines in 1989 with 329 reports (compared with 206 in 1988), from veterinary surgeons, farmers and the public, comments the Veterinary Medicines Directorate (VMD). Suspected adverse reactions to clostridial/pasteurella vaccines in sheep were a dominant feature and important experience was gained both in terms of liaison with the farming press, and in handling large scale incidents involving PML products. The general trend towards increased reporting of adverse drug effects continues. The UK is the only EC member state to have a PML system and the VMD is looking with some urgency at ways of ensuring the more representative reporting of all categories of drug. Substantial liaison with the veterinary pharmaceutical industry occurred during the year and 204 product reports were requested from companies.     

Principles of transfusion medicine in small animals.

The purpose of this review was to provide the reader with an updated overview of small animal transfusion medicine, and an approach to integrating it into private practice, based on a review of the veterinary and human literature spanning the last 3 decades. Electronic, online databases that were searched included CAB International and Medline; multiple keywords or subject headings were searched that were appropriate to each of the sections reviewed: canine and feline blood groups, blood-typing and crossmatching, donors, blood collection, storage, blood components, blood transfusion, blood component therapy, blood substitutes, and adverse reactions. The safe use of blood component therapy requires knowledge of blood groups and antibody prevalence, and knowledge of the means to minimize the risk of adverse reactions by including the use of proper donors and screening assays that facilitate detection of serological incompatibility. The 2 assays available to the practitioner are crossmatching, which is readily done in-house, and blood typing. Blood typing is available in the form of a commercial testing kit, through use of purchased reagents, or via a request to an external laboratory. The risk of potentially fatal adverse reactions is higher in cats than in dogs. The decision to transfuse and the type of product to administer depend on several factors, such as the type of anemia and the size of the animal. In conclusion, transfusion medicine has become more feasible in small animal practice, with improved access to blood products through either on-site donors, the purchase of blood bank products, external donor programs, or the availability of blood component substitutes.     

Evaluation of serum allergen-specific IgE for the diagnosis of food adverse reactions in the dog

A new monoclonal enzyme-linked immunoassay (ELISA; CMG IMMUNODOT, Fribourg, Switzerland) measuring food antigen-specific serum IgE was used in an attempt to investigate food allergen-specific IgE in dogs. The serum of eight dogs with clinically proven adverse reactions to specific proteins was tested for beef, cow's milk, pork, lamb, hen's egg, soybean, fish mix (cod/sole), peanut, maize and wheat flour. The control group consisted of three healthy dogs, three dogs with nonallergic skin disease, two dogs with atopy, a cat and a horse. Only three mild positive reactions to beef, lamb and peanut, respectively, were found in this study; the sera were from two control dogs with the clinical diagnosis of dermatophytosis and atopy. None of the animals with confirmed food adverse reactions showed positive reactions. This study indicates that the diagnosis of food adverse reactions in the dog by measuring allergen-specific IgE with the used mononuclear ELISA is unreliable.     

Investigation of developmental toxicity and teratogenicity of macrolide antibiotics in cultured rat embryos

Macrolides are considered to be one of the safest anti-infective groups in clinical use, with severe adverse reactions being rare. However, there are limited data about their embryotoxicity and teratogenicity. We aimed to investigate and compare the effects of these agents on embryonic growth and development. Rat embryos were cultured in vitro for 48 h in rat serum. Whole rat serum was used as a culture medium for the control group while different concentrations of spiramycin and azithromycin (1.25-6.25 microg/ml), and clarithromycin (2.5-30 microg/ml) were added to rat serum for the experimental groups. Dose-dependent effects of macrolides on embryonic developmental parameters were compared using morphological methods. Embryos were evaluated for the presence of any malformations. After morphological examination of the embryos, total DNA was extracted from the cells using standard procedures to determine fragmentation of nuclear DNA of embryonic cells. When compared with the control embryos, the macrolides significantly decreased all growth and developmental parameters dose dependently. While clarithromycin was found to cause more developmental toxicity than spiramycin and azithromycin, azitromycin was determined to have more teratogenicity potential. Compared with controls, there was no difference regarding the fragmentation of nuclear DNA of all the agents used. According to these results, when the toxic and teratogenic potential of the used agents compared, because of the lower toxic and teratogenic effects observed with spiramycin, this agent may be preferred for parturients.     

Veterinary pharmacovigilance. Part 4. Adverse reactions in humans to veterinary medicinal products

Although seemingly rare, adverse reactions to veterinary products do occur. These may arise from inadvertent exposure during use or as a result of occupational accidents. They are often mild in nature and include adverse effects such as minor skin reactions. However, more serious reactions may occur, and they are not restricted to the effects of the veterinary medicines themselves. For example, high-pressure injection injuries may occur as a result of accidents occurring during animal vaccination operations. This paper reviews some of these events, mentions where appropriate the regulatory actions taken, and describes some of the measures used to minimise such effects in the future, and serves to bring the issues discussed here to the attention of pharmacologists, pharmacoepidemiologists and others who train those who use veterinary medicinal products.     

Veterinary pharmacovigilance. Part 5. Causality and expectedness

In the European Union and elsewhere there is a requirement to ascribe causality to adverse drug reactions which occur in treated animals. In the EU, the ABON system of causality assessment is used but the assignment of causality assigned is not always self evident, and it may be complicated for a variety of reasons. In this paper, the approaches to causality assessment, based on a number of key criteria which examine the administration of the drug in relation to the sequence of ensuing events and the presence of biological plausibility are examined, along with the utility of using algorithms to facilitate this process. Unexpected adverse drug reactions usually require expedited reporting, depending on national or regional regulatory requirements. Again, deciding on what might constitute an expected (or unexpected) adverse reaction, particularly when a product may be intended for use in a number of species, and when within any one species a number of breeds may be treated, is not necessarily a straightforward issue. However, an approach to facilitate the decision- making process, based on a similar approach used in the pharmacovigilance of human medicinal products is discussed.     

Reactions to tick antitoxin serum and the role of atropine in treatment of dogs and cats with tick paralysis caused by Ixodes holocyclus: a pilot survey

OBJECTIVE: To determine the incidence and nature of adverse reactions of dogs and cats to tick antitoxin serum and to re-evaluate the role of atropine in the treatment of tick paralysis. DESIGN: A retrospective questionnaire of veterinarians. PROCEDURE: Questionnaires were posted to 320 veterinarians in tick-endemic regions of Australia. Questions referred to dogs and cats treated for tick paralysis over a period of three years: the number treated, treatment protocols and adverse systemic reactions to tick antitoxin serum. Ninety completed questionnaires were returned and responses analysed. RESULTS: Veterinarians reported that approximately 3% of dogs exhibited adverse reactions immediately following treatment with tick antitoxin serum. Eighteen percent of these reactions were described as anaphylaxis, with the remaining 82% attributed to the Bezold-Jarisch reflex. Six percent of cats treated with tick antitoxin serum reacted adversely and the majority of reactions (63%) were ascribed to the Bezold-Jarisch reflex. Atropine was used routinely by 10% of responding veterinarians in the treatment of dogs and cats with tick paralysis. A similar number of veterinarians used atropine only in selected cases. Most veterinarians (76%) reported that they never used atropine in the treatment of tick paralysis in either dogs or cats. Within the survey population, premedication with atropine reduced the number of Bezold-Jarisch reactions following tick antitoxin administration approximately five-fold in dogs and four-fold in cats. CONCLUSIONS: Data from this pilot survey indicate that more cats than dogs have adverse systemic reactions to tick antitoxin serum and that the majority of these reactions in both dogs and cats could be related to the Bezold-Jarisch reflex. The number of reactions to tick antitoxin serum in dogs and cats could be significantly reduced by the routine use of atropine prior to administration of tick antitoxin serum.     

Mechanisms of neuromodulation by a nonhypophysiotropic GnRH system controlling motivation of reproductive behavior in the teleost brain

Fine tuning of the nervous system in response to intrinsic and extrinsic cues is necessary for successful reproductive behavior. Gonadotropin releasing hormone (GnRH) was originally identified as a hypophysiotropic hormone that facilitates the release of gonadotropins from the pituitary. Although later studies reported their presence, the nonhypophysiotropic GnRH systems, which consist of two groups located in the terminal nerve (TN) and the midbrain tegmentum, respectively, has long been overshadowed by the hypophysiotropic GnRH system. By taking advantage of the teleost brains in which all three GnRH systems are well developed, the anatomical and electrophysiological properties of all three groups of GnRH neurons have been studied. However, despite our increasing endocrinological knowledge, we know very little about the manner of information flow by nonhypophysiotropic neuromodulatory GnRH neurons in the brain. In this article, we will review recent advances in the studies of nonhypophysiotropic GnRH neurons from cellular to behavioral levels. We will first discuss general features of the information processing by peptides and then introduce our recent approaches toward the understanding of the excitation-secretion coupling mechanism of single GnRH neuron using our newly developed primary culture system of isolated TN-GnRH3 neurons. We also introduce autocrine/paracrine regulation of TN-GnRH3 neurons by NPFF peptides for synchronization among them. In addition, we highlight recent advances in the neuromodulatory action of GnRH peptide on the information processing of sensory neuronal circuits and reproductive behavior. These multidisciplinary approaches will greatly advance our understanding of the complex action of GnRH peptides in relation to the brain control of reproduction.     

The role of bisphosphonates in the management of patients that have cancer.

Bisphosphonates are pharmacologic agents widely used in people for managing pathologic bone resorptive conditions. Based on their physicochemical properties, bisphosphonates concentrate within areas of active bone remodeling and induce osteoclast apoptosis. Appropriate use of bisphosphonates for treating companion animals requires a thorough understanding of how bisphosphonates exert their biologic effects. This review article highlights general properties of bisphosphonates, including their pharmacology, mechanisms of action, adverse side effects, anticancer mechanisms, surrogate markers for assessing response, and potential clinical utility for treating dogs and cats diagnosed with malignant skeletal tumors.     

Current vaccination strategies in puppies and kittens.

Motivation in writing this article stems from many things: a lack of time spent in the veterinary curriculum discussing vaccines, a growing concern(by the general public and the veterinary community) regarding adverse reactions associated with vaccines, and a desire to prevent a recurrence of preventable infectious diseases resulting from a fear-driven cessation of vaccine administration. The objectives of this article are to present a basic review of immunology as related to vaccines, to discuss general guidelines for pediatric vaccines in canine and feline patients,and to offer suggestions as to how we can most positively influence our patients' health from the first visit.     

Veterinary Products Committee working group report on feline and canine vaccination

* The working group was set up by the Veterinary Products Committee in response to current concern in both the public domain and in the scientific community about possible health risks related to the routine vaccination of cats and dogs. The working group concluded that vaccination plays a very valuable role in the prevention and control of the major infectious diseases in cats and dogs. Although adverse reactions to vaccination, including lack of efficacy, occasionally occur, the working group concluded that the overall risk/benefit analysis strongly supports their continued use. * Although for some diseases there is evidence of a longer duration of immunity following vaccination than the one year which is typically recommended on the product literature, there is currently insufficient information to propose revaccination intervals other than those proposed by the manufacturer and approved by the regulatory process. * Notwithstanding this, in view of the occasional occurrence of adverse reactions, the working group recommends that the product literature indicates that the regime for booster vaccinations is based on a minimum duration of immunity rather than a maximum. The working group further recommends that the product literature should state that a risk/benefit assessment should be made for each individual animal by the veterinary surgeon in consultation with the owner with respect to the necessity for each vaccine and the frequency of its use. * The evidence suggests that cats appear to be susceptible to the occasional development of sarcomas at sites of injection and there is some further evidence to suggest that, although other products may be involved, this may be more associated with the use of vaccines containing aluminium-based adjuvants. The working group therefore recommends that a generic warning to this effect should appear on the product literature for all feline vaccines administered by injection. The working group also highlighted the need for professional and educational bodies in the UK to bring to the attention of veterinary practitioners appropriate methods for prevention, diagnosis and treatment of this serious condition. * The working group considered in depth the monitoring of adverse reactions, including the advantages and disadvantages of surveillance schemes. A range of options for carrying out further epidemiological (analytical) studies was also considered. However, the working group emphasised that surveillance schemes, and the UK Veterinary Medicines Directorate (VMD) Suspected Adverse Reaction (SAR) Surveillance Scheme in particular, provided a very valuable resource. The large database within the VMD scheme (collected since 1985) was analysed as part of this report. Figures were derived in terms of incidence (reporting rate) of certain clinical signs per 10,000 doses, and risk factors as identified by statistical analysis. However, due to a number of constraints, the analysis was not fully comprehensive and the interaction of possible risk factors was not determined. * Product-related control charts were developed in order to detect changes in incidence rates of adverse reactions (per 10,000 doses sold) both within and between different vaccines. Such charts provide a powerful way to detect changing trends in incidence and, when used in conjunction with product characteristics, they may identify possible causes. In general, the data showed that the incidence of adverse reactions to cat and dog vaccines per 10,000 doses of product sold was relatively low. Although under-reporting is a feature of such surveillance schemes, it does appear that, overall, vaccination of cats and dogs should be considered safe and effective. * Finally, the working group was conscious, while preparing this report, of the extensive media coverage that has been given to the issue of the safety of human vaccines, in particular the mumps, measles and rubella (MMR) vaccine. The working group emphasises that the conclusions and recommendations included in this report relate only to the vaccines used in cats and dogs. The issues identified are specific to the diseases and species examined and no attempt should be made to draw analogous conclusions in relation to vaccines administered to humans.