S-adenosyl-L-methionine

S-adenosyl-L-methionine (SAMe) is an endogenous coenzyme composed of ATP and the sulfur-containing amino acid methionine. The methyl group attached to the sulfur of methionine is chemically reactive such that it can be donated (i.e., transmethylation) to a number of acceptor substrates. Up to 80% of methionine in the body is used to form SAMe in the liver, which is the major, but not sole, site of methylation reactions. Regeneration of SAMe depends on vitamins B₆ and B₁₂ and folic acid.¹⁷⁵ Transmethylation represents the primary function of SAMe, although sulfhydryl (transulfation) and aminopropyl (aminopropylation) groups also are donated. As such, SAMe is involved in more than 40 metabolic reactions in the body. Substrates are variable and include nucleic acids, proteins, and lipids. SAMe donates methyl groups to diverse compounds such as choline, creatine, carnitine, norepinephrine, DNA, and transfer RNA.

Aminopropylation yields compounds that affect cell and tissue repair. Transmethylation is important in detoxification, energy utilization, gene transcription and membrane functions that influence growth, and cellular signaling and adaptation. Transmethylation is necessary for formation of the phsopholipid bilayer of outer cell membranes and membrane fluidity. After donating its methyl group, SAMe is converted to S-adenosylhomocysteine, the precursor to transsulfuration reactions. Transsulfuration also is important, resulting in the formation of sulfur and thiolated compounds, glutathione (GSH; one of the principle antioxidants of the liver), cysteine (the rate-limiting substrate for GSH formation), and sulfates. Each is particularly important in detoxification and conjugation reactions, including bile conjugation and bile flow. Glutathione has many additional effects on cellular biology, including gene transcription, triggering proinflammatory cell signaling and apoptosis, and also is important as an intracellular scavenger of oxygen radical.

The importance of SAMe in GSH synthesis suggested a possible role in liver disease. Studies in humans have demonstrated that SAMe is associated with an increase in hepatic GSH in chronic liver disease. Bile flow increases, presumably in response to increased sulfate bioavailability; sulfated bile acids are more soluble than others. Lieber¹⁷⁵ reviewed the role of SAMe in the body and its role in the treatment of liver disease in humans.¹⁷⁶ In an original research report, Center and coworkers¹⁷⁷ also reviewed the role of SAMe, with an emphasis in the liver. Multiple hepatic functions are dependent on GSH. Howver, SAMe formation from methionine decreases with severe liver disease as a result of downregulation of SAME synthetase. Sequelae include impairment of multiple hepatic functions as well as retention of methionine, which may contribute to hepatic insufficiency.

Because SAMe is unstable and is destroyed in the GI tract, it must be administered as an enteric-coated product. After absorption, oral bioavailability of SAMe is low on account of first-pass metabolism. Gender differences in oral bioavailability exist for SAMe in humans, with peak concentrations threefold to sixfold higher in women compared with men. SAMe is minimally bound to serum proteins (in humans) and is able to penetrate into and accumulate in cerebrospinal fluid.¹⁷⁴

A case report¹⁷⁸ described the successful treatment of acetaminophen overdose (1 g/kg) in a dog with SAMe and supportive care; treatment was not begun until 48 hours after ingestion. Center and coworkers¹⁷⁷ examined the safety and effects of SAMe on the redox potential in red blood cells and the liver in normal, healthy cats (n=15) receiving 48 mg/kg of SAMe (Denosyl) orally once daily for 113 days. Plasma SAMe concentrations increased in concert with each dose. Peak concentrations approximating 1 to 1.5 μg/mL occurred between 2 to 4 hours after each dose; the disappearance half-life after oral dosing approximated 3 hours. Concentrations did not accumulate during the 113-day dosing period. Unmetabolized SAMe appears to be eliminated almost equally in urine and feces. In humans and normal cats, SAMe was not associated with adverse events. In clinically normal cats, the redox status of both red blood cells and hepatocytes was increased after 113 days of SAMe administration. Further, red blood cells became more resistant to osmotic lysis. Hepatic cysteine, GSH, and protein increased, the latter attributed to an anabolic effect of SAME. Bile flow also increased, and histologic improvement was noted in the seemingly normal cats that had asymptomatic nonsuppurative portal inflammation.

SAMe is among the supplements for which comparison of labeled and actual contents may not match. The hygroscopic nature of SAMe contributes to quality assurance issues in that improper formulation and storage can result in the loss of active ingredient. The lack of premarket approval suggests that consumers should take a proactive approach to ensuring the quality of purchased products. Manufacturers appear to have improved the predictability of high-quality product in that eight of eight manufactured products tested by Consumer Laboratories and reported on its website in 2007 passed evaluation (as of January 2010). This compares to 2003, in which one product was found with only 30% of its listed amount, and in 2000, when close to 50% of tested products contained less than the labeled content (www.consumerlab.com). Enteric-coated products are available to protect SAMe from GI acidity; among the tests implemented by Consumer Laboratories is assurance of proper dissolution of enteric-coated products.

SAMe is available in several salt forms, each of which weighs a different amount and thus contributes variably to the total weight in mg. Care should be taken to dose on the active ingredient (i.e., SAMe). Salts include tosylate, disulfate tosylate, disulfate ditosylate, and 1,4-butanedisulfonate (Denosyl). For example, 200 mg of S-adenosyl-methionine disulfate tosylate contains only 100 mg of SAMe. The salt name should be included on the label as part of the chemical name, and the label should indicate the amount of active ingredient. SAMe also can be reviewed in the Herb and Plant Supplement at consumerlab.com¹⁷⁹

SAMe may be involved in a number of drug–diet interactions. Because it inhibits uptake of serotonin, any other compound that does likewise should be avoided or used cautiously. This includes antidepressant behavior-modifying drugs such as monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, tricyclics, tramadol, and selected herbs (such as St. John’s wort).

Animal studies and clinical human studies indicate that SAMe improves biochemical parameters of liver function.¹⁸⁰

Endogenous concentrations are reduced in patients with cirrhotic liver disease. Production of sulfated compounds and phosphatidylcholine subsequently is reduced. In animal studies SAMe improved bile secretion impaired by a variety of toxins and by pregnancy. Drug-induced hepatotoxicity and chronic liver disease were also reduced, without occurrence of serious side effects.¹⁷⁶ SAMe may act synergistically with UDCA for treatment of chronic progressive liver disease.¹⁸¹ Although absorbed well after oral administration, SAMe undergoes extensive first-pass metabolism.¹⁸⁰ The compound is so hygroscopic that it is unstable unless protected; it might be most.

prudent to use products in bubble packets. Tablets cannot be broken without risking loss of efficacy. Caution is recommended when purchasing SAMe; an independent investigation that compared the content of SAMe with the labeled amounts found 6 of 13 products to be mislabeled. SAMe is marketed with silymarin (discussed in the next section) by Nutramax Laboratories for use in animals.

Milk Thistle

Silymarin has been reviewed by the Herb and Plant Supplement Encyclopedia at consumerlab.com. A member of the daisy family (Asteraceae), silymarin is one of the most important medical constituents of ripe seeds of the blessed milk thistle plant (Silybum marianum). The name reflects the legend that attributes the white leaf veins to a drop of the Virgin Mary’s milk and the location of the hidden infant Jesus during the family’s flight from Egypt. Other synonyms for milk thistle include Marian thistle, Mary thistle, St. Mary’s thistle, Lady’s thistle, Holy thistle, sow thistle, thistle of the blessed virgin, Christ’s crown, Venus thistle, heal thistle, variegated thistle, and wild artichoke.

Silymarin is a combination of seven flavonolignans (a flavanoid). The most prevalent is silybinin (silybin), which itself is two different compounds, with others including silychristin (or silicristin), and silydianin (also silidianin). Although all parts of the plant have been used medicinally,¹⁸² the concentration of silymarin is highest in the seeds and leaves. Generally, the flavonoids are extracted. Silybin is often complexed with phosphatidylcholine, which improves its bioavailability. Dosing should be based on silybinin equivalents. As with flavonoids, the active ingredient of silymarin are potentially potent antioxidants, scavenging hydroxyl radicals, superoxide anions, and lipid oxygen radicals owing to lipid peroxidation.

Animal models (including tetrachloromethane hepatotoxicity in dogs and a variety of other hepatotoxicants) support a hepatoprotective effect. Its mechanism of hepatoprotection is not known. Suggested mechanisms include increased hepatic regeneration (by stimulating RNA polymerase, ribosomal RNA, and potentially DNA synthesis), scavenging of oxygen radicals, “stabilization of ” hepatocyte cell membranes, and competitive inhibition of toxins that might otherwise bind to hepatic and damage cell membrane receptors (e.g., Amanita phalloides). In rat and mice models of acetaminophen toxicosis, silymarin was associated with higher concentrations of hepatic glutathione and superoxide dismutase in experimental compared with control animals. Silymarin can also bind to steroid receptors, although the clinical relevance of this is not clear. Antifibrotic effects have been demonstrated in animal models. Finally, antinflammatory effects may reflect inhibition of lipoxygenase and subsequent leukotriene synthesis.¹⁸²

Silymarin is poorly water soluble, and concentrated products are considered necessary for effective absorption. According to Consumer Laboratories, most studies involving silymarin are based on extract products that contain 70% to 80% silymarin on a weight basis. However, some products composed of seed powder contain only 1.5% silymarin. Quality assurance is likely to be an issue with silymarin: of eight products tested by Consumer Laboratories, only two contained the labeled amount. The remaining seven products ranged from 19% to 85% (median 64%). When properly labeled, the source of milk thistle (generally the seed) should be noted on the product. Care must be taken when dosing on the basis of label information; doses range from 15 to 1200 mg, reflecting in part the source and type of preparation. For example, pills made from seed powder contain about 9 to 15 mg of silymarin compared with 112 to 240 mg for pills made from dry extracts. Differences in doses may also reflect different salt preparations. In humans the phosphatidylcholine preparation may be more orally bioavailable, leading to a dose that is lower (1.5 to 3 mg/kg twice daily) compared with a 70% extract (3 mg/kg twice to thrice daily).

As a flavonoid, silymarin is an inhibitor of P-glycoprotein and should be used cautiously with drugs known to serve as substrates for the transport protein. Silymarin may also inhibit selected CYP450 (specifically P450 2C9) enzymes.

Milk thistle is used to prevent or treat a number of medical conditions, including hepatitis (acute or chronic), and to protect the liver from toxicants, including medications. Milk thistle is the most common alternative medicine used in humans for treatment of liver diseases, with more than 50% of users claiming efficacy. Other proposed health benefits of silymarin include improved diabetic control. An intravenous preparation of silybinin is available in Europe for treatment of mushroom poisoning caused by A. phalloides. Note that as of January 2010, of the 10 milk thistle products tested by Consumer Laboratories, nine did not pass, the primary reason being that the actual amount was less than the label claimed amount.

Choline

Choline is an indispensable metabolite of the body. It forms part of a number of endogenous compounds, particularly phospholipids. Phosphatidylcholine, lysophospholipids, plasmalogens, and sphingomyelins are phospholipids that contain choline. The mode of action of choline as a lipotropic agent is unknown. It may promote conversion of liver fat into choline-containing phospholipids, which are more rapidly transferred from the liver into blood. Choline is also essential for synthesis of phospholipids that are used in intracellular membranes concerned with lipoprotein synthesis. It is thought that the lipotropic agents methionine, betaine, and lecithin are beneficial because they contain choline or promote choline synthesis. The requirement for choline is well recognized in all conditions predisposing to fatty infiltration of the liver, including diabetes mellitus, malnutrition, and cirrhosis. Greater than normal quantities of choline seem to be necessary for prevention of a fatty liver when the liver is already damaged. Choline deficiency is not the only cause of fatty liver in these conditions, nor will choline supplementation alone restore the liver to full functional competence. Choline is, however, extremely valuable in the multitherapeutic approach to prevention and cure of fatty liver.

Selenium and Vitamin E

Selenium is now known to be essential for tissue respiration and is protective against dietary hepatic necrosis. It is extremely active and is only required in minute amounts. Vitamin E enhances the action of selenium, but both are required.

Selenium is an essential component of glutathione peroxidase, which catalyzes oxidation of reduced glutathione:

This glutathione peroxidase catalyzes removal of hydrogen peroxide and fatty acid hydroperoxides and thus exerts a protective effect on all cells but especially on muscle, liver, and erythrocytes. The essential substances required for removal of peroxides are reduced glutathione and glutathione peroxidase. Vitamin E maintains glutathione in the reduced form by preventing formation of hydroperoxides; it is an antioxidant and thus reduces the amount of glutathione peroxidase required. Cysteine (N-acetylcysteine) is required for the reduced sulfhydryl radical of glutathione and is generally present in adequate quantities. Selenium and vitamin E enhance each other’s action and together protect cells, especially hepatocytes, against harmful buildup of peroxides.

Vitamins

In the presence of liver disease, the fat-soluble vitamin K should be supplemented because hepatic stores may be quite rapidly depleted. The water-soluble vitamins of the B-complex group are frequently employed in therapeutic regimens for hepatic insufficiency. Few controlled studies have been carried out in this regard, but the rationale behind their clinical use is based on ensuring an adequate supply of metabolic cofactors.

Hydroxocobalamin (previously called vitamin B₁₂) is stored in the liver, mainly in mitochondria, but there is also a microsomal fraction. This microsomal vitamin may be of importance in hepatic protein metabolism. Microsomal cell fractions from the livers of hydroxocobalamin-deficient animals are defective in the incorporation of methionine and alanine into protein. General liver protein synthesis is depressed in hydroxocobalamin deficiency.

Hydroxocobalamin has a lipotropic effect. It is involved in metabolism of labile methyl groups and in formation of choline. Hydroxocobalamin is also necessary for overall utilization of fat. When intake is low, however, the demand for this vitamin in hematopoiesis exceeds that for any other clinically recognizable physiologic function.

Glucose and Fructose

The liver resists many forms of injury when its stores of carbohydrate and protein are adequate; its efficiency is impaired when hepatocytes are laden with fat. Administration of a hypertonic solution of glucose and fructose produces favorable responses in a variety of hepatic abnormalities. A high glycogen content appears to protect liver cells from damage, and inhibition of gluconeogenesis (which occurs with administration of both insulin and glucose) may play an important role. Under the influence of insulin, hepatocytes undergo glycogen storage, hypertrophy, and hyperplasia. Insulin has a major anabolic effect on the liver.

Megaesophagus

Myasthenia gravis is the most common cause of secondary megaesophagus in dogs. It is diagnosed on the basis of response to edrophonium chloride, a short-acting anticholinesterase.¹⁸⁴ Effects of the drug on skeletal muscle occur within 1 minute of intravenous administration and last up to 10 minutes or longer in some myasthenic patients. Drug therapy of megaesophagus associated with myasthenia gravis targets improvement in muscular activity with anticholinesterase therapy (pyridostigmine bromide, 1 to 3 mg/kg orally every 12 hours) and suppression of the immune response with glucocorticoid or other immunosuppressive therapy (e.g., azathioprine). Pyridostigmine improves appendicular muscle strength but may not improve pharyngeal or esophageal function. Prednisone tends to be the preferred glucocorticoid but may contribute to muscle weakness. Azathioprine does not have many of the side effects of glucocorticoids, but remission takes longer to achieve (up to several weeks), and neutropenia may limit treatment. Mycophenolate mofetil is a lymphocyte-inhibiting immunomodulator used orally to prevent graft-versus-host rejection in human renal transplant patients. The drug inhibits purine synthesis but only in lymphocytes (both B and T lymphocytes), and side effects are limited to GI upset. The drug can be given orally, causing response within 4 hours of administration. The drug has proved efficacious for treatment of myasthenia gravis in dogs (5 to 10 mg/kg every 12 hours orally).¹⁸⁵ Thyroid hormone replacement (thyroxine) may also prove helpful. Treatment for megaesophagus for which an underlying cause cannot be found is difficult. A number of drugs that stimulate GI smooth muscle have been recommended, including metoclopramide and cisapride, with varying reports of success. Neither of these two prokinetic drugs are likely to be effective in the striated muscle of the esophagus; further, enhanced lower esophageal sphincter tone might impede esophageal emptying. Bethanechol may stimulate propagating contractions in selected dogs. Drugs that relax the lower esophageal sphincter (anticholinergics and calcium channel blockers) have not proved effective. A major focus for treatment of myasthenia gravis is prevention of aspiration pneumonia and treatment or prevention of esophagitis.

Esophagitis

Esophagitis should be treated by correction of the underlying etiology. It is commonly associated with ingestion of a corrosive or hot (thermally) material. The feline esophagus appears to be particularly susceptible to drug-induced esophagitis (discussed in the following section). Antibiotic therapy in such cases should be reserved for esophageal perforation. The mucosa can be protected by administration of sucralfate administered as a slurry (1 g in 10 mL warm water), 5 to 10 mL every 6 to 8 hours. Lidocaine solution (Xylocaine viscous solution) may be administered orally (2 mg/kg every 4 to 6 hours) to minimize pain. Esophagitis caused by gastroesophageal reflux should respond well to medical management. In addition to protecting the damaged mucosa with sucralfate, drug therapy targets increasing gastric pH and tightening the lower esophageal sphincter. Antisecretory drugs (e.g., famotidine, omeprazole) help minimize damage induced by gastric acid and pepsin. Among the antihistaminergic drugs, ranitidine and nizatidine have prokinetic activity in humans comparable to that of cisapride, an effect evident within 1 hour after administration.¹²⁸ Interestingly, a peppermint–caraway oil preparation induced relief from dyspepsia equal to that produced by cisapride in human patients.¹⁸⁶ Antacids may also prove beneficial; products containing alginic acid may provide additional protection of the esophagus by providing a barrier of foam. Prokinetic drugs should be administered to tighten the lower esophageal sphincter. Indeed, metaclopramide or cisapride is probably as effective as antisecretory drugs in preventing further esophageal damage associated with gastric reflux. Glucocorticoids can be used to minimize esophageal stricture formation resulting from damage to the esophagus that extends into the muscular layers. Therapy should include tapered doses of glucocorticoids followed by reevaluation at 2-week intervals. Pentoxifylline may be an alternative or adjuvant therapy, particularly for drug-induced esophagitis.¹⁸⁷

Gastroesophogeal Reflux

Up to 60% of humans are considered to be at risk for developing perioperative gastroesophogeal reflux (GER), whereas GER was demonstrated in 17% to 55% of healthy dogs. The difference in incidence of GER between these studies might be attributable to differences in the anesthetic agents used.

Metaclopramide prevents GER in unanesthetized dogs, as was demonstrated experimentally.¹⁸⁸ Wilson and coworkers¹⁸⁹ also prospectively studied the effect of metoclopramide on GER (defined when esophageal pH to <4 or an increase to >7.5 that lasted more than 30 seconds) in anesthetized dogs. Animals were undergoing orthopedic surgical procedures; anesthetic protocols (morphine and acepromazine as premeds and thiopental for induction) and surgical positioning were the same in treatment and placebo (saline) groups. Blinded and randomization methods were not clear. The authors determined, after reviewing the medical records of dogs undergoing the same surgical procedures and anesthetic protocols, that 55% of dogs experienced GER. A high dose (1 mg/kg followed by constant-rate infusion [CRI] 1 mg/kg/hr) but not a low dose (0.4 mg/kg followed by 0.3 mg/kg/hr CRI) of metoclopramide reduced the relative risk of GER by 54%. The timing of metoclopramide administration in relation to anesthesia was not provided. Vomiting occurred preoperatively in 55% of animals but was not a predictive factor for the risk of GER. No adverse effects attributed to treatment were identified. Preoperative vomiting in response to preanesthetic agents was not a risk factor for GER in dogs, whereas the duration of surgery (but not anesthesia) tended to be a risk factor.¹⁹⁰ Wilson and coworkers¹⁹⁰ compared the effects of pre-anesthetic morphine to mepiridine with or without acepromazine in healthy dogs (n = 30) using a randomized design. When compared with morphine, treatment with meperidine alone or with acepromazine before anesthesia was associated with a 55% and 27% risk reduction in risk of developing GER. In this same study, GER was detected in 51 of 90 dogs within 36 minutes of induction isoflurane (n = 14), halothane (n = 19) or sevoflurane (n = 18).

Esophogeal Motility and Oral Medications

The association of doxycycline administration with esophageal lesions in cats^191,191a has led to several studies focusing on passage of medications through the feline esophagus. In one study, approximately 50% of capsules were retained in the midcervical esophagus of cats for longer than 240 seconds. Trapped capsules passed into the stomach if a small amount of food was administered.¹⁹² A prospective study used fluoroscopy to document the esophageal transit of barium tablets (20 mg) or capsules (size 4) in cats.¹⁹³ The percentage of swallows needed for successful passage (movement of the medication into the stomach) of each medication was determined when administered with or without a follow-up bolus of water (6 mL). Success was only 36.7% 5 minutes after administration, compared with 90% at 30 seconds and 100% at 90 seconds if the medication was followed with a water bolus. The study was performed in a nonrandomized fashion, with the “wet” study always following 5 minutes after a “dry” study. Retention of dry medicaments was generally in the cervical esophageal region.¹⁹³ Treatment should consist of an antisecretory drug, sucralfate, and metoclopramide. An anti-inflammatory may be helpful; glucocorticoids have been used, but pentoxyfylline might also be considered.

Acute Gastritis

Acute gastritis is best treated by resolution of the underlying cause, whether it is diet, infectious agents or chemicals (including drugs or toxins), or metabolic diseases (e.g., renal or liver disease). Chemicals, including hydrochloric acid and bile acids, can induce vomiting as a result of direct damage or hypertonicity. Inflammation, if allowed to progress, can result in erosion and ulceration. Although most patients with acute gastritis improve in 1 to 5 days, some patients require supportive therapy.¹⁹⁴ Depending on the patient, supportive therapy (in addition to nothing given orally) may include fluid therapy, antiemetics, and protectants or adsorbents. Fluid therapy with balanced crystalloids may require the addition of potassium. Bicarbonate is rarely indicated; glucose supplementation may be indicated in some patients. Any of the antiemetics previously discussed can be used, although phenothiazine derivatives should be withheld until volume replacement has begun. Metaclopramide is useful when given either peripherally or centrally; maropitant is likely to be very effective. Among the protectants, bismuth subsalicylate has proved most useful in decreasing vomiting associated with acute gastritis. However, gastric distention from the drug may cause the animal to vomit; therefore prudence is indicated in its use.

Gastric Ulceration and Erosion

There is no sensitive indicator of damage to the GI mucosa; damage may be quite extensive before hematemesis or melena is noted. Damage to the GI mucosa (erosion or ulceration) probably occurs more frequently than anticipated. For example, up to 25% of human patients admitted to intensive care units have gastric erosions; by the third day of hospitalization, this number increases to 90%. The risk of translocation of enteric pathogens is increased in these patients, suggesting an important role for prophylactic anti-ulcer therapy. Sucralfate has been recommended as the preferred method of prophylaxis in patients in whom enteral nutrition is not possible.¹⁹⁵ Diseases in which mucosal damage should be anticipated and treatment implemented include but are not limited to mast cell disease, renal disease, liver disease, and IBD. The underlying cause of ulceration must be resolved; additionally, antisecretory drugs and antacids are indicated for treatment of mucosal damage.

Gastric Dilatation–Volvulus

Therapy for gastric–dilatation volvulus (GDV) focuses on management of this acute and potentially life-threatening disease and long-term prevention. Medical management of the patient with acute disease focuses on resolution of the dilatation or volvulus and treatment of the sequelae of the syndrome. The sequelae of GDV that are most life-threatening are decreased cardiac preload (compression of the posterior vena cava and hepatic portal systems by the enlarged stomach), ischemia of the gastric wall (with loss of the mucosal barrier and increased risk of perforation), and congestion of abdominal viscera with subsequent endotoxemia and disseminated intravascular coagulation. Although they are potentially later in onset, cardiac arrhythmias also may become life-threatening. Shock should be treated with a balanced crystalloid electrolyte solution or hypertonic saline. Shock doses of glucocorticoids (methylprednisolone) may ameliorate some of the signs or clinical sequelae of endotoxemia although evidence for such use is lacking. Free radical scavengers (deferoxamine or allopurinol) may help reduce damage caused by reperfusion. Methylprednisolone may also be helpful in minimizing the effects of oxygen radicals The impact of prophylactic lidocaine on reperfusion injury was retrospectively studied in dogs (n = 51; 47 nontreated dogs served as control). Animals receiving lidocaine for cardiac arrhythmias were excluded from study. Dogs received either a loading dose (2 mg/kg intravenously) followed by CRI or a CRI alone (0.05 mg/kg/min) for at least 3 hours. No difference was detected in survival or complications between the two groups, although hospitalization was longer in the treatment group.²⁰⁴

Decompression of the dilated stomach can be facilitated by chemical restraint or sedation. Oxymorphone may be the drug of choice. Cardiac arrhythmias are most commonly ventricular in origin but may include atrial arrhythmias such as fibrillation. Intravenous lidocaine is the preferred drug for ventricular arrhythmias, administered initially as an intravenous bolus followed by a CRI (75 μg/kg/min). Procainamide can be used (intravenously, including CRI if lidocaine is ineffective; mexiletine) may be preferred. Amiodarone may also be used to acutely treat atrial fibrillation. Use of anti-secretory drugs is recommended to minimize the effects of hydrochloric acid on the already damaged mucosa. Although antimicrobials may be indicated, their use ideally is limited to situations in which contamination is known (i.e., surgical) or translocation is likely. Corrective surgery, including gastropexy, may be indicated. Medical management of chronic GDV has not been well established. Motility modifiers (metaclopramide, cisapride) and H₂-receptor antagonists may be indicated, particularly after an acute episode, to minimize the accumulation of gastric secretions. However, their efficacy has not been established.

Gastric Motility Disorders

Dietary management of delayed gastric emptying should precede pharmacologic management. Underlying causes, including electrolyte abnormalities, should be corrected, and use of concurrent drugs (e.g., anticholinergics, alpha-adrenergics, opioid antagonists) that might alter motility or response to prokinetic agents should be discontinued. Prokinetic agents can be added when dietary management fails; cisapride is preferred.

Diarrhea

Viral Enteritis

There is no specific treatment for diarrheas of viral origin. Fluid therapy, electrolyte replacement, and antiemetics are indicated, depending on the severity of clinical signs. Among the viral causes of diarrhea, canine parvovirus stands out for its severity and life-threatening nature. Intensive, aggressive care such as that offered at tertiary hospitals can increase survival rates to 96% compared with 67% at local practitioners. The rate of survival with no therapy may range from 64% to 79%.²¹¹ Supportive therapy centers around the intravenous administration of balanced electrolytes (e.g., lactated Ringer’s solution) with potassium replacement. Damage to the mucosal barrier and risk of bacterial translocation should be addressed with parenteral antibiotics. The use of the viral neuromidase inhibitor olstamavir may be helpful in this regard. Antibiotics should target both aerobes and anaerobes. E. coli was identified as an organism associated with septicemia in canine parvovirus^212,213; however, C. perfringens may also play a role.²¹⁴ Because of the life-threatening nature of sepsis, combination therapy with a beta-lactam antibiotic (amoxicillin may be preferred to cephalexin because of a better anaerobic spectrum) and an aminoglycoside (gentamicin, amikacin) is recommended. Vomiting and the life-threatening nature of the illness preclude oral administration of antibiotics. Ceftiofur has been used by some clinicians because of its efficacy toward E.coli; however, its limited spectrum (toward anaerobes) might limit efficacy for treatment of parvovirus-associated bacteremia; adverse events also may be an issue. Fluorinated quinolones should be avoided if possible because of the risk of cartilage defects in young, growing animals. Because fluid therapy is likely to be intensive in these patients, and because most patients are pediatric, an increased volume of distribution should be anticipated and higher higher doses of antimicrobials, particularly water soluble, may be indicated. Treatment of septic shock may include drugs that target eicosanoids and other mediators of endotoxic shock. Prevention of endotoxemia or its effects, is reasonable, although reaching consensus regarding effect through randomized clinical trials is limited by study designs.²¹¹ Glucose may be added when indicated by clinical signs consistent with septicemia. Glucocorticoids and flunixin meglumine have historically been advocated to ameliorate some of the negative sequelae resulting from endotoxemia, with benefits more likely if treatment occurs within 4 hours of the onset of endotoxemia. Shock doses of glucocorticoids should be used. Controversy regarding the use of flunixin meglumine centers primarily on the risk of GI damage. However, damage is generally so severe at the time of clinical presentation that it is reasonable to assume that the use of a single dose of flunixin meglumine is not likely to contribute to further damage. An additional benefit of flunixin meglumine is its potent visceral analgesic effect, which may be important is alleviating the marked pain and its negative pathophysiologic sequelae. Because cyclooxygenase 2 is the predominant eicosanoid mediating the sequelae of shock, any of the newer injectable NSAIDs that target cyclooxygenas 2 (e.g., carprofen, meloxicam, firocoxib) presumably should be equally effective in treatment or prevention of endotoxic shock. Opioids should be avoided because of their inhibitory effect on expelling luminal contents.

Although currently experimental, compounds targeting endotoxin may prove to be an important adjuvant to patients suffering from sepsis. Examples include endotoxin serum or a bacterial toxoid (Salmonella typhimurium; 10 mL/kg). The latter is commercially available. Transfusions with fresh whole blood or plasma can be beneficial in some dogs, particularly those that are hypoproteinemic or anemic. The impact of a recombinant amino terminal fragment of bactericidal permeability-increasing protein (rBPI₂₁; an antimicrobial and endotoxin-neutralizing agent) was studied in dogs (n = 40) with viral enteris. Treatment (3 mg/kg intravenously over 30 minutes, followed by 3 mg/kg intravenously over 5.5 hours) was implemented using a randomized placebo (n = 9 dogs treated with canine plasma protein) controlled design. Outcome measures included plasma endotoxin concentration, severity of clinical signs, and survival of parvovirus. No treatment effect could be identified ; however, contributing factors were insufficient sample size and biased patient selection toward animals that are less ill than the average infected animal.²¹¹

Treatment of diarrhea associated with parvovirus is generally not indicated. Until the mucosa has had time to heal, drugs intended to prevent or resolve diarrhea are not likely to be effective.

Bacterial Enteritis

The role of antimicrobial therapy in the treatment of diarrhea should be closely examined. Bacterial infection is not a major cause of diarrhea, nor does infection appear to perpetuate small intestinal diseases. More important, use of antimicrobial agents does not appear to improve the course of most acute diarrheas. Antimicrobials (neomycin, ampicillin) may, in fact, worsen diarrhea, perhaps because of suppression of normal microflora. Use of antimicrobials for treatment of diarrhea should be based on a diagnosis of intestinal bacterial infection (overgrowth detection, based in part, on fecal gram staining) or in cases of mucosal damage sufficiently severe to allow bacterial translocation. In the latter case, clinical signs generally include hemorrhagic diarrhea, fever, and abnormal white blood cell counts. Systemic antimicrobial therapy is indicated for bacterial translocation.

Despite the low incidence (less than 4% of cases of acute diarrhea), bacterial infections have been associated with both acute and chronic enterotoxigenic diarrhea of both small and large intestines. Diagnosis and antibacterial treatment are best based on culture and susceptibility data when possible. The most likely therapy for each of the infecting organisms is enrofloxacin, trimethoprim–sulfonamide combinations, and chloramphenicol for Salmonella; erythromycin, enrofloxacin, furazolidone, doxycycline, neomycin, clindamycin, or chloramphenicol for C. jejuni; a prolonged course of trimethoprim–sulfonamide combinations, tetracycline, or chloramphenicol for Yersinia enterocolitica (prognosis is guarded); metronidazole for C. difficile; and amoxicillin, ampicillin, metronidazole, tylosin, or clindamycin for C. perfringens. For E. coli the role will be difficult to establish. Clostridium piliformis (formerly Bacillus piliformis: Tyzzer’s disease) is a less common, although rapidly fatal, cause of acute hemorrhagic enterocolitis. The organism appears to be nonresponsive to antimicrobials, wih therapy being supportive in nature. Salmon poisoning (Neorickettsia helminthoeca) is an endemic, fatal cause of diarrhea in dogs in the Pacific Northwest. As with other rickettsial organisms, tetracycline (oxytetracycline, doxycycline) is the treatment of choice. Oral therapy (in the absence of vomiting) includes tetracycline, chloramphenicol, sulfonamides, and penicillins. Therapy should continue for 2 to 3 weeks; the trematode vector can be treated with fenbendazole for 10 to 14 days (50 mg/kg, once daily). Because bacterial infections as a cause of diarrhea are often associated with some type of toxin production, motility modifiers should be avoided. Bismuth subsalicylate may be beneficial for both its adsorbent and antiinflamamtory effects.

Hemorrhagic Gastroenteritis

This syndrome of uncertain etiology is characterized by a packed cell volume (PCV) that may be as high as 80%. Hemoconcentration rather than dehydration is the cause. Treatment requires prompt and rapid but appropriate volume replacement with a balanced electrolyte solution until the PCV falls below 50%. Fluid therapy should continue for an additional 24 hours to maintain the PCV at 50% or lower. Disseminated intravascular coagulopathy may develop if fluid therapy is not instituted rapidly.

Chronic Diarrhea

Treatment of chronic diarrhea should be based on removing the underlying causes. This is perhaps more important than in acute diarrhea because drugs used to symptomatically treat acute diarrhea should not be continued on a long-term basis. Chronic IBD is discussed later as a separate entity.

Bacterial overgrowth is increasingly being recognized as a cause of chronic intermittent small bowel diarrhea in dogs. Because no sensitive, specific, and widely available diagnostic test is available, diagnosis is difficult unless an underlying cause (e.g., partial intussusceptions, tumors, foreign body) can be identified. Oral treatment should include broad-spectrum antibiotics, such as tylosin (10 to 20 mg/kg every 12 hours) or metronidazole, a drug effective against anaerobes (10 to 20 mg/kg every 12 hours). The use of probiotics should be considered as previously discussed.

Intestinal fungal disease may also manifest as chronic diarrhea. Prognosis is generally poor to fair. Intestinal histoplasmosis should be treated with an orally administered azole drug. Itraconazole is the drug of choice (5 to 10 mg/kg every 12 hours) followed by ketoconazole (10 to 15 mg/kg every 12 hours); both drugs should be given 3 to 4 months after clinical signs of remission. Voriconazole also might be considered. Amphotericin B can be given in addition to an azole drug, particularly for severe cases. Currently, no antifungal drug has been effective for treatment of pythiosis (previously phycomycosis). Surgical resection followed by imidazole therapy (itraconazole or ketoconazole) is indicated in animals in which the disease is diagnosed before tissue damage and infiltration.

Protozoal diseases of the small intestine include coccidioidomycosis, cryptosporidiosis, and giardiasis. Pentatrichomonas hominis also has been associated with diarrhea, particularly in puppies and kittens. Diagnosis of each infection is based on identification of the organism or of cysts in feces. Treatment of coccidioidomycosis includes sulfadimethoxine (50 to 65 mg/kg once daily orally for 10 days); trimethoprim–sulfonamide combinations (30 mg/kg orally once daily for 10 days), quinacrine (10 mg/kg orally once daily for 5 days), or amprolium (100 mg [small dogs] to 200 mg [large dogs] of 20% powder once daily in gelatin capsules, or 1 to 2 teaspoons of 9.6% amprolium per gallon of free-choice water for 1 to 2 weeks). There is no effective treatment of cryptosporidiosis in dogs. This infection is generally self-limiting in immunocompetent animals. A number of therapies can be used to treat giardiasis. Metronidazole (25 to 30 mg/kg orally twice daily for 5 to 10 days) is the treatment of choice, although up to a third of animals may not respond. Metronidazole benzoate has demonstrated efficacy in treatment of feline giardiasis based on a study in 26 chronically infected cats, 10 of which also were infected with Cryptosporidium parvum.²¹⁵ Cats were treated with 25 mg/kg orally twice daily for 7 days; the drug was prepared as a solution. It is not clear if the dose was based on active ingredient (i.e., metronidazole base) or total drug. All cats were negative for three consecutive fecal examinations (based on indirect immunofluorescence assay) for the 15 day after treatment study period. Albendazole (25 mg/kg orally every 12 hours for 2 days) can be used in dogs, but safety and efficacy have not been reported in cats. Fenbendazole (50 mg/kg orally once a day for 3 days) may also be effective. Furazolidone (4 mg/kg orally every 12 hours for 5 to 10 days) can be used in cats, although toxicity may limit its use. For nonresponsive cases in dogs, quinacrine (6.6 mg/kg orally every 12 hours for 5 days) can be used, although side effects (anorexia, lethargy, vomiting, and fever) are common. Ipronidazole (126 mg/L drinking water) is a poultry drug that can be used for treating groups of animals. Tinidazole (currently not available in the United States; 44 mg/kg once orally) may also be useful. Pentatrichomoniasis should respond to a 5-day course of metronidazole therapy; tinidazole for 3 days may also be useful. Both drugs can be used according to previously described dosing regimens.

Short Bowel Syndrome

Short bowel syndrome occurs after surgical removal of a large portion of the small intestine. Resultant malabsorption results in malnutrition and diarrhea. The impact of the resection on bowel function and the ability of the remaining bowel to adapt to the loss depend on the extent and site of resection. Dogs have functioned with an absence of clinical signs following resection of up to 85% of the small intestine. Preservation of the ileum is important because of its role in slowing transit and absorption of vitamin B₁₂ and bile acids. Medical management focuses primarily on correction of secondary ill effects. Exocrine pancreatic insufficiency should be treated with enzyme supplementation. Gastric hypersecretion should be treated with H₂-receptor antagonists. Bacterial overgrowth should be treated with appropriate antimicrobial therapy (e.g., metronidazole, tylosin). Cholestyramine can be used to bind excessive bile acids that result in diarrhea. Occasionally, motility modifiers may be indicated to slow transit time. The opioids are preferred because of their effects on segmentation and thus retention of luminal contents.

Diarrhea

Diarrhea associated with the large intestine should be approached in the same manner as diarrhea of the small intestine. Chronic IBD is discussed as a separate entity.

Pathophysiology

IBD is characterized by infiltration of inflammatory cells in the gastric or intestinal mucosa (or both).^194,223 Its emergence in predisposed animals is facilitated by the large immune system and its multivariate responses presented by the GI tract, coupled with the vast number of antigens from ingested microbes, parasites, food, toxins, endogenous microbes or their products, and other materials. Increased intestinal permeability to antigens probably plays a role, but it is not clear if this is an initiating event or a sequela. Disruption of the intricate balance between microbe and host leads to breakdown of mucosal tolerance. This key event leads to initiation, progression, and reemergence of disease.²²³ Loss of mucosal tolerance generally requires a loss of the normal barrier, as might occur with loss of cadherins. Immunologic dysfunction largely reflects altered T-cell [CD-4] activity. High concentrations of IL-10 and 18, and TGF-β promote T cell differentiation to the Th-1 phenotypes, resulting in high concentrations of IL-2, INF-γ, and TNF-alpha.²²⁴ A third factor in the loss of mucosal tolerance is the presence of endogenous microflora.

German and coworkers²²³ reviewed IBD in dogs, and Allenspach and coworkers²²⁵ described risk factors for therapeutic failure. Canine IBD is a group of diseases that are highly variable in cause and presentation. Manifestations and treatment depend on cell type (with lymphocytic–plasmacytic most common, followed by eosinophilic), region affected (any location but most commonly small intestine) and breed (e.g., histiocytic [large macrophages] ulcerative colitis of Boxers, protein-losing enteropathies of Soft Coated Wheaten Terriers, gluten sensitivity of Irish Setters, and immunoproliferative enteropathy of Basenjis).²²³ The type of predominating cell (lymphocytic, plasmocytic, eosinophilic, or histocytic) that causes inflammation can serve as a basis of the classification and, to some degree, treatment of IBD.²²⁶ Overgrowth of small intestinal bacteria in response to either a primary (e.g., idiopathic) or secondary (e.g., acquired) disorder has been studied as a potential cause, particularly in German Shepherd Dogs; IgA deficiency has been suggested.²²³ Although commonalities exist between human and canine IBD, the most common forms in human include ulcerative colitis and Crohn’s disease. Ulcerative colitis is diffuse and superficial, involving predominantly neutrophils, with some lymphocytes and plasma cells, particularly in the ileum. Crohn’s disease is focal and segmental, characterized by chronic pyogranulomatous inflammation. When extrapolating therapeutic options between human and canine or feline IBD, considerations must also include differences in the pathophysiology of the diseases among species. Even within species, preferred therapies and extent of response is too variable among canine and feline populations to be predicted without supportive diagnostic (histopathologic) data. Accordingly, treatment should be approached individually (Table 19-5). A scoring system has been proposed for dogs to facilitate treatment.²²⁶

Table 19-5 Products for Treatment of Inflammatory Bowel Disease

∗ Foams adhere to mucosa and are for colonic disease. Administered at night.

† Histocytic ulcerative colitis.

The “4-R’s” approach to treatment of Crohn’s disease in humans includes removal (underlying causes such as inappropriate diet), replacement (missing nutrients, such as vitamin B₁₂), re-inoculation with “friendly” bacteria (L. acidophilus and L. bulgaricus along with fructose oligosaccharides), and repair. Dietary considerations in the role of (human) IBD have been reviewed by Shah.²²⁷ The role of gut flora, GI immunity, and IBD based on models and spontaneous disease has been reviewed in humans.^228,229 A series of studies using interleukin 10–deficient mouse colitis models demonstrated the influence of different bacterial substrates at different sites of inflammation. Inflammation best responded to a combination of vancomycin–imipenem or neomycin–metronidazole compared with ciprofloxacin and metronidazole. Response to the latter was effective for acute but not chronic colonic inflammation. Narrow-spectrum antimicrobials such as ciprofloxacin were more effective in preventing but not treating experimentally induced colitis²³⁰ (see also the discussion of antibiotic-responsive diarrhea). Studies have demonstrated that inflammatory disease will not evolve experimentally in microbe-free environments but can be experimentally induced by transfer of T-cells reactive to bacterial antigens. In human patients with IBD, lesions are worse in those areas with highest microbial counts. Although the role of potential pathogens has been intensively studied, emerging data suggest that it is the commensal, rather than pathogenic, microbes that are contributing to the disease. As such, perpetuation of the disease may reflect abnormal signaling between host immune system and microbes and a loss of host tolerance for microbes. Accordingly, treatment for IBD targets not only suppression of the inflammatory response but also manipulation of the contributing microbiota with either antimicrobials or probiotics.

Unfortunately, IBD is a diagnosis of exclusion and is made after other causes of inflammatory disease of the GI tract have been ruled out. Food allergies or intolerance; infections by fungal, bacterial, or parasitic organisms; and neoplasms must be ruled out or their role in the pathophysiology identified and treated accordingly. Confirmation of the diagnosis is based on biopsy, which also is necessary to identify the predominant inflammatory cell associated with the disease and the most appropriate therapy. For example, eosinophilic infiltrates may respond to dietary management alone. Monitoring response to therapy should include, in addition to clinical signs, serum folate and cyanocobalamin concentrations; serum albumin levels can be used as a monitoring tool in animals with protein-losing enteropathy. Allenspach and coworkers²²⁵ retrospectively determined that hypocobalaminemia (<200 ng/mL), along with hypoalbuminemia, is a risk factor for therapeutic failure.

Initial medical management may vary with the severity and length of disease. In dogs, particularly, elimination of an irritating diet and antibiotic-responsive causes might be considered before biopsy. This is best accomplished by a well-designed clinical trial in the patient. The role of diet in human IBD has been well reviewed.²²⁷ Feeding the animal an elimination diet containing novel or highly digestible protein foods or (particularly for colonic disease) a high-fiber diet (e.g., yams, sweet potatoes, pumpkin) might be considered first. The role of diets with altered n:3 to n:6 omega-fatty acid ratios or hydrolyzed diets (protein molecules are small and presumably nonantigenic) is not yet clear but may be promising.²²³

Antiinflammatories remain the cornerstone of therapy for IBD in dogs and cats. Use of glucocorticoids should be reserved for animals in which biopsy has confirmed a diagnosis of IBD. Indiscriminate use of glucocorticoids can be dangerous, particularly in areas in which fungal causes of GI disease are not uncommon. In addition, use of glucocorticoids in patients with GI lymphoma may render the neoplasia resistant to further glucocorticoid therapy used as part of a combination antineoplastic regimen. Glucocorticoids are indicated in dogs and cats with lymphocytic–plasmacytic IBD. Prednisolone (2.2 mg/kg/day orally) should result in clinical response within 1 to 2 weeks. Therapy should continue at the same rate for another 2 weeks (beyond clinical response) and then slowly be tapered. More severe cases of IBD or cases that do not initially respond to prednisolone may respond to dexamethasone (0.22 mg/kg/day orally).Because glucocorticoids impair healing in the gastrointestinal mucosa (by virtue of cyclooxygenase 2 inhibition), antisecretory and cytoprotectant drugs are indicated. Indeed, their use is indicated in general to facilitate healing development of multidrug resistance has been implicated as a cause of therapeutic failure with glucocorticoids in some human patients with IBD; expression of mucosal multidrug resistance may ultimately be used to determine response of IBD patients to therapy.²³¹ Several mechanisms of glucocorticoid resistance have been described in humans and may be relevant to dogs or cats.²³² These include heterogenicity of the disease process itself, overexpression of the MDR1 gene causing increased P-glycoprotein–mediated efflux of glucocorticoid from target cells; impaired glucocorticoid–receptor signaling; and activiation of epithelial proinflammatory mediators such as nuclear factor kappa B.

Humans generally do not tolerate systemic glucocorticoids as well as dogs or cats, leading to effective alternative therapies for IBD.²³³ For example, 80% of human ulcerative colitis cases are successfully controlled with a variety of 5-aminosalicylic acid preparations. Rectal glucocorticoid foams have also proven useful for diseases involving the colon. “Topical” budesonide is as effective as systemic glucocorticoids and is better tolerated than systemic glucocorticoids. Glucocorticoids are the cornerstone of therapy for Crohn’s disease; more severe disease responds to higher doses of steroids. The extrapolation of these treatments to dogs and cats is limited in part because colonic disease is not as common (limiting applicability of therapies targeting the colon). Further, the extent of first-pass metabolism of budesonide is not known. A number of therapies should be considered in dogs or cats that do not respond to initial therapy or for which glucocorticoids are not tolerated or contraindicated. Various immunomodulators should be considered. In humans, these have included cyclosporine and mycophenolate mofetil. Allenspach and coworkers²³⁴ reported on the use of cyclosporine for treatment of IBD in dogs (Chapter 19). Overall, cyclosporine was considered effective in 78% of the animals. In humans, long-term cyclosporine may facilitate long-term control when used in combination (but not alone) with other immunomodulating drugs. Leukotrienes appear to be involved in chronic allergic diseases such as IBD, atopy, and asthma. A role has been described in signaling and trafficking between eosinophils and lymphocytes in affected tissues, and in the IL-5 eotaxin induced differentiation, proliferation, and release of eosinophils at the level of the bone marrow. Accordingly, leukotriene receptor antagonists (e.g., zafirlukast or montelukast; see Chapter 29) might be considered as the sole agent in mild disease in those animals in which glucocorticoids are contradicted, in combination for nonresponders, or as dose-sparing agents. The role of TNF-alpha in Crohn’s disease of humans has led to some scientific support for pentoxifylline (also referred to as oxpentifylline).²³⁵ It has proved useful in mouse models of colitis²³⁶ and in humans as a dose-sparing agent when combined with glucocorticoids or directed polypeptide therapy.²³⁷

Sulfasalazine (20 mg/kg every 12 to 24 hours orally in cats; 50 mg/kg/day divided every 8 to 12 hours in dogs) may also be beneficial in cats and dogs with IBD. Response may take 1 to 2 weeks. As a sulfonamide, sulfasalazine may cause immune-mediated diseases ascribed to other sulfonamide antibiotics; use of the drug should be based on a histologic diagnosis whenever possible. Newer 5-aminosalicylate (sulfasalazine-like drugs) such as mesalazine and olsalazine (10 to 20 mg/kg every 12 hours) might be considered; both may decrease tear production in dogs. Omega fatty acid (fish oil) products also may be helpful for their antiinflammatory effects; response may take several weeks.

Animals that continue to be unresponsive to medical management of IBD may respond to azathioprine (0.3 mg/kg every other day, orally in cats; 2.2 mg/kg/day in dogs). Response may take up to 5 weeks. Side effects of azathioprine are sufficiently severe that a diagnosis of severe IBD should be confirmed (based on biopsy) before its use. White blood cell counts should be monitored weekly and the drug temporarily discontinued if neutrophil counts drop below 2000/uL.

The role of directed polypeptides in the management of refractory human IBD is emerging.^238,239 Emerging therapies are targeting co-stimulatory molecules which are responsible for initial interactions between T cell receptors and macrophage MHC antigen complexes.²²⁴ Endotoxin and cytokines interact directly or indirectly with a variety of co-stimulatory molecules, including CD40-ligands (with T-cells) and B-7, an immunoglobulin that serves as a ligand for C28 (also a T cell co-stimulatory molecule). Because many of these therapies represent proteins foreign to dogs and cats and because animals are already affected by a dysfunctional immune system, caution is recommended with their use. Side effects can be profound in humans and may preclude adaptation to dogs or cats. Use in dogs and cats should be implemented only after collecting intensive scientific support.

Antibiotic therapy is intended to resolve bacterial overgrowth that might be contributing to the inflammatory process and either mimicking or contributing to IBD. However, response may just as likely reflect immunomodulation rather than antimicrobial therapy. Therapy for overgrowth in the large intestine should target clostridial organisms (metronidazole or ampicillin), whereas broader-spectrum drugs (tylosin, ampicillin) should be used for small intestinal disease. C. perfringens overgrowth in the small intestine may be difficult to detect; drug therapy that targets this organism includes tylosin and ampicillin. Metronidazole therapy in conjunction with glucocorticoids is indicated not only for its antibacterial effects but also because it appears to have immunomodulatory capabilities; indeed, this may explain why it may be effective as the sole therapy in some cases of IBD.

Nonhypoproteinemic dogs with lymphocytic–plasmacytic enteritis responded to a combination of oral antiinflammatory agents (prednisone, 1 mg/kg twice daily slowly decreased to 0.5 mg/kg every 48 hours) and antimicrobial agents (metronidazole 10 mg/kg twice daily for 21 days); most dogs also received oral cimetidine (0.5 mg/kg bid) and metaclopramide (0.5 mg/kg bid) for 90 days.²⁴⁰ Treatment dogs (n = 16) received a prescription diet. A group of normal animals (n = 9) were studied as untreated controls. Dogs were studied for 120 days, with outcome measures including clinical signs, endoscopic lesions and histopathy of endoscopic biopies. After treatment, the mean activity index diminished from 7.3 at baseline to 1.7, 0.8, 0.5, and 0.19 at baseline, on days 30, 60, 90, and 120, respectively. Further, gastric and duodenal endoscopic lesions decreased in 75% of animals, although no significant reduction was detected histologically.

Hostutler and coworkers²⁴¹ have retrospectively described a series of cases (n = 9) of canine histoycytic ulcerative colitis responsive to antibiotics. The common drug among all nine dogs was enrofloxacin, with or without combinations of amoxicillin or metronidazole. Four of the dogs had failed to respond to antiinflammatory therapy that included combinations of prednisolone, azathioprine, or sulfasalazine, with or without other antibiotics, for a duration of 1 to 20 weeks. The remaining five dogs responded to antibiotics alone. Diarrhea resolved within 3 to 12 days of treatment with enrofloxacin at standard recommended doses. Although three dogs remained asymptomatic for 7 to 14 months, some dogs have required therapy for 2 to 21 months or longer.

Among the more promising approaches of therapy that do not directly suppress inflammation is the use of probiotics (see the earlier discussion of biotherapeutics). Probiotics are intended to replace the pathogens with healthy flora that have developed host tolerance. Their use in patients with IBD should be strongly considered; however, notably lacking is scientific evidence regarding their use. Necssary information ranges from characterization of the normal state of microbiota in the canine and feline gastrointestinal tract to its state in patients with IBD; the optimal replacement microbiota; and clinical trial evidence of response when used as either sole or combined therapy. Further, deficiencies in product quality may limit effective response. None the less, attention must be given to this approach to therapy. The role of probiotics in the treatment of IBD in humans has been reviewed.^228,229 Randomized controlled clinical trials in humans have demonstrated resolution or improvement of IBD compared with controls (placebo or 5-aminosalicylic acid) after treatment with probiotics containing bifidobacteria, lactobacilli, and streptococci as core microbes.^228,229 However, because the pathophysiology of IBD and endogenous microbiota (and presumed response to biotherapeutic) varies with site, age, diet, species, and other factors, scientific evidence of efficacy of biotherapeutics in IBD may be slow to emerge. Human and mice model data are not necessarily relevant to either dogs or cats; studies in target species are needed to support efficacy. Further, the microbiota of individuals with IBD is different from that in normal animals and (has been described as unstable). Accordingly, although biotherapeutics are largely safe in normal animals, the unknown impact of colonization of microbes in the diseased intestine mandates that discretion (and knowledge) accompany biotherapeutic use. Marteau and coworkers²²⁸ reviewed the role of biotherapeutics in the treatment of IBD. Several studies suggest that E. coli and Bacteroides vulgatus, both normal flora, in particular, may be reasonable targets of therapy. Members of bifidobacteria and lactobacilli generally tend to be the most likely organisms to provide protection against IBD, but species differences in normal flora are likely to mandate clinical trials in target species as a basis of proof.

Associated clinical signs of IBD that may require medical management include vomiting, small or large bowel diarrhea, flatulence, and occasionally GER. Hematochezia may be present with colitis. Diarrhea is the primary presentation of IBD in dogs. Vomiting occurs less commonly with gastric and enteric IBD; hematochezia occurs consistently in colitis. Anorexia and weight loss occur to variable degrees in IBD. Use of antisecretory drugs is indicated, in part to provide GI protection; sucralfate likewise is indicated, particularly in the presence of erosive or ulcerative disease and glucocorticoid therapy.

Supplementation of cobalamin should be considered at least in cats with chronic inflammatory disase of the small intestine associated with hypocabalaminemia. Ruaux and coworkers²⁴² studied 19 cats severly deficient in cobalamine (based on serum concentrations) during and after treatment (250 units subcutaneously once weekly) for 4 weeks.

Treatment for Helicobacter spp. might also be considered. Leib and coworkers²¹⁶ demonstrated marked improvement in dogs with IBD when they were treated for Helicobacter spp. Chronically vomiting dogs with spirochetes and either normal or inflamed stomach or duodenum (based on biopsy samples) were studied. Dogs were assigned to receive twice daily for two weeks “triple” therapy (amoxicillin 15 mg/kg, metronidazole 10 mg/kg and bismuth subsalicylate at 13 to 26 mg/kg [0.25 to 2 262-mg tablets, depending on body size), either with or without famotidine (0.5 mg/kg). Potential therapeutic benefits of bismuth subsalicylate include antibacterial effects, altered microbial adhesion, protection agains ulcerative effects, and decreased resistance to metronidazole (as reviewed by Leib and coworkers²¹⁶). Placebos apparently were not given and blinding was not ascribed; assignment to either group was by coin toss, and although other therapies were discouraged, some dogs did receive other antibiotics as well as antiinflammatory therapies. Dogs were reevaluated at 4 weeks and 6 months. No significant treatment effect emerged in the famotidine group, with the frequency of vomiting reduced by 86% and organisms eradicated in approximately 75% of dogs in both groups. On the basis of this study, the authors concluded that famotidine did not enhance response to therapy; however, caution is recommended in basing therapy on this conclusion, in part becausethe ability of the study to detect a famotidine effect was not identified. In humans eradication of Helicobacter might be expected in more than 90% of human patients receiving “quadruple” (i.e., with antisecretory drugs) therapy. As with other investigators, recrudescence or re-infection of dogs with Helicobacter after presumably successful eradiction (based on the presence of the organism rather than molecular techniques) is not unusual. In Leib’s study²¹⁶ close to 50% of dogs negative for Helicobacter at 4 weeks were positive by 6 months, suggesting improved therapy is still needed.

Acute Hepatic Failure

Supportive therapy includes intensive fluid therapy with a balanced electrolyte solution to which potassium chloride, B vitamins, and (particularly in the presence of hypoglycemia or septicemia) glucose has been added. Coagulopathies are likely to reflect disseminated intravascular coagulopathy (stimulated by massive endothelial damage in the liver), impaired coagulation protein synthesis, or both. Clinical coagulopathies should be treated with heparin and replacement therapy (fresh whole blood or plasma or fresh frozen plasma). Rapid destruction of hepatic storage sites of vitamin K may also contribute to bleeding disorders, and replacement therapy may be indicated. Gastric ulceration should be anticipated and GI bleeding minimized by the use of antisecretory drugs. However, cimetidine is not recommended because of its negative effects on hepatic enzyme activity; omeprazole likewise might be used only cautiously. Antibiotics are indicated because of increased risk of bacteremia. Bacteria are likely to be gram-negative coliforms or anaerobes from the GI tract or Staphylococcus spp. Combination antimicrobial therapy is indicated for full antibacterial coverage. No documented studies have established the usefulness of drugs intended to support the liver as it heals or overcomes acute hepatic necrosis. Intrahepatic glutathione is an important scavenger of oxygen radicals, and its depletion probably contributes to inflammatory damage. Replacement in the form of acetylcysteine (e.g., Mucomyst) is certainly indicated for acetaminophen overdose but also might be considered in any case of acute hepatic necrosis. Cimetidine, a potent inhibitor of hepatic microsomal enzymes, might be considered in cases of acute hepatic failure associated with the formation of toxic drug metabolites, such as acetaminophen. However, its routine use in other cases of acute disease is discouraged because of its inhibitory effects.

Treatment for hepatic encephalopathy focuses on decreased absorption of encephalotoxins generated by microbes from protein and fat degradation. Medical management should be implemented in conjunction with dietary management. Lactulose is a semisynthetic disaccharide that is metabolized by colonic bacteria to lactic acid. In addition to the osmotic laxative effect, which causes evacuation of the luminal contents, acidification of the contents results in ionization of ammonia, precluding its absorption across the rectal mucosa. It can be administered either orally or, in severe cases of encephalopathy, as a retention enema (three parts lactulose to seven parts saline, administered at 20 mL/kg every 4 to 6 hours). The enema should be retained for 15 to 20 minutes. Lactitol is an alternative to lactulose that is less sweet and perhaps better tolerated. It is administered as a powder (500 mg/kg daily orally). Oral doses for long-term management with either lactulose or lactitol should generate two to three soft stools a day. Povidone–iodine (10%) given as an enema also acidifies luminal contents and provides some antibacterial activity. Selective microbial decontamination may reduce formation of encepahlotoxins. Neomycin (22 mg/kg orally twice daily or as an enema in water) also decreases bacteria responsible for formation of encephalotoxins. Other antimicrobials used for long-term management of hepatic encephalopathy include metronidazole (7.5 mg/kg orally every 8 to 12 hours) and ampicillin (22 mg/kg orally every 8 hours). With severe encephalopathy glucose-containing fluids may help prevent accumulation of ammonia in neurons.

Benzodiazepine receptors increase in patients with hepatic encephalopathy; use of benzodiazepine receptor antagonists such as flumazenil can be effective in human patients, but its efficacy is less well established in animals. If the drug is used, animals should be monitored for seizures. Intracranial pressures may increase in some patients; treatment should include mannitol (1 mg/kg of a 20% solution intravenously over 30 minutes, at 4-hour intervals) and furosemide. Glucocorticoids appear to offer no advantage to patients suffering from hepatic encephalopathy and may be contraindicated for treatment of increased intracranial pressure associated with hepatic encephalopathy.

Vomiting in patients with acute or chronic liver disease should be treated with antiemetics active at the CTZ or emetic center. Metoclopramide has been the first drug of choice, followed by a phenothiazine derivative; maropitant might reasonably replace either. Impaired hepatic function may increase the duration of action of the drug, whereas dehydration may increase plasma drug concentrations. Dosing regimens should take these changes into account. Volume replacement should take place before treatment with phenothiazine antiemetics in the dehydrated patient.

Chronic Hepatic Diseases