Mechanisms of anticancer drug resistance.

Chemotherapy agents are extremely important in the treatment of liquid malignancies, such as lymphoma, myeloma, and chronic lymphocytic leukemia. In addition, chemotherapy agents have proven effective in the adjuvant treatment of solid tumors, such as osteosarcoma, hemangiosarcoma, transitional cell carcinoma, and others. Unfortunately, chemotherapy resistance in these situations is the most significant cause of treatment failure. Therefore, the ability to predict, treat, or circumvent resistance is extremely likely to improve clinical outcomes. This article has reviewed the most widely investigated forms of chemotherapy resistance, such as reduced drug accumulation, increased DNA damage repair, decreased apoptosis, and others; however, new mechanisms are being found at an alarming pace. In addition, investigations to date have routinely centered on single-cell mechanisms of drug resistance, and cancer is truly a three dimensional disease. The elucidation of mechanisms surrounding (1) how tumors interact with their normal microenvironment, (2) how tumors interact in a three-dimensional environment, and (3) a better understanding of basic tumor physiology and biology may supersede in importance those previously elucidated single-cell mechanisms of chemoresistance.     

Common procedures in the pet ferret.

The domestic ferret is an increasingly popular pet in North America and Europe and may easily be incorporated into the structure and workings of most small animal hospitals. Not only does treatment of ferrets provide case diversity and intellectual challenges to the veterinarian but it may increase revenue, because most ferret owners have several ferrets. The diagnostic and supportive care procedures used commonly in ferrets are similar to those used in dogs and cats. This article presents the common diagnostic and supportive care procedures used in ferrets, with special emphasis on some of the unique aspects that make these procedures easier to learn and perform.     

A review of equine sepsis

Sepsis is defined as an exaggerated, systemic inflammatory response to infection and is a common condition in horses. Systemic inflammatory response syndrome (SIRS) associated with bacterial infection is a hallmark of sepsis. Sepsis in neonatal foals is a common sequela of failure of passive transfer and, in addition to development of SIRS, may be characterised by bacteraemia, pneumonia, enterocolitis, omphalophlebitis, meningoencephalitis or arthritis. Sepsis in mature horses is most commonly observed secondary to gastrointestinal lesions that result in disrupted mucosa and bacterial translocation into circulation (endotoxaemia). Pleuropneumonia and metritis may also cause sepsis in mature horses. Diagnosis of sepsis is based on SIRS criteria as well as suspected or confirmed infection. Due to the relatively low sensitivity of microbial culture and the subjectivity of sepsis scoring, many sepsis biomarkers are being studied for their usefulness in diagnosis and prognostication of sepsis in horses. Treatment of sepsis requires an intensive care approach that includes antimicrobial drug administration, fluid resuscitation and pressure support, and treatment for inflammation, endotoxaemia and coagulopathy. Early recognition of sepsis and prompt antimicrobial drug treatment are critical for a successful outcome. Multiple organ dysfunction syndrome may occur in severe cases of sepsis, with common manifestations including laminitis and coagulopathies. Although prognosis for septic mature horses depends highly on the primary disease process, the overall survival rate in septic neonatal foals ranges from 26 to 86%, with most studies indicating a survival rate of 45–60%.     

Equine coronavirus: An emerging enteric virus of adult horses

Equine coronavirus (ECoV) is an emerging virus associated clinically and epidemiologically with fever, depression, anorexia and less frequently colic and diarrhoea in adult horses. Sporadic cases and outbreaks have been reported with increased frequency since 2010 from Japan, the USA and more recently from Europe. A faeco‐oral transmission route is suspected and clinical or asymptomatic infected horses appear to be responsible for direct and indirect transmission of ECoV. A presumptive clinical diagnosis of ECoV infection may be suggested by clinical presentation, haematological abnormalities such as leucopenia due to lymphopenia and/or neutropenia. Confirmation of ECoV infection is provided by specific ECoV nucleic acid detection in faeces by quantitative PCR (qPCR) or demonstration of coronavirus antigen by immunohistochemistry or electron microscopy in intestinal biopsy material obtained ante or post mortem. The disease is generally self‐limiting and horses typically recover with symptomatic supportive care. Complications associated with disruption of the gastrointestinal barrier have been reported in some infected horses and include endotoxaemia, septicaemia and hyperammonaemia‐associated encephalopathy. Although specific immunoprophylactic measures have been shown to be effective in disease prevention for closely‐related coronaviruses such as bovine coronavirus (BCoV), such strategies have yet not been investigated for horses and disease prevention is limited to basic biosecurity protocols. This article reviews current knowledge concerning the aetiology, epidemiology, clinical signs, diagnosis, pathology, treatment and prevention of ECoV infection in adult horses.     

Standing sedation and pain management for ophthalmic patients.

Several ocular procedures, including examination, removal of corneal foreign bodies, nictitans surgery, eyelid repair, and tumor excision,can be successfully performed in the appropriately restrained and sedated standing horse. Sedation is best achieved with xylazine,with or without the addition of acepromazine. Additional analgesia can be provided with appropriate local anesthetic blocks.Surgical conditions are greatly improved by using an auriculopalpebral and supraorbital block and topical anesthetics. More elaborate standing sedation involving continuous rate infusions of lidocaine or detomidine combined with butorphanol may facilitate more involved surgery with appropriate support staff and equipment in animals that are at high risk for general anesthesia or when the latter is not an option. Short-term or long-term analgesia is most commonly provided with nonsteroidal anti-inflammatory drugs, but several newer techniques, including lidocaine and butorphanol infusions, may be effective. Topical treatment with opioids to provide analgesia and opioid antagonists to enhance corneal healing is an exciting new development that may revolutionize our approach to corneal ulcer therapy in the future if current research findings are supportive.     

A Fresh Look at the Process of Arriving at a Clinical Prognosis Part 1: Laminitis

Laminitis is a disease that represents a loss of the normal homeostatic mechanisms that control the day-to-day function of the distal phalanx. The degree or severity to which homeostasis is affected is directly related to the severity and the final outcome for the equine patient. A systematic approach including the physical examination, digital radiography, venography, and newer techniques such as computer tomography and magnetic resonance imaging can assist the clinician in developing a prognosis for the acute and chronic laminitis case. How quickly we are able to return the foot back to a normal state of homeostasis or the response to treatment is important as a predictive value for outcome.     

Treatment of canine hemangiosarcoma: 2000 and beyond

Canine hemangiosarcoma (HSA) is an aggressive and malignant neoplasia with a grave prognosis. Surgery and chemotherapy have limited success in prolonging survival times and increasing quality of life in dogs with HSA. Advances in medical oncology are resulting in increased survival rates and a better quality of life for veterinary cancer patients. An understanding of mechanisms of metastasis has led to the development of new treatments designed to delay or inhibit tumor spread. Promising new treatment options include novel delivery systems (inhalation or intracavitary chemotherapy); use of immunomodulators such as liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine; antimetastatic agents such as inhibitors of angiogenesis (interferons, thalidomide), matrix metalloproteinase inhibitors, and minocycline; dietary modifications; and gene therapy. Inhibitors of angiogenesis seem to be safe and, unlike conventional chemotherapy, do not induce drug resistance. Although many of the newer approaches are still under development and review, the use of multimodality therapy incorporating innovative treatment modalities may offer the best therapeutic option for dogs affected with HSA.     

Hypoadrenocorticism in small animals

The diagnosis and treatment of hypoadrenocorticism can be one of the greatest challenges faced by veterinary practitioners, as Addison's disease may have many faces and many presentations. Although the disease is most often diagnosed in dogs, cats may also suffer from Addison's disease. The practitioner must have a high index of suspicion to make a diagnosis of hypoadrenocorticism. This index of suspicion is based on knowledge of the common signalment, history, physical examination, and laboratory findings. Diagnosis of hypoadrenocorticism is supported by appropriate choice of diagnostic endocrine tests that are described in detail in this article. Once a diagnosis of hypoadrenocorticism has been made, expedient treatment is of foremost concern. Timely treatment using fluids, corticosteroids, and supportive care will ensure a successful outcome; the emergency treatment of Addison's is covered briefly in this article and fully in another article in this issue. The purpose of this review was to describe the clinical diagnosis and chronic treatment of hypoadrenocorticism in dogs and cats.     

Drug hypersensitivity reactions targeting the skin in dogs and cats

Adverse drug reactions (ADRs) can be dose dependent or idiosyncratic. Most idiosyncratic reactions are believed to be immune-mediated; such drug hypersensitivities and allergies are unpredictable. Cutaneous reactions are the most common presentation of drug allergies. In veterinary medicine it can be difficult to assess the true prevalence of adverse drug reactions, although reports available suggest that they occur quite commonly. There are multiple theories that attempt to explain how drug allergies occur, because the pathogenesis is not yet well understood. These include the (pro)-hapten hypothesis, the Danger Theory, the pi concept, and the viral reactivation theory. Cutaneous drug allergies in veterinary medicine can have a variety of clinical manifestations, ranging from pruritus to often fatal toxic epidermal necrolysis. Diagnosis can be challenging, as the reactions are highly pleomorphic and may be mistaken for other dermatologic diseases. One must rely heavily on history and physical examination to rule out other possibilities. Dechallenge of the drug, histopathology, and other diagnostic tests can help to confirm the diagnosis. New diagnostic tools are beginning to be used, such as antibody or cellular testing, and may be used more in the future. There is much yet to learn about drug allergies, which makes future research vitally important. Treatment of drug allergies involves supportive care, and additional treatments, such as immunosuppressive medications, depend on the manifestation of the disease. Of utmost importance is to avoid the use of the incriminating drug in future treatment of the patient, as subsequent reactions can be worse, and ultimately can prove fatal.     

Plant hazards.

A variety of plants, seeds, and nuts can cause toxicosis in small animals. Some plants are not as toxic as commonly believed by the general public. Conversely, plants or nuts that are consumed by human beings can be toxic to their pets. Most plant toxins do not have specific treatments or antidotes. As a result, treatment is often limited to decontamination plus symptomatic and supportive care.     

Prolonged anesthetic recovery

Failure to awaken, delayed awakening, and blunted responsiveness following anesthesia constitute a continuum which must be recognized, diagnosed accurately, and responded to appropriately. One must determine whether it is a normal recovery for this animal or a pathological delay. A delayed recovery results in continued depression of many organ systems. The possible etiologic factors, some obvious, others quite obscure, must be considered quickly to provide the patient with the best possible care. Diminished responsiveness is usually the result of a complex interaction between multiple factors. A systematic approach to treatment first begins by ensuring cardiac output, oxygenation, ventilation, and supportive care in all patients. Then consider the potential causes for prolonged recovery and either rule them out or treat them. First consider the potential causes for central nervous system depression. Several commonly encountered medical conditions enhance sensitivity to or decrease the elimination of anesthetic and sedative agents. The astute clinician will be aware of the medical condition and its impact on anesthetic drug effect and elimination to avoid prolonged recoveries.     

Ocular pharmacology.

Application of sound ocular therapeutic principle is more difficult in food animals than most other species. Financial or husbandry constraints limit the practitioner's ability to use the entire range of ocular drugs available or to use them with adequate frequency. These problems may be dealt with by using systemically administered drugs when effective or by employing vehicles or delivery techniques that necessitate minimal dosing frequency. By far the most important medically treatable eye disease encountered in food animal practice is IBK. Effective therapies include systemic administration of long-acting oxytetracycline, subconjunctival administration of a variety of antibiotics, or topical application of benzathine cloxacillin. Infectious conjunctivitis in sheep and goats due to a variety of agents may be treated successfully with tetracycline in most cases. Conjunctivitis and keratitis secondary to IBR virus usually are given supportive therapy only, although specific antiviral drugs have been used in the treatment of herpetic eye disease in other species. Anterior uveitis is best treated by corticosteroid and mydriatic therapy in addition to treatment of the underlying cause, if identified.     

Recent advances in equine abdominal surgery

Laparoscopy is a minimally invasive procedure that has applications as a diagnostic, therapeutic and prognostic technique. Specialized equipment is necessary to perform equine laparoscopy, and there is a large range of instruments, both disposable and non-disposable available. Laparoscopic procedures described include ovariectomy, cryptorchidectomy, adhesiolysis and herniorrhaphy. Laparoscopy can be performed in a standing or dorsally recumbent position, depending on surgeon preference, patient status and the procedure to be performed. Stapling equipment is frequently used in gastrointestinal surgery in horses. Advantages include decreased surgical time and a decrease in the risk of contamination. Stapling equipment is often used in creating anastomoses, both in the large and small intestines, as well as in vessel ligation. New surgical techniques intended to decrease adhesion formation include the use of carboxymethylcellulose and bioresorbable patches. Indwelling abdominal drains can be used for peritoneal lavage following surgery and also appear to decrease the risk of adhesion formation. Improvements in post-operative care, including the treatment of post-operative ileus and endotoxaemia can significantly improve the outcome of horses that have undergone surgery for abdominal disorders. Recommendations for the use of prokinetic agents in horses with ileus vary widely. Prokinetic agents include local anaesthetics, macrolide antimicrobials, cholinergic agonists and dopamine antagonists. Endotoxaemia is common in horses following surgery for gastrointestinal disorders. The antibiotic polymyxin B binds to the circulating endotoxin molecule, decreasing its half-life in the intra-vascular space and reducing associated inflammation. This drug appears to be an effective and affordable treatment option for horses with endotoxaemia. The use of specific cyclooxygenase inhibitors in veterinary medicine have been studied recently. Selective cyclooxygenase-2 inhibitors may provide comparable anti-inflammatory and analgesic properties to the non-selective non-steroidal anti-inflammatory drugs. These drugs appear to have similar clinical effectiveness and will hopefully minimize deleterious side effects. The optimal healing of ventral midline incisions in horses is related to many factors including appropriate suture patterns and bite size, in addition to appropriate post-operative exercise recommendations. Recent advances in surgical techniques and post-operative care should decrease the morbidity and mortality associated with abdominal surgery. This article provides an overview of some of these advances.     

Antiviral therapy for ocular viral disease.

Ophthalmic manifestations of viral disease are commonly encountered in veterinary practice. Although the number of antiviral agents is rapidly increasing, the efficacy of many of these drugs against animal viral pathogens may not be known. Furthermore, some of these newer medications may, in fact. be toxic to animal patients. Continued research on the efficacy of these medications in treating viral diseases of veterinary importance is warranted.A thorough review of the ever-growing body of literature is imperative before instituting any new or unknown antiviral therapy.At this time, feline HSV-1 infections remain the most well understood of the ocular viral infections that veterinary practitioners may be called on to treat. Ironically, the number of antiviral agents proven to be effective in naturally occurring clinical cases of FHV-I remains quite limited. With new medications being investigated, this paucity of information on efficacious antiviral therapeutic agents will hopefully improve.     

Toxicology of selected pesticides, drugs, and chemicals. Boric acid

With the advent of boric acid insecticides, accidental ingestion of the compound can be encountered in animals. Toxic levels of boric acid most commonly cause vomiting, depression, and, occasionally, diarrhea. Boric acid is, however, cytotoxic to all cells. If a sufficiently high level is ingested, seizures, renal tubular nephrosis, and, rarely, hepatotoxicity may be noted. Gastrointestinal evaluation and supportive care are usually of primary therapeutic importance, although in severe cases, exchange transfusion and/or peritoneal dialysis may be required to decrease blood boron concentrations.     

New perspectives in cardiology: pharmacodynamic classification of antiarrhythmic drugs

Recent advancements in cardiac pharmacology and physiology have led to the identification of many new antiarrhythmic drugs and a better understanding of basic arrhythmogenic mechanisms. These parallel developments prompted a new nomenclature system for classifying the clinically important antiarrhythmic drugs according to their predominant electrophysiologic actions in cardiac cells. Antiarrhythmic drugs are now grouped into 4 main classes: classes I through IV. Class I agents comprise the standard membrane-stabilizing drugs such as lidocaine, quinidine, and procainamide; newer class I agents include disopyramide, aprindine, tocainide, and flecainide. Class II agents decrease sympathoadrenal excitation of the heart, and the clinically relevant members of this type act through blockade of the cardiac beta 1-adrenergic receptors; propranolol is the prototype. Class III agents selectively prolong the cardiac action potential and refractory period, and bretylium and amiodarone represent this group. Class IV agents are the calcium entry blocking drugs such as verapamil. An understanding of this classification system is essential to the internist and cardiologist who are beset with an emerging array of new antiarrhythmic drugs and affiliated pharmacodynamic terminologies.     

Emergency treatment of limb fractures in large and small ruminants

Limb fractures in cattle have to be treated as emergencies. The success or failure of treatment depends on a careful examination and adequate emergency treatment by the veterinarian. The most important rules in an emergency treatment are the evaluation of the general systemic conditions and the initiation of whatever supportive care is required. Further attention should be paid to thoroughly rinsing and disinfecting open wounds and to immobilizing fractures for transport purposes. In 39 cases the localisation and the type of fracture were determined and the clinical relevance of a careful examination and emergency treatment was evaluated. Metacarpal fractures were the most common type of fracture. Open fractures were more likely to occur in cases of insufficient immobilisation than with properly attended patients (p less than 0,01). Open fractures have a poorer prognosis than closed fractures (p less than 0.002).     

Respiratory medicine in pigeons.

This article covers the factors causing respiratory disease in pigeons. The major infectious agents are discussed in detail. Clinical signs, diagnosis, prevention, and treatment recommendations for the most commonly found pathogens are included. Husbandry recommendations are also covered.     

Role of prokinetic drugs for treatment of postoperative ileus in the horse

All horses undergoing coeliotomy for an acute abdominal crisis are at risk of developing ileus and should receive therapy aimed at promoting gastrointestinal function by restoring fluid and electrolyte balance. Adequate analgesia and prevention against peritonitis, bacteraemia and endotoxaemia should be provided. Horses that at the time of surgery have a strangulating or non-strangulating small intestinal obstruction should be considered to be at greater risk of developing a persistent ileus that is refractory to treatment than those horses with lesions involving the large intestine. In horses considered to be at greater risk of developing a persistent ileus, the use of prokinetic agents should be considered. Agents that may be used to improve gastrointestinal motility include adrenergic receptor antagonists, cholinergic agonists, benzamides, dopamine antagonists, macrolide antimicrobials, opiate receptor agonists and antagonists, somatostatin analogues and local anaesthetics. There are limited studies into the use of these agents in the horse. Until further research provides more information on motility disorders following intestinal surgery and the efficacy of prokinetic agents in this species, only selective use of some of these drugs can be recommended.