What's new in drug therapy for small animals? (Proceedings)

Central and Peripheral Nervous System

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 swab and the cost is approximately $65.

Zonisamide

(Zonegran®; 8 to 12 mg/kg divided twice to three times daily, po) 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. Zonisamide has been studied in normal cats. A single dose of 10 mg/cat resulted in a Cmax of 13 mcg/ml at 4 hr; the elimination half-life of 33 hrs. The drug was well tolerated. 10 mg/cat (or 2 mg/kg) once daily is a reasonable beginning dose in cats. Levetiracetam (Keppra®) is an anticonvulsant approved for use in humans. Its mechanism of action is not known. It is renally excreted (60%) and to a lesser degree, metabolized by the liver. However, it has a short half-life (as short as 2 hrs in some dogs and cats) that necessitates 8 or less hour dosing. However, it is extremely well tolerated in dogs and has been safely used in dogs and cats as well as an add-on anticonvulsant at 20 mg/kg every 8 hrs po. Its short half-life may indicate CRI for acute management of seizures. Use for treatment of seizures associated with PSS should be considered.

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. Avoid other drugs which inhibit the uptake of serotonin 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, its mechanism is similar to gabapentin and, like gabapentin may also have anticonvulsant activity. Hydromorphone (0.1 mg/kg) was studied SC in cats and compared to previous reports of IV and IM administration (Robertson 200x FMS). The authors found the drug to cause more side effects, a longer onset to effect and a shorter duration of antinociception, and thus generally unacceptable. Buprenorphine was studied in cats and a dose of 0.04 mg/kg was found to provide more analgesia and longer duration of action with no increase in side effects compared to 0.01 and 0.02 mg/kg/. Meloxicam was demonstrated to be safe (both GI and renal) in cats when administered at 0.03 mg/kg once daily for 5 to 6 months. However, an analysis of adverse events reported in cats suggests that cats are more susceptible to renal side effects, and, adverse events reported for meloxicam are more likely to involve the kidney, compared to carprofen.

Immunologic

(See also proceedings on Glucocorticoids and Non-glucocorticoid immunomodulators, this same proceedings). "Soft" Glucocorticoids. Among the mechanisms whereby undesirable side effects of glucocorticoids can be minimized is topical administration of drugs which are potent for the glucocorticoid receptor but also rapidly metabolized should the drug be absorbed into systemic circulation. Examples include beclamethasone, budesonide and fluticasone proprionate, steroids designed specifically for use in inhalant metered doses. Their potency when inhaled varies in clinical trials, with fluticasone propionate being most potent and budesonide and beclomethasone dipropionate approximately equipotent. Time of onset in humans to budesonide is approximately 10 hrs based on evidence of clinical improvement at that time. Improvement can be expected over the next 1-2 days, with maximum effects potentially not being evident until 2 weeks after therapy has begun.

Budesonide is also available as an oral prepration. It is rapidly metabolized in the liver by CYP3A4. Inhalant drug is generally considered to be absorbed (as much as 25%). The side effects of glucocorticoids might be reduced with "soft" preparations, but probably will not be avoided by topical therapy. Drugs which impaire CYP3A4 (eg, CsA) may increase the plasma drug concentration of budesonide over 7 fold. Even by itself, budesonide appears to suppress the hypothalamic-adrenal-pituitary axis in dogs based on a clinical trial in dogs (n=6) with IBD. Budesonide has been used to treat CIBD in dogs . Budesonide has been recommended in dogs (1– 3 mg daily depending on dog size) although no scientific or anecdotal information has been published regarding its efficacy in animals. Means to reduce these side effects include combination drug therapies. Cyclosporine is a T-cell specific immuomodulator 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®) is not as dependent on bile acids for oral absorption and is more bioavailable. 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*hr/ml is recommended. However, trough concentrations of 400-600 ng/ml or a 2 hr peak 800-1400 ng/ml also have been recommended for transplantation patients. Both are relevant only with twice daily dosing. A clinical trial in cats receiving either CsA (5 mg/kg qd; n=18) or prednisolone (1 mg/kg qd; n=11) for treatment of atopy reported no difference between groups. However the proportion of responders was actually greater at P ≤ 0.06 in cats receiving CsA (61%) compared to prednisolone (41%) based on a linear analog scale; further, while 10/18 CsA cats improved ≥ 50%, only 2/7 responded at that level for pred (based on canine scoring system). Drug concentrations (unfortunately) were not determined. 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 ketaconazole 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 bioavialable 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. 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 inlieu 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.

Endocrine

Glargine did not differ in its effects when given once (0.5 U/kg) or twice (0.25 U/kg)daily in normal cats (n=6; crossover). Interestingly, the fluctuation in glucose concentrations is less dramatic with once daily dosing. Both glargine and protamine zinc insulin have a longer duration of effect in normal cats (n=9) compared to lente insulin. However, whereas time to peak effect did not differ among insulins, time to first nadir was longer for glargine was 14 hr compared to 4 and 5 hr for PZI and lente, respectively. Cats with DM (n=46) responded well to porcine zinc insulin (Canisulin®) (studied for 16 + weeks). Insulin started at 0.25 to 0.5 IU/kg every 12 hrs (maximum starting dose of 2 IU/injection). 28 cats were classified as stable during the treatment period.

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 lymphocyts 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.

Pruritis. 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 pruritis. When administered at 6 µg/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. Pentoxyfylline is a methylxanthine derivitive (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 pruritis 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 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 (¼th 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 glucocorcorticoids. 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. Biweekly 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 immunmodulatory 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.

Respiratory System

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 0.2 mg/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 leukotrienes 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 such as monetlukast warrants further 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: Glucocorticoids: The addition of inhaled glucocorticoids has increased asthmatic control in humans. Beclomethasone was among the first aerosol glucocorticoids developed for inhalant therapy. Systemic side effects associated with deposition of glucocorticoids on the pharynx and central airways and local side effects in the upper airway (eg, dysphonia in up to 50% of the patients) led to the inclusion of "spacers" that removed larger particles before they penetrated the pharynx. Additionally, administration of glucocorticoids removed by first pass metabolism (eg, budesonide or fluticasone [preferred]) decreased the risk of systemic exposure to swallowed drug. However, poor compliance of inhaled glucocorticoids in human patients led to the development of combinations of steroids with long-acting beta2 agonists (eg, salmeterol/fluticasone or formoterol/budesonide). Although compliance has improved, concern has arisen that the beta2 agonists will mask clinical signs that might otherwise indicate worsening of the disease. Indeed, recent studies of the efficacy of inhaled beclomethasone diproprionate found improvements to be short-lived, probably because the inhaled drug does not control inflammation well. Reduced airway caliber will further decrease efficacy by reducing drug delivery to the peripheral airways. In human asthmatics, deposition studies reveal that the majority of drug is deposited on central airways. Yet, anti-inflammatory therapy should target both large and small airways if inflammation is to be suppressed. Thus, systemic therapy should be considered (either as sole therapy or in addition to systemic therapy) in animals with moderate to severe disease. Note that the peak effect of inhaled glucocorticoids may not occur for 1 to 2 weeks after therapy has begun.

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 beta2 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). Becaused the bioavailability of these products markedly varies, therapeutic drug monitoring should be used to confirm therapeutic concentrations (10 to 20 (µg/ml) particularly if the patient does not appear to be responding. Theo-Dur® is among the most bioavailable in dogs. Terbutaline (Brethine®: 0.2 mg/kg po every 8-12 hrs [D]; 1.25 to 2.5 mg/cat po every 12 to 24 hrs) is a specific beta2-agonist that can be used for bronchodilation while avoiding cardiac stimulation. It can be used in patients that have not responded to theophylline; the two can be combined for potential additive effects.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 vomition 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-anticouagulant 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 pathyophysiology, 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 increased contractility (more effectively than currently available cardiac glycosides) but also helps ameliorate neurohumoral responses by causing peripheral vasodilation and thus reduced preload & afterload. The increase in renal perfusion helps ameliorate some activiation of the rennin-angiotensin-aldosterone system. Marketed by Boeringer Ingelheim as Vetmiden® in other countries, the drug is not available in the US. It thus far has proven equal to or superior to ACE inhibitors in dogs with congestive heart failure. ACE Inhibitors 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).

ACE Inhibitors & Renal Disease

Control of phosphorus is crictical 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).

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 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 glomerulosclrerosis. A renal protective effect has also been described for all ACE inhibitors for generalized renal disease. The prescence 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.

Antimicrobials

Antibiotics

A generic amoxicillin-clavulanic is available for humans. Note that generic therapeutic equivalence demonstrated for a product in humans does not necessarily equate to similar behavior when the generic is used in animals. The ratio of clavulanic acid varies with the human products, with the 400 mg capsule have the same ratio (4:1) as the small animal product. Vancomycin (10 to 20 mg/kg IV over 30 minutes or PO every 8 hrs) is a time dependent bactericidal inhibitor of cell walls whose spectrum includes Gram positive and anaerobes. It is available for oral administration ONLY for treatment of GI (it is not absorbed orally) susceptible microbes (eg, Clostridium). It is renally excreted. Its use is prohibited in food animals. Indications include MRSA/MRSI and potentially resistant enterococci. Linezolid targets the 30 and 50s ribosomal subunits of Gram positive isolates. It is orally available (10-20 mg/kg once daily PO or IV). It inhibits monoamine oxidases and should not be used in combination with behavior modifiying drugs. In addition, allergies and peripheral neuropathies have been reported in humans. It is a substrate for P-glycoprotein. Toxicities are limited to nephrotoxicity when combined with another nephrotoxic drugs. Indications are as with vancomycin. Rifampin (10-20 mg/kg PO every 8-12 hr dogs, 24 hr cats) inhibits RNA polymerase. Its spectrum includes Gram Positive and anaerobes. Because resistance develops rapidly, it should never be used by itself. It accumulates in WBC. It also is a substrate for P-glycoprotein. An advantage of rifampin is that it accumulated in WBC and that it can be combined with most other antimicrobials. It is a potent inducer of drug metabolizing enzymes and should be used cautiously with other drugs metabolized by the liver. Note that it will discolor body fluids orange (urine looks hemorrhagic) and it may increase serum alkaline phosphatase. Otherwise it is a safe drug. Clostridium difficile is rapidly joining MRSA as an epidemiologic concern. The role of antimicrobial use in the advent of resistance is well recognized. Among the different methods which might control the advent of resistance is de-escalation. De-escalation –differs from "restrictive" use that precludes the use of certain antimicrobials (eg, aminoglycosides) hospital envioronents. The latter is probably an inappropriate approach if it precludes the use of the most appropriate antimicrobial for the patient. The former focuses on 1. avoiding indiscriminant use in the face of limited evidence of infection; 2. narrowing the spectrum of the drug such that microbes are not broadly exposed to drugs; 3. limiting the duration (but not dose) of the drug such that exposure time is less. Fluorinated quinolones: Consideration should be made to use the highest recommended dose of any FQ when treating E coli. Its use is associated with the emergence of MDR E coli. Oral bioavailability of ciprofloxacin in cats is poor (0 to 20%). All currently veterinary approved FQs are associated with retinal degeneration in cats. The mechanism is not clear. Bayer Animal Health has demonstrated safety of enrofloxacin when administered at 5 mg/kg and has demonstrated changes in the retina (based on ERG) in 1/6 cats receiving 20 mg/kg and all cats receiving 50 mg/kg. In contrast, marbofloxacin at 27 mg/kg for 6 weeks and 54 mg/kg for two weeks was not associated with retinal lesions. Some early evidence supports (but does not confirm) that changes may be associated with the effects of UV radiation on the retina in cats treated with FQs. Until the mechanism of damage is identified, dosing cats at night, or keeping animals out of sunlight when receiving fluorinated quinolones might be considered. Cefovecin: the long half-life of this drug which allows once a week administration reflects tight binding to circulating plasma proteins which thus serve as a depo form. Although once a week administration is appropriate for the approved organisms (Staph intermedius, Streptococcus), care should be taken when using it to treat other organisms including Staph aureus and E coli: the MIC 90 of these isolates is substantially higher and a second dose at 4 days, or a higher initial dose, might be prudent. Judicious use of this drug will be critical to avoid emergent resistance. Metronidazole hydrochloride often requires recompounding; however, its bitter taste is hard to mask. Metronidazole benzoate is an alternative medication that is not nearly as bitter.. When using the benzoate salt of metronidazole, the dose should be about 60% higher (divide the dose by 0.6) than the metronidazole hydrochloride salt if dosing is based on the total ingredient (ie, 10 mg metronidazole hydrochloride = 16.7 mg metronidazole benzoate). The oral bioavailability of the benzoate salt is markedly variable, ranging from 28 to 80% in cats. 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. Lysine (400 mg/day) has been shown to decrease viral shedding in adult cats latently infected with feline herpes virus. However, Lysine ( n=147; either 250 mg of < 5 months or 500 mg if ≥ 5 months, added to a small amount of food) was compared to no treatment (n=147) in healthy cats admitted to an animal shelter during a three month period (February – April). Cats were vaccinated according to the shelter's protocol. Lysine was discontinued if clinical signs of conjunctivitis or UTI emerged. The incidence of conjunctivitis or URI did not differ during the study period. 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.