Categories
Animal Physiology

Effectors ― the responses to sensory information

Having gathered various types of sensory information, animals have to take appropriate action based upon the information gathered.

Effectors may be defined as anything capable of producing a biological response. This can range from muscles producing movement ― an overt biological response ― to endocrine glands secreting hormones to alter some aspect of metabolism, e.g. insulin reducing blood sugar levels. Many types of response are effected in response to sensory stimuli, some of which will be briefly mentioned now.

Some animals possess the ability to change the color of their skin. Such changes occur for a variety of reasons including camouflage and communication to other animals. Such signals may be to animals of the same species, for example, to obtain a mate, or to animals of other species, for example, to deter predators. The color change occurs because the skin of the animal contains pigment containing cells called chromatophores. Animals which possess such cells include squids, octopods, some flat fish (e.g. flounder), chameleons, frogs and snakes. Chromatophores are under neural or endocrine control, or in some cases both. They have the ability to alter the dispersal of pigment within the cell in minutes or seconds, thus altering the overall appearance of the animal. The mechanism by which this occurs differs from species to species. In cephalopods (e.g. squid and octopus), each chromatophore is bounded by muscle cells and the contraction and relaxation of these muscles alter the dispersion of the colored pigment. When the muscles contract, the chromatophore ‘enlarges’ and the pigment disperses. When the muscles relax, the chromatophore shrinks and the pigment becomes concentrated. Contraction and relaxation of these muscle cells is under neural control. In contrast, the chromatophores of amphibians function by simple dispersion of the pigment within the chromatophore. In many cases, this is under endocrine control.

Virtually all animals possess a system of glands whose secretions result in a variety of biological responses and which are activated under appropriate conditions. However, there are many other glands which serve more specialized functions. Some of these have already been mentioned, e.g. glands which release attractant pheromones. Other examples of such glandular secretions serve a more aggressive role ― For example, skunks release a foul-smelling substance when attacked. The bombardier beetle, Brachinus, sprays attackers with a fluid which has a temperature of 100°C. The tip of the abdomen of this beetle contains two separate chambers. One chamber contains the reactants necessary for the production of this hot fluid; the second chamber contains the necessary enzymes required for the reaction to proceed. The release of reactants into this second chamber allows the production of this hot fluid to occur and its release at potential predators. In addition to the two examples given above, there are many more subtle responses which are not observed. For example, the release of insulin into the bloodstream after a meal in order to maintain appropriate blood sugar levels is a response to disturbance of blood sugar levels.

However, as previously stated, perhaps the most obvious response that animals make is that of movement.

Categories
Drugs

Aminophylline Theophylline

Phosphodiesterase Inhibitor Bronchodilator

Highlights Of Prescribing Information

Bronchodilator drug with diuretic activity; used for bronchospasm & cardiogenic pulmonary edema

Narrow therapeutic index in humans, but dogs appear to be less susceptible to toxic effects at higher plasma levels

Therapeutic drug monitoring recommended

Many drug interactions

What Is Aminophylline Theophylline Used For?

The theophyllines are used primarily for their broncho dilatory effects, often in patients with myocardial failure and/or pulmonary edema. While they are still routinely used, the methylxanthines must be used cautiously due to their adverse effects and toxicity.

Pharmacology/Actions

The theophyllines competitively inhibit phosphodiesterase thereby increasing amounts of cyclic AMP which then increase the release of endogenous epinephrine. The elevated levels of cAMP may also inhibit the release of histamine and slow reacting substance of anaphylaxis (SRS-A). The myocardial and neuromuscular transmission effects that the theophyllines possess maybe a result of translocating intracellular ionized calcium.

The theophyllines directly relax smooth muscles in the bronchi and pulmonary vasculature, induce diuresis, increase gastric acid secretion and inhibit uterine contractions. They have weak chronotropic and inotropic action, stimulate the CNS and can cause respiratory stimulation (centrally-mediated).

Pharmacokinetics

The pharmacokinetics of theophylline have been studied in several domestic species. After oral administration, the rate of absorption of the theophyllines is limited primarily by the dissolution of the dosage form in the gut. In studies in cats, dogs, and horses, bioavail-abilities after oral administration are nearly 100% when non-sustained release products are used. One study in dogs that compared various sustained-release products (), found bioavailabilities ranging from approximately 30-76% depending on the product used.

Theophylline is distributed throughout the extracellular fluids and body tissues. It crosses the placenta and is distributed into milk (70% of serum levels). In dogs, at therapeutic serum levels only about 7-14% is bound to plasma proteins. The volume of distribution of theophylline for dogs has been reported to be 0.82 L/kg. The volume of distribution in cats is reported to be 0.46 L/kg, and in horses, 0.85-1.02 L/kg. Because of the low volumes of distribution and theophylline’s low lipid solubility, obese patients should be dosed on a lean body weight basis.

Theophylline is metabolized primarily in the liver (in humans) to 3-methylxanthine which has weakbronchodilitory activity. Renal clearance contributes only about 10% to the overall plasma clearance of theophylline. The reported elimination half-lives (mean values) in various species are: dogs = 5.7 hours; cats = 7.8 hours, pigs = 11 hours; and horses = 11.9 to 17 hours. In humans, there are very wide interpatient variations in serum half-lives and resultant serum levels. It could be expected that similar variability exists in veterinary patients, particularly those with concurrent illnesses.

Before you take Aminophylline Theophylline

Contraindications / Precautions / Warnings

The theophyllines are contraindicated in patients who are hypersensitive to any of the xanthines, including theobromine or caffeine. Patients who are hypersensitive to ethylenediamine should not take aminophylline.

The theophyllines should be administered with caution in patients with severe cardiac disease, seizure disorders, gastric ulcers, hyperthyroidism, renal or hepatic disease, severe hypoxia, or severe hypertension. Because it may cause or worsen preexisting arrhythmias, patients with cardiac arrhythmias should receive theophylline only with caution and enhanced monitoring. Neonatal and geriatric patients may have decreased clearances of theophylline and be more sensitive to its toxic effects. Patients with CHF may have prolonged serum half-lives of theophylline.

Adverse Effects

The theophyllines can produce CNS stimulation and gastrointestinal irritation after administration by any route. Most adverse effects are related to the serum level of the drug and may be symptomatic of toxic blood levels; dogs appear to tolerate levels that may be very toxic to humans. Some mild CNS excitement and GI disturbances are not uncommon when starting therapy and generally resolve with chronic administration in conjunction with monitoring and dosage adjustments.

Dogs and cats can exhibit clinical signs of nausea and vomiting, insomnia, increased gastric acid secretion, diarrhea, polyphagia, polydipsia, and polyuria. Side effects in horses are generally dose related and may include: nervousness, excitability (auditory, tactile, and visual), tremors, diaphoresis, tachycardia, and ataxia. Seizures or cardiac dysrhythmias may occur in severe intoxications.

Reproductive / Nursing Safety

In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, hut there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans.)

Overdosage / Acute Toxicity

Clinical signs of toxicity (see above) are usually associated with levels greater than 20 mcg/mL in humans and become more severe as the serum level exceeds that value. Tachycardias, arrhythmias, and CNS effects (seizures, hyperthermia) are considered the most life-threatening aspects of toxicity. Dogs appear to tolerate serum levels higher than 20 mcg/mL.

Treatment of theophylline toxicity is supportive. After an oral ingestion, the gut should be emptied, charcoal and a cathartic administered using the standardized methods and cautions associated with these practices. Patients suffering from seizures should have an adequate airway maintained and treated with IV diazepam. The patient should be constantly monitored for cardiac arrhythmias and tachycardia. Fluid and electrolytes should be monitored and corrected as necessary. Hyperthermia may be treated with phenothiazines and tachycardia treated with propranolol if either condition is considered life threatening.

How to use Aminophylline Theophylline

Note: Theophyllines have a low therapeutic index; determine dosage carefully. Because of aminophylline/theophylline’s pharmacokinet-ic characteristics, it should be dosed on a lean body weight basis in obese patients. Dosage conversions between aminophylline and theophylline can be easily performed using the information found in the Chemistry section below. Aminophylline causes intense local pain when administered IM and is rarely used or recommended via this route.

Aminophylline Theophylline dosage for dogs:

a) Using Theochron Extended-Release Tablets or Theo-Cap Extended-Release Capsules: Give 10 mg/kg PO every 12 hours initially, if no adverse effects are observed and the desired clinical effect is not achieved, give 15 mg/kg PO q12h while monitoring for adverse effects. ()

b) For adjunctive medical therapy for mild clinical signs associated with tracheal collapse (<50% collapse): aminophylline: 11 mg/kg PO, IM or IV three times daily. ()

c) For adjunctive therapy of severe, acute pulmonary edema and bronchoconstriction: Aminophylline 4-8 mg/kg IV or IM, or 6-10 mg/kg PO every 8 hours. Long-term use is not recommended. ()

d) For cough: Aminophylline: 10 mg/kg PO, IV three times daily ()

e) As a broncho dilator tor collapsing trachea: 11 mg/kg PO or IV q6- 12h ()

Aminophylline Theophylline dosage for cats:

a) Using Theo-Dur 20 mg/kg PO once daily in the PM; using Slo-Bid 25 mg/kg PO once daily in the PM (Johnson 2000) [Note: The products Theo-Dur and Slo-Bid mentioned in this reference are no longer available in the USA. Although hard data is not presently available to support their use in cats, a reasonable alternative would be to cautiously use the dog dose and products mentioned above in the reference by Bach et al — Plumb]

b) Using aminophylline tablets: 6.6. mg/kg PO twice daily; using sustained release tablets (Theo-Dur): 25-50 mg (total dose) per cat PO in the evening ()

c) For adjunctive medical therapy for mild clinical signs associated with tracheal collapse (<50% collapse): aminophylline: 5 mg/kg PO, two times daily. ()

d) For adjunctive therapy for bronchoconstriction associated with fulminant CHF: Aminophylline 4-8 mg/kg SC, IM, IV q8-12h. ()

e) For cough: Aminophylline: 5 mg/kg PO twice daily ()

Aminophylline Theophylline dosage for ferrets:

a) 4.25 mg/kg PO 2-3 times a day ()

Aminophylline Theophylline dosage for horses:

(Note: ARCI UCGFS Class 3 Aminophylline Theophylline)

NOTE: Intravenous aminophylline should be diluted in at least 100 mL of D5W or normal saline and administered slowly (not >25 mg/min). For adjunctive treatment of pulmonary edema:

a) Aminophylline 2-7 mg/kg IV q6- 12h; Theophylline 5-15 mg/kg PO q12h ()

b) 11 mg/kg PO or IV q8-12h. To “load” may either double the initial dose or give both the oral and IV dose at the same time. IV infusion should be in approximately 1 liter of IV fluids and given over 20-60 minutes. Recommend monitoring serum levels. ()

For adjunctive treatment for heaves (RAO):

a) Aminophylline: 5-10 mg/kg PO or IV twice daily. ()

b) Aminophylline: 4-6 mg/kg PO three times a day. ()

Monitoring

■ Therapeutic efficacy and clinical signs of toxicity

■ Serum levels at steady state. The therapeutic serum levels of theophylline in humans are generally described to be between 10-20 micrograms/mL. In small animals, one recommendation for monitoring serum levels is to measure trough concentration; level should be at least above 8-10 mcg/mL (Note: Some recommend not exceeding 15 micrograms/mL in horses).

Client Information

■ Give dosage as prescribed by veterinarian to maximize the drug’s benefit

Chemistry / Synonyms

Xanthine derivatives, aminophylline and theophylline are considered to be respiratory smooth muscle relaxants but, they also have other pharmacologic actions. Aminophylline differs from theophylline only by the addition of ethylenediamine to its structure and may have different amounts of molecules of water of hydration. 100 mg of aminophylline (hydrous) contains approximately 79 mg of theophylline (anhydrous); 100 mg of aminophylline (anhydrous) contains approximately 86 mg theophylline (anhydrous). Conversely, 100 mg of theophylline (anhydrous) is equivalent to 116 mg of aminophylline (anhydrous) and 127 mg aminophylline (hydrous).

Aminophylline occurs as bitter-tasting, white or slightly yellow granules or powder with a slight ammoniacal odor and a pKa of 5. Aminophylline is soluble in water and insoluble in alcohol.

Theophylline occurs as bitter-tasting, odorless, white, crystalline powder with a melting point between 270-274°C. It is sparingly soluble in alcohol and only slightly soluble in water at a pH of 7, but solubility increases with increasing pH.

Aminophylline may also be known as: aminofilina, aminophyllinum, euphyllinum, metaphyllin, theophyllaminum, theophylline and ethylenediamine, theophylline ethylenediamine compound, or theophyllinum ethylenediaminum; many trade names are available.

Theophylline may also be known as: anhydrous theophylline, teofillina, or theophyllinum; many trade names are available.

Storage / Stability/Compatibility

Unless otherwise specified by the manufacturer, store aminophylline and theophylline oral products in tight, light-resistant containers at room temperature. Do not crush or split sustained-release oral products unless label states it is permissible.

Aminophylline for injection should be stored in single-use containers in which carbon dioxide has been removed. It should also be stored at temperatures below 30°C and protected from freezing and light. Upon exposure to air (carbon dioxide), aminophylline will absorb carbon dioxide, lose ethylenediamine and liberate free theophylline that can precipitate out of solution. Do not inject aminophylline solutions that contain either a precipitate or visible crystals.

Aminophylline for injection is reportedly compatible when mixed with all commonly used IV solutions, but may be incompatible with 10% fructose or invert sugar solutions.

Aminophylline is reportedly compatible when mixed with the following drugs: amobarbital sodium, bretylium tosylate, calcium gluconate, chloramphenicol sodium succinate, dexamethasone sodium phosphate, dopamine HCL, erythromycin lactobionate, heparin sodium, hydro cortisone sodium succinate, lidocaine HCL, mephentermine sulfate, methicillin sodium, methyldopate HCL, metronidazole with sodium bicarbonate, pentobarbital sodium, phenobarbital sodium, potassium chloride, secobarbital sodium, sodium bicarbonate, sodium iodide, terbutaline sulfate, thiopental sodium, and verapamil HCL

Aminophylline is reportedly incompatible (or data conflicts) with the following drugs: amikacin sulfate, ascorbic acid injection, bleomycin sulfate, cephalothin sodium, cephapirin sodium, clindamycin phosphate, codeine phosphate, corticotropin, dimenhydrinate, dobutamine HCL, doxorubicin HCL, epinephrine HCL, erythromycin gluceptate, hydralazine HCL, hydroxyzine HCL, insulin (regular), isoproterenol HCL, levorphanol bitartrate, meperidine HCL, methadone HCL, methylprednisolone sodium succinate, morphine sulfate, nafcillin sodium, norepinephrine bitartrate, oxytetracycline, penicillin G potassium, pentazocine lactate, procaine HCL, prochlorperazine edisylate or mesylate, promazine HCL, promethazine HCL, sulfisoxazole diolamine, tetracycline HCL, vancomycin HCL, and vitamin B complex with C. Compatibility is dependent upon factors such as pH, concentration, temperature, and diluent used and it is suggested to consult specialized references for more specific information.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information.

Human-Labeled Products:

The listing below is a sampling of products and sizes available; consult specialized references for a more complete listing.

Aminophylline Tablets: 100 mg (79 mg theophylline) & 200 mg (158 mg theophylline); generic; (Rx)

Aminophylline Injection: 250 mg (equiv. to 197 mg theophylline) mL in 10 mL & 20 mL vials, amps and syringes; generic; (Rx)

Theophylline Time Released Capsules and Tablets: 100 mg, 125 mg 200 mg, 300 mg, 400 mg, 450 mg, & 600 mg. (Note: Different products have different claimed release rates which may or may not correspond to actual times in veterinary patients; Theophylline Extended-Release (Dey); Theo-24 (UCB Pharma); Theophylline SR (various); Theochron (Forest, various); Theophylline (Able); Theocron (Inwood); Uniphyl (Purdue Frederick); generic; (Rx)

Theophylline Tablets and Capsules: 100 mg, 200 mg, & 300 mg; Bronkodyl (Winthrop); Elixophyllin (Forest); generic; (Rx)

Theophylline Elixir: 80 mg/15 mL (26.7 mg/5 mL) in pt, gal, UD 15 and 30 mL, Asmalix (Century); Elixophyllin (Forest); Lanophyllin (Lannett); generic; (Rx)

Theophylline & Dextrose Injection: 200 mg/container in 50 mL (4 mg/mL) & 100 mL (2 mg/mL); 400 mg/container in 100 mL (4 mg/ mL), 250 mL (1.6 mg/mL), 500 mL (0.8 mg/mL) & 1000 mL (0.4 mg/mL); 800 mg/container in 250 mL (3.2 mg/mL), 500 mL (1.6 mg/mL) & 1000 mL (0.8 mg/mL); Theophylline & 5% Dextrose (Abbott & Baxter); (Rx)

Categories
Diseases

Treatment of Systemic Arterial Thromboembolism

Euthanasia In cats that are in acute pain that have a poor prognosis due to severe cardiomyopathy, euthanasia is a humane means of dealing with the problem. Systemic throm-boembolism is often a horrible complication of cardiomyopathy, the treatment options are all relatively poor, and rethrombosis is common. Consequently, although one should not automatically give up on a patient, one should not give false hope either.

Pain Control Cats that present in pain must be treated appropriately for their pain. Appropriate drugs include a fentanyl patch, oxymorphone (intramuscularly, intravenously, or subcutaneously) and butorphanol tartrate (subcutaneously). Aspirin does not produce adequate pain control. Oxymorphone may produce excitement in some cats. The analgesic properties of butorphanol are five times that of morphine, and it remains a nonscheduled drug by the Food and Drug Administration. Its respiratory depressant effects equal that of morphine. Consequently, one must be careful when administering this drug to a patient with dyspnea. Acepromazine may be administered intravenously in addition as an anxiolytic agent to cats that still appear distressed after the administration of the analgesic or to cats that become agitated after oxymorphone administration. The pain abates with time (usually hours) as sensory nerves undergo necrosis.

Palliative Therapy Beyond pain control, many cats with systemic arterial thromboembolism receive only supportive care or the administration of drugs with no proven benefit. The primary outcome of arterial occlusion depends upon the extent of occlusion and the time to spontaneous reperfusion. Poor prognostic factors for short-term survival include worsening azotemia, moderate to severe pulmonary edema or pleural effusion, malignant arrhythmias, severe hypothermia, disseminated intravascular coagulation, and evidence of multiorgan embolization. Long-term, cats may lose an affected leg because of ischemic necrosis, die of toxemia, remain paralyzed from peripheral nerve damage, or regain full or partial function of their legs. About 50% of cats that are not treated definitively will regain all or most caudal limb motor function within 1 to 6 weeks. Return of function presumably is due to the cat’s own thrombolytic system (e.g., plasmin) disrupting the thromboembolus. The degree and rapidity of the dissolution depend on the activity of a particular cat’s thrombolytic system and the size and quality of the thromboembolus. Usually, cats that have some evidence of caudal limb flow recover more rapidly than do cats with no evidence of flow. Presumably this is because the size of the thromboembolus in cats with some flow is smaller. With total occlusion, some cats recanalize within days (others never recanalize).This extreme variability makes it very difficult to render a prognosis for a particular patient at presentation.

Palliative therapy may be only cage rest and pain control or can include administering drugs such as heparin, aspirin, or arteriolar dilators along with the cage rest. No drugs administered for palliation have any proven benefit over cage rest alone.

Heparin is commonly administered in the hopes of preventing new thrombus formation on top of the existing thromboembolus or in the hope of preventing a new thrombus from forming in the left atrium. However, no evidence indicates that heparin is of benefit in cats with STE. Heparin does not aid in thrombolysis. Heparin can be administered at an initial dose of 100 U/lb intravenously followed by a maintenance dose of 30 to 100 U/lb subcutaneously every 6 hours. The dose should be tailored to each individual cat to increase the activated partial thromboplastin time (aPTT) to at least 1.5 times baseline.

Indomethacin is effective at preventing vasoconstriction distal to the thromboembolus when administered to experimental cats prior to creating an aortic thrombus. Theoretically aspirin could do the same thing. However, no evidence indicates that it improves collateral blood flow.

The administration of drugs that dilate systemic arterioles (e.g., hydralazine, acepromazine) has been advocated. These drugs act by relaxing the smooth muscle in systemic arterioles. The exact anatomy of collateral vessels is not well described, but they are probably larger vessels than arterioles. They contain smooth muscle, because they can open and close. The ability of arteriolar dilators to counteract serotonin and thromboxane A2-induced vasoconstriction is unknown.

Definitive Therapy Definitive treatments for systemic arterial thromboembolism in cats include administration of exogenous fibrinolytic agents, balloon embolectomy, rheolytic thrombectomy, and surgery. All definitive procedures are associated with high mortality and common recurrence of the thromboembolus days to months after the initial removal.

Surgery Surgical removal of systemic thromboemboli is generally thought to be associated with high mortality and is not frequently performed. Cats with systemic arterial thromboembolism commonly have underlying cardiac disease, and many are in heart failure. They are poor anesthetic risks, and reperfusion syndrome may be produced. In reperfusion syndrome the muscles of the legs prior to removal of the systemic arterial thromboembolism undergo necrosis, cellular breakdown, and the release of potassium and hydrogen ions from the cells into the interstitial spaces. Sudden reperfusion carries these ions into the systemic circulation, causing acute and often severe hyperkalemia and metabolic acidosis. Surgical intervention may be a viable option if careful monitoring and treatment for reperfusion syndrome with insulin and glucose, sodium bicarbonate, or calcium (or a combination of these therapies) can be initiated immediately if it occurs.

Balloon embolectomy The procedure of choice in human medicine is balloon embolectomy. The author has had limited experience with balloon embolectomy. In this procedure the femoral arteries are isolated and a small balloon embolec-tomy catheter is passed from one femoral artery into the aorta. The femoral arteries are not extremely difficult to isolate. The catheter is pushed past the thromboembolus, and the balloon is then inflated and the catheter withdrawn, along with throm-boembolic material. The catheter is passed sequentially, first in one artery and then in the other. Usually this sequence must be repeated several times. Reperfusion syndrome may occur with balloon embolectomy.

Thrombolytic therapy Thrombolytic therapy is a possible means of dealing with cats with systemic arterial thromboembolism using fibrinolytic agents. Thromboemboli in cats are composed of red cells, strands of fibrin, and possibly platelets. Fibrinolytic agents cleave plas-minogen to plasmin. Plasmin hydrolyzes fibrin, resulting in thrombolysis. Different agents vary in their ability to bind specifically to fibrin-bound plasminogen and in their half-lives. Efficacy and complication rates appear to be very similar in humans. Complications consist primarily of hemorrhage due to fibrinolysis and rethrombosis. Fibrinolytic agents can be very effective at lysing systemic thromboemboli. However, the author and colleagues currently treat few cats with systemic arterial thromboembolism with these agents because reperfusion syndrome and rethrombosis are common.

Tissue plasminogen activator (t-PA) and streptokinase have been used in cats. Tissue plasminogen activator is an intrinsic protein present in all mammals. Numerous reports exist of the use of t-PA for the lysis of thrombi as therapy for acute myocardial infarction, pulmonary thromboembolism, and peripheral vascular obstruction in humans and experimental animals. The activity of genetically engineered t-PA in feline plasma is 90% to 100% of that seen in human plasma. The half-life of t-PA is quite short. Heparin must be administered concomitandy to prevent acute rethrombosis but does not need to be administered with streptokinase because it has a longer half-life. A clinical trial with t-PA in cats with aortic thromboemboli has shown acute thrombolytic efficacy (shortened time to reperfusion and ambulation) associated with the administration of t-PA at a rate of 0.1 mg to 0.4 mg/lb/hr for a total dose of 0.4 to 4 mg/lb intravenously. Forty three percent of cats treated survived therapy and were walking within 48 hours of presentation. Post-t-PA angiograms demonstrated resolution of the primary vascular occlusion. Thus acutely, t-PA effectively decreases the time to reperfusion and return to function in cats with aortic thromboemboli. However, 50% of the cats died during therapy in this clinical trial, which raises extreme concerns regarding acute thrombolysis. Fatalities resulted from reperfusion syndrome (70%), congestive heart failure (15%), and sudden arrhythmic death, presumably the result of embolization of a small thrombus to a coronary artery (15%). Severe hemorrhage into the region distal to the systemic arterial thromboembolism causing anemia was also a common complication. The cats that successfully completed t-PA therapy exhibited signs of increasing neuromuscular function and ambulatory ability within 2 days of presentation. This contrasts with 1 to 6 weeks before seeing similar signs of improvement in most cats exhibiting spontaneous resolution.

Mortality due to reperfusion syndrome can be reduced if the patient can be observed continuously by an individual trained to identify clinical and electrocardiographic evidence of hyperkalemia, if intensive monitoring of electrolytes and blood pH can be performed, and if aggressive medical therapy for hyperkalemia and metabolic acidosis can be initiated very quickly. This means dedicated care 24 hours a day until the thromboembolus is lysed. Thrombolysis may occur within 3 hours or take as long as 48 hours.

If reperfusion syndrome was the only major complicating factor in cats treated with thrombolytic agents, continued use in selected patients might be warranted. However, 90% of the cats that were successfully treated in the aforementioned clinical trial

had another systemic arterial thromboembolism within 1 to 3 months. Rethromboembolism occurred despite aspirin, warfarin, or heparin administration. In addition, t-PA is expensive. Consequently, the author does not currently use t-PA for systemic arterial thromboembolism in cats.

Streptokinase has clinical efficacy very similar to t-PA in human patients with coronary artery thrombosis. Streptokinase is less expensive. No controlled clinical trials of streptokinase use for systemic arterial thromboembolism in cats are available, and the author’s clinical experience with the drug has been generally negative. There has been one small experimental study in which throm-bin was injected between two ligatures placed at the terminal aorta to create a soft thrombus, followed by removal of the ligatures. Streptokinase was administered as a loading dose at 90,000 III followed by 45,000 IU/hr for 3 hours. This dose produced evidence of systemic fibrinolysis in a separate group of normal cats but without evidence of severe fibrinolysis or bleeding. In most cats there was no angiographic change and no improvement in limb temperature. There was a tendency for the thrombus weight to be lower in the treated cats when compared with control cats at postmortem examination. However, lysis of a fresh thrombus created with thrombin is probably much different from trying to lyse an established thromboembolus. Streptokinase is usually unsuccessful, may hasten the death of some cats through bleeding complications, and should not be routinely used.

Rheolytic thrombectomy Rheolytic thrombectomy is an experimental catheter-based system used for the dissolution of the thromboembolus using a high-velocity water jet at the end of the catheter that breaks up the thromboembolus and sucks it back into the system using the Venturi effect. Anesthesia is required and blood transfusion is almost always needed. The catheter is passed from the carotid artery to the region of the thromboembolus. The author and colleagues have used it in six cats. The procedure successfully removed the thromboembolus in five cats but only three left the hospital. Time from onset of clinical signs to thrombectomy was several hours to 8 days. The cat that had the procedure 8 days after the event had residual neurologic deficits but was the longest survivor. Interestingly, reperfusion syndrome has not been a common complication.

Adjunctive therapy Cats with systemic arterial thromboembolism are commonly in heart failure at the time of presentation. Medical therapy with furosemide and an angiotensin-converting enzyme inhibitor is often indicated. Cats that are in pain usually do not eat or drink. Fluid therapy is warranted but must not aggravate or produce heart failure

Cats that take a long time to recover caudal limb function or that only attain partial function may develop regions of skin and muscle necrosis, especially on the distal limbs. These regions may need to be debrided surgically. Cats that lose the function of only one leg or that do not regain function of one leg benefit from amputating that leg. Cats that have perma-nendy lost muscle function distal to the hock may benefit from arthrodesis.

Prognosis The short-term prognosis for life is guarded in cats without heart failure. Cats with a rectal temperature lower than 98.9° F had a worse prognosis in one study. Ifi The long-term prognosis is highly variable and depends on the ability to control the heart failure and the events surrounding the STE. One of the most common causes of death within the first 24 hours is euthanasia. In one study, cats lived between 3 and 30 months after the initial episode. The average survival time was about 10 to 12 months. In another study, MST for cats that recovered and were discharged from the hospital was approximately 4 months but was only about 2.5 months in cats that were also being treated for heart failure. The long-term prognosis for limb function depends on the ability of the cat to lyse its own clot or on the success of intervention. Many biologic variables determine whether or not reperfusion will spontaneously occur. A significant percentage of cats will develop a new thromboembolus, days to months after recovery.

Prophylaxis Feline patients with myocardial disease, especially those with an enlarged left atrium, should be considered at risk for developing intracardiac thrombi and signs of peripheral arterial thromboembolism, although the incidence appears to be low. Preventing peripheral thrombosis is, in theory, one of the most important therapeutic objectives for the veterinarian managing cats with severe myocardial disease. The ideal means of preventing thrombosis is resolution of the underlying myocardial disease. This is usually only possible in a cat with dilated cardiomyopathy secondary to taurine deficiency.

At-present, the only option available is to manipulate the patient’s coagulation system in an attempt to alter the delicate balance between the pathways that promote clotting and those that inhibit thrombus formation to reduce the patient’s thrombogenic potential. At this time, antiplatclet and anticoagulant therapies are the only means of preventing thrombus formation in cats with myocardial disease. Unfortunately, they are often ineffective and, in the case of warfarin, can produce serious side effects. Experience is similar in human medicine.

Antiplatelet therapy Prostaglandins enhance platelet aggregation via activation of cyclic adenosine monophosphate (cAMP). Aspirin (acetylsalicylic acid) acetylates platelet cyclooxygenase, preventing the formation of thromboxane A2, a potent prostaglandin-like platelet aggregating substance. The inhibition of platelet cyclooxygenase is irreversible, and bleeding time is restored to normal only after the production of new platelets. The inhibition of endothelial cyclooxygenase is reversible. The dose of aspirin recommended in cats is 10 mg/lb every third day. Whether or not this dose allows endothelial cyclooxygenase to recover or not in cats is undetermined. At this dose, aspirin has a half-life of 45 hours in the cat. In humans, doses as low as 20 to 100 mg/day inhibit platelet cyclooxygenase; however, no evidence suggests that this low dose has any more benefit than conventional daily doses of 625 to 1250 mg. In one study in cats, no difference was seen in thromboembolus recurrence between cats on low dose (5 mg/cat every 72 hours) and high dose (greater than or equal to 40 mg/cat every 72 hours). No evidence indicates that any dose of aspirin is effective at preventing the formation of an intracardiac thrombus in cats with myocardial disease. Clinical impression of aspirin’s efficacy varies between clinicians. Cats that have already experienced one systemic arterial thromboembolism are the only appropriate population in which to study the efficacy of an agent meant to prevent STE. Aspirin does not prevent recurrence of peripheral thromboembolism in this population.

Glycoprotein IIb and IIIa, an integrin present on platelet surfaces, is a receptor for fibrinogen, fibronectin, and von Willebrand factor. It mediates aggregation, adhesion, and spreading of platelets. The binding of prothrombin to glycoprotein IIb and IIIa also enhances the conversion of prothrombin to thrombin. Glycoprotein IIb and IIIa antagonists have been developed, and one (abciximab) increased mucosal bleeding time and reduced thrombus area when combined with aspirin (when compared with aspirin and placebo).

Anticoagulant therapy Available anticoagulants include heparin, the low molecular weight heparins, and warfarin. Heparin binds to a lysine site on AT, producing a conformational change at the arginine-reactive site that converts AT from a slow, progressive thrombin inhibitor to a very rapid inhibitor of thrombin and factor Xa. AT binds covalently to the active serine centers of coagulation enzymes. Factor Xa bound to platelets and thrombin bound to fibrin are protected from activation by the heparin-antithrombin III complex. Heparin may be administered intravenously or subcutaneously. Repeated intramuscular injection is discouraged because local hemorrhage may result. Some owners can administer heparin subcutaneously at home but the method is not ideal. The author and colleagues have noted rethrombosis with heparin therapy in some cats with cardiac disease. The dose of heparin for preventing thrombosis in cats is unknown.

Low molecular weight heparins include nadroparin calcium, enoxaparin sodium, dalteparin, ardeparin, tinzaparin, reviparin, and danaparoid sodium. The low molecular weight heparins have fewer bleeding complications in experimental animals, improved pharmacokinetics over heparin, are administered subcutaneously, and do not require monitoring in most situations. Although heparin does not reduce red cell aggregation in slow-moving blood, heparin and low molecular weight heparins are effective at preventing deep vein thrombosis in humans. Consequently, they may be beneficial in preventing intracardiac thrombus formation in cats with cardiomyopathy. No controlled studies are available. The author empirically uses enoxaparin sodium at a dose of 2.2 mg/lb every 12 hours subcutaneously in cats that have recovered from an systemic arterial thromboembolism or that have a severely enlarged left atrium and SEC.

Warfarin sodium is an oral anticoagulant (). Warfarin exerts no anticoagulant effect in vitro. In vivo, inhibitory effects on synthesis of clotting factors begin immediately. However, clotting is unaffected until already existing clotting factors decline. Therefore a delay occurs between initial administration and effect on the prothrombin time (FT). Historically, oral warfarin therapy has been monitored with the PT.This test measures the activity of factors II, VII, and X. The factor depressed most quickly and profoundly (usually factor VII) determines the FT during the initial days of therapy. The FT is performed by measuring the clotting time of platelet-poor plasma after the addition of thromboplastin and calcium, a combination of tissue factor and phospholipid. Intra- and interlaboratory variation in the FT was a significant problem for laboratories in the past, when crude extracts of human placenta or rabbit brain were the only source of thromboplastin. The international normalized ratio (INR), developed by the WHO in the early 1980s, is designed to eliminate problems in oral anticoagulant therapy caused by variability in the sensitivity of different commercial sources and different lots of thromboplastin. The INR is used worldwide by most laboratories performing oral anticoagulation monitoring and is routinely incorporated into dose planning for human patients receiving warfarin. When the anticoagulant effect is excessive, it can be counteracted by administering vitamin K,. However, once synthesis of factors 11, VII, IX, and X is reinstituted, time must elapse before factors achieve concentrations in the plasma that will adequately reverse the bleeding tendency. If serious bleeding occurs during therapy with warfarin, it may be stopped immediately by administering fresh blood or plasma that contains the missing clotting factors. Other drugs can modify the anticoagulant actions of warfarin by altering the bioavailability of vitamin K by altering the absorption, distribution, or elimination of the coumarins; by affecting synthesis or degradation of clotting factors; or by altering protein binding of the warfarin. The maintenance dose should be evaluated daily during the initial titration (3 days), then every other day (twice), and then weekly until a safe and stable dose regimen is determined. The therapeutic effect should be reevaluated periodically (at least once per month). The recommended initial dose is 0.1 to 0.2 mg per cat every 24 hours orally to a 6 to 10 lb/cat. The dose may then be increased to maintain an INR of 2.0 to 3.0. It can take up to 1 week for new steady state conditions to be achieved. The efficacy of warfarin at preventing recurrent thrombosis in cats with cardiac disease has been reported. M-s In one report, out of 23 cats examined retrospectively, 10 experienced a new thromboembolic episode while being administered warfarin. Two of these cats had at least two new episodes. In the other report, eight of 18 cats on warfarin experienced a new thromboembolic episode. This may be some improvement over the 75% recurrence rate reported for aspirin alone after t-PA therapy, but these results are still disappointing.i:,h In the first report, four cases also died suddenly (which could have been caused by thromboembolLsm). Three of these cats did not have postmortem examinations. The one cat that did have a postmortem examination had a thrombus present in its left atrium. One cat also died of a renal infarct that produced renal failure. Four cats appeared to have bleeding complications. In the second report, one cat died of a hemoabdomen and one was suspected to have an acute intracranial hemorrhage resulting in death. Consequendy, it appears that warfarin therapy can produce fatal complications. However, it should be noted that these studies were performed without using the INR for monitoring.

Categories
Drugs

Acarbose (Precose)

Oral Antidiabetic

Highlights Of Prescribing Information

  • Antihyperglycemic agent that reduces the rate & amount of glucose absorbed from the gut after a meal; may be useful for mild reductions in blood glucose in dogs or cats
  • Contraindications: Underweight animals, known hypersensitivity, diabetic ketoacidosis, inflammatory bowel disease, colonic ulceration, partial intestinal obstruction or predisposition to obstruction, chronic intestinal disease with marked disorders of digestion or absorption & when excessive gas formation would be detrimental
  • Dose-dependent diarrhea & flatulence are the adverse effects most likely to be noted
  • Give with meals (preferably right before)
  • Expense may be an issue

What Is Acarbose Used For?

May be useful for mild reductions in blood glucose concentrations (250-350 mg/dl range) in dogs and cats with non-insulin-dependent diabetes mellitus and as adjunctive treatment of insulin dependent diabetes mellitus.

Before you take Acarbose

Contraindications / Precautions / Warnings

Acarbose is contraindicated in patients with known hypersensitivity to the drug, diabetic ketoacidosis, inflammatory bowel disease, colonic ulceration, partial intestinal obstruction or predisposition to obstruction, chronic intestinal disease with marked disorders of digestion or absorption, and when excessive gas formation would be detrimental. Acarbose is not indicated in patients of low body weight (some say normal body weight as well) as it may have deleterious effects on nutrition status. Use caution in patients with renal dysfunction or severe liver disease.

Adverse Effects

Adverse effects reported in cats include flatulence, soft stools and diarrhea; in dogs, diarrhea and weight loss. Adverse effects are more likely at higher doses.

While acarbose alone does not cause hypoglycemia, it may contribute to it by reducing the rate and amount of glucose absorbed when the patient is receiving other hypoglycemic agents (insulin, oral hypoglycemics).

Overdosage / Acute Toxicity

Acute overdosages are likely to cause only diarrhea and flatulence. No treatment should be necessary. Should acute hypoglycemia occur secondary to other antihypoglycemics, parenteral glucose should be administered. If treating orally, use glucose (do not use sucrose).

How to use Acarbose

Acarbose dosage for dogs:

a) For dogs poorly controlled with insulin and dietary therapy when another reason for the poor control cannot be identified: Initially 12.5-25 mg total dose per dog PO with each meal. Give only at the time of feeding. May increase dose after two weeks to 50 mg per dog and then to 100 mg per dog (in large dogs, >25 kg) if response has been inadequate. Greater chance of diarrhea at the higher dosages. ()

b) 12.5-20 mg (total dose) per meal PO ()

Acarbose dosage for cats:

a) 12.5-25 mg (total dose) PO with meals. When acarbose is used with a low carbohydrate diet it may improve glycemic control and reduce insulin dependence. ()

b) 12.5 mg per cat PO twice daily with meals. May be able to reduce insulin dosage and thereby reduce hypoglycemia occurrence. ()

c) 12.5-20 mg (total dose) per meal PO ()

Client Information

  • ■ Give immediately prior to feeding for best results
  • ■ If diarrhea becomes a problem, contact veterinarian
  • ■ Acarbose does not cause low blood sugar, but it may contribute to it if the animal is receiving other hypoglycemic agents (insulin, oral hypoglycemics)
  • ■ May take up to two weeks for maximal effect

Chemistry / Synonyms

A complex oligosaccharide antihyperglycemic agent, acarbose occurs as white to off-white powder, is soluble in water and has a pKa of 5.1.

Acarbose may also be known as: Bay-g-5421, Precose, Asucrose, Glicobase, Glucobay, Glucor, Glumida, or Prandase.

Storage / Stability

Do not store tablets above 25°C (77°F); protect from moisture.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

Human-Labeled Products: Acarbose Tablets: 25 mg, 50 mg & 100 mg; Precose (Bayer); (Rx)

Categories
Horses

Aerosolized Drug Delivery Devices

Aerosolized drug therapy has been the standard treatment approach in human medicine for patients with noninfectious respiratory disease for 20 years. Administration via inhalation improves drug safety and efficacy by reducing the total therapeutic dose, minimizing drug exposure to other body systems, and allowing direct delivery of the drug to the lower respiratory tract. In most instances, the response to aerosolized drug administration is more rapid than to systemic drug administration. The equine patient is an ideal candidate for inhalation therapy for several reasons: a highly cooperative nature, obligate nasal breathing, rostrally placed and large nares, slow breathing rate and inspiratory flows, and a spectrum of diseases amenable to topical treatment.

However, initially devices such as nebulizers designed for delivery of aerosolized drugs to the lower respiratory tract of horses were cumbersome, expensive, and marginally efficacious. Today, efficient systems for drug delivery are being developed rapidly and inhalation therapy has become increasingly popular for treatment of lower respiratory tract disease. The most important aspects of aerosol administration for horses are efficient pulmonary drug delivery and ease of administration. The disadvantages of the aerosol route of administration include inability to access obstructed airways, high start-up costs, frequency of drug administration, potential for direct airway irritation by some aerosol preparations, respiratory contamination with environmental microorganisms, and contributions to air pollution from propellants. To date, inhalation therapy for horses has focused predominantly on administration of bronchodilating agents and corticosteroid preparations for treatment of recurrent airway obstruction (heaves). Aerosolized antimicrobial agents are under investigation for treatment of bacterial infection of the lower respiratory tract in horses. Bioactive proteins (insulin, antithrombin III, growth hormone) and hormones in aerosol currently being studied in humans may have future application in the horse.

Aerosols are denned as a gas containing finely dispersed solid or liquid suspended particles. The primary determinants of the efficiency of pulmonary deposition of an aerosol preparation include size, shape, viscosity, density, and hygroscopic growth of particles. Most therapeutic aerosols are heterogeneous (heterodispersed), and their aerodynamic behavior is described best by the mass median aerodynamic diameter (MMAD). Aerosol preparations with an MMAD of 1 to 5 microns produce the best therapeutic results in humans and are the target particle size for inhalation therapy in horses. These small particles penetrate deep within the respiratory tract, and particles less than 2 microns can penetrate alveoli. The cross-sectional area (cm2) of the lung increases dramatically at the level of the respiratory zone; therefore the velocity of gas flow during inspiration rapidly decreases at this level. Because the velocity of gas falls rapidly in the region of the terminal bronchioles, small particles sediment out in these airways. Moderate-size particles (5 to 10 microns) frequently settle out by sedimentation in larger more central airways (trachea, bronchi). Large aerosolized particles (>10 microns) affect the upper respiratory tract via inertial impaction. The majority (90%) of particles below the target size (<0.5 microns) are inhaled and exhaled freely and rarely affect the respiratory tract.

In addition to particle size, the patient’s tidal volume, inhalation and exhalation flow rates, and upper respiratory tract anatomy affect pulmonary drug deposition. Because these physiologic factors, in particular nasal breathing, affect pulmonary drug deposition, equine clinicians cannot extrapolate data generated from human subjects regarding specific drugs or devices to equine patients. Finally, all aerosolized solutions should be isotonic with neutral pH and should not contain chemical irritants such as benzalkonium, ethylenediaminetetraacetic acid (EDTA), chlorbutol, edetic acid, and metabisulfite.

Metered-Dose Inhalant Systems

Mechanical Nebulizers

Ultrasonic nebulizers and jet nebulizers are ozone-friendly delivery systems, used as alternatives to metered-dose inhaler. Ultrasonic nebulizers produce aerosol particles using vibrations of a quartz (piezoelectric) crystal, and particle size is inversely proportional to the operating frequency. High quality ultrasonic nebulizers are required to produce satisfactory particle size. Jet (pneumatic) nebulizers operate by the Venturi effect (dry air compressor) to fragment therapeutic solutions into aerosol particles.

The diameter of particles generated by a jet nebulizer is inversely proportional to the airflow, and minimum gas flow rates of 6 to 8 L/min are required to generate suitable particle diameter (<5 μm) for pulmonary delivery. Jet nebulizers are readily accessible, inexpensive, and easy to use. The primary disadvantage of jet nebulization is noise generated by the system. Ultrasonic nebulizers are silent; however, they are expensive and fragile. High pressure jet nebulization (Hudson RCI, Temecula, Calif.) using a delivery system developed for horses (Nebul, Agritronix Int, Meux, Belgium) delivers approximately 7% of the drug to the pulmonary system, and ultrasonic nebulization (Ultra-Neb, DeVilbiss, Somerset, N.J.) delivers approximately 5% of the drug to the pulmonary system. Deposition of radiolabeled drug into peripheral pulmonary fields using jet nebulization is superior to ultrasonic nebulization. Pulmonary contamination with environmental bacteria and fungi may occur using these aerosol delivery systems; therefore rigorous disinfection of the equipment is required to avoid this complication. Aerosol therapy via jet and ultrasonic nebulization requires an administration time of approximately 10 to 20 minutes, versus less than 2 minutes for many metered-dose inhaler drug dosages.

Dry Powder Inhalant (DPI) Devices

Categories
Veterinary Medicines

CaniLeish for Dogs

Scientific discussion

This medicine is approved for use in the European Union

CaniLeish is a lyophilisate and solvent for suspension for injection, intended for the active immunisation of Leishmania negative dogs from 6 months of age to reduce the risk to develop an active infection and clinical disease after contact with Leishmania infantum.

The active substance of CaniLeish is Leishmania infantum excreted secreted proteins (ESP).

CaniLeish was eligible for the submission of a dossier for granting of a Community marketing authorisation via the centralised procedure under Article 3 (2) (a) of Regulation (EC) No 726/2004 which refers to medicinal products intended for use in animals containing a new active substance which was not authorised in the Community. The Committee also confirmed that the requirements for veterinary products intended for Minor Use or Minor Markets (MUMS) were met and therefore the provisions of the relevant guideline were applicable for this application.

No specific inspection was considered necessary with regard to CaniLeish. The presented pharmacovigilance system was considered satisfactory.

The benefits of CaniLeish are the stimulation of active immunity in Leishmania negative dogs from 6 months of age to reduce the risk to develop an active infection and clinical disease after contact with Leishmania infantum. The onset of immunity is 4 weeks after the primary vaccination course and the duration of immunity is 1 year after the last (re-)vaccination.

The most common side effects are moderate and transient local reactions that may occur after injection such as swelling, nodule, pain on palpation or erythema. These reactions resolve spontaneously within 2 to 15 days. Other transient signs commonly seen following vaccination may be observed such as hyperthermia, apathy and digestive disorders lasting 1 to 6 days. Allergic-type reactions are uncommon and appropriate symptomatic treatment should then be administered.

Canine leishmaniosis is a widespread infectious disease in endemic areas of the Mediterranean basin, Asia and America. This is a zoonosis considered as a serious veterinary problem with an increasing impact on public health. The disease is due to the development and multiplication in the macrophages and mononuclear cells of a protozoan parasite – Leishmania infantum. The infected dogs constitute the main domestic reservoir and play a central role in the accidental transmission of parasites to humans. The parasite is transmitted from an infected dog to a non-infected dog by the bites of sandflies of the genus Phlebotomus. The outcome of the infection is highly variable. Infected dogs may develop symptomatic infection resulting in death if not treated or develop only one or many mild symptoms but a high percentage of infected animals remain asymptomatic.

List of main abbreviations used frequently through the scientific discussion

BSA: Bovine Serum Albumin

Cv: coefficient pf variation (validation of methods)

CMLA: canine macrophage leishmanicidal activity

Con A: Concanavalin A

DTH: Delayed Type Hypersensitivity

ESP: Excreted Secreted Proteins

IFA: indirect fluorescent antibody test

IgG: Immunoglobulin G

LIP: Leishmania infantum promastigotes

IFN-y: Interferon gamma

IL: Interleukin

LLT: Lymphoblastic Transformation test

NNN medium: Novy – Nicolle – Mac Neal medium

Ph. Eur: European Pharmacopeia

PSA: Promastigote Surface Antigens

SC: Subcutaneous

Sd: Standard deviation (validation of methods)

SLA: Soluble leishmania antigens

SPC: Summary of Product Characteristics

Thl: Type 1 T helper cell (lymphocyte)

TSE: Transmissible spongiform encephalopathy

CaniLeish: Quality assessment

Qualitative and quantitative particulars of the constituents

Each dose of 1 ml of vaccine contains the following:

Freeze-dried fraction:

Substances Quantity per dose
Active ingredient Excreted-Secreted proteins (ESP) Not less than 100 µq
Adjuvant Quillaja saponaria purified extract
Excipients mannitol
sucrose
Trometamol

Liquid fraction: for 1 ml of solvent

Substances Quantity per dose
Excipients Sodium chloride Water for injection 9 mg Qs 1 ml

The active substance Excreted-Secreted Proteins are constituted of parasitic proteins that are characterised by a defined protein pattern. The quantitative formulation of the vaccine relies on a quantification of the total protein content by a non-specific test. Among these proteins, some antigens have a major role for induction of immunity.

In addition to the quantitative test, other tests (based on proteomic analyses) were developed to appreciate the quality of the parasitic proteins. These tests confirmed the representativeness of the protein patterns obtained at the end of the production process.

Containers

Freeze-dried fraction: A 3 ml insulin type vial made of neutral borosilicate type I glass is used (Ph. Eur. 3.2.1.) and sealed with a buthyl elastomer rubber lyophilisation stopper and an aluminium cap.

Liquid fraction (solvent): A 3 ml insulin type vial made of neutral borosilicate type I glass is used (Ph. Eur 3.2.1.) and sealed with a buthyl elastomer rubber stopper and an aluminium cap.

Treatment:

Vials: dry heat sterilization for sterilization and depyrogenation is implemented (according to Ph. Eur. 5.1.1)

Stoppers: autoclaving takes place.

Filling and stopping are conducted under a class A environment.

The certificates of controls conducted were provided and were acceptable.

Development Pharmaceutics

Canine leishmaniosis is a widespread infectious disease in endemic areas of the Mediterranean basin, Asia and America and is a zoonosis considered as a serious veterinary problem with an increasing impact on public health. The disease is due to a protozoan parasite – Leishmania infantum ( = Leishmania chagasi in South America). The infected dogs constitute the main domestic reservoir and play a central role in the transmission of parasites to humans. The parasite is transmitted from an infected dog to a non-infected dog by the bites of sandflies of the genus Phlebotomus.

In the sandfly (vector), the parasites exist as multiplicative procyclic promastigotes and infective metacyclic promastigotes (after differentiation in the digestive tract). After transmission to the mammalian host, through the bite of infected sandflies, the parasites enter into macrophages. They persist as intracellular amastigotes living predominantly in the phagolysosome of macrophages. After initial infection, amastigotes may replicate some time before triggering an inflammatory and adaptative immune response.

Method of manufacture

Flow charts of the production processes and steps were provided.

Lyophilisate

In the first phase the excreted secreted proteins active substance is produced after culture of the Leishmania infantum. In the second phase the final product is formulated / manufactured. The formulation is based on fixed antigen content per dose and a fixed amount of adjuvant. Constituents of the excipients and adjuvant are weighed, dissolved in water and sterilised. The L. infantum ESP active substance is added under stirring and sterile conditions. The pH of the excipient and adjuvant fraction is adjusted if necessary. After formulation, the product is filled, freeze-dried and packaged. The sealed vials are stored at 5+/-3 °C in a cold room until controls and release.

Liquid fraction (solvent)

This phase starts with the preparation of the vials and stoppers for liquid preparation, the production of the diluent, then sodium chloride powder is weighed, dissolved in water for injection, and sterilised. Then diluents bottles are filled, stopped and sealed and the sealed vials are autoclaved.

Control of starting materials

Starting materials listed in a pharmacopoeia

Dimethyl sulfoxide, hydrochloric acid concentrated mannitol, sodium chloride, sodium hydrogen carbonate, sodium hydroxide, sucrose, trometamol, highly purified water and water for injection. For all the above materials certificate of analyses were provided and found acceptable.

Starting materials not listed in a pharmacopoeia

Starting materials of biological origin

Description of starting materials of biological origin

Active substance: Leishmania infantum – origin and history

Origin: isolated from a man in Morocco in 1967.

History: the strain was adapted to aseric medium and parasites were selected and cloned using defined media. The resulting parasite strain thus originates from the Leishmania infantum reference strain and was used for the construction of the seed lot system.

Master seed

Three amplifications were performed on defined and aseric medium. A cryopreservant was added on the last harvest before storage in liquid nitrogen.

Working seed

The working seed comprises the master seed undergone a few passages. The amplifications were performed on defined and aseric medium. A cryopreservant was added on the last harvest before storage in liquid nitrogen.

Controls

The following controls are preformed on the master and working seed: identity, purity, stability after passages and research for extraneous agents.

The absence of extraneous viruses was investigated in the seeds (Master seeds and working seeds) based on the Ph. Eur. monograph 062. All tests produced satisfactory results.

Hemin chloride

Use: growth factor in the culture media

Source/origin: porcine origin – animals from the Netherlands subject to ante and post-mortem examination.

Controls were considered adequate taking into account the suppliers documentation on origin/source, the gamma irradiation certificate, the tests of sterility, growing capacity, physical and chemical characteristics, assay. In order to further guarantee the absence of risk of transmission of extraneous agents through the use of porcin hemin on the vaccine production process, the applicant:

• implemented a systematic control of extraneous viruses in this raw material before irradiation treatment

• provided a validation of the irradiation method to inactivate viruses

• provided a validation of the viral clearance efficacy of the dissolution of hemin chloride in sodium hydroxide 1M for storage before its use in the vaccine production.

Based on the above data, the applicant conducted a risk assessment, which was acceptable and justified that the risk of transmission of extraneous agents through the use of hemin is close to nil.

Purified extract of Quillaja saponaria

Use: adjuvant

Source/origin: vegetal origin

Controls were considered adequate taking into account the supplier’s documentation and identification by liquid chromatography. Amongst the tests performed on adjuvant by the supplier, there is testing of the haemolytic activity and HPLC profile.

Viral risk assessment

A detailed risk assessment was presented in compliance with Ph. Eur. 5.2.5. and Ph. Eur. 5.1.7 requirements.

Considering:

• the extraneous agent testing performed on the seed lot, manufacturing process including dilutions in aseric and defined culture media,

• the use of only one starting material of biological origin (hemin chloride from porcine origin) which is carefully sourced and undergoes drastic production process as well as irradiation

• absence of use of cells or substrates that could propagate hypothetical viral infectivity,

It can be concluded that the risk of transmitting extraneous agents through the use of this vaccine is close to nil.

Starting materials of non biological origin

Starting material purchased from defined suppliers

These are powder media used as components of the Leishmania infantum culture medium. Detailed composition was provided. These media are composed of aminoacids, vitamins and other components (salts, sugars, nucleotides) all from vegetable, mineral, yeast or chemical origin.

In-house media

Leishmania infantum parasites (LIP) culture medium

• Freeze-drying excipient: Composition: sucrose , mannitol, trometamol, water for injection

Specific measures concerning the prevention of the transmission of animal spongiform encephalopathy

A detailed risk assessment was presented in accordance with Ph. Eur. monograph 1483 and existing guidance documents.

Considering:

• that seed materials are prepared in aseric and axenic media and knowing that TSE infectivity is recognised to be established and maintained in vitro with high difficulty and only with cells of neural origin,

• the absence of use of serum and starting material of TSE susceptible species for the manufacture of the vaccine,

• the indication of the vaccine for dogs, which are not susceptible to TSE by subcutaneous route It can be concluded that the risk of transmitting TSE agents through the use of this vaccine is nil.

On the basis of the above the CVMP concluded that the starting materials of animal origin used in the production of the final product comply with the current regulatory texts related to the TSE Note for Guidance (EMEA/410/01-Rev.2) and Commission Directive 1999/104/EEC.

Overall conclusion on quality

The quality part was adequately documented. The production process is relatively simple and relies on the culture of Leishmania infantum in aseric and defined media which allows the removing of Leishmania through adequate processing steps and the recovering of Excreted Secreted Proteins that constitute the active substance of the vaccine.

An overview of the production process and the controls performed during the production of the freeze-drying fraction containing the active substance and of the liquid fraction was presented. The nature of the raw materials, manufacturing process, controls and treatments applied enable to ensure sterility of the vaccine and absence of introduction of any extraneous agent, and to ensure consistency and homogeneity of the production. This is ensured by the controls performed on raw materials and vaccine products as well as process parameters investigated and recorded during the manufacture.

Many tests have been developed by the applicant which enable to:

• Specifically identify the active substance and thus specific recognition of a major protein by specific antibodies after its migration by electrophoresis is achieved allowing confirmation of the presence of this major antigen and its integrity.

• Quantify the active substance: ESP are the only proteins present in the vaccine. A non-specific protein assay allows quantification of the total amount of proteins. This quantification is used to formulate the vaccine on a fixed target. As no protein is added in the finished product, this amount can be controlled by a newly developed test performed on the final vaccine.

• Validate the purity of the active substance: An electrophoresis in defined conditions ensures the conformity of the protein pattern with the expected profile. Validation demonstrated that this kind of test allows detection of the presence of an extra-protein or the over-expression on one particular protein.

On the final product, in addition a potency test is performed which allows to test the activity of the vaccine and the ability to induce an immune response.

These tests provide clear specifications for the active substance and ensure the consistency and homogeneity of the vaccine production and hence the safety and the efficacy of the released batches.

CaniLeish: Safety assessment

CaniLeish is a freeze-dried vaccine containing Excreted Secreted Proteins of the Leishmania infantum parasite in the promastigote form, adjuvanted with a purified extract of Quillaja saponaria.

One vaccine dose is formulated with a fixed target of protein – 110 µg of ESP – adjuvanted with 60 µg of purified extract of Quillaja saponaria and reconstituted with one dose of diluent before use. The vaccine is intended for the immunisation of healthy dogs against Leishmania infantum infection. The regimen of vaccination recommends three subcutaneous injections of one dose of vaccine at 3 weeks intervals in dogs from 6 months of age onwards (primary vaccination). An annual booster immunisation with one dose of vaccine is recommended (re-vaccination scheme).

The adjuvant of the vaccine (purified extract of Quillaja saponaria) belongs to saponins and derivatives which are known to have haemolytic activity. This lytic action on erythrocytes membrane depends on the structure of the saponin itself and on the physicochemical properties of the cells. For this reason, the applicant tested the effect of CaniLeish on dog erythrocytes and haemolytical analysis including red blood cell counts were performed during safety studies.

Overall conclusion on safety assessment

The safety of the vaccination with CaniLeish was investigated primarily in Leishmania free Beagle dogs receiving 3 standard doses (as described in the SPC) or repeated administrations or an overdose (2 doses) of a vaccine formulated with an overage of antigen. Studies demonstrated that mild local reactions such as swellings associated or not with redness, pain or scabs and a weak hyperthermia may be observed after vaccination that will resolve spontaneously within few days. These reactions have been described in the SPC and are regarded as acceptable post-vaccination reactions for a canine vaccine.

The tolerance of the vaccine was good in the dogs that had been in contact with the parasite before the first injection in one of the conducted field studies and therefore considered a statement in section “Special precautions for use” was included:

“Injection of the vaccine to dogs already infected by Leishmania infantum did not show any specific adverse reactions other than those described in section 4.6”.

For the user there is a risk of self injection, which is however very low. In addition, appropriate warnings and advice on the SPC have been included. For the environment there is negligible risk that the vaccine components may cause unexpected effects to the environment. As the target species is dogs there was no requirement for residue studies.

CaniLeish: Efficacy assessment

The following information on the epidemiology, cycle of transmission, disease and immunity related to Leishmania infantum (dossier + bibliography) are considered important for better understanding the rationale followed in the laboratory and field trials presented. Therefore some important information on the disease is presented below.

Overall conclusions on efficacy

The vaccine is intended to be used in Leishmania free dogs from 6 months of age onwards to protect against Leishmania infantum after 3 vaccine injections as primo-vaccination and an annual single booster vaccination.

Studies presented in this dossier confirmed the difficulty to assess the efficacy of a vaccine against a parasitic disease with heterogeneous evolution and manifestation.

The demonstration of efficacy of the vaccine was based on a key field trial of 2 years duration involving vaccinated and control dogs submitted to natural exposure to infection in zones with high infection pressure. After these 2 years, the vaccine was demonstrated to reduce the number of dogs developing an active infection in the vaccinated group and for a dog to significantly reduce the probability to become infected and to develop a clinical disease. The benefit of the vaccination was therefore estimated in zones with high infection pressure where it may decrease the risk to develop an active infection and a symptomatic disease after contact with the parasite for vaccinated animals. In conditions with weak prevalence of the disease, no clear benefit of the vaccination could be established. This may be linked to the high number of animals needed to demonstrate the benefit in lower prevalence zone.

Laboratory studies provide limited information despite many biological investigations including humoral (IgGland IgG2, against ESP and PSA, total IgG) and cellular (lymphoblastic transformation test, IFNy ELISPOT assay, canine macrophage leishmanicidal activity) immunity evaluation. No biomarker or immunological profile correlated with protection or infection could be defined. Nevertheless data on experimental challenges showed that infection can be detected from 4 to 9 months after the experimental infection and allowed a constant and homogenous response to vaccination. However such responses could not be clearly linked to protection and future response of the dogs to infection.

Considering the diversity of evolution of the infection and the variable incubation period that may last for months, it was difficult to define for this vaccine periods such as onset or duration of immunity and protection in a laboratory studies but a duration of immunity lasting a year after the last re-vaccination and an onset of immunity of 4 weeks were supported by the field data.

CaniLeish: Benefit risk assessment

CaniLeish is a vaccine intended to reduce the incidence of asymptomatic and symptomatic forms of Leishmania infection by induction of a specific cell-mediated immunity in vaccinated dogs. It is based on the role of the Excreted Secreted Proteins of L. infantum to induce cellular immune response. The vaccine is made of a freeze-dried pellet and a diluent. The adjuvant – purified extract of Quillaja saponaria – known to participate to the activation of the cellular immune response is included in the freeze-dried fraction.

The assessment of the application dossier took into account that this vaccine is intended for a limited market and some reductions in requirements according to the guideline on Data requirement for immunological veterinary products for minor use and minor species (EMEA/CVMP/IWP/123243/2006) were implemented.

Benefit assessment

Direct therapeutic benefits

The objective is to induce sufficient immunity to Leishmania free dogs from 6 months of age to reduce the risk to develop an active infection and clinical disease after contact with Leishmania infantum.

Field trials demonstrated that the product is capable of reducing the number of Leishmania free dogs developing an active infection and significantly reduce the probability to become infected and to develop a clinical disease after contact with Leishmania infantum. The benefit of the vaccination was estimated in zones with high infection pressure where it may decrease the risk to develop an active infection and a symptomatic disease after contact with the parasite for vaccinated animals.

Additional benefits

CaniLeish is the first vaccine to be authorised for the prophylaxis against Leishmania infantum in Europe. The duration of immunity for the vaccine has been shown to be 1 year after the last re-vaccination and the onset of immunity 4 weeks.

Vaccination has been shown to be safe for Leishmania infected animals. Risk assessment Main potential risks

a) There is a risk of moderate and transient local reactions may occur such as swelling, nodule, pain on palpation or erythema. These reactions resolve spontaneously within 2 to 15 days. Other transient signs commonly seen following vaccination may be observed such as hyperthermia, apathy and digestive disorders lasting 1 to 6 days. Allergic-type reactions are uncommon and appropriate symptomatic treatment should then be administered

b) For the user there is a very low risk of self injection. Appropriate warnings and advice on the SPC will serve to minimise this risk.

c) For the environment there is negligible risk that the vaccine components may cause unexpected effects to the environment.

Specific potential risks, according to product type and application

a) Efficacy results do not show complete protection of vaccinated dogs. Despite vaccination a percentage of dogs still became infected with Leishmania infantum and from those vaccinated dogs that became infected a percentage of animals also developed clinical signs of the disease.

b) The benefit of the vaccination was established in zones with high infection pressure, whereas no clear benefit could be established in areas of low infection pressure.

c) In dogs developing Leishmaniosis (active infection and/or disease) despite vaccination, proceeding with the vaccine injections showed no benefit.

Risk management or mitigation measures

a) Appropriate warnings have been placed in the SPC to warn of the potential risks to the target animal, end user and environment.

b) Appropriate warnings have been placed in the SPC to clarify the limitations of the indication, the limitations of benefit in low infection areas and the lack of benefit in continuing the vaccination in vaccinated dogs that have developed the disease.

Evaluation of the benefit risk balance

Leishmaniosis is an important disease in dogs that is endemic in the Mediterranean countries of Europe, the Middle East and many subtropical areas of the world. In the past decade, an increased incidence of canine leishmaniosis in endemic zones as well as spread of the infection to non-endemic areas of Europe has been observed. Canines are the main reservoir for the parasites and play a relevant role in transmission to humans. The aetiological agent – Leishmania infantum – is transmitted by sandflies of the genus Phlebotomus.

In endemic areas dogs become exposed immediately. Evolution of the infection in dogs is then complex and unpredictable. Some will develop protective immunity, some remain asymptomatic after infection and may relapse later and others develop a clinical disease. It is considered that establishment of infection and development of the disease both depend on the host’s immunological response and that once the parasite escapes immunity and is able to multiply, no clearance is possible anymore. Infection may evolve over a period of a few weeks to several months toward disease patterns that can be extremely variable and polymorphic, which makes it difficult to classify dogs within specific categories.

Along with typical clinical signs and history of exposure, the diagnosis is based on microscopic identification of the parasite or PCR testing on bone marrow samples. Serological techniques may reveal active infection.

The management of dogs infected with Leishmania is currently based on sanitary and/or medical prophylaxis but up to now, both showed limited capacity to fulfil eradication, or even control of canine leishmaniosis.

Sanitary measures are based on preventing physical contact of dogs with vector, reducing the microhabitats to sandflies, and employing insecticide (environmental or topical). Despite implementation of all these measures, canine Leishmaniosis could not be reduced efficiently. Moreover culling of seropositive dogs has not proved to be efficient; although this solution was adopted in Brazil it currently has failed to prevent the number of human cases to increase.

If applied medical treatment in diseased dogs consists of symptomatic treatments associated to leishmanicidal molecules (meglumine antimoniate, aminosidine, miltefosine) which reduce or eliminate clinical symptoms but do not achieve parasitological cure. The epidemiological risk persists and dogs that respond to chemotherapy can nevertheless experience clinical relapse after the cessation of treatment or during it. Besides, these medicines have shown to have a number of disadvantages such as price, repeated injections, hepato- and nephrotoxicity, which can make compliance to treatment quite difficult to achieve.

On the basis of the above and although efficacy results have not shown complete protection of vaccinated dogs, it can be concluded that vaccination against Leishmaniosis can become a valuable and/or complementary alternative to the existing tools, despite the limits of the vaccine. Despite the fact that complete protection against Leishmaniosis or eradication of the disease cannot be achieved, this vaccine is able to reduce the risk for developing active infection and disease at the individual scale and to participate to reduction of incidence of the disease at the level of a dog population. Additionally and although the epidemiological impact of the vaccination cannot be estimated from the provided data of this application, it is nevertheless expected that improvement of the situation in dogs with regard to Leishmaniosis will also have a positive impact on human health. Finally, no risk has been linked to the use of this vaccine in dogs (included infected ones with Leishmaniosis).

Hence, the benefit-risk assessment of this vaccine appears favourable for this vaccine, within the limits highlighted in the SPC.

Conclusion on benefit risk balance

The information provided in the dossier and in response to points raised is sufficient to confirm an overall positive benefit risk balance.

Conclusion

Based on the original and complementary data presented the Committee for Medicinal Products for Veterinary Use (CVMP) concluded that the overall benefit-risk balance was considered favourable for authorisation.

 

Categories
Conditions

Neurological Conditions

Afghan myelopathy

A progressive disease of the white matter of the spinal cord. Symptoms include pelvic limb ataxia and paresis progressing to thoracic limb involvement, tetraplegia and eventually death from respiratory paralysis.

Ambylopia and quadriplegia

This is a lethal inherited condition of Irish Setters. Puppies are unable to walk and progression to visual impairment, nystagmus and seizures occurs.

Arachnoid cysts

Arachnoid cysts are a rare cause of focal spinal cord compression in young dogs. Neurological deficits depend on the site of the lesion.

Atlantoaxial subluxation

This is seen primarily in young dogs of Toy breeds which present with neck pain and neurological deficits in all four limbs due to cervical spinal cord compression. A variety of congenital defects including a lack of or hypoplasia of the dens and shortening of the axis lead to instability of the atlantoaxial articulation. The condition may also be acquired in any breed as a result of fracture of the dens or damage to the ligamentous support. (See also Odontoid process dysplasia under Musculoskeletal conditions.)

Birman cat distal polyneuropathy

A degenerative polyneuropathy which results in hypermetria in all limbs, progressive pelvic limb ataxia and a tendency to fall. The condition is believed to be hereditary.

Cerebellar degeneration

Cerebellar cells can undergo premature aging, degeneration and death (termed abiotrophy) leading to signs of cerebellar dysfunction (intention tremor, ataxia, hypermetria and menace deficits). In most cases the condition is believed to be hereditary.

Cerebellar malformation

Congenital malformations of the cerebellum include hypoplasia and aplasia of the whole or part of the cerebellum. Some may have a genetic basis, others result from a teratogen. Clinical signs are seen as soon as the animal becomes mobile and are non-progressive. They include hypermetria, head tremor and a wide-based stance. There is no treatment, but animals may make suitable pets if not severely affected.

Cervical vertebral malformation (wobbler syndrome)

This is a developmental malformation and malarticulation of the caudal cervical vertebrae seen in large- and giant-breed dogs, particularly the Dobermann and Great Dane. Clinical signs result from spinal cord compression and include neck pain and gait abnormalities (e.g. ataxia and paresis) which are worse in the pelvic limbs.

Congenital deafness

This has been observed in numerous breeds (especially Dalmatians and blue-eyed white cats) and usually results from a partial or complete failure of development of the organ of Corti.

Congenital vestibular disease

Young animals may present with signs of peripheral vestibular dysfunction including head tilt, circling, and falling. Nystagmus is not a common feature of the congenital condition. There is no treatment, symptoms may improve with time as the animal compensates.

Vestibular disease may also be acquired secondarily to a variety of causes including middle-ear infections in breeds predisposed to ear disease. An idiopathic form may be seen in older dogs.

Dalmatian leukodystrophy

This rarely reported progressive neurological condition results in visual deficits and progressive weakness. On gross pathology there is atrophy of the brain, lateral ventricle dilation and cavitation of the white matter of the cerebral hemispheres.

Dancing Dobermann disease

This is believed to be a neuromuscular disease of the gastrocnemius muscle, the underlying cause is not known. It has only been reported in Dobermann Pinschers and affected dogs initially flex one pelvic limb whilst standing. As progression occurs to involve the other pelvic limb the dog is seen to alternately flex and extend each pelvic limb in a dancing motion.

Degenerative myelopathy

A degenerative disease primarily seen in German Shepherd Dogs over five years of age. Diffuse degeneration of the white matter of the thora-columbar spinal cord results in progressive pelvic limb ataxia, paresis and loss of conscious proprioception. The cause in unknown.

Demyelinating myelopathy of Miniature Poodles

A rare, possibly inherited condition characterised by diffuse spinal cord demyelination. Pelvic limb paresis progresses to paraplegia and tetraplegia. Spinal reflexes are hyperactive.

Dermoid sinus

A dermoid sinus is a developmental defect arising from the incomplete separation of the skin and neural tube. It may be found midline in the cervical, cranial thoracic or sacrococcygeal regions. In cases where the sinus communicates with the dura mater, neurological signs may be seen. The condition is most commonly found in the Rhodesian Ridgeback and is believed to be hereditary in this breed.

Discospondylitis

Infection of the intervertebral disc with osteomyelitis of adjoining vertebral bodies. Infection occurs secondarily to spinal surgery, foreign body migration or septic emboli from the skin, urinary/genital tract, or from a concurrent endocarditis. Clinical signs may include pyrexia, anorexia, spinal pain and paresis.

Distal symmetrical polyneuropathy

This distal polyneuropathy has been reported in young adult Great Danes and other large breeds of dog. Symptoms include pelvic limb paresis that progresses to tetraparesis, and atrophy of limb and head muscles. There is no treatment.

Eosinophilic meningoencephalitis

This condition has been reported in six male dogs, three of which were Golden Retrievers. Cerebrospinal fluid analysis demonstrated pleo-cytosis with an eosinophil percentage of 21-98%. There was a concurrent peripheral blood eosinophilia in four of the cases. Symptoms included behavioural abnormalities and seizures.

Episodic falling

Seen in Cavalier King Charles Spaniels in the UK. During exercise, a bounding hind-limb gait develops. This progresses to a bunny-hop with arched spine, and eventually collapse often with the thoracic limbs crossed over the back of the head. There is no loss of consciousness and recovery is rapid. Some improvement may be seen with diazepam. The cause is unknown.

Giant axonal neuropathy

This is a rare inherited neuropathy of German Shepherd Dogs. The cause is unknown. Distal nerves in the pelvic limbs and long tracts of the central nervous system are affected first, giving rise to paresis, loss of spinal reflexes and pain perception in the pelvic limbs. Megaoesophagus and loss of bark occur later. There is no treatment.

Glycogenosis (glycogen storage disease)

A group of rare diseases resulting from a deficiency of one or more enzymes involved in glycogen degradation or synthesis. Glycogen accumulates in a variety of tissues including the central nervous system, muscle and liver resulting in clinical signs including seizures and muscular weakness.

Granulomatous meningoencephalitis

This is an inflammatory condition of unknown cause. The disease may be focal or diffuse and may affect any part of the central nervous system, leading to a wide range of clinical signs including seizures, ataxia, nystagmus and visual deficits. The disease is usually chronic and progressive. Small-breed dogs are most commonly affected with Poodles representing about 30% of diagnosed cases.

Hemivertebrae

Hemivertebrae are congenitally malformed vertebrae most commonly seen at the level of thoracic vertebrae 7-9. Neurological signs, e.g. pelvic limb ataxia, paresis, faecal and urinary incontinence, may result from spinal cord compression.

Hereditary ataxia

Progressive ataxia results from degeneration of the white matter of the cervical and thoracic spinal cord in young Smooth-haired Fox Terriers and Jack Russell Terriers.

Hound ataxia

A degenerative myelopathy seen in Foxhounds and Beagles in the UK. Degenerative changes are most severe in the mid-thoracic spinal cord but may extend to involve the brainstem, caudal cerebellar peduncles or sciatic nerve. Signs include pelvic limb weakness and ataxia. Muscle atrophy and loss of spinal reflexes is not seen. The cause is unknown but a link has been suggested to an all-tripe diet.

Hydrocephalus

Hydrocephalus occurs where there is dilation of all or part of the ventricular system of the brain, and may be congenital or acquired (usually secondary to neoplasia or inflammatory disease). Symptoms include a domed cranium, seizures and altered mental status.

Hyperaesthesia syndromes

Increased sensitivity to tactile and painful stimulation may result in self-mutilation which varies in severity from rippling of the skin when touched or excessive licking to auto-amputation. Some cases are due to underlying neuropathies or are forms of seizure; however, in others no underlying cause is identified. Treatments tried include phenobarbitone, megoestrol acetate and prednisolone. Success has been variable.

Hyperlipidaemia

Hyperlipidaemia (high blood lipid levels) is a familial condition of Miniature Schnauzers and cats which is believed to be associated with a reduced activity of lipoprotein lipase resulting in defective lipid metabolism. Affected animals may experience seizures as well as abdominal distress and pancreatitis.

Hyperoxaluria

A condition seen in Domestic Short Hair cats in which young cats develop acute renal failure and neurological disease. Signs include anorexia, depression, enlarged painful kidneys, weakness, reduced spinal reflexes and poor response to pain. Oxalate crystals are found deposited in the kidney tubules, and swellings of the proximal axons of the ventral horn cells are found in the spinal cord on post-mortem. There is no treatment and the condition carries a grave prognosis.

Hypertrophic neuropathy

An inherited neuropathy reported in the Tibetan Mastiff which results in generalized weakness, hyporeflexia and dysphonia from seven to ten weeks of age. There is no treatment and the prognosis is guarded.

Hypoglycaemia

Hypoglycaemia is a common metabolic cause of seizures. It may result from a variety of causes including insulinoma, hypoadrenocorticism, severe liver disease and sepsis. Young dogs of Toy breeds may develop hypoglycaemia easily when stressed, fed an inadequate diet or affected by gastrointestinal disease. Hunting dogs which are not fed on the morning of a hunt may also be predisposed to hypoglycaemia as a result of physical exertion.

Hypomyelination

Hypomyelination of the central nervous system has been seen in several breeds of dog and is known to be hereditary in some cases. Signs usually start at a few weeks of age with generalized body tremors which worsen with excitement. Hypomyelination of the peripheral nervous system has been seen in two Golden Retriever litter-mates with pelvic limb weakness and depressed spinal reflexes.

Idiopathic facial paralysis

Paralysis of the facial nerve results in drooping of the lip, paralysis of the eyelids and impaired ear movement on the affected side. Acute onset facial paralysis may occur in adult dogs without evidence of an underlying cause.

Intervertebral disc disease

Degeneration of the intervertebral discs resulting in extrusion or protrusion of the nucleus pulposus may result in spinal cord compression and pain/paresis. Nuclear extrusion occurs early in chondrodystrophoid breeds, e.g. Pekingese, Dachschunds, Beagles, Welsh Corgis, French Bulldogs, some Spaniels and Basset Hounds giving rise to signs in younger dogs.

Leukoencephalomyelopathy of Rottweilers

This is believed to be an inherited condition. Degeneration of the myelin of the spinal cord, brainstem, cerebellum and sometimes optic tracts results in ataxia, tetraparesis and loss of conscious proprioception, with increased spinal reflexes and muscle tone. Vision is usually unaffected. The condition progresses over 6-12 months.

Lissencephaly

A developmental anomaly where the cerebral cortex has reduced or absent gyri or sulci resulting in a smooth appearance. Clinical signs are usually seen from a few months of age and may include behavioural abnormalities, lack of training, aggressive behaviour, visual deficits and seizures.

Lumbosacral stenosis

Stenosis (narrowing) of the lumbosacral vertebral canal and/or intervertebral foramina causes compression of the lumbosacral nerve roots. Clinical signs may include pain on palpation of the area, pelvic limb paresis or lameness, tail paralysis, hypotonia of the anal sphincter and bladder atonicity (‘lumbosacral syndrome’). It is most commonly seen in adult German Shepherd Dogs.

Lysosomal storage diseases

These rare diseases result from a failure of normal metabolic processes due to a deficiency of an enzyme within the lysosomes of neuronal tissues. As a result, substrate accumulates, causing cellular dysfunction and eventually death. One of a variety of lysosomal enzymes may be affected. Symptoms usually occur before one year of age and may include ataxia, tremors, seizures, dementia and blindness. Most lysosomal storage diseases are believed to be inherited as an autosomal recessive trait.

Meningitis and polyarteritis

This is a vasculitis of meningeal arteries which results in clinical signs of recurrent fever, anorexia and cervical rigidity. In some cases paresis or tetraparesis may be seen. An immune-mediated aetiology has been suggested and some cases may respond to high-dose, long-term prednisolone treatment.

Meningoencephalocoele

A lethal malformation where part of the brain and meninges is herniated through a defect in the skull.

Multisystem neuronal degeneration

A slowly progressive degenerative disease of young Cocker Spaniels. Diffuse neuronal loss throughout the subcortical, brainstem and cerebellar nuclei results in symptoms including loss of recognition of the owner, apathy, hyperactivity, hypersexuality and aggression.

Muscle cramping

An inherited disorder of Scottish Terriers. Affected dogs are normal at rest but exercise may provoke muscle spasms which in its mildest form appear as pelvic limb stiffness. Severe attacks cause rigidity of all muscles including facial muscles causing the dog to fall over into a tightly curled ball. Consciousness is maintained and the animal makes a spontaneous recovery. The cause is unknown but it is believed to be a disorder of central nervous system neurotransmitters. A similar condition has been reported in Dalmatians and Norwich Terriers.

Myasthenia gravis

Decreased numbers of acetylcholine receptors on the post-synaptic muscle membrane leads to defective neuromuscular transmission. The disease can be congenital or acquired. Clinical signs in dogs include muscle weakness on exercise which improves with rest, and megaoesophagus. The onset may be chronic or acute and the condition can be generalised or focal. Signs in cats include drooling, ventroflexion of the neck, regurgitation, weakness and lameness.

Narcolepsy/cataplexy

Narcolepsy is characterised by excessive sleepiness at inappropriate times, whilst cataplexy is acute flaccid paralysis from which the animal makes a complete recovery after a few seconds to several minutes. In dogs, cataplexy seems to be the more prominent and is often associated with excitement, e.g. eating or playing.

Neuroaxonal dystrophy

A degenerative central nervous system disorder of unknown cause, seen primarily in Rottweilers. Pathological findings include swellings of the distal axons within the central nervous system and cerebellar atrophy. Symptoms include ataxia, hypermetria and intention tremors which may be slowly progressive over several years.

Partial seizures

Partial seizures result from a focal discharge from the brain. The appearance of the seizure varies with the location of the discharge but may include fly-biting, star-gazing, tail-chasing or self-mutilating behaviour.

Polyradiculoneuritis

This is an inflammatory condition affecting multiple nerve roots resulting in pelvic limb weakness which rapidly progresses to quadriplegia. An idiopathic form may be seen in any breed, however the condition has been seen following raccoon bites in hunting breeds such as the Coonhound. An immunological reaction to raccoon saliva may be the underlying cause in these cases.

Primary brain tumours

Primary brain tumours are derived from tissues of the nervous system including nerve cells, glial cells, meninges and neuroepithelial cells. They are generally solitary and most cases will present with signs of a space-occupying lesion in the brain, the specific signs varying with the location. Meningiomas and gliomas are the most common primary brain tumours in dogs. Meningiomas are the most common primary brain tumours in the cat and may be single or multiple in this species.

Progressive axonopathy

See Sensory neuropathy.

Pug encephalitis

A rare, necrotising meningoencephalitis of unknown aetiology seen in Pugs. Symptoms are often acute in onset and include seizures, depression, head-pressing, circling, blindness with normal pupillary reflexes and opisthotonus. The condition is progressive and there is no treatment. Most cases are euthanased.

Pyogranulomatous meningoencephalomyelitis

An acute, rapidly progressive disease of unknown cause seen in mature Pointers. Mononuclear and polymorphonuclear inflammatory infiltrates are found throughout the central nervous system but especially in the cervical spinal cord and lower brainstem. Dogs suffer from cervical rigidity, ataxia and sometimes seizures. The prognosis is poor. A temporary remission in response to antibiotics may be seen.

Rottweiler distal sensorimotor polyneuropathy

A polyneuropathy of Rottweilers resulting in paraparesis progressing to tetraparesis, reduced spinal reflexes, hypotonia and neurogenic atrophy of limb muscles. The condition progresses over twelve months.

Sacrocaudal dysgenesis

Congenital malformation of the sacrococcygeal spinal cord and vertebral column which results in locomotor problems in the hind legs and faecal and urinary incontinence.

Sensory neuropathy

Sensory neuropathies have been seen in a number of breeds. In Pointers signs of self-mutilation associated with loss of pain sensation predominate, whereas in Dachshunds loss of proprioception and ataxia may be seen. In Boxers the condition is termed progressive axonopathy and is characterised by pelvic limb hyporeflexia, hypotonia and proprioceptive loss.

Shaker dog disease

This condition has been most commonly observed in dogs with white hair coats, particularly Maltese and West Highland White Terriers. Dogs develop a fine whole-body tremor which may worsen with excitement and stress. Other signs may include nystagmus, menace deficits, proprioceptive deficits and seizures. There may be an underlying mild lymphocytic encephalitis and affected animals are usually responsive to immunosupressive doses of corticosteroids with benzodiazepines.

Spina bifida

This is a developmental defect resulting from the failure of the two halves of the dorsal spinous processes to fuse, most commonly in the lumbar spine. Protrusion of the spinal cord or meninges may result in symptoms including pelvic limb ataxia, paresis and urinary or faecal incontinence. If no protrusion occurs the condition is termed ‘spina bifida occulta’.

Spinal dysraphism

This is a congenital malformation of the spinal cord resulting in a wide-based stance and bunny-hopping gait of the hind-limbs. It may be associated with hemivertebrae or spina bifida. The condition is non-progressive.

Spinal muscular atrophy

This is a condition where premature degeneration of various neuronal cell populations of the brainstem and ventral horn of the spinal cord result in generalised weakness which may progress to muscular atrophy and tetraparesis/plegia.

Spongiform degeneration

Spongiform degenerations are rare disorders resulting in vacuolation of the brain and spinal cord which may result in a wide variety of neurological signs.

Springer Spaniel rage syndrome

Seen in young adult Springer Spaniels which become aggressive to people including their owners. No intracranial lesion has been found to explain this behaviour.

True epilepsy

Recurrent seizures caused by functional disorders of the brain. The high incidence in certain breeds of dog suggests an inherited basis.

Categories
Conditions

Neoplastic Conditions

Actinic keratosis

These lesions are often associated with chronic sun exposure, so are generally seen in pale-skinned areas of animals with outside access. Lesions may be single or multifocal, and plaquelike or papillomatous with hyperkeratosis. They may progress to squamous cell carcinoma which has the potential for local invasion and distant metastasis.

Adrenocortical tumour

Adrenocortical tumours are responsible for 15-20% of hyperadrenocorticism cases in the dog, and 20% in the cat (see under Endocrine conditions). They are usually unilateral (although 10% of cases have bilateral tumours) and may be adenomas or carcinomas. The latter may be invasive and metastasise.

Anal sac adenocarcinoma

Anal sac adenocarcinoma is a malignant tumour which is palpable as a discrete or infiltrative mass in the anal sac. These tumours are often associated with hypercalcaemia and metastasise early to the sublumbar lymph nodes, spleen and lung. They are rare in the cat.

Anaplastic sarcoma

A poorly-differentiated malignant soft-tissue tumour derived from the mesenchymal connective tissues of the body.

Basal cell tumour

These common skin tumours arise from the basal epithelial cells which give rise to the epidermis. They are usually well-circumscribed, firm, freely-mobile masses found in the dermis and subcutis around the head and neck. They are generally slow-growing and benign in behaviour, rarely metastasising.

Benign fibrous histiocytoma

These rare skin tumours may be reactive proliferations rather than true neoplasias. Lesions can be solitary or multiple and predilection sites include the face, legs and scrotum.

Canine anterior uveal melanoma

See under Ocular conditions.

Canine cutaneous histiocytoma

These skin tumours are commonly seen in young dogs, and appear as solitary, firm, well-circumscribed intradermal nodules on the head, limbs or trunk. Occasionally the surface will ulcerate. They are benign and most will regress spontaneously over a period of months.

Chemodectoma

Chemodectomas are derived from the chemoreceptor cells of the aortic and carotid bodies which detect changes in the blood pH, oxygen and carbon dioxide levels. Chemodectoma of the aortic body arises at the heart base and is reported more frequently than carotid body tumours which arise at the bifurcation of the carotid artery and present as a cervical mass. Both are relatively uncommon in the dog and cat, but brachycephalic dogs appear predisposed. Chemodectomas may be locally invasive and have the potential to metastasise.

Chondrosarcoma

This is the second most common primary bone tumour of dogs accounting for 5-10% of cases. It is generally slower growing and metastasises less frequently than the osteosarcoma.

Colorectal cancer

Intestinal canacer is not common in the dog or cat. In the dog, cancer of the large intestine is more common than that of the small intestine, adenocarcinoma/carcinoma being the most common malignant tumour. In cats most tumours arise in the small intestine.

Cutaneous papillomas

These are pedunculated or vegetative skin growths found in older dogs and are distinct from the virally-induced papillomas found on the mucous membranes of young dogs. They are considered benign.

Cutaneous plasmacytoma

These neoplasms are derived from plasma cells. They occur commonly on the digits, the lips, the chin and the ear canal.

Fibromatous epulis

A common oral tumour of the dog presenting as a firm gingival mass. These tumours are benign, neither invading locally nor metastasising.

Fibroma

These are uncommon benign neoplasms. They are usually solitary, well-circumscribed lesions.

Fibrosarcoma

A fibrosarcoma is a malignant tumour derived from fibrous tissues and may be found in many sites including the bone, skin, spleen and oral cavity. Tumour behaviour varies with the site and histological grade. In general, fibrosarcomas are locally invasive but have a relatively low rate of metastasis (25% has been suggested for oral fibrosarcoma).

Haemangioma

Haemangiomas are benign tumours arising from the vascular endothelial cells of the dermis and subcutis. They are common in dogs but rare in cats. They appear as well-circumscribed blue/purple masses.

Haemangiosarcoma

This is a highly malignant tumour arising from vascular endothelial cells. Primary sites include the right atrium of the heart, spleen, liver, skin, bone, nervous system, kidney, bladder and oral cavity. Metastasis to a wide variety of sites is common, in many cases micrometastasis having occurred by the time of diagnosis.

Haemangiopericytoma

These common tumours are derived from vascular pericytes. They are usually well-circumscribed and are often found on the limbs. Metastasis is rare, but they frequently recur locally, so treatment of choice is wide surgical excision or amputation.

Histiocytosis

A disorder of histiocytes which takes two forms, both relatively rare. In Malignant histiocytosis, proliferation of histiocytes results in solid tumour masses in a variety of organs including the spleen, liver, lymph nodes and lung. The disease is rapidly progressive and fatal. It has been most commonly reported in the Bernese Mountain Dog, but occasionally in other breeds. Systemic histiocytosis follows a more chronic, fluctuating course and involves the skin, eyes and peripheral lymph nodes. Systemic histiocytosis has only been reported in the Bernese Mountain Dog and is more often seen in younger dogs than the malignant form.

Insulinoma

See under Endocrine conditions.

Intestinal adenocarcinoma

See under Gastrointestinal conditions.

Keratoacanthoma

Also known as intracutaneous cornifying epithelioma. These benign cutaneous neoplasms can be solitary or multiple.

Limbal melanoma

See under Ocular conditions.

Lipoma

Benign tumours of fat cells which are generally found in the subcutaneous tissues. They are common, affecting up to 16% of dogs. Infiltrative lipomas are locally invasive making surgical excision more difficult, but they do not metastasise.

Liposarcoma

These rare malignant tumours arise from the subcutaneous lipoblasts. These tumours are infiltrative but rarely metastasise.

Lymphosarcoma

Lymphosarcoma is a malignant lymphoproliferative disease also commonly termed malignant lymphoma. Lymphosarcoma is the most common haematopoietic tumour in the dog and cat. Lymphosarcoma may be classified anatomically by the location of the disease (multicentric, mediastinal, alimentary, cutaneous or extranodal), histologically or immunophenotypically as B-cell or T-cell.

Malignant histiocytosis

See Histiocytosis.

Mammary tumours

These are common in both the dog and the cat. Mammary tumours are derived from the epithelial and sometimes myoepithelial tissues of the mammary glands. In dogs approximately 50% are benign, in cats over 80% are malignant. Entire animals or those spayed after several seasons are predisposed. Behaviour varies depending on the histological grade, but malignant mammary tumours may be very aggressive, metastasising to the local lymph nodes, lungs and occasionally the abdominal organs and bone.

Mast cell tumours

Mast cell tumours are relatively common in dogs, representing up to 20% of skin tumours. They may present in a wide variety of forms so need to be included in the differential of all skin masses. Behaviour varies from benign to highly-aggressive malignant tumours which have the potential to metastasise (usually to the liver, spleen or kidney). Cutaneous mast cell tumours are less common in the cat, but systemic and intestinal forms of mast cell tumour may also be seen in this species.

Melanoma

Melanomas represent 4-6% of canine skin tumours and 1-2% of all feline skin tumours. They present as firm, pigmented dermal masses and are more common in dark-skinned dogs. Those found on the digits and close to mucocu-taneous junctions tend to be more malignant and may metastasise to local lymph nodes, lungs and other more distant sites.

Myxoma/myxosarcoma

These rare neoplasms arise from fibroblasts and occur more frequently on the limbs, dorsum or inguinal regions. Myxomas are benign and myxosarcomas are malignant.

Nasal cavity tumours

The most common nasal cavity tumours diagnosed in the dog are carcinomas (in particular adenocarcinomas). Other types include sarcomas (fibrosarcoma, chondrosarcoma or osteosarcoma), lymphoma and melanoma. Most are malignant, causing local invasion and progressive destruction, but are slow to metastasise. Dolichocephalic dogs, particularly of large and medium size, are reported to be at increased risk. In the cat, adenocarcinoma is the most common tumour followed by lymphoma.

Non-epitheliotropic lymphoma

This uncommon neoplasia is a form of cutaneous lymphosarcoma. It is usually generalised or multifocal. Nodules are seen in the dermis, and spread to the lymph nodes and internal organs may occur.

Osteosarcoma

Osteosarcoma is the most common of the malignant primary bone tumours in the dog. It is rapid in growth and highly invasive and destructive. Osteosarcoma of the appendicular skeleton of dogs is highly malignant and metastasises early (commonly to the lungs). In common with other primary bone tumours, appendicular osteosarcoma is more common in large- and giant-breed dogs. Osteosarcoma of the axial skeleton (including the skull) is generally considered less malignant. Osteosarcoma in the cat is also less aggressive. See also under Musculoskeletal conditions.

Pancreatic carcinoma

A tumour of the duct cells of the pancreas. Uncommon, but usually highly malignant.

Parathyroid tumours

Parathyroid tumours are uncommon in the dog and cat. Functional adenomas are the most common type of parathyroid tumour resulting in primary hyperparathyroidism and hypercalcaemia (see Primary hyperparathyoidism under Endocrine conditions). Adenomas are benign and well-encapsulated. Adenocarcinomas may invade locally and metastasise.

Perianal (hepatoid) gland adenoma

These are benign tumours that arise from the modified sebaceous glands of the perianal area. They appear as well-circumscribed raised lesions which may ulcerate. Perianal gland adenocarcino-mas may occur, but are less common.

Phaeochromocytoma

See under Endocrine conditions.

Pilomatricoma

A rare benign tumour of the hair follicle. Pilomatricoma presents as a solitary, firm mass in the dermis or subcutis, without ulceration of the overlying epidermis. They usually occur over the back and limbs of dogs. They are rare in cats.

Pituitary tumours

The most common pituitary tumour in the dog is the adenoma of the corticotrophic cells of the anterior lobe. These tumours are generally functional, resulting in an overproduction of adrenocorticotrophic hormone (ACTH) and hyperadrenocorticism (see under Endocrine conditions). Carcinomas do occur and are generally non-functional but are more invasive and likely to metastasise. In the cat, pituitary tumours may be associated with hyperadrenocorticism as above, but tumours of the somatotrophic cells of the anterior pituitary also occur resulting in an overproduction of growth hormone and acromegaly.

Primary bone tumours

Primary bone tumours are relatively uncommon in the dog and represent <5% of all tumours. The most common tumours are osteosarcomas and chondrosarcomas, others, including fibrosarcomas and haemangiosarcomas, occur less frequently. In dogs, the risk of primary bone tumours of the appendicular skeleton increases with body size/weight. They generally occur in older dogs, but in giant breeds they may be seen at an earlier age. Primary bone tumours are uncommon in the cat. See also Osteosarcoma and Fibrosarcoma.

Primary brain tumours

See under Neurological conditions.

Renal cystadenocarcinoma

See under Renal and Urinary conditions.

Schwannoma

This rare neoplasm arises from the Schwann cells of the nerve sheath and can be dermal or subcutaneous. In dogs they occur most commonly on the limbs, head and tail. They are often alopecic and occasionally pruritic or painful.

Sebaceous gland tumours

One of the most common skin tumours of the dog, but less common in the cat. They may be single or multiple. There are various his-tologic types: sebaceous hyperplasia presents as small, lobulated wart-like lesions; sebaceous epitheliomas present as firm dermal masses with hairless overlying skin. Other types include sebaceous gland adenomas and adenocarcinomas. With the exception of adenocarcinomas, sebaceous gland tumours are generally benign in behaviour.

Squamous cell carcinoma of the skin

These are relatively common malignant tumours which arise from keratinocytes. Various predisposing factors have been identified, such as exposure to ultraviolet light, pollutants and pre-existing chronic dermatitis.

Squamous cell carcinoma of the digit

Squamous cell carcinoma is the most common cutaneous tumour of the digit in dogs. It is locally invasive, resulting in bone lysis, and metastasises more frequently than squamous cell carcinomas found in other cutaneous sites.

Sweat gland tumours

These may be adenomas or adenocarcinomas. They are uncommon in the dog and rare in the cat. They may present as small solitary nodules in the dermis and subcutis with or without ulceration. An inflammatory form of adenocarcinoma is poorly circumscribed and more infiltrative. Adenocarcinomas are highly invasive and may metastasise to local and regional lymph nodes, and occasionally to more distant sites, e.g. the lungs.

Systemic histiocytosis

See Histiocytosis.

Testicular neoplasia

Testicular neoplasia is common in the dog. There are three main tumour types: Sertoli cell tumours, seminomas and interstitial cell tumours. Certain breeds seem at increased risk. The incidence of Sertoli cell tumour and seminoma is higher in undescended testes than normally descended testes.

Thymoma

Thymoma is a tumour of the epithelial cells of the thymus gland which is situated in the cranial mediastinum. It is uncommon in both dogs and cats. Thymomas are generally benign and slow growing. Symptoms relate to the presence of a cranial mediastinal mass and may vary: cough, dyspnoea, regurgitation and occasionally obstruction of the cranial vena cava leading to facial and forelimb oedema (‘precaval syndrome’). Autoimmune conditions such as Myasthenia gravis may be associated with thymoma.

Thyroid Carcinoma

See Thyroid neoplasia in dogs under Endocrine conditions.

Trichoblastoma

These are common benign skin tumours, appearing as solitary, domed masses. They may become dark in colour and ulcerate.

Trichoepithelioma

A benign tumour of the hair follicle. They present as solitary, firm masses in the dermis or subcutis, often with ulceration of the overlying epidermis. They usually occur over the back and limbs of dogs, but are rare in cats.

Tricholemmoma

This rare, benign tumour occurs most commonly on the head and neck.

Categories
Conditions

Endocrine conditions

Adult-onset growth-hormone-responsive dermatosis

A poorly-understood syndrome of unknown cause. Basal growth hormone levels are low and unresponsive to stimulation. Other pituitary functions seem normal. The condition is characterised by bilaterally symmetrical areas of alopecia and hyperpigmentation initially in the areas of friction, e.g. the neck.

Central diabetes insipidus (CDI)

A polyuric state caused by a complete or partial lack of antidiuretic hormone (vasopressin) which is normally produced in the neuro-hypophysis of the pituitary. Urine specific gravity is usually hyposthenuric. In the dog, most cases are idiopathic, but the condition may be acquired secondary to trauma, neoplasia or cystic malformations of the neurohypophysis. Although rare, there are a few reports of suspected hereditary CDI.

Congenital nephrogenic diabetes insipidus (congenital NDI)

NDI is a polyuric state caused by the reduced responsiveness of the renal tubules to anti-diuretic hormone. Acquired NDI occurs secondarily to a wide variety of disorders. Congenital NDI is an extremely rare condition of which there are only a few reports in the dog.

Congenital hypothyroidism

Congenital hypothyroidism occurs where there is a congenital defect in thyroid hormone production or transport and results in disproportionate dwarfism. It is suspected it may also be a cause of neonatal death or fading puppy syndrome.

Cushing’s syndrome

See Hyperadrenocorticism.

Diabetes mellitus

Diabetes mellitus occurs where there is hyper-glycaemia resulting from an absolute or relative lack of insulin. Where the blood glucose level exceeds the renal threshold, glycosuria results.

Hyperadrenocorticism (Cushing’s syndrome)

One of the most commonly diagnosed endocrinopathies in the dog, but rare in the cat. Hyperadrenocorticism occurs where there is a sustained and inappropriately elevated secretion of cortisol from the adrenal cortex. Hyperadrenocorticism may be pituitary dependent, where there is excessive adrenocor-ticotrophic hormone (ACTH) secretion leading to bilateral adrenal cortical hyperplasia and increased cortisol secretion, or it may be adrenal dependent where there is a unilateral or bilateral functional adrenocortical tumour.

Hypoadrenocorticism

Hypoadrenocorticism is a condition wherein there is inadequate adrenocortical hormone production leading to a deficiency in miner-alocorticoids and/or glucocorticoids. Primary hypoadrenocorticism (Addison’s disease) results most commonly from immune-mediated destruction of the adrenal cortices leading to deficiencies of all adrenocortical hormones. Whilst there is no apparent breed predilection, a hereditary factor has been suggested in some breeds. It is very rare in the cat.

Hypothyroidism

Hypothyroidism is a common endocrine disease in the dog. There is a deficiency in the secretion of thyroid hormone either as a result of thyroid gland destruction (primary hypothyroidism), inadequate pituitary production of thyroid stimulating hormone (TSH) (secondary hypothyroidism) or inadequate hypothalamic secretion of thyrotropin releasing hormone (TRH) (tertiary hypothyroidism). Many breeds seem predisposed to hypothyroidism, most notably Dobermann Pinschers and Golden Retrievers.

Immune-mediated destruction of the thyroid gland (Lymphocytic thyroiditis) is a common cause of primary hypothyroidism and has been demonstrated to be hereditary in laboratory Beagles and a family of Borzois.

Insulinoma

Insulinomas are functional insulin-secreting tumours of the pancreatic beta cells. Insulin secretion is independent of the normal negative feedback control, resulting in hypoglycaemia. These tumours are generally malignant with a high metastatic potential.

Lymphocytic thyroiditis

See Hypothyroidism.

Phaeochromocytoma

Uncommon in dogs and rare in cats, phaeochro-mocytomas are catecholamine-secreting tumours of the adrenal medulla. Most are slow-growing and benign, but some are malignant and may invade locally, and/or metastasise. The high level of circulating catecholamines produced results in hypertension and tachycardia.

Pituitary dwarfism

Pituitary dwarfism results from a failure of growth hormone secretion in an immature animal. The most striking abnormality is a failure to grow, animals remaining of small stature, but with normal proportional shape (proportionate dwarfism). There may be concurrent failure of other pituitary hormones (panhypopituitarism). The condition is most commonly seen in the German Shepherd Dog but has been identified in several other breeds.

Primary hypoparathyroidism

This is an uncommon condition, wherein lymphocytic plasmacytic destruction of the parathyroid glands results in a deficiency of parathyroid hormone and hypocalcaemia.

Primary hyperparathyroidism

Primary hyperparathyroidism is usually the result of a functional parathyroid adenoma (see also Parathyroid tumours under Neoplastic conditions). The excess of parathyroid hormone results in hypercalcaemia. The Keeshond seems particularly susceptible to the condition.

Thyroid neoplasia in dogs

Most thyroid tumours in the dog are invasive and malignant carcinomas presenting as readily detectable masses in the neck. Adenomas do occur but are usually small and rarely detected during life. Thyroid tumours in the dog are generally non-functional, only 5-20% being functional, producing clinical signs of hyper-thyroidism. Up to 30% of cases become hypothyroid as normal thyroid tissue is destroyed by the tumour. The remainder are euthyroid.

Categories
Diseases

How Does The Body React To Heart Failure?

Many conditions and different heart diseases can progress into heart failure. Regardless of the cause, there is an initial fall in cardiac output that lowers arterial pressure. Clinical signs observed in heart failure are mainly the result of chronic activation of compensatory mechanisms to restore and maintain blood pressure. The cardiovascular system is part of a biologic control system that works in co-operation with the central nervous, renal, and endocrine systems to keep cardiovascular variables at physiologic levels. Maintenance of arterial blood pressure and effective plasma volume are the main priorities of this integrated system. Changes are sensed by high-pressure baroreceptors in the aortic arch and carotid sinus, by mechanoreceptors in the ventricular myocardium, by volume receptors in the atria and great veins, and by the juxtaglomerular apparatus in the kidneys. During episodes of low blood pressure, a reactive neuroendocrine activation occurs to re-establish normal blood pressure. The immediate response is a decrease in parasympathetic drive and an increase in sympathetic drive, causing vasoconstriction (increasing arterial impedance) and tachycardia (increasing cardiac output). Vagal responses tend to be immediate and short-lived, whereas sympathetic responses are slower but last longer. A decrease in renal blood flow causes the release of renin and activation of the renin-angiotensin-aldosterone system (RAS), contributing to vasoconstriction and causing sodium and water retention, which increases the circulating volume. Compensatory mechanisms are acute responses that evolved to maintain an animal’s life during and immediately after an episode of bleeding. During heart failure, however, compensatory mechanisms are chronically activated. In an effort to maintain blood pressure, the cardiovascular system allows the venous pressure to increase and redistributes cardiac output, maintaining blood flow mosdy to essential organs. Compensation cannot be viewed as an isolated response of the circulation. The heart and the myocardial cells undergo changes to adapt to ventricular dysfunction. A common characteristic of all compensatory responses is that the short-term effects are helpful, but the long-term effects are deleterious. In acute injuries to the heart, cardiac output decreases and acute heart failure may occur; this phase, known as transient breakdown, initiates activation of the compensatory mechanisms. In small animals, heart failure is usually a chronic problem, and the transient breakdown phase merges with the following phase. As compensation occurs, cardiac output and clinical signs steadily improve, because the heart and circulation are performing extra work; this compensated phase is known as stable hyperfunction. Chronic hyperfunction leads to progression of left ventricular dysfunction, myocardial cell death, the development of clinical signs, and death, the exhaustion and progressive cardiosclerosis phase.

Neuroendocrine Activation

Peripheral Compensation

Central Compensation (the Heart)

The heart participates actively in the compensation for the decrease in cardiac output. Sympathetic activation leads to an increase in the heart rate, inotropy, and lusitropy, all of which increase cardiac output. In addition, hypertrophy helps normalize cardiac output by increasing the stroke volume. Compensatory mechanisms that act on the heart are shown in Central (Cardiac) Compensatory Mechanisms in Heart Failure.

Central (Cardiac) Compensatory Mechanisms in Heart Failure

Response Mechanism Potential Benefit Potential Harm Manifestations Correlates
Sympathetic desensitization Downregulation of beta2 adrenoreceptors, uncoupling of beta2 adrenoreceptors, depletion of myocardial norepinephrine Energy sparing Decreased contractility Low-output signs (e.g., depression, lethargy, hypotension) Beta-adrenoreceptor blockade may reverse sympathetic desensitization.
Tachycardia Sympathetic activation, parasympathetic withdrawal Increased cardiac output Increased MVO2 Tachycardia, decreased heart rate variability Decrease in heart rate variability correlates with mortality.

Increase in heart rate correlates with sympathetic activation and severity of congestive heart failure.

Increased inotropy Sympathetic activation Increased stroke volume Increased MVO2
Increased relaxation Sympathetic activation Improved diastolic function (lusitropy) Increased MVO2    
Appearance of slow myosin in the atria Changes in isogene expression Decreased cost to achieve normal tension, energy sparing, increased atrial kick Atrial failure   Changes do not occur in the ventricles of dogs and cats.
Reduced myocardial ATPase activity Unknown (altered isoenzymes?) Facilitation of high-pressure, low-speed work; energy sparing Slowed

contraction rate,

decreased contractility

Low-output signs Myocardial

ATPase activity is increased in high-output congestive heart failure (e.g.. thyrotoxicosis).

 

Pressure overload (concentric hypertrophy) Increased afterload, renin-angiotensin-aldosterone system activation, increased levels of TNF-alpha and other cytokines Unloading of individual muscle fibers, decreased wall stress and MVO2 Imbalance in energy demand and supply, focal necrosis, fibrosis, increased collagen formation, diastolic dysfunction Cardiomegaly, increased diastolic dysfunction and venous congestion Pressure overload induces cardiomy-opathy of overload.

Growth-inhibitory drugs (e.g., angiotensin-converting enzyme inhibitors, nitrates) may delay development of cardiomyopathy of overload.

Volume overload (eccentric hypertrophy) Fiber slippage, increased tension Increased

compliance(?); increased stroke volume with same ejection fraction (dilatation)

Increased wall stress and MVO2; pressure hypertrophy Cardiomegaly Increased wall stress leads to pressure hypertrophy.

ACE, Angiotensin-converting enzyme; ATPase, adenosine triphosphatase; CHF, congestive heart failure; MVO2, myocardial oxygen consumption; TNF-alpha, tumor necrosis factor alpha.

Tachycardia

During heart failure, sympathetic tone increases (increasing the heart rate) and parasympathetic tone decreases, a combination that leads to tachycardia. It is usually believed that sinus rates above 160 beats/min imply not only parasympathetic withdrawal but also sympathetic activation. The end result is an increase in the heart rate and a decrease in heart rate variability. The increase in the heart rate helps normalize arterial pressure, but at a high price: an increase in MVO2. A decrease in heart rate variability is a negative prognostic factor for overall mortality in human patients with myocardial infarct. In dogs with chronic mitral valve disease, a decrease in heart rate variability correlates with the severity of congestive heart failure Patients with decreased heart rate variability are also less likely to respond to vasodilator infusion. The increase in the heart rate in patients with heart failure parallels sympathetic activation, which in turn correlates with the severity of the heart failure.

Increased Inotropy and Lusitropy

Beta-adrenergic stimulation caused by increased sympathetic tone during heart failure increases calcium entry in the atrial and ventricular cells, calcium release from the sarcoplasmic reticulum, and the interaction between contractile proteins. All these actions increase contractility. Beta-adrenergic stimulation also increases lusitropy by increasing calcium efflux from the cell and calcium uptake by the sarcoplasmic reticulum. The increase in calcium entry is largely responsible for the positive inotropic effect; the facilitated dissociation from troponin and increased calcium uptake by the sarcoplasmic reticulum are the key factors in causing a positive lusitropic effect. Beta-adrenergic stimulation increases cardiac output, but also increases MVO2 and contributes to myocardial remodeling.

Myocardial Growth

Cardiac mass is increased in patients with heart failure, apparently as a result of a combination of reactive fibrosis and myocyte hypertrophy, along with alterations in the cytoskeletal structure in the myocyte. An increase in afterload and neuroendocrine activation lead to left ventricular hypertrophy. Hypertrophy reduces the load in individual cells and increases cardiac output. Hypertrophy causes growth of myocyte and nonmyocyte cells in the extracellular matrix of the myocardium. The growth of myocytes and nonmyocyte cells occurs independent of each other. Chronic anemia and thyrotoxicoses cause myocyte growth without the involvement of fibroblasts, whereas hypertrophy secondary to pressure overload is accompanied by reactive fibrosis that is not secondary to myocyte necrosis. Increases in preload, afterload, sympathetic activation, and growth hormone induce myocardial growth, whereas activation of the RAS, prostaglandin E2, transforming growth factor-beta] (TGF-beta|), and insulinlike growth factor-1 (IGF-1) induce remodeling of the cardiac interstitium. All these substances induce expression of proto-oncogenes and growth-regulating genes that play an important role in the mediation of hypertrophy. Structural remodeling of myocardial collagen matrix contributes to the progression of heart failure.

Hypertrophy in patients with congestive heart failure results in a ventricle that is not normal. Morphologic, biochemical, and genetic changes cause ventricular remodeling, leading to progression of the left ventricular dysfunction. The appearance of a “slow” myosin, a more efficient myosin that spares energy in the heart, has been detected in the atria but not the ventricles of dogs with congestive heart failure. Pressure-induced hypertrophy unloads the individual myocardial cells and decreases wall stress and MVO2. However, hypertrophied ventricles have a capillary deficit and a decreased number of mitochondria, leading to a state of energy starvation. The chronic energy starvation leads to necrosis, fibrosis, an increase in the collagen concentration, and diastolic dysfunction. Volume-induced hypertrophy decreases wall stress and MVO2 and helps maintain stroke volume, probably by increasing compliance. Fiber slippage, however, causes further dilatation of the heart, again increasing wall stress and MVO2 and favoring progression of the left ventricular dysfunction.