WHAT’S NEW IN DRUG THERAPY FOR SMALL ANIMALS?
Dawn Merton Boothe, DVM, PhD, Dip ACVIM ACVCP
VTPP, TAMU, CVM, College Station, Texas 77843-4466
409 845 9368/email dboothe@cvm.tamu.edu
CENTRAL NERVOUS SYSTEM
Chemical Restraint: Newer alpha2 agonists such as medetomidine (0.75 mg/m2 IV or 1.0 mg/m2 IM;dogs) are associated with fewer cardiovascular effects and longer duration of activity compared to xylazine. Medetomidine provides both sedation and analgesic and is labeled for use in dogs for clinical procedures that require short term chemical restraint. The effects can be reversed with atipamezole, (4 times the dose of medetomidine, or 1.0 mg/m2 or 0.2 mg/kg) an alpha 2 antagonist. Like xylazine, medetomidine can cause vomiting and cardiovascular suppression. Propofol (induction: 7mg/kg; maintenance 0.51 mg/kg in the cat; and 4 to 8 mg/kg [depending on whether or not premeds were used) induction, 0.51 mg/kg in dogs; IV; or IV drip of 0.4 mg/kg/min) is a short acting inducing agent that can be used in lieu of an ultrashort thiobarbiturate. It has no analgesic properties and can be used as an inducing agent, or for short (1 hr or less) procedures. The primary advantage of this drug is smooth recovery with minimal "drug" hangover. It offers no other advantages to thiobarbiturates. It can cause profound respiratory depression if given too rapidly. It is an oil at room temperature and contains no preservatives, hence must be handled aseptically.
Etomidate (0.5 - 3 mg/kg; following opioids, 0.5 to 1 mg/kg; IV) is another ultrashort nonbarbiturate IV anesthetic that can be used for rapid and smooth induction of anesthesia. It is associated with rapid recovery, wide safety margin, no accumulation with multiple doses, and minimal depression of the CNS. It can cause pain on injection, and also is expensive (10 to 15 times the cost of thiopental). Because it modulates GABA (an inhibitory neurotransmitter), it has been recommended for seizures in refractory patients. It also decreases cerebral blood flow and oxygen consumption, and has been recommended in patients with cerebral trauma.
Anticonvulsants. Pertinent potassium bromide points: 1. A loading dose is recommended for rapid control of seizures (90 to 120 mg/kg for 5 days which will achieve 1 to 1.5 mg/ml). To assure maintenance dose (20 to 30 mg/kg orally a day) maintains what loading dose achieved, monitor post-load (day 6 or more) and one month later. If the two do not match, modify the maintenance dose appropriately. 2. Bromide can be used (in limited cases?) as sole therapy; targeted concentrations should be higher (2.0 to 2.5 mg/ml). 3. Grogginess is expected, is more likely with a loading dose, tends to resolve after 1 to 2 weeks, and can be reduced by decreasing phenobarbital concentrations in 25% increments. Make sure bromide is at 1.5 mg/ml before reduction occurs in difficult patients. 4. The drug can be used safely in cats at canine doses; safety of loading has not been established in cats. Steady-state concentrations occur at 6 to 8 weeks. 5. Single (trough) samples are sufficient for monitoring. 6. A number of veterinary pharmacies will formulate the drug, but at a potentially great cost. The drug can also be made by dividing a 1kg bottle of the salt in 4 equal parts. One part can be added to a 1 liter bottle of spring water purchased at a local grocery store (first remove about 0.5 liter, add the bromide, and enough water to make the bromide dissolve, and fill the remaining volume with corn syrup for flavoring). 7. The therapeutic index of bromide is not large. Although therapeutic targets have not been well established in the dog, a range of 1.0-3.5 mg/ml is recommended in dogs also receiving phenobarbital. Remember, however, that this is a range that encompasses 95% of animals and where the individual patient responds may be at either end or the middle of the range. Monitoring should be established to determine the patient’s target. 8. Therapeutic drug monitoring is available at several laboratories including new corporate labs. However, several of these labs are now using ion selective probes. Until precision and accuracy of this method has been proven, bromide should be measured by UV spectrophotometry (information regarding monitoring can be found at http//www.cvm.tamu.edu/vcpl).
Felbamate is the newest anticonvulsant that we have studied. Very effective for any type of seizure either alone or in combination, this drug has fallen out of favor in the human sector because of a low incidence of bone marrow dyscrasias. We have found the drug very effective and safe when used in combination with phenobarbital, again for the refractory epileptic. This drug can not be monitored, but is so safe that the dose can simply be increased with minimal risk of toxicity. Its half-life is 14 hours; twice daily dosing should be sufficient, but in animals whose liver enzymes are induced by phenobarbital, the half-life may be shorter, requiring 8 hour intervals. We start with 30 mg/kg bid and increase the dose in 15 mg/kg increments; we add a third dose if our dose gets above 45 mg/kg. The biggest disadvantage of this drug is cost. Gabapentin is another human anticonvulsant being used in animals. Its advantage is renal elimination. It has a short half-life and requires 8 hour dosing. We have had little luck in controlling refractory seizures with this drug, even at very high doses. Again, cost is an issue.
Behavior modifying drugs. Most behavior modifiers have the ability to modify multiple central nervous system neurotransmitters. Most notably affected are the biogenic amines including serotonin and dopamine (and to a lesser degree, epineprhine etc). Acetylcholine and histamine, and alpha adrenergic receptors may also be affected. Since these neurotransmitters are affected centrally, they can affect many physiologic functions. Because physiology and drug disposition varies markedly between animals, adverse reactions to the drugs should be anticipated. Adverse effects include sedation, anticholinergic effects, and others related to enhanced biogenic amine actions. These drugs should be used cautiously; many of the side effects are not detected easily in animals. Amitriptyline (1-2mg/kg, bid po [D};0.5-2 mg/kg bid -sid po [C]) is a tricyclic antidepressant (TCA) that has been used safely for control of separation anxieties, obsessive/compulsive behaviours and in cats, urinary spraying. Adverse reactions have been noted in both dogs and cats (CNS signs, gi upset). Response may take a couple of weeks; gradual withdrawal should take place over several weeks. Clomipramine is a TCA that inhibits uptake of 5-HT (serotonin) and thus tends to be more selective in its actions. It also potentiates norepineprhine, although this may not be the mechanism of antidepressant activity. Because of this relative selectivity, it tends to be safer than other tricyclics. (Dose: Increasing doses at 14 d intervals: 1 mg/kg , then 2mg/kg, then 3 mg/kg po bid [D]; 0.5 mg/kg sid po [C] X 14d, then double for 14 x day, then triple X 14D [D], up to 3 mg/kg per day.) This drug currently is undergoing approval in dogs. Doxepin (3-5 mg/k PO bid to tid [D]) is characterized by greater antihistaminergic actions and may be more useful for chronic pruritis. Prozac (fluoxetine)(1 mg/kg po sid, dogs) is a serotonin specific re-uptake inhibitor (not a tricyclic) antidepressant. Its actions tend to be selective for serotonin compared to other antidepressants. Thus, it tends to be safer than other drugs. However, up top 12 % of human patients must discontinue Prozac because of side effects, including hypertension, insomnia, anorexia, mania, etc. One nonscientific report in dogs noted adverse effects (changes in weight, appetite and activity, plus gastrointestinal and CNS signs) in up to 50% of dogs receiving the drug. As with many behavior modifying drugs, therapy for several weeks may be necessary before effects are seen (due to drug accumulation as well as pharmacologic effects). Drugs should not be discontinued rapidly. These drugs should not be used in combination; in epileptic patients; or patients with hypertension and/or cardiac diseases. The TCA and other antidepressant drugs are used to treat stereotypic behavior including that resulting in skin lesions. The most common behaviors are related to grooming, such as lick granuloma or hair chewing. Pruritis has also become a common indication for antidepressant therapy. Acral Lick Dermatitis has been treated with these drugs as well as naltrexone, a narcotic antagonist. Increased release of endogenous opioids have been detected in self mutilating behaviors in experimental anima. Opioid antagonists may eradicate endorphin-mediated "self-reward" and analgesia. Like naloxone, naltrexone is a pure opioid antagonist but it characterized by a higher oral efficacy and longer duration of action. An uncontrolled study of the use of naltrexone in dogs with acral lick dermatitis reported a 64% success rate. A dose of 2.2 mg/kg po sid (1.0 mg/kg SC) was increased to 2.2 mg/kg po bid if there was no response after 10 days. Dogs were treated for 1 month; lesions returned when the drug was discontinued, and time of recurrence varied from 1 week to 3 years after the drug was discontinued. One animal which failed to respond to naltrexone responded to nalmefene, another narcotic antagonist.
Deprenyl (selegiline) has recently been approved for treating hyperadrenocorticism in dogs, but originall recieved attention as a drug which will prolong life expectancy in dogs. As a monoamine oxidase inhibitor (selective for B enzyme), it presumably increases dopamine (and other biogenic amine) neurotransmitters in the brain. In doing so, it may prevent the formation of chemicals damaging to the brain, or it may help the scavenging of oxygen radicals and thus prevent the development of slow brain damage. The tabloid announcing this drug neglected to note that it is also metabolized to amphetamine and metamphetamine in dogs/people. In rats, the drug did indeed prolong life expectancy (9 months in one study, 3 months in another) when started at an early age. However, young dogs treated with this drug are more active (repetitive, nonsensical movements particularly in females, increased sexual activity). An advantage of this drug is that is effects are selective for monamine oxidases in the brain, but not for the rest of the body. In addition, deprenyl also appears to be an oxygen radical scavenger and appears to stimulate neuronal regeneration. The primary animal (dog) claims for deprenyl will be for treatment of hyperadrenocorticism (1 to 2 mg/kg sid potentially for life; anticipate up to 70% efficacy and cognitive disorders (0.5 mg/kg sid) in very geriatric (> 15 yrs?) dogs. The major impact this drug has had in the human health sector is in patients with Parkinson's disease: the time at which L-Dopa must be started is prolonged, and life expectancy in patients with this disease is prolonged.
Control of Pain: Central Analgesics: Opioids: Mixed Agonists/Antagonists: Buprenorphine (0.005-0.03 mg/kg IV,IM,SQ, epidural [D]) is a schedule V thebaine derivative with analgesic effects which are 25 or more times potent than morphine. Although its onset of action takes longer than morphine, its effects last much longer (in man). Like morphine, buprenorphine induces dose-dependent respiratory depression; like butorphanol, a ceiling is reached. Although respiratory depression has not been a problem in human patients receiving the drug, it is noteworthy that the these effects are not fully reversible with antagonists such as naloxone. Cardiovascular side effects are limited. An added advantage of buprenorphine is its ability to reverse opioid-induced sedation while maintaining analgesia. It has been recommended as the reversal agent of choice (ie, in lieu of naloxone) in patients receiving neuroleptanalgesics.
Fentanyl (Duragesic) is now also available as a transdermal drug delivery system intended for control of pain. A transdermal drug delivery system provides slow, continuous drug delivery that is intended to deliver a fairly constant plasma drug concentration. Peak and trough concentrations, which might cause toxicity and therapeutic failure, respectively, are thus avoided. The fentanyl transdermal patch system has been approved for use for control of cancer pain in people. The system consists of a patch comprised of an adhesive layer that attatches to the skin. A "release" membrane controls the rate of release of drug from the reservoir. Because the amount of drug that is released is proportional to the size (area) of the patch, the "dose" is amount of drug (in µg) released per unit time (h). The system is available in different sizes: 25, 50, and 100 µg/h Note that because the relationship between skin and patch, and the characteristics of the skin is different between dogs (or cats) and people, the rate of drug delivery (and elimination from the skin) is different. The fentanyl patch has been studied in dogs and found to be an effective means of constant, slow drug delivery with the following caveats. The time to reach "steady-state" , or therapeutic concentration of the drug approximates 24 hours, thus necessitating the anticipation of the need for shorter-term control of pain (ie, post-operative pain). Patches should be applied 12 to 24 hours prior to the anticipated need for analgesia. Likewise, after the patch is removed, a similar 24 hour period must elapse before drug is no longer detectable in the patient. Intravenous fentanyl (30 µg/kg as a "guesstimate") can be given at the time of patch application in order to "load" the patient in need of immediate analgesia. Patches that are sent home with the patient should be collected when removed from the animal in order to minimize the risk of drug abuse by pet owners. Animals occasionally take off the patch and swallow it; however, the risk of drug toxicity is minimized since it is unlikely that the close contact necessary for drug delivery will occur between the mucosa and the patch. In addition, first pass metabolism of any fentanyl that is absorbed will limit the amount of drug that reaches systemic circulation. Application of the patch requires clipping, usually in the thoracic area. A small dog, or cat, should be managed with a 25 µg/h patch; dogs weighing kg should be treated with the 50 µg/h patch; kg, the 75 µg/h patch; and dogs > kg should be treated with the 100 µg/hr patch. The rate of delivery of the patch is likely to be variable among animals; in dogs, the 50 µg/h patch delivered at a rate of 13.7 to 59.8 µg/hr. Thus, the onset and the duration of analgesia will vary with each animal. The duration of analgesia has not been determined in controlled studies, but is likely to range from several days to more than one week. Control of Pain: Local Analgesics: Bupivicaine is a local anesthetic similar to lidocaine in action but can provide analgesia lasting up to 6 hours. It has been used most commonly in small animals patients for body wall nerve blocks (eg, intracostal prior to and following thoracotomy), intrathoracically (eg, post thoracotomy or for pleuritis) and epidurally. We have splashed declaws with the drug prior to wound closure. Epidural administration of local anesthetics is also associated with myoneural and autonomic blockade which, in the case of bupivicaine, can last up to 12 hours post administration. Onset of analgesia for buprenorphine takes longer (30 to 60 minutes) but effects can last up to 36 hours. Drugs intended for epidural use should be diluted in saline (1 ml/5 kg dog). Opioids can also be diluted in local anesthetic (lidocaine) in order to achieve a rapid onset (5 to 10 minutes) of analgesia with prolonged effects. Like lidocaine, the major toxicity is seizures.
Control of Pain: Osteoarthritis. Nonsteroidal anti-inflammatories: Piroxicam is a NSAID used in humans for its potency in the treatment of inflammatory bone and joint diseases. Unlike many NSAIDs, it is chondroprotective. Reported half-life in the dog ranges from 45 minutes to more than 12 hours. Until this controversy is resolved, the drug should be used cautiously and at long intervals in dogs. Appropriate dosing regimens have not been established in the dog. The recommended dose is 0.3 mg/kg every 48 hours. In addition to its antiinflammatory effects, piroxicam has received attention as an anticancer drug due to its immunomodulatory effects. Meloxicam is similar to piroxicam, but is a selective cyclooxygenase II inhibitor and as such should not be associated with as severe effects as other NSAIDs cause. The drug is not yet available in the US. Ketoprofen (1.1 mg/kg [D] up to bid po; 0.5 mg/kg [C] po, sid) is a nonsteroidal approved for use in horses. Among the nonsteroidals, it stands out for its apparent potential ability to inhibit both prostaglandins and leukotrienes, although this benefit is still very controversial. Studies suggest that one hour after anesthetic recovery, ketoprofen is an effective post-operative analgesic. It is approved for use in cats in Europe. Scientific data regarding the use of this drug in dogs is currently not available. However, ketoprofen dose cause gastrointestinal distress at therapeutic doses in some animals; thus, caution should guide its use in dogs. Carprofen is a new NSAID recently approved l for use in dogs. Like the glucocorticoids, carprofen appears to inhibit cyclooxygenase II (COXII), the enzyme responsible for forming constitutive prostaglandins associated with inflammation. Cycloxygenase I (COXI), the enzyme responsible for the formation of constituative ("protective") prostaglandins is minimally impaired. Hence, compared to other NSAIDs, carboprofen is equally or more effective than most other NSAIDs studied in the control of inflammation, and presumably the pain associated with inflammation of OA. Carprofen also appears to be chondroprotective. Even more appealing is the safety of this product. However, although safety was supported in clinical trials, now that the drug is in wide spread use, it is apparent that gastrointestinal toxicity will occur in some animals and clients should be counseled regarding indications of gastrointestinal upset. Deaths have been reported. An idiosyncratic hepatopathy has been reported in a limited number of dogs; Pfizer is investigating this adversity. Carprofen is approved for use in cats in Europe and Canada. However, cats (and people) do not enjoy the same safety of carprofen as do dogs and its use in cats should be limited to 2 o 3 days. Carprofen should also prove useful for short term management of post-operative pain (and perhaps even pre-operative?). Meloxicam and etodolac (studied in dogs at 10 to 15 mg/kg once daily orally) are two NSAIDs approved for use in humans that also appear to be relatively selective for COX II. Etodolac appears to be particularly effective in inhibiting PGE-2 synthesized by chondrocytes and synoviocytes and was approved for once daily use. However, its half-life is similar to that of carprofen, which suggests that carprofen also may be effective once daily.
Chondroprotective Agents: A variety of other drugs have been used to control pain associated with musculoskeletal inflammation. Chondroprotective agents include those drugs or nutraceuticals which help protect the cartilage as it attempts to repair itself. Most of these drugs include some combination of chondroitin sulfates and glucosamines. Presumably, the damage cartilage uses these compounds for synthesis of PGNs, thus conserving energy. These drugs should be considered as sole agents or in combination with other drugs. It is likely that the earlier in the process they are used, the more effective they will be. A lag time to effect should be anticipated; likewise, lifelong therapy may be necessary. Their use should not be limited to DJD; rather they might be considered to support joints that have undergone traumatic, surgical or infectious injury. Animals suffering from DJD have responded favorably to Adequan, a polysulfated glycosaminoglycan. PSGAGS are used to form PGN aggregates, which provide a backbone for collagen in joints. PSGAGs not only provide replacement materials, but protect chondrocytes and inhibit inflammation, particularly that mediated by prostaglandins. Studies have shown resolution of some lesions; reports in dogs (uncontrolled studies) suggest that in some instances, DJD may be reversed. Note that other musculoskeletal diseases may be targeted with this drug (eg, OCD; trauma; etc). Use of this drug (4mg/kg IM twice weekly X 4 weeks or more) is indicated for DJD associated with any joint (including hip dysplasia). The drug has also been used effectively for some lameness in which a cause could not be identified. The drug has been used in the cat at this same dose. It is important to detect the need for and initiate therapy with the polysulfated aminoglycans early. Adequan is similar in structure to heparin and at high doses, coagulation times may be prolonged for about 7 to 8 hours after treatment. Treatment prior to surgery, particularly if coupled with aspirin, is not recommended. Otherwise there appear to be no adverse affects to this drug. Adequan was just recently approved for use in dogs.
Pentosan polysulfate is another disease modifying agent that was recently approved for use in humans.. It is derived from beechwood cellulose. It is comprised of sulfated xylanopyranoses. The drug was recently approved for use in humans for the treatment of interstitial cystitis, but has also been used to treat joint diseases associated with cartilage damage. The drug probably acts similar to PSGAGs by incorporating into the cartilage matrix. It also appears to modulated cytokines. It is apparently available both in injectable (IM or IA) or oral form. The calcium derivative of the drug has been shown to be 10 to 20% bioavailable after oral administration. In the canine Pond Nuki model of osteoarthritis, osteochondrosis dessicans and a model using fragmented coronoid process (3 mgkg IM once weekly) (both experimental and clinical trials) treatment with pentosan has been associated with more rapid recovery compared to untreated dogs, and less cartilage scarring. Like Adequan, it may lso prolong clotting times through effects on antithrombin III and platelets.
Note that tetracycines appear to inhibit metalloproteinases, enzymes important in cartilage degradation, perhaps by chelation of the divalent cations upon which metalloproteinases are dependent. Doxycycline or minocycline, lipid soluble tetracyclines, are more likely to penetrate the joint. The prophylactic dose of doxycycline is 1.75 mg/kg bid orally; when used for 8 weeks in animals subjected to cruciate ligament transection, damage to the cartilage was less than untreated dogs.
Nutraceuticals represent the newest "drug" therapy for treatment of DJD in dogs and cats. The term nutraceuticals has been recently coined to denote those products that are administered in the diet, but have a potential therapeutic (and toxic?) benefit. However, they can not be labeled as such without FDA approval. There are many nutraceuticals with therapeutic (illegal?) claims, many of which have no foundation. However, some food additive precursors such as glycoflex and flexagen have been used by many veterinarians or pet owners with some evidence (subjective) of benefit. Nutramax has several clinical studies ungoing supporting the use of their product, Cosequin. Other more questionalbe products include the mussel mucopolysaccharides/mixed glycosaminoglycans/chelating metals/etc found in Glyco-flex (VetrScience Laboratories, 20 New England Drive, Essex Junction, VM, 800 882 9993. These products are administered as precursors of the cartilage matrix. Presumably, as precursors, they are "picked up" and used by chondrocytes - which would otherwise use a lot of energy to synthesize these products - for repair of damaged cartilage. Flex-A-Gan (MSM or methylsulfonylmethane) is a naturally occurring metabolite of DMSO that has also received attention as a food-additive for control of musculoskeletal inflammation. As a metaboliteof DMSO, its advantage is primarily that of scavenging oxygen radicals which might be contributing to the inflammatory process.
HEMOPOIETIC
A number of recombinant factors are being made commercially or experimentally available. Products that have been studied in animals include erythropoietin granulocyte CSF, macrophage CSF, hormones, (insulin, growth hormone,) and immune modulators such as interferon, tumor necrosis factor, and interleukins. It is important to remember that most are proteins, or peptides 600 to 100,000 daltons in size. Parenteral administration (they are not orally bioavailable intact) may be associated with a rapid half-life and immunogenicity among the species. Recombinant human, canine and bovine products have been made. In general, canine recombinant products appear to be less antigenic in cats compared to human products.
Erythropoietin. Recombinant human erythropoietin (100 U/kg SC 3 X each week until response [4-12 weeks] then 50 to 75 U/kg as needed to maintain HCT at 30% [D] to 25% [C])is available as a formulated product (EPOGEN; AMGEN Inc, Thousand Oaks, CA; Procrit, Florida Infusion). The drug is indicated only in cases of EPO deficiency such as may occur with chronic renal disease and selected neoplasms. Antibodies may occur in greater than 25% of patients, destroying endogenous as well as exogenous EPO, thus leading to a more profound anemia. Once antibodies develop, the drug must be discontinued and can not be started again. White blood cells and platelets do not seem to be affected. Most patients also improved clinically (ie, appetite increase, improved hydration). Iron supplementation is indicated. Hypertension should be resolved prior to initiation of therapy and potentially hypertensive animals should be closely monitored. Granulopoietin (5 µg/kg sc sid to bid for 2 to 3 days or as needed to maintain WBC) has been studied in both dogs and cats. rh-CSF increases neutrophils within 12 hours and the increase persists for 2 to 3 weeks. rc-CSF in dogs and cats increases wbc day 1 through 19 of cyclic neutropenia, or cancer chemotherapy. However, antibodies are often present by day 23. The canine recombinant product is much less likely than the human recombinant product to cause the formation of antibodies in cats. Indications for bone marrow stimulation have ranged from iatrogenic bone marrow suppression associated with anticancer chemotherapy agents to resolution of leukopenia (neutropenia) in parvo puppies. The human drug is not generally available, but apparently can be purchased. It is, however, expensive (see AMGEN above).
Oxyglobin® (Biopure Corporation:www.oxyglobin.com) is a hemoglobin-based oxygen carrying fluid derived from polymerized bovine hemoglobin. It increases plasma and total hemoglobin concentration and thus increases arterial oxygen content. Conditions studied in controlled canine clinical trials included immune mediated hemolysis (n=30), blood loss (gastrointestinal, traumatic, surgical, rodenticide intoxication) (n=25), and ineffective erythropoiesis (idiopathic, red blood cell aplasia, ehrlichiosis) (n=9). Relative to pre-treatment, plasma hemoglobin concentration significantly increased (p = 0.001) and clinical signs associated with anemia (lethargy/depression, exercise intolerance, and increased heart rate) significantly improved (p = 0.001) following treatment with Oxyglobin. Treatment success was defined as the lack of need for additional oxygen carrying support (i.e., blood transfusion) for 24 hours following the completion of infusion with Oxyglobin. Success in the treatment group was 95% compared with 32% in untreated control dogs.
Because it is a free solution (rather than in red blood cells), antibody formation generally associated with administration of intact red blood cells is avoided. However, antigenicity to bovine hemoglobin may result in antibodies. Repeated administration of the product apparently has not been studied. Because it is a foreign protein, anaphlyactic reactions are possible. The elimination half life of the drug (it is eliminated like hemoglobin by reticuloendothelial cells) in dogs is estimated to range between 30 and 40 hours. As such, 90% of the drug will be gone within 5 to 7 days after infusion. As a protein, the compound provides oncotic draw and its use in patients already suffering from volume overload (eg, congestive heart failure) or in cases of accidental overdose ( >10 mL/kg/hr) can be associated with circulatory overload and its negative sequelae (eg pulmonary edema, pleural effusion, increased central venous pressure, dyspnea, or coughing). Oxyglobin® will mildly decrease PCV immediately post infusion and an increase total and plasma hemoglobin concentration for at least 24 hours. PCV and RBC couns will not be accurate measures of anemia for 24 hours following administration. Adequate hydration is important,but overhydration should be avoided because of the to the plasma expanding properties of Oxyglobin®. Administration of other colloidal solutions should be avoided. Oxyglobin has an average MW of 180 kD, with 50% of the hemoglobin polymers between 65 kD and 130 kD. As such, it has colloidal properties similar to dextran 70 and hetastarch. However, because it is a polymerized hemoglobin, the molecules are much larger than hemoglobin, and the compound is not likely to be filtered by the kidney (thus, avoiding renal side effects of hemoglobinuria). The most likely side effect is circulatory volume overload. Central venous pressure (CVP) or clinical signs indicative of circulatory overload should be monitored during and immediately following administration of Oxyglobin®. Transient changes or side effects reported by Biopure Corporation following administration of Oxyglobin include: yellow-orange discoloration of the skin, sclera and gums, red-dark-green discoloration of feces, brown-black discoloration of urine, vomiting, diarrhea, and decreased skin elasticity occurred within 48 hours of dosing. The frequency and/or intensity of these clinical signs were dose dependent. The product is intended as a one time use only at a recommended dosage of Oxyglobin® dose of 30 mL/kg IV at a rate of up to 10 mL/kg/hr. Oxyglobin® may be warmed to 37° C prior to administration. It can not be frozen but is stable for 24 months. It is approved for use in dogs, but apparently has been studied in cats. The price will be about $30/kg, although animals may not the full 30 ml/kg.
ENDOCRINE
Ipodpate is a biliary radiocontrast agent that apparently is useful for short term control of hyperthyroidism at a dose of 15 mg/kg PO bid. Its actions are probably similar to iodine (Lugol’s etc, causing impaired synthesis and or release of thyroid hormones. Iodoine uptake appears to be reduced and T4 conversion to T3 may be decreased. However, the effects of hyperthyroidism will become refractory s in several months.
Although diethylstilbesterol products have been removed from the market, DES itself apparently is still available. Compounding pharmacies apparently can obtain the drug and recompound it into useable form. Recommendations through internet etc have included the use of Premarin (a conjugated estrogen human product) in lieu of DES. However, Premarin is steroidal in action whereas DES is not, suggesting that safety issues may be a concern. It is the author’s recommendation to avoid any estrogen products until safety has been documented. Phenylpropanalomine or the tricyclic antidepressant are alternatives that might be considered.
Hyperadrenocorticism. Deprenyl has been approved for use to treat pituitary-dependent hyperadrenocorticism in dogs. The mechanism (presumed) is correction of dopamine "deficiency" in the pituitary and return to the normal hypothalamic pituitary adrenal axis. As such, adrenal destruction typical of mitotane does not occur. Based on clinical signs and corticol measurements, up to 70 to 80% of animals can be expected to respond (1 to 2 mg/kg orally once daily). However, not all animals will sufficiently respond; therapy may need to be life long, and the disease may eventually progress to the point that traditional organophosphate therapy must be implemented. The major advantage of deprenyl may be in offsetting the time to administration of more dangerous drugs. The manufacturer suggests that ACTH and low dexamethasone response testing are not necessary. Clinical signs may not resolve for 4 to 6 months.
Diabetes Mellitus. Oral hypoglycemics, including the sulfonylureas and biguanidines, are used in humans with non-insulin-dependent diabetes mellitus. The sulfonylureas reduce hyperglycemia by: stimulating beta cells to secrete insulin; increase insulin effects in the liver and on carbohydrate transport in muscle and fat; and decrease hepatic glucose output. Glipizide is a sulfonylurea that has been studied in cats suffering from non-insulin dependent diabetes mellitus. Glipizide (5-10 mg po bid in dogs; 5 mg bid in cats; monitor glucose, particularly if used in conjunction with insulin) can be tried in cats with mild to moderate persistent hyperglycemia. It is contraindicated in ketosis or pancreatic beta-cell failure. However, it has been used in conjunction with insulin in animals non-responsive to insulin in order to increase receptor sensitivity to insulin (ie, patients with hyperaddrenocorticism or on glucocorticoids) Side effects include hypoglycemia, and vomiting. Note that the use of this drug may (it is currently being studied) contribute to continued pancreatic failure due to amyloid deposition. 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, enzymes degradation of complex, oligo, di, trisaccharides is inhibited and glucose absorption is decreased. Post prandial hyperglycemia is minimized. Indications in people 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%). These clinical signs tend to resolve once accommodation of flora) has occurred. Hypoglycemia is not a sequelae. The use of this product in animals has not been establisihed; the dose in people is 25 mg) with each meal. Metaformin (Glucophage) is a newer hypoglycemic agent approved for people, being studied in cats. In humans, it increases sensitivity to insulin decreases hepatic glucose formation, but does not increase insulin release. Thus, it does not increase insulin secretion thus may not cause beta cell exhaustion or amyloidosis. PZI insulin is generally the preferred insulin for use in the cat. However, it was withdrawn from the market, and after a brief reemergence, was re-withdrawn due to quality control manufiacturing issues. For difficult to control cats, it can be formulated by pharmacies (Blue Ridge Pharmacy Raleigh, North Carolina; beef- pork (919)-781-7986 or 800-374- 8006 @ $65 per vial plus shipping, or IDEXX 1-888 794 3399@ $35 per vial plus $7 /shipping. Generally shipped as 10 ml of 40 units). Other insulin preparations (usually, Ultralente) will need to be used if PZI can not be acquired, although its use is perhaps less successful than in the cat. Removal of all non-human recombinant insulin products may ultimately occur. Human ultalente insulin may be more potent in cats, thus necessitating a lower dose. If difficulty is encountered in controlling an animal, resolution of clinical signs (rather than normalizing glucose) may be a more reasonable target. The diluents used for insulin are pH adjusted. These are provided free of charge by the manufactures, and are preferred to water or saline which may alter the shelf-life of the insulins. Diluted insulin should be replaced every 2 to 3 months. Although refrigeration is not necessary, it is recommended.
Diabetes Insipidus: Vasopressin which has only been available as a nasal spray (give subconjunctivally) is now 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.
Urinary Incontinence: Since diethylstilbesterol has been removed from the market, Premarin, a conjugated estrogen, has been recommended as its replacement (0.625 mg for a 60 lb animal). We strongly discourage use of this compound which is different in structure and potentially action compared to DES (a nonsteroidal compound). Several veterinary pharmacies can compound DES for your patients.
DERMATOLOGIC
Cyclosporine is a T-cell specific immuomodulator that is approved for use in humans for immune suppression of graft vs host transplant rejection, autoimmune disorders, keratitis sicca and red cell aplasias. A recent placebo controlled clinical trial provides strong evidence that the drug is a non-surgical alternative to treatment of perianal fistulas in dogs. When given at a dose (as little as 3 to mg/kg but up to 5 to 109 mg/kg; orally daily) which maintains trough concentrations at 400 to 600 ng/ml, improvement occurred in all treated animals within 4 weeks, with resolution in 85% of the dogs occurring by the 16th week of treatment. Trough concentrations as low as 100 ng/ml may be effective. Recrudescence of the syndrome appears to occur in a small number of animals, with subsequent retreatment apparently effective in resolving the lesions. Misoprostol, a PGE analogue has been studied for treatment of chronic pruritis. 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. Cyclosporine also is being studied for treatment of chronic pruritis.
GASTROINTESTINAL
Apomorphine is back on the market, but is very expensive ($25.00/capsule)?. If reformulation is possible, a 1 gm vial of power can be purchased at PCCA (a compounding group in Houston; 1-800-331-2498) for about $100. However, you must do this through a pharmacy which is a member of PCCA (many are; just ask your pharmacist). (Note, that reformulation may not be necessary if the drug is being applied topically).
Selected anticancer drugs which induce emesis in humans responds to antiserotonergic drugs. Isolated reports have suggested that antiseratonergics such as cyproheptidine (Periactin) : 1mg/cat, po, sid will resolve some cases of vomiting, particularly that mediated by the CRTZ (ie, blood-borne chemicals) in dogs. These drugs are also being used to treat some cases of anorexia in cats and, in humans, are proving useful for the treatment of selected diarrheas. Ondansetron is another antiserotonergic anti-emetic. This drug is used in human patients to control emesis associated with cancer chemotherapeutic agents. We have had luck with this drug in controlling refractory vomiting associated with cancer chemotherapy, some parvoviruses, and other non-responsive vomiters (dose 1 mg/kg PO; or 0.5 mg/kg loading dose followed by 0.5 mg/kg IV infusion per hour). This drug is expensive.
Prokinetic drugs facilitate gastrointestinal motility. Cisapride (0.16-1.25 mg/kg po tid (d); 2.5/5/10 if <11/11-40/>40 lbs tid po [d]; 0.5 mg/kg po tid [d]: TTams, ACVIM 1994) is a prokinetic drug currently under investigation in animals. Like metaclopramide, it is a prokinetic; but unlike metaclopramide, it is effective throughout the gastrointestinal tract. As such, it may prove to be useful for megacolon and megaesophagus.It does not penetrate the blood-brain barrier, and thus does not have any central antiemetic efficacy. Remember that metaclopramide acts centrally to antagonize dopamine and peripherally to potentiated actetylcholine. Its central effects can alter several endocrine feedback loops (eg, patients with Cushing’s disease or diabetes mellitus) and can lower seizure threshold. Use of cisapride is indicated in these patients. Neither metaclopramide nor cisapride should be used in conjunction with anticholinergics.
Gastrointestinal Ulceration. Treatment of gastroduodenal ulceration is usually oriented towards protecting the mucosa (sucralfate) and decreasing gastric acid secretion. Histamine (H2) receptor antagonists, and particularly cimetidine, have been used most consistently. Ranitidine, although more expensive, is more potent, can be administered twice dailey (0.5-1 mg/kg po bid) and is associated with fewer drug interactions. Famotidine can be administered once daily (0.5-1.0 mg/kg PO, IV bid to sid). Omeprazole is a benzimidazole antacid. The mechanism of action reflects inhibition of the K+/H+ ATPase pump in the gastric parietal cell. Thus, it will inhibit gastric acid secretion regardless of the cause. It is the most potent and may be the most effective antacid drugs. Because it accumulates in the parietal cell, effects will continue after the drug has been discontinued; in addition, the drug need be administered only once a day. However, maximum efficacy may be delayed (7 days compared to 2 days for H2 antagonists). (0.7 to 2 mg/k po q 12 to 14 hrs). Currently, indications for the use of omeprzole in dogs include gastrinomas, mast cell tumors, unresponsiveness to H2-receptor antagonists, esophagitis, and Helicobacter pylori (felis) infections. Gastric hypertrophy, a sequelae of increased gastrin levels, may be an undesireable side effect. Prostaglandin E2 (Misoprostol) is a synthetic prostaglandin analogue used to treat gastrointestinal ulceration. Prostaglandins impart a protective effect on the gastrintestinal mucosa by increasing mucus and bicarbonate excretion, limiting gastric acid secretion, increasing mucosal blood flow and enhancing mucosal epithelialization. Although Misoprostil (2-5µg/kg po bid) might be indicated for the treatment of ulceration regardless of the lesion, specific indications would include prophylaxis or treatment of ulcerations induced by nonsteroidal anti-inflammatories; mucosal erosion accompanying liver disease may also respond to prostaglandin E2. Side effects include gastrointestinal cramping and diarrhea. Although sucralfate is not a new drug, it is noteworthy to note that its use is indicated not only for its "band-aid" effects on damaged mucosa. In addition, it is able to stimulate local prostaglandins, scavenge oxygen radicals and to promote angiogenesis, all of which are critical to promotion of healing in the damaged mucosa. Helicobacter felis, like Helicobacter pyloris in humans, may play a role in gastrointestinal ulceration. Treatment is oriented toward increasing gastric pH with antisecretory drugds (ie, omeprazole or ranitidine); and antibiotics effective against the organism (metronidazole; amoxicillin; teteracyclines). Current triple therapy includes omeprazole, clarithromycin and amoxicillin. Bismuth compounds act to disrupt the integrity of bacterial cell walls and can be an effective part of combined therapy (used as bismuth subsalicylate).
Chronic Hepatitisis. Ursodeoxycholic acid (UDCA) is a natural bile acid constituting a very small portion of the bile acid pool. It is a degradation production of chenodeoxycholic acid. Among the bile acids, UDCA has the lowest hydrophobic-hydrophilic balance, the lowest capacity to make micelles, and the least potential for cholestatic or cellular membrane toxicity. Since cholestatic liver disease may be associated with accumulation of toxic bile acids, treatment with UDCA is appealing. Its efficacy in a variety of chronic liver diseases has been established. Its mechanism of action is not well understood but is probably related to bile acid metabolism. The use of UDCA in dogs suffering from selected cholestatic liver diseases has been documented. The disposition of UDCA has been studied in healthy cats. Sporadic vomiting and diarrhea were reported, but otherwise the drug appears to be safe. Scientific studies establishing its safety and efficacy in diseased animals are indicated.
S-Adenosyl-L-Methionine (SAMe) is another 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. Recently, an abstract has reported the protective effect of a combination of both of these compounds, compared to either alone, on hepatocytes.
RESPIRATORY SYSTEM
Theophylline is currently available in slow release preparations that allow twice daily dosing in dogs and potentially 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). Note that the bioavailability of these products vary. 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.
In humans, N-acetylcysteine is the most widely used mucolytic drug. While it appears to be efficacious following aerosolization, more recently, oral administration has become the preferred route. In Europe, the drug is available in solid and powder dosing forms. Unfortunately, only the solution, which is unpalatable and malodorous, is approved for use in the United States. Regardless of the route of administration, the mechanism of acetylcysteine reflects destruction by the free sulfhydryl group of the disulfide bonds of mucoprotein. Smaller molecules are less viscid and not able to efficiently bind to inflammatory debris. In addition, 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. At higher oral doses, acetylcysteine will also induce vomition. Acetylcysteine is often used in combination with aerosolized antimicrobials because it may improve antibacterial penetration of infected mucus. Acetylcysteine improved air exchange in a study of dogs with experimentally induced methacholine bronchoconstriction. In humans, acetylcysteine is rapidly absorbed from the gastrointestinal tract and extensively distributed to the liver, kidneys and lungs, where it may accumulate. It is rapidly metabolized by the liver to cysteine and cystine. The indications for oral acetylcysteine therapy in people include 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. Acetylcysteine therapy is associated with few adverse affects. In humans, doses as high as 500 mg/kg are well tolerated, although vomition and anorexia can occur. In animals, the dose for acetaminophen toxicity can be tried for respiratory disease (140 mg/kg PO or IV as 5% [50 mg/ml] followed by 70 mg/kg q 4 [8 to 12?]; a 20% [200 mg/ml] solution can probably be given orally). Because it is metabolized to sulfur containing products, it should be used cautiously in animals suffering from liver disease characterized by hepatic encephalopathy. Aerosolization of N-acetylcysteine can cause reflex bronchoconstriction due to irritant receptor stimulation and should be preceded with bronchodilators.
Zafirlukast (Accolate®), Zileuton (ZyfloTM) represent a new approach to the treatment of asthma in humans. These drugs are specific lipoxygenase inhibitors (zileuton) (as opposed to cyclooxygenase inhibitors) or leukotriene receptor antagonists (zafirlukast) and , thus inhibit formation of or the actions of leukotrienes. LTs are very potent causes of inflammation in the lungs, causing marked edema, inflammation, bronchoconstriction Since feline asthma is very similar to human asthma, these drugs may be useful for treatment thereof. However, they do not target other mediators of pulmonary inflammation. They may also be useful in dogs with bronchial (or lung?) diseases associated with inflammation. The drugs have not yet been studied in animals but currently are being used at in both dogs and cats (Accolate: 0.15 to 0.2 mg/kg po 12 to 24 hours).
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
Enalapril is an angiotensin converting enzyme inhibitor used to reduce afterload in patients suffering from congestive heart failure. In patients in which cardiac reserve threatens renal perfusion, renal disease may be more likely as therapy is begun if the increase in cardiac output caused by afterload reduction is not sufficient to compensate for renal afferent arteriolar dilation. 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. 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 po). Note, however, with the availability of a veterinary labeled product, legal justification for the use of lisinopril or ACE inhibitors other than enalapril is limited. Benazepril and its active metabolite, benazeprilate offer another example. The metabolite is much more active than parent drug. In contrast to other ACE inhibitors, these drugs are not renally excreted. Dose is 0.25 to 0.5 mg/kg orally, once daily. Another indication of ACE inhibitors 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.
Amlodipine is a calcium channel blocker that , like nifedipine, has effects predominantly on smooth muscle vasculature rather than cardiac muscle. Its peripheral actions include decreased total peripheral resistance and thus it is indicated to treat hypertension, particularly that not associated with the neurohumoral responses accompanying congestive heart failure (ACE inhibitors are recommended for CHF). At a dose of 0.625 mg/kg bid orally, patients should be monitored to guide therapy using a targeted pressure of < 150 mm Hg. Other indications include mocardial failure associated with a lack of response to enalapril, and i ntolerance to diuretics. When combined with other therapies it should be used at a dose of 0.1 to 0.2 mg/kg sid to bid. Studies comparing its efficacy to enalapril in cats with primary hypertension or hypertension associated with renal disease are currently underway.Note that the drug does not impact the renin-angiotensin-aldosterone system and will not combat compensatory sodium-water retention in CHF.
The treatment of hypertrophic cardiomyopathy traditionally has focused on the use of beta-blockade in order to decrease cardiac rate and contractiliy. Propranolol, a non-selective beta-blocker is the most commonly used drug. However, respiratory distress may be worsened by blockade of beta2 receptors in the respiratory tract. Diltiazem (0.5 to 1.5 mg/kg po [D]; 1.75 to 2.45 mg/kg bid to tid po [C]; note that the drug is metabolized by acetylation which is deficient in the dog but not the cat) a calcium channel blocker that decreases cardiac contractility, improves cardiac compliance and distensibility and decreases myocardial oxygen demand. Heart rate may also be decreased. The drug can also be used in dogs with congestive heart failure associated with tachycardia if digoxin has not sufficiently slowed the heart rate. Two preparations are available to facilitate ease of administration. Diltiazem CD can be given at a rate of 10 mg/kg once daily orally. Diltiazem XR is prepared as a capsule which containes 4 60 mg pellets (total 240 mg capsule). Cats can be dosed by removing one of the pellets and administering half of the pellet once daily. An IV preparation of diltizem is also available for emergency life threatening supraventricular tachycardias (0.2-0.4 mg/kg IV followed by 0.4 mg/kg/min). Diltiazem is recommended in lieu of propranolol particularly in cats not responding to propranolol, or cats suffering from respiratory distress. If hypertrophy is asymmetric (IVS>LVFW), the outflow path from the left ventricle may be partially obstructed. Beta-blockers are indicated if outflow obstruction is present. Atenolol ([C] 12.5 mg sid po, increase 50% or go twice daily if heart rate does not slow sufficiently; treat on an individual basis) is a selective beta 2 blocker indicated in cats with outflow obstruction and respiratory distress. It may be preferred to diltiazem if the patient's heart rate is elevated. Studies suggest that the drug probably should be given twice a day rather than once daily.
ANTIMICROBIALS
Enrofloxacin is now labeled as once daily therapy (2.5 to 20 mg/kg once or divided twice daily). Note that a culture and susceptiblity information is not likely to reflect new breakpoints based on the higher dose. The higher dose is indicated for difficult to penetrate tissues, particularly involving infections with Pseudomonas aeruginosa and other problematic infections. The efficacy of enrofloxacin is enhanced by metabolism to ciprofloxacin. Orbafloxacin is also labeled for once daily therapy. Difloxacin is the newest flourinated quinolone approved for use in dogs. Compared to the other FQ’s, its volume of distribution appears to be slightly larger (3.8 l/kg). However, when comparing tissue to serum ratios, it does not appear that difloxacin distributes into tissues any better than enrofloxacin. Difloxacin is eliminated in the bile and undergoes enterohepatic circulation thus prolonging its half-life. However, the fluorinated quinolones are concentration (not time dependent), thus enhanced prolonged half-life probably does not contribute to antimicrobial efficacy. Note that the data that describes efficacy of difloxacin against Pseudomonas is based only on an n of 5. Also note that technical monographs are comparing the drugs based on drug concentrations . However, comparisons should be based not on similar doses, but on the relationship between dose, plasma drug concentrations and breakpoint MIC. For example, athough 2.5 mg/kg may generate higher PDC of orbifloxacin compared to enrofloxacin, a higher concentration of orbifloxicin is necessary for antimicrobial efficacy. For example, the breakpoint of enrofloxacin is 2.0 µg/ml but for orbifloxacin, it is approximately 4 µg/ml. The breakpoint MIC of orbafloxacin is approximately twice that of enrofloxacin, suggesting that plasma drug concentrations should be twice as high for orbafloxacin compared to enrofloxacin for equal efficacy. Thus, a dose of 2.5 mg/kg of either drug will result in peak PDC that are approximately half of the breakpoint, suggesting that a similar dose provides equal efficacy regardless of differences in PDC. Importantly, note that orbafloxacin’s distribution to tissues does not appear to be as good as that of enrofloxacin and difloxacin; also, efficacy against gram-negative organisms (based on MIC 90 compared to tissue concentrations especially for Pseudomonas) also appears to be less for orbafloxacin. The spectrum of the FQ’s is essentially the same, and patterns of resistance are likely to be similar.
Current research in humans (and to a lesser degree in veterinary patients) indicates that once daily dosing of aminoglycosides (gentamincin or amikacin) probably should be the rule (or a maximum of twice) rather than three times daily dosing of amikacin. The rationale is based on the efficacy of the aminoglycosides correlating more closely to the ratio of maximum plasma concentrations compared to the MIC; and the safety of the drugs being positively correlated to low plasma drug concentrations occurring sometime during the dosing interval. Recommendations are to give the same daily dose, but at less frequent intervals. Ceftiofur is a third generation cephalosporin. However, unlike many other third generation cephalosporins, it is not effective against many problematic gram-negative organisms, including Pseudomonas. In addition, unlike most cephalosporins, it is not predictably effective against Staphylococcus sp and use in such infections that are serious, life threatening or chronic should be based on culture and susceptibility. Finally, the approved dose is for urinary tract infections. Because the drug concentrates in the urine, urine concentrations are much much higher than soft tissue concentrations will be. Thus, the 4.4 mg/kg dose may be insufficient for many infections. Safety of the drug at higher concentrations has not been established and unsubstantiated reports of blood dyscrasias indicate caution in using the drug in an extralabel fashion. However, in its favor, ceftiofur is metabolized to an active metabolite, thus prolonging the duration of effective drug concentrations which is important for beta-lactam antibiotics. Imipenem/cilastin is a beta-lactam antibiotic (beyond the penicillins) effective against gram positive and gram negative, aerobic organisms. It has excellent tissue distribution. MICs are generally less than 0.05 µg/ml. It can be used intravenously or parenterally (IM) (2.0 to 7.5 mg/kg up to tid). Its use should probably be reserved for life threatening situations. All are susceptible to destruction by beta-lactamases. Azithromycin and clarithromycin are macrolide antibiotics similar to erythromycin in its actions and spectrum. Their spectrum includes Gram positive organisms such as Streptotoccus and Staphylococcus, selected Gram negative organisms, including Bordatella. Selected Chlamydia organisms are also included in its spectrum. Advantages compared to erythromycin include longer elimination half-life and larger distribution volume, due primarily to great accumulation in tissues. Azithromycin is characterized by close to 100% bioavailability following oral dosing in the dog, but approximately 50% bioavialability following oral dosing in cats. Twenty-four hours following a dose of 5 mg/kg, plasma concentrations of parent drug and its metabolite approximate 1 µg/ml, but tissue concentrations range from 1.2 µg/ml (brain) to approximately 50 µg/ml (bile). Concentrations in the lung approximate 18 µg/ml and bone 12 µg/ml. The breakpoint MIC for azithromycin is > 2 µg/ml, thus concentrations substantially higher than the MIC are achieved in most tissues in the cat following 5 mg/kg orally. The time course of drug in tissues is complicated, but concentrations decline little in cats for 72 hours following administration. Azithromycin has been used in catteries at 5 mg/kg every 7 days orally. The dose for dogs is 10 (to 40) mg/kg orally a day. Doses of clarithromycin in dogs range from 2.5 to 10 mg/kg bid po. Silver sulfadiazine is an It is effective against gram positive, gram negative, and yeast organisms used to prevent/ or treat wound sepsis associated with burns in people. Because the spectrum includes Pseudomonas aeruginosa it may be useful for "last ditch" effort treatment for otitis externa. The ointment should be dilute with water to usable consistency and used to pack cleaned ears twice daily for 3 weeks.
Cefpodoxime is an orally bioavailable 3rd generation cephalosporin that is a pro-drug. Its spectrum includes gram negative ( most Enterobacteriaceae but not Pseudomonas), and Gram positive but not anaerobic organisms. As with many cephalosporins, it is relatively resistant to beta-lactamases destruction. It may be superior to Clavamox but inferior or equal to enrofloxacin in its spectrum. Like most beta-lactams, it is eliminated in the kidneys. Side effects which occur in up to 15% (humans) are gastrointestinal. The drug appears to be safe in dogs (5 to 10 mg/kg bid). Cefixime is an orally bioavailable 3rd generation cephalosporin related to ceftizoxime. It also is beta-lactamase resistant with a spectrum which includes Gram negative organisms, but with no efficacy against Pseudomonas and, unlike many cephalsporins, a poor efficacy against Staphylococcus. Absorption is impaired by food and it is highly protein-bound leading to a relatively long half-life (a preferred characteristic of beta-lactam antibiotics). The drug is renally excreted. Indications in people include UTI and respiratory tract infections. Doses of 5 mg/kg once to twice daily have been recommended in dogs. Dapsone is an antibacterial used in people to treat atypical mycobacterium infections. Leprosy is generally associated with granulamatous inflammation and dapsone may have modulatory effects on the inflammatory component. In addition, in humans, it is used at 0.7 to 1.1 mg/kg bid to treat Brown recluse spider bites.
Amphotericin still is the most efficacious antifungal drugs. However, its nephrotoxicity is notorious. Alternative delivery systems have been designed to reduce toxicity without a loss in efficacy. Newer preparations include liposomes (Ambisome®), colloid dispersion (Amphocile®) and lipid complexes (Intralipid®). The dose is mixed with 35 ml of 20% solution which is infused over two hours. Subcutaneous adminstration has also been described for the standard amphotericin B solution; however, while the product appears to be safer, efficacy has not been established using this route. Among the imidazole antifungal drugs, the indications for ketoconazole are limited only because itraconazole and fluconazole are better choices. The latter two tend to be equally efficacious. Exceptions include CNS infections because fluconazole penetrates the BBB better; and for treatment of aspergillosis, itraconazole is preferred. Treatment of coccidiodomycosis will require higher doses of either drug (10mg/kg twice daily).
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