What's new in small-animal drug therapy (Proceedings)

CENTRAL AND PERIPHERAL NERVOUS SYSTEMS. A test is available to detect the MDR-1 genetic deletion that leads to P-glycoprotein deficiencies in collies and related breeds. This deficiency has been linked to CNS toxicities caused by ivermectin and loperamide as well as (potentially) many other drugs. Owners of potentially affected dogs should be tested not only to be aware of possible CNS drug toxicities but also to try to minimize breeding (http://www.vetmed.wsu.edu/announcements/ivermectin/ownerinfo.asp). The sample is a buccal mucosal brush and the cost is approximately $60.

Anticonvulsants. Bromide.Bromide competes with chloride for renal tubular resorption. Chloride will be retained whereas bromide will be excreted. Increased dietary intake of chloride will result in increased renal excretion; increase may reflect a greater proportion in the diet (note moist diets contain more salt than the dry diet, even of the same brand name), in water, a greater total food intake, or through dietary or other supplements. Bromide should be measured before and at 3 and 12 weeks after the chloride intake changes. See gabapentin below. Zonisamide (Zonegran®; 8 to 12 mg/kg divided twice to three times daily, po) is a sulfonamide anticonvulsant approved for use to treat epilepsy in humans. Zonisamide appears to inhibit neuronal voltage-dependent sodium and T-type calcium channels. Additionally, ZNS modulates the dopaminergic system and accelerates the release of γ-amino butyric acid (GABA) from the hippocampus. Like phenytoin, ZNS is less likely to affect normal neuronal activity. A potential advantage of ZNS is free radical scavenging which protects against the destructive nature of radicals, especially in neuronal membranes. As with most sulfonamides, elimination includes both a hepatic (induced by Phenobarbital) and renal elimination. Its elimination half-life in dogs is 16 hours; accumulation in RBC and slow release allows twice daily therapy is reasonable. It can be monitored (see Auburn University), although not as easily as bromide or Phenobarbital; the therapeutic range recommended in humans is 10 to 40 mcg/ml. It has been used safely in combination with Phenobarbital for control of refractory seizures in dogs. As with any sulfonamide, at high concentrations (including those necessary to control seizures in some dogs), thyroid hormone synthesis will be impaired within several weeks of start of therapy. Function will return to normal but only when therapy is d/c. The protocol for thyroid hormone replacement, which is probably indicated once hypothyroidism has been documented, has not been well established. Levetiracetam ( Keppra®) is an anticonvulsant approved for use in humans. Its mechanism of action appears to be interference with release of neurotransmitters from the synaptic vesicle. . It is renally excreted (60%) and to a lesser degree, metabolized by the liver. However, it has a short half-life (as short as 1 to 2 hrs, but generally 4 to 5 hrs) that is supportive of 8 hour dosing. It is characterized by a very wide therapeutic margin (dogs tolerate 1200 mg/kg) and has been safely used in both dogs and cats as well as an add-on anticonvulsant at 20 mg/kg every 8 hrs po. We have also used Keppra as a CRI in animals who have not responded to alternative anticonvulsants, and in patients with PSS who have seizured. It can be monitored in our laboratory. Because its half-life is short, anticipate that drug concentrations may drug 50 to 95% during an 8 hr dosing interval; you may want to collect both a peak and trough sample to measure half-life. If only one sample can be collected, collect a trough sample. Note that the peak concentration may be well above the therapeutic range to make sure concentrations above the minimum throughout the dosing interval.

Control of Pain: (See NSAID, this same proceedings) Tramadol has become a popular analgesic; its mechanism of action results in multimodal pain control (mu receptor agonist and reuptake inhibitor of serotonin and others). However, the dose necessary to maintain analgesia in the dog is up to 5 mg/kg every 8 hr. Its efficacy is dependent, in part, on an active metabolite which is more potent that the parent compound. The cat makes less of the active metabolite and may actually need a dose that is equal to or higher than that in dogs. Avoid other drugs which inhibit the uptake of serotonin (eg, SAMe, St. Johns Wort, behavior modifying drugs) and taper the dose to avoid signs of withdrawal if treating longer than several days. Note that tramadol is available in combination with acetaminophen which is great for dogs but must be avoided in cats (whereas tramadol itself can be used in cats). Amantadine is an N-methylD-aspartate receptor antagonist (as is ketamine, and to some degree, dextromethorphan)that can be used (3 mg/kp po once daily) in combination with a wide variety of other oral analgesics. Although use in dogs has not yet been reported, pregabalin (Lyrica®) has been approved for use in humans to treat chronic (neuropathic) pain. A schedule V drug (because of the risk of withdrawal), its mechanism is similar to gabapentin and, like gabapentin may also have anticonvulsant activity. Gabapentin (Neurontin®) is a renally eliminated human anticonvulsant whose actions appear to involve gamma amino butyric acid receptors. The drug has been used as an add-on anticonvulsant in dogs refractory to Phenobarbital. It has a short elimination half-life and thus may requiring 8 hour dosing intervals. Efficacy as sole anticonvulsant is questionable even at high doses. However, recently Pfizer has pursued a chronic (neuropathic) pain label. Dosing in humans starts low (1 to 2 mg/kg tid),gradually increasing to 10 mg/kg tid. Note that any drug that impacts the CNS should be gradually discontinue to avoid withdrawal.

ENDOCRINE. Hyperglycemia. Acarbose (Precose ®) is a complex oligosaccharide that is bacterial in origin. The enzyme inhibits the degradation of alpha- amylase, and glucosidase of pancreatic and intestinal origin. As a result, enzymatic degradation of complex, oligo, di, trisaccharides is inhibited and glucose absorption is decreased.. Post-prandial hyperglycemia subsequently is minimized. However, hypoglycemia is not a sequelae. Indications in humans are non-insulin dependent diabetes mellitus. Because carbohydrates that otherwise would be absorbed are metabolized in small intestine, a number of gastrointestinal side effects occur including pain, diarrhea, and flatulence (77% in humans). These clinical signs tend to resolve once accommodation of flora) has occurred. This product has been studied in diabetic dogs using 25 to 50 mg/kg depending on size. Mean serum glucose pre and 8 hr post proandial, and glycosylated hemoglobin were lowered in dogs receiving both insulin and acarbose compare to insulin and a placebo. Side effects of weight loss and watery stool were evident in normal dogs receiving 200 mg in another study. Glargine insulin (Lantus() is one example of several injectable human recombinant long acting insulin analogue that differ from human insulin by the replacement (for glargin, asparigine is substituted with two glycines) and/or addition (for glargine, two asparagines) of amino acids. The resulting insulins are an attempt to prolong action and resolve peaks. Glargine is described as "peakless" in humans, thus mimicking more closely endogenous glucose/insulin/ relationships. The potency in humans is similar to insulin. Concentrations of insulin remain relatively constant for a 24 hour period following subcutaneous administration. In healthy nondiabetic cats, glargine was similar to PZI and porcine lente insulin in time to onset and nadir glucose concentration, but time to reach nadir was longer for glargine. Time to return to baseline glucose was similar for glargine and PZI which was longer than lente. Concentrations were not peakless. However, a subsequent study in diabetic cats suggested that glucose concentrations might indeed flatten. The starting dose of 0.5 U/kg ideal body weight should begin at a BID dosing interval for cats with glucose > 360 mg/dl, and at 0.25 U/kg if less than 360 mg/dl. Animals should be hospitalized for 3 days and a 12 hr glucose curve is recommended with samples at 4 hr intervals. Doses should not be increased the first week. The insulin should not be mixed with anything (insulin release is pH dependent) and the product should be kept refrigerated (where it can be kept for up to 6 months). Urine glucose should remain below 2+ (assuming overdosing and hyperglycemic overswing is not occurring). Trilostane is a synthetic competitive inhibitor of 3-β-hydrosysteroid dehyrodgenase, which prevents formation of progesterone and subsequent formation of steroidal hormones, including endogenous corticosteroids. It has been used successfully to treat human hyperadrenocorticism of various causes. The drug has been studied in the United Kingdom in dogs with naturally occurring PDH. Doses varied with weight: 30 mg if less than 5 kg 60 mg for 5 to 19 kg and 120 mg if > 60 kg once daily. Medication was well tolerated; mean dose necessary to control PDH was approximately 20 mg/kg with larger dogs requiring more on a mg/kg basis. Response was based on resolution of clinical signs, baseline and post – stimulation cortisol and urinary cortisol creatinine ratio (although the latter did not change statistically across time). Percent of animals controlled was 40% at 10 days, 57% at 90 days, and 80% at 180 days. Time to response was initially 89 days, but as the investigators became more adept, the duration was reduced to 40 days. A starting dose of 10 mg/kg once daily was suggested. Trilostane also has been successfully used in at least one cat to control clinical signs when treated with 30 mg/kg once daily orally and a dog with an adrenal tumor. Trilostane is being obtained through compounding internet services. Acquisition and sale of the drug in this form is perceived by the FDA to be illegal. However, written documentation for patient driven importation can be obtained from the Division of Compliance of the FDA (240 276 9200).

URINARY Phenopropanolomine has not been removed from the market and is available from some compounding pharmacies. Psuedoephedrine has been used in Australia as an alternative (15, 30, 45, 60 and 75 mg total dose for dogs ranging in size from < 10 kg to > 60 kg).Vasopressin® has been available only as a nasal spray (give subconjunctivally), but now is available as a 0.1 mg and 0.2 mg tablet. Human bioavailability of the tablet is only 5 to 15% of the intranasal drug. Since each nasal drop contains about 0.1 mg (and assuming a same level of bioavailability), the oral dose in the dog would be about 1 to 2 tablets a day. Currently, the nasal drops are probably still less expensive and the oral tablets.

Renal Disease: Control of phosphorus is critical for slowing the development of complications associated with secondary hyperparathyroidism. Generally this is accomplished with aluminum containing phosphate binders. Either the hydroxide or carbonate anion can be used. Of the two, aluminum carbonate is available as a capsule which can be pulled apart and added to food (divide a 125 or 250 mg capsule up twice to three times daily). Constipation associated with their use can be treated with either a bulk laxative or laculose (see gastrointestinal). Calcitriol (1,25, dihydroxycholecalciferol; 1,25-dihydroxy Vitamin D). Vitamin D requires two activation steps before it is capable of controlling calcium balance. The final step of activation is the formation of the 1,25 dihydroxy vitamin takes place in the kidneys. The enzyme necessary for inactivation becomes deficient with renal disease resulting in a deficiency. Vitamin D facilitates calcium absorption from the gastrointestinal tract and its absence can (2.5 to 3.5 ng/kg po/day) contribute to the calcium/phosphorous imbalances leading to secondary hyperparathyroidism of renal disease. Calcitriol therapy, if begun sufficiently early in the course of renal disease, decreases the risk of nephrocalcinosis, the magnitude of hyperparathyroidism and can slow the progression of glomerularsclerosis. Although it should be implemented as early as possible, calcitriol is not indicated in all patients. It should not be used if the product of serum calcium and phosphorus exceeds 60; phosphorus should be less than 6 mg/dl and ideally less than 4 mg/dl. Use in the presence of high serum phosphorus will increase the risk of nephrocalcinosis. Serum calcium must be measured as long as the patient is receiving the drug. Monitoring should occur weekly for 4 weeks, then bi weekly for a month. The interval can then be increased to monthly for several months followed by 3 to 6 month intervals as necessary.

Twenty-five percent of cats with renal disease also may be suffering from an iron deficiency, perhaps due to chronic blood loss associated with gastritis. Iron (ferrous sulfate) can be supplemented prophylactically (1 mg/cat/day po) or as a treatment in mildly anemic cats, prior to treatment with erythropoietin at 15 mg/cat/day. Severe iron deficiency anemia may require parenteral therapy (iron dextran 50 mg/cat/day, IM). EPO should be administered when the PCV is between 12 and 19%, as is indicated by clinical signs, and after alternate causes of anemia (eg, iron deficiency, gastrointestinal bleeding, etc) have been ruled out. This should take approximately 2 months; if more rapid, the dose s should be decreased in order to avoid polycythemia. Hypertension may occur if the PCV is too elevated and is more likely in patients already hypertensive. Treatment begins at 50 to 150 Units/kg/cat 3 times weekly until a PCV of 30 to 35% is reached. Daily therapy can be initiated with severe anemia, but not in hypertensive patients. A maintenance dose of 50 U/kg/cat 2 to 3 times per week begins once the targeted PCV is achieved. Up to 25 to 40% of cats receiving human recombinant EPO will develop antibodies as indicated by a drop in PCV several weeks to several months after therapy has increased the PCV. Anabolic steroids might be implemented in those patients that can not tolerate EPO. ACE Inhibitors and Renal Disease A study in dogs with CHF found life expectancy to increase from 300 days to 800 days when treated with benazepril. However, the efficacy of ACE inhibitors in treatment of canine CHF remains controversial. In patients in which cardiac reserve threatens renal perfusion, renal disease may be more likely. Renal blood flow in such patients is dependent upon the ability of the kidney to auto-regulate: constriction of the efferent arteriole forces blood flow from the renal artery into the glomerulus in the presence of reduced renal blood flow, thus maintaining the glomerular filtration rate (GFR). Treatment with an ACEI precludes autoregulation. However, if cardiac output increases in response to decreased afterload sufficiently to compensate for the loss of efferent arteriolar constriction, GFR is minimally impacted. Sodium wasting (including excessive use of diuretics), and drugs which modify (decrease) renal prostaglandins (NSAIDs, aminoglycosides) may predispose the patient to renal disease once ACE inhibitors are begun. Tests indicative of renal function should be monitored the first several weeks of therapy and the ACEI dose or interval should be adjusted to the minimum effective dose. Benazepril, like enalapril, is a prodrug, and must be converted to its active metabolite, benazeprilate. Approved for use in dogs in Canada, it is administered once daily (0.25 to 0.5 mg/kg orally). In contrast to enalapril, altered renal function does not appear to alter the kinetics of benazepril in dogs. Lisinopril is a renally-eliminated ACE inhibitor approved for human use. In contrast to enalapril, it requires no pro-drug activation by the liver. Its elimination is impacted only with marked decrease in GFR. Indications in animals would include liver disease. Another advantage is that it can be given once daily (0.5 mg/kg orally). A relatively recently recognized indication of ACEI is proteinuria. The mechanism by which ACE inhibitors decrease proteinuria is not known, but may include changes in hydrostatic pressure or direct action on the glomerular membrane. Decreasing protein exposure to renal tubular cells appears to decrease the progression of glomerular disease to glomerulonephritis and prolong or reduce the development of glomerulosclerosis. A renal protective effect has also been described for all ACE inhibitors for generalized renal disease. The presence of microalbuminemia might be considered a potential indication of ACE inhibitor therapy. Benazepril is approved for use in cats in Australia for treatment of chronic renal insufficiency. A study of in 201 cats in Sweden found the drug to prolong life expectance to 402 days compared to 126 days in cats that did not receive the drug (2.5 to 5 mg a day).Therapy for congestive heart failure no longer is limited to response to secondary neurohumoral effects, but now must also target cardiac remodeling induced by these responses.

IMMUNOLOGIC (See also proceedings on Glucocorticoids and Non-glucocorticoid immunomodulators, this same proceedings).Cyclosporine is a T-cell specific immunomodulator approved for use in humans for immune suppression of graft vs host transplant rejection, autoimmune disorders, keratitis sicca and red cell aplasias. The standard preparation is very lipophilic and as such must be prepared in oil and oral absorption is bile acid dependent; oral bioavailability ranges from 20 to 50%. The newer microemulsion preparations (Atopica® or Neoral®) are not as dependent on bile acids for oral absorption and is more bioavailable. Note that although many generic preparations are available, the therapeutic equivalence of these products is based on human rather than dog and cat kinetics. "Modified cyclosporine" made by some companies appears to be much more bioavailable than others. Accordingly, although CsA appears to be much better tolerated in dogs and cats compared to humans, monitoring may be important to avoid the risk of toxicity. Note that the immunomodulatory effects generally will necessitate twice daily dosing (5 mg/kg twice daily) because of the short half-life of the drug in dogs and cats (3 to 9 hrs). With the exception of atopy (as per approval data), once daily dosing of cyclosporine is not likely to be preferred. In humans, peak concentrations are more predictive of area under the curve; a target of 4500-5000 ng/ml is recommended. However, trough concentrations of 400-600 ng/ml (2 hr peak 800-1400 ng/ml) also have been recommended for transplantation patients. Both are relevant only with twice daily dosing. Similar studies have not been performed in animals. Note that often a more cost effective approach for reaching target concentrations is decreasing the interval rather than increasing the dose. Doubling concentrations will require doubling the dose, but tripling concentrations will require a 4 fold dose increase, and quadrupling the drug concentrations will require an 8 fold dose increase. Although ketoconazole has been used to increase concentrations, this approach is recommended only if both a peak and trough sample can be collected so the half-life can be monitored. We have measured half-lives of > 150 hrs; for such patients, drug concentrations do not reach steady-state for close to 4 weeks and concentrations may accumulate to toxic levels. As an apparent inhibitor of p-glycoprotein, an eflux carrier of intracellular drugs, Vitamin E may increase oral absorption of cyclosporine. This may be particularly useful (10 IU/kg with each oral cyclosporine administration) for Sandimmune®, which is less bioavailable than the newer, more bioavailable microemulsion preparation, Neoral®. Finally, note that CsA is involved in many drug interactions because of both its impact on drug metabolism and p-glycoprotein. The combination of prednisone (prednisolone) with CsA may result in higher concentrations of one or the other, which may be of benefit in the patient with immune mediated diseases. Monitoring should be considered when other drugs are added or discontinued. Therapeutic drug monitoring is strongly recommended, particularly when using adjuvant drugs to decrease the cost of cyclosporine. Tacrolimus is similar to cyclosporine in its actions, toxicities and indications. It is available as an ointment and was associated with cure of perianal fistulas in 50% of dogs treated for up to 16 weeks; 90% of animals responded. It has been compounded as an ophthalmic ointment but is commercially available as both ophthalmic and topical ointments (cost of ointment is about $110/60 gms). Mycophenolate mofetil is a lymphocyte specific immunomodulating drug that was developed in humans for treating graft versus host rejection in lieu of cyclosporine which is too toxic. The drug impairs lymphocyte synthesis of a essential metabolite. It is a pro-drug that must be activated by the liver. The drug is very safe in humans, with side effects limited to gastrointestinal signs. The drug has been used successfully in dogs (20 mg/kg bid orally) to treat myasthenia gravis and, more recently, other immune mediated disorders that no longer respond to glucocorticoids, or if cyclophosphamide can not be tolerated. However, toxicity in 1 out of 6 experimental animals indicates that prudence is warranted with its use in clinical cases, and reservation of its use to non-responders.

The use of leukotriene receptor antagonists (see respiratory) should be considered in any inflammatory disease associated with eosinophilic (and to a lesser degree, lymphocytic) influx. In humans, therapy targets the bone marrow; leukotrienes appear to have a role in stimulating stem cells to differentiate and mature into eosinophilic precursors. They also appear to stimulate the release into systemic circulation.

DERMATOLOGIC. The treatment of atopy, chronic inflammatory bowel disease and respiratory inflammatory disease (ie, asthma) might be approached similarly by focusing on the commonality of the diseases (antigen exposure; initial tissue response; generation of local mediators that become systemic; impact of mediators at the level of the bone marrow; bone marrow response through cytokines such as interleukin – 5 [chemokines including eotaxin; leukotrienes may act as signal between interleukins and cells], release of inflammatory cells, movement of inflammatory cells to the cite of tissue response. Tissue responses involving eosinophils and lymphocytes are particularly conducive to this approach. Treatment might target both the tissue associated with clinical signs and response at the level of the bone marrow. Treatment also should include adjuvant therapy specific for the control of clinical signs in each of the target tissues.

Pruritus. Misoprostol, a PGE analogue, is one of the most potent inhibitors of mast cell degranulation known (Silverstein 1998) and recently has been studied for treatment of chronic pruritus. When administered at 6 ug/kg PO tid, 60% of animals improved by > 50% within 3 weeks. It may act synergistically when combined with the antihistamines hydroxyzine or , clemastine. The effects of misoprostol on mast cells should warrant is consideration as part of the armamentarium used for palliative therapy in dogs or cats with mast cell disease. Pentoxifylline is a methylxanthine derivative (similar to theophylline) with minimal respiratory or cardiac effects. Its ability to change rheological properties (perhaps by changing red blood cell deformability, or blood viscosity) (Amrus 1990) and potential anti-inflammatory effects (including potential antiplatelet aggregation) has led to its use in dermatomyositis, atopy, and pruritus associated with atopy (Asanuma 1997). It also has been used for treatment of immune-mediated diseases of the skin. Metabolites of the compound contribute a large component of pharmacologic activity; it currently is being studied in dogs (Rees 1999) (10-15 mg/kg orally twice daily, for 2 to 6 weeks). Tapoxalin (Zubrin®) might also be considered.

Hydroxyzine hydrochloride has recently become very expensive. However, a ** benzoate salt is available that is less expensive and appears to be equally bioavailable in humans (not studied in animals). The drug should be dosed as with the hydrochloride sale. In contrast to older drugs, newer antihistaminergic drugs prevent mast cell degranulation as well as block the effects of histamine at the receptor. Thus, these drugs should be more effective compared to traditional antihistamines. Examples include cetrizine (Zytrec( 2.5 to 10 mg once daily, orally), Loratidine (Claritine, 0.25 to 0.5 mg/kg sid orally) and fenoxfenadine (Allegra(, 30 mg/kg orally twice daily).

GASTROINTESTINAL. Maropitant (Cerenia®) represents the newest class of drugs to treat vomiting. Approved for use in dogs (2 mg/kg po; 1 mg/kg SQ) to prevent acute vomiting; 8 mg/kg po to prevent motion sickness), the dog is an neurokinin receptor antagonist, thus blocking the effects of substance P in the vomiting center. The drug appears safe with clinically relevant signs of adverse events not apparent until 40-50 mg/kg reac hed. Mirtazapine is a (human) antidepressant that blocks uptake of serotonin and noreprineprhine. It has been used to stimulate both feline (1/4th of a 15 mg tablet) and canine appetites. Dirlotapide (Slentrol®) is a selective microsomal triglyceride transfer protein inhibitor that blocks the packaging of chylomicrons and thus their absorption from the lymphatic system of the gastrointestinal tract. Despite the local effect, food intake should decrease from 20 to 40% with a 3% weight loss per month (most occurs in the first month). The dose may need to be be adjusted with time and rebound weight gain will occur if an appropriate weight management program is not implemented. Vomiting and diarrhea and decrease concentrations of vitamins A or E (clinical relevance not clear) may occur during some phase of therapy.

Treatment of chronic inflammatory bowel disease includes asulfasalazine, a combination of 5-amino-salacylic acid (5-ASA) with sulfapyridine. The sulfonamide component might be considered undesirable, and products have been developed in human medicine which contain 5-ASA but not a sulfonamide. These include mesalamine (10-20 mg/kg [D] PO every 6-8 hrs) and osalazine sodium (10-20 mg/kg PO every 12-24 hrs). The former is also available in an enema preparation for treatment of disease limited to the lower bowel. The aspirin in these products -like that in asulfasalazine -can be absorbed (including that in enema form) and caution is recommended to avoid aspirin overdose. The product is available in a slow release preparation that releases drug only in the colon and ileum and thus limit effects to the lower bowel. Oral absorption also may be reduced. The drug delivery system may pass with the feces apparently intact; however, drug movement out of the capsules occurs in the gastrointestinal tract. The role of glucocorticoids for treatment of IBD is well documented and will not be reviewed in depth in this manuscript. More severe cases of IBD or cases that do not initially respond to prednisolone may respond to dexamethasone (0.22 mg/kg/day orally). The development of multidrug resistance has been implicated as a cause of therapeutic failure with GLCs in some human patients with IBD; expression of mucosal multidrug resistance may ultimately be used to determine response of IBD patients to therapy. Equally well known are the side effects of glucocorticoids. In human medicine, glucocorticoids that under go extensive first pass metabolism (ie, budesonide) or with marked topical anti-inflammatory activity (beclomethasone) have been developed in order to minimize side effects while maintaining efficacy. Budesonide has been recommended in dogs (1– 3 mg daily depending on dog size; tablet size is not conducive to easy compounding) although no scientific or anecdotal information has been published regarding its efficacy in animals. Budesonide has been associated with suppression of the HPA axis in dogs. Cyclosporine (discussed above) has proven variably effective in human patients with Crohn's diseases at concentrations above 250 ng/mL. Like cyclophosphamide, chlorambucil is a nitrogen mustard DNA alkylating anticancer agent, but is the least toxic among this class of drugs. Animals that continue to be unresponsive to medical management of IBD or those animals in which GLCs are contraindicated (eg, diabetes mellitus, renal disease) may respond to chlorambucil (if lymphocytic; 15 mg/m2 days 1,2,3 and 4 of every 21 days (C); 1 mg/cat sid until response or 2 mg PO q2--5 days). Although myelosuppression can be significant, it generally occurs slowly (30 days) and is readily reversible with discontinuation of drug therapy. Bi weekly blood counts should be implemented in patients receiving this drug. For mild cases of IBD involving eosinophils and lymphocytes, leukotriene antagonists should be considered (zafirlukast (0.15 to 0.2mg/kg orally once daily) or montelukcast (0.5-1.0 mg/kg po sid). Alternatively, these drugs might be used in combination with other drugs (delineated above or below) in any stage particularly in animals that do not respond to or can not take (eg, renal failure) glucocorticoids. Animals that continue to be unresponsive to medical management of IBD may respond to chlorambucil (if lymphocytic; 15 mg/m2 days 1,2,3 and 4 of every 21 days; or 2 mg PO q4-5 days). Azathioprine (0.3 mg/kg every other day, orally) is more toxic in cats compared to dogs and should be used cautiously. Response may take up to 5 weeks. Adjuvant therapy for CIBD should include antisecretory drugs (eg, ranitidine,famotidine, omeprazole) as indicated to facilitate healing and prevent worsening of damages in gastroduodenal or small intestinal disease. Note that omeprazole (and cimetidine; ranitidine less so) is potent inhibitor of the metabolism of many drugs and should not be used in combination with drugs which might be associated with adverse drug events if clearance is impaired. Sucralfate should be used to facilitate healing of damaged mucosa. Folate and cobalamin also might be supplemented because they become depleted with chronic inflammatory disease of the small bowel. Glucosamine/chondroitin sulfate supplements should be considered in patients with damaged gastrointestinal mucosa as occurs with IBD. Studies in humans with IBD suggest a deficiency in the formation of the mucosal barrier due to an inability to form n-acetylglucosamine. Preliminary studies support improvement in clinical signs in patients receiving 500-1500 mg (about 7.5 to 25 mg/kg) three times daily. The role of antibiotics in treatment of IBD is not clear. Because intolerance to endogenous microbes is a generally agreed upon contributor to the pathophysiology of IBD, the use of antibiotics is appealing. Mechanisms might include selection pressure towards organisms that are less harmful; indeed, with time, differential ability of microbes to generate an immune response might lead to selective antimicrobial therapy. The immunomodulatory effects of antibiotics also may contribute to resolution of clinical signs. Treatment for Helicobacter spp might also be considered in animals whose condition does not respond to therapy. Treatment of this organism may become a more important target for IBD therapy as we learn more about its role. Metronidazole has been associated with marked clinical improvement in some human patients with CIBD (Crohn's disease) and has become a generally accepted therapy in small animal patients with IBD (15 – 20 mg/kg bid po). Alternatively, doxycycline might be considered; both drugs appear to have immunomodulatory effects. Enrofloxacin (and other fluoroquinolones) are increasingly recognized for their efficacy alone for treatment of some CIBDs (eg, boxers).S-Adenosyl-L-Methionine (SAMe) is a naturally-occurring compound distributed throughout the body, including the liver. As a major methyl donor, it activates enzymes responsible for the synthesis and metabolism of hormones and neurotransmitters, and cellular constituents such as nucleic acids, phospholipids and proteins. Its synthesis is markedly decreased in patients with chronic liver disease. SAMe appears to be responsible for sulfation of hepatotoxic endogenous bile acids and thus promotes bile acid secretion. Its relative absence in liver disease may contribute to intrahepatic cholestasis and the progression of liver disease. In addition, SAMe may also directly protect the liver from continued damage by methylating hepatic cell membrane phospholipids, thus allowing enhanced membrane fluidity. Studies in cell cultures, experimental animals, and human patients afflicted with liver disease have documented the efficacy of SAMe when administered orally for control of liver disease associated with cholestasis. As with UCDA, scientific studies establishing the safety and efficacy of SAMe in diseased animals are indicated.

RESPIRATORYSYSTEM Feline Asthma: Recent advances in the treatment of human asthma increasingly are leading to its treatment as a systemic rather than simply local allergic disease. In particular, the bone marrow response to allergens, and subsequent release of eosinophils, is recognized to be an important systemic process in allergic inflammation. Several cytokines, and in particular, the eotaxin IL-5, contribute to eosinophil movement from the bone marrow to local tissues. In humans, the number of eosinophil/basophil progenitors in the bone marrow declines with the peak allergy season, suggesting that the mature cells are circulating systemically. A central role of IL-5 has been supported through a number of studies documenting increased concentrations in asthmatics. Eosinophilia, lung damage and airway hyperresponsiveness are blunted in IL-5 deficient antigen-challenged mice. Sources of IL-5 include TH2 lymphocytes, mast cells, eosinophils and bone marrow stroma. Among its actions are promotion of differentiation and maturation of progenitor cells, release of mature eosinophils, promotion of survival and inhibition of apotosis. T-cell recruitment to the lungs may play a key role in inflammation. The role of LTs is not clear, although cysteinyl LTs are expressed on a number of bone marrow progenitor cells and appear to be involved (based on effects of antagonists) in eosinophil/basophil progenitor differentiation. Leukotrienes are very potent causes of inflammation in the lungs, causing marked edema, inflammation, and bronchoconstriction. The recent approval of drugs that specifically inhibit the formation of LTs or their actions have offered a new avenue of control of respiratory inflammatory disease (e.g., asthma) in human medicine. Zafirlukast (Accolate) is a leukotriene receptor antagonist (LRA), whereas zileuton (Zyflo) is a lipoxygenase inhibitor. Comparative studies in animals and humans suggest that, of the two, zafirlukast (0.15 to 0.2mg/kg orally once daily) or montelukast (0.5-1.0 mg/kg po sid) is more effective and less likely to increase hepatic enzymes (and thus is safer) among different species. and can be administered less frequently (every 8 to 12 hours compared with every 6 to 8 hours for zileuton). Zafirlukast is associated with very few side effects in human patients. However, a recent report delineates severe acute hepatopathy in three human patients receiving zafirlukast for at least 5 months .In human clinical trials, LRA inhibit early and late phase bronchoconstriction and increased bronchial hyperresponsiveness in response to allergens, accumulation of inflammatory cells and mediators in bronchial lavabe fluid, and acute bronchospasms stimulated by exercise, cold air and aspirin. Their use has been associated with improvement of asthma either as sole therapy (in lieu of low dose inhaled glucocorticoids) in milde to moderate asthma or as add-on therapy regardless of diseases severity in glucocorticoids non-responders. The role of LAR in the treatment of feline asthma has had some, albeit limited attention. Because receptors for leukotrienes have not been found in the smooth muscle of airways in cats, the use of antagonists have been questioned. However, with the recent approach to asthma as a systemic response mediated at the level of the bone marrow, the use of LRA warrants futher and strong consideration. Glucocorticoids: In 1997, the National Heart Lung Blood Institute Expert Panel Guidelines recommended control of mild persistent asthma with a single, long-term control medication with anti-inflammatory properties. Glucocorticoid efficacy for treatment of respiratory inflammatory disease is dependent on achieving therapeutic concentrations in and below the epithelium of all diseased airways. However, whereas systemic therapy might provide the most consistent exposure to diseased airways, it also provides the greatest exposure to tissues other than the lungs, leading to adverse effects. Administration of glucocorticoids by aerosol has decrease many of the side effects associated with systemic glucocorticoids use in humans. Indeed, the preferred treatment for humans with mild disease is low-dose inhaled glucocorticoids. However, short courses (5 to 7 days) of high doses of oral glucocorticoids are used to treat acute exacerbations of asthma. Inhalant Devices: Beta-adrenergics: With the advent of metered doses inhalers in the 1960s, beta-adrenergics became a common therapy for treatment of human asthma. Short-acting β2 agonists administered by aerosol include albuterol (preferred), pirbuterol, bitolerol and terbutaline whereas longer-acting (in humans) products include salmeterol (preferred) and formoterol. The drugs differ in their effect and use. Short acting products are associated with rapid symptomatic relief in human asthmatics when used at appropriate doses. However, use at high doses has been associated with an increase in mortality in humans, leading to their recommended use on an "only as needed" basis. On the other hand, improvement in pulmonary function in humans was sustained with prolonged used of long-acting beta-adrenergics and thus such use was not associated with a decrease in symptomatic relief afforded by short-acting drugs. Note that time to onset of long acting drugs may be up to one hour. Although minimally effective by themselves for control of inflammation, long-acting beta-adrenergics appear to enhance responsiveness to glucocorticoids. Rebound hyperresponsiveness does not appear to occur with rapid discontinuation of the long-acting drugs. Tolerance may occur to the effects of beta-adrenergics, probably due to down regulation of receptors, , particularly in the presence of triggering events (such as exercise in humans). Because beta-adrenergics do not provide as much anti-inflammatory control, their efficacy may be reduced in the presence of inflammation and combination therapy with an anti-inflammatory drug (eg, inhaled or systemic glucocorticoids), or use of theophylline may be indicated. Theophylline is available in slow release preparations; however, the kinetics of release of these products are designed for humans and vary among animals. Selected products allow twice daily dosing in dogs and once daily dosing in cats (Theodur®: 25 mg/kg sid in pm po [C]; 20 mg/kg bid po [D]; Slo-bid®: 25 mg/kg bid to sid [C] 20 mg/kg sid). Because the bioavailability of these products markedly varies, therapeutic drug monitoring should be used to confirm therapeutic concentrations (10 to 20 (g/ml) particularly if the patient does not appear to be responding. Theo-Dur® is among the most bioavailable in dogs. N-acetylcysteine serves as a precursor to glutathione, a major scavenger of free oxygen radicals associated with inflammation. The drug also appears to induce respiratory tract secretions, probably via a gastro-pulmonary reflex. The drug can be used orally or IV, with indications in people including toxic inhalants (including tobacco smoke), bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, tuberculosis, pneumonia and emphysema and the adult respiratory distress syndrome. Installation of a 10-20% solution has also been used to clean and treat chronic sinusitis and the drug is of benefit in treatment of chronic obstructive pulmonary disease. It also appears to facilitate treatment of bacterial infections of the respiratory tract. Acetylcysteine therapy is associated with few adverse affects. In a small number of human patients, IV administration has been associated with an anaphylactoid reaction which can be minimized by administration of histamine receptor (subtype 1) antagonists. In humans, doses as high as 500 mg/kg are well tolerated, although vomiting and anorexia can occur. Doses of 250 to 500 mg (total) twice daily are reported to be effective. N-acetylcysteine appears to have benefits in other inflammatory conditions, including septic shock. Because it is metabolized to sulfur containing products, it should be used cautiously in animals suffering from liver disease characterized by hepatic encephalopathy, but it can be used to help protect the liver following any drug-induced hepatotoxicity. Rutin (50 mg/kg po bid) is a non-anticoagulant coumarin used to treat selected causes of peripheral limb edema in human patients. The edema should be associated with protein exudation (ie, edema due to permeability changes or lymphatic blockage). The drug, available in health food stores, acts to stimulate macrophage removal of proteins and thus removes the oncotic flux of fluid into tissues. Indications include appropriate causes of peripheral limb edema and pleural effusions associated with proteinatious secretions (ie, chylothorax). Response may take several weeks to months. There appear to be no toxicities associated with the drug.

CARDIOVASCULAR. Carvedilol. Is a "third" generation beta blocker that also is characterized by alpha adrenergic blockade. Blockade is relatively selective for beta-1 receptors. Its combined effects result in decreased total peripheral resistance and preload without compromise of cardiac output or reflex tachycardia. Decreased heart rate may not be as dramatic as with other beta-blockers. In human patients with left ventricular failure, it has reduced mortality. A marked advantage of this drug is potential anti-oxidant antiproliferative effects in the heart as well as decreased myocardial cell fibrosis, apotosis and remodeling (as occurs with other beta-blockers, such as metaprolol; 0.2-0.4 mg/kg bid po). As such, the drug may decrease progression of myocardial failure; indeed, it is approved for such use in humans. The dose has not been well established, but dogs are started out at ½ of a 3.125 mg/ tablet once to twice daily. If the dose is well tolerated (blood pressure does not decrease), then the dose is doubled in two weeks. Among the diuretics, spironolactone also has been associated with a beneficial effect on myocardial remodeling in patients with dilated cardiomyopathy and its use should be considered early in the pathophysiology, including as part of combination therapy. Pimobendan is a positive inotropic drug that targets phosphodiesterase (III) and is a calcium sensitizer. As such it not only increases contractility (more effectively than currently available cardiac glycosides) but also helps ameliorate neurohumoral responses by causing peripheral vasodilation and thus reduced preload & afterload. Increased renal perfusion helps ameliorate some activation of the rennin-angiotensin-aldosterone system. As such, it also appears to provide some protection against mediators of myocardial remodeling. Time of treatment remains to be confirmed and may vary with cardiologist. However, early (and of course, late) in the disease process warrants consideration. Quality of life demonstrably improves; impact of quantity of life is less clear. Pimobendan can be coupled with essentially any other cardiac drugs.

Tamiflu® (olsetamivir) has been used to decrease mortality of parvovirus by 75-100% (2 mg/kg PO every 12 hr); cost will be approximately $0.25/kg Voriconazole (we have used it at 5 mg/kg twice daily), a synthetic deriviative of fluconazole, is the first of the "second generation" triazole compounds to be approved by the FDA. Compared to fluconazole, voriconazole contains a fluorine molecule and a methyl group which greatly enhances its spectrum compared to fluconazol. As with other azoles, its spectrum includes a variety of infecting fungal organisms. Voriconazole also is effective against C. neoformans, Trichosporon beigelii and Saccharomyces cerevisiae. Killing studies with Aspergillus demonstrate that, in general, amphotericin B is less efficacious than voriconazole. Pharmacokinetics of voriconazole apparently have not been performed in either the dog in the cat, but in humans, are complicated by a marked variable half-life and drug interactions typical of ketaconazole (ie, inhibition of drug metabolizing enzymes). Because this drug is associated with both adverse reactions (including visual defects, hepatotoxicity), care must be taken with extrapolating drug metabolizing enzymes. The long halflife (6 to 24 hr depending on the dose in humans) will require 5- 6 days of dosing; a loading dose consisting of a double daily dose is recommended for the first day of therapy (the drug is dosed at 3 to 6 mg/kg twice daily to yeiled 3 to 6 µg/ml in the plasma). Extrapolations to animals must be made cautiously because the drug undergoes non-linear pharmacokinetics in humans, probably due to saturation of drug metabolizing enzymes. The drug is cleared primarily by hepatic metabolism to inactive metabolites by CYP 2C19 (the primary isoenzyme), 2C9, and 3A4 being involved. Selected humans are considered "poor metabolizers" of the drug because of variation in CYP 2C19. The drug has been used apparently successfully by the author in combination therapy with terbinafine to treat a retrobulbar opportunistic fungal disorder in a dog. Terbinafine (20-40 mg/kg once daily) is an allylamine antifungal that inhibits sqalene epoxidase and ultimately formation of ergosterol. It is particularly efficacious against dermatophytes, but is also efficacious against Sporothrix schenckii and Apergillus. Because of its different mechanism of action, it might be used in combination with other antifungals effective against these two organisms. Recent evidence suggests that it also may be efficacious against histoplasmosis; combination with traditional antifungals should be considered for such therapies, including treatment of coccidioidomycosis.

Biotherapeutics: Probiotics "are live microorganisms which when administered in adequate amounts confer a health benefit on the host . In contrast to probiotics, prebiotics refer to non-digestible food ingredients (including dietary fiber) that beneficially effect the bacterial population. They differ from other fermentable carbohydrates in that they interact with selective microorganisms. For example, fructo-oligosaccharides and inulin, transgalactosylated oligosaccharides and soybean oligosaccharides selectively promote the growth of bifidobacteria. Synbiotics contain both pre and probiotics, with "syn" implying a synergistic effect of the prebiotic on the probiotic portion of the combination products. The total body microbiota (human) includes 1012 to 1012 bacteria, outnumber other cells by approximately 10 fold; 30% of dry fecal matter represents microbes. The number of species in the gastrointestinal tract (again in humans) is estimated to be between 400 and 500. Only a fraction are conducive to culture. Their role is critical, protecting against invasion of pathogenic strains of bacteria, facilitating normal bowel smooth muscle function, supporting digestion of certain foods, and contributing to nutrition through the production of vitamins (vitamin K; vitamin B in some species) and other nutrients (eg, short-chain fatty acids) (Dethlefsen 2006). Microbes impact the maturation and maintence of the intestinal immune system, influence cell proliferation and facilitate energy salvage (eg, through conversion of nutrients to short chain fatty acids). Among the organisms most commonly cited as beneficial are Lactobacillus and Bifidobacterium. Bacterial by products also have a number of adverse effects. Protein byproducts, produced primarily in the distal colon, include ammonia and amines resulting from deaminations; these products are associated with pro-carcinogenic effects (eg, nitrosamines). Cysteine and methionine degradation yields sulfides, which inhibit colonic use of butyrate. Anaerobic colonic fermentation of aromatic amino acids tyrosine to phenols and tryptophan to indoles, and their subsequent metabolism, yields several procarcinogenic compounds. Bacterial deconjugation and dehydroxylation of bile acids contribute to their enterohepatic circulation; other compounds conjugated by compounds such as taurine, glycine, sulfate may likewise be recycled. Many of these determinental compounds play a role in hepatic encephalopathy as well.

The use of pre and probiotics in dogs has been reviewed by Rastall (2004). Lactobacillus acidophilus DSM 13241 was fed (2X109 CFU/d) was studied in 15 healthy dogs decreased the number of culturable Clostridum sp and was associated with an increases in indices indicative of immunomodulation (incrased serum IgG, monocytes, decrease plasma nitric oxide). Prebiotics which have been studied (Rastall 2004) include lactosucrose and fructo-oligosaccharides. Feeding 1.5 g lactusucrose/d for 2 weeks to healthy dogs (n=8) increased Bifidobacteria and decreased Clostrdium sp. Bifidobacteria and Lactobacillus also increased and Clostridium and Enterobacteracea decreased In cats receiving 0.75 g/day. A decrease in toxin levels and odor also was described for both dogs and cats. Fructo-oligosaccharides fed at a rate of 4 g/day to adult health dogs (n=20) increased Bifidobacteria and Lactobacillus and decreased Clostridium sp. Although both lactate and butyrate increased, ammonia, dimethylsulfide, and hydrogen sulfide also increased. Fructo-oligosaccharides at a rate of 0.75% in the diet of adult healthy cats for two weeks decrease Clostridium sp and E. coli. Rastall (2004) also described the formulation of a symbiotic containing Lactobacilli cultured from one dog, following the tradition of probiotics being based on microbes isolated from the target species. Among the isolates cultured, L.mucosae, L. acidophilus, and L. reuteri, were subjected to prebiotic carbohydrates.

The number of CFU ingested as probiotics is minor compared to the normal microbiota (Lenoir-Wijnkoop 2007). However, they transit through regions of the gastrointestinal tract that are sparsely populated and as such, may transiently become the dominant microbe. Pre, probiotics and synbiotics purportedly impart a number of beneficial effects as has been and continues to be demonstrated using a variety of in vitro and in vivo models (as reviewed by Schrezenmeir 2007 and Lenoir-Wijnkoop 2007). Probiotics have been demonstrated to have an impact on a large diversity of potential health problems (Lenoir-Wijnkoop 2007). Included are gingival disease, gastric infections by Helicobacter pylorus (and thus medical conditions associated with infection), pancreatitis, antibiotic-induced diarrhea, (most promise included Lactobacillus GG, Lactobacillus sporogenes, and Saccharomyces boulardii), infectious Diarrhea, (but not C. difficile colitis), inflammatory bowel disease, liver Disease, bacterial translocation, urinary tract infection andoxalate urolithiasis; the roll in allergic diseases is evolving. Probiotics and related compounds are not approved drugs and undergo no premarket approval process. As such, data supporting quality assurance, safety and efficacy for each product may not exist. Consumer Laboratories (www.consumerlab.com) has reviewed issues specifically related to quality assurance of a probiotic product. These include: 1. Labeling. Labels should list all types of bacteria or yeast, including genus and species. Labels generally list the number of colony forming units (CFU); generally 1 to 10 billion (109 to 1010 ) CFU are recommended (in humans) per day. 2. Viability of organisms, which may decrease during time of manufacture versus purchase due to exposure to heat, moisture and oxygen; 2.presence of contaminating (potentially pathogenic) organisms, including E. coli, Salmonella spp, Staphylococcus aureus and Pseudomonas aeruginosa (as per FDA requirements); and 3. the extent of enteric protection of selected organisms, including L. bulgaricus,S. thermophilus and Leuconostoc and Lactococcus sp. Organisms which generally do not need protection include most Lactobacillus, Bifidobacterium and Streptococcus, or organisms present as spores, including Bacillus and some Lactobacillus. Of 24 products (21 human, 3 pet) reviewed by Consumer Laboratories (October 2007), 5 (4 human, 1 pet) failed to contain the labeled amount of microbes, 6 (4 human, 2 pet) failed to provide at least 109 CFU per serving (generally those that also failed to contain labeled amount) and 1 (pet) failed due to microbial contamination (with mold). Two of the pet and 4 of the human products did not include the number of CFU on the label.

Ongoing Clinical Trials: Note that we are seeking therapeutic drug monitoring (blood) samples and a small sample of drug from cats receiving selected drugs as a transdermal gel, and in a separate clinical trial, samples of drugs compounded for either dogs or cats. Please see http://www.vetmed.auburn.edu/index.pl/research_announcements2.