Cytokines

More than 13 chemokine receptors are associated with rheumatoid arthritis, and at least 16 chemokines interact with these receptors.⁹ Both constitutive (responsible for physiologic trafficking and homing of the adaptive immune response) and inducible (responsible for effector white blood cell recruitment, including lymphocytes) responses are involved. A number of the chemicals also are responsible for angiogenesis. The inappropriate production of chemokines is associated with formation of an ectopic germinal center, which contributes to an uncontrolled immune response. Consequently, drugs directed toward chemokine receptors offer a therapeutic approach to control.

TNFα induces a broad spectrum of activity. Cytotoxicity of multiple cell types, including tumors, reflects both apoptosis and necrosis. A large number of proteins are targeted, along with other central mediators of the inflammatory process and immune activation. Examples include nuclear factors (e.g., NFκB), nitric oxide synthetase (NOS), cell-surface molecules, MHC classes I and II, and secreted proteins such as IL (e.g., -l, -6, -8), IFN, granulocyte-macrophage colony-stimulating factor, platelet-derived growth factor, urokinase plasminogen activator, and TNF-α itself. When administered exogenously, high concentrations of TNFα causes a toxic syndrome similar to septic shock. Bacterial lipopolysaccharide is the most potent stimulator of macrophage TNFα production. TNFα appears to mediate ischemia–reperfusion injury after transplantation of the liver, kidney, intestine, heart, lung, and pancreas and is a marker cytokine during organ rejection. Inhibitors have proved useful in human medicine for treatment of a number of autoimmune diseases, including Crohn’s disease, rheumatoid arthritis, psoriasis, and ankylosing spondylitis. Indications included corticosteroid-resistant graft-versus-host disease after bone marrow transplantation.¹⁰

Not surprisingly, the pervasive role of TNFα has led to the development of drugs that inhibit its actions. Included are glucocorticoids, pentoxifylline, and monoclonal immunoglobulin G (IgG) antibodies (e.g, infliximab, etanercept and the “humanized” adalimumab) etanercept, a humanized soluble TNFα receptor (TNFR) construct, and onercept, a TNFα–binding protein.¹⁰ A variety of other drugs targeting TNFα or its receptors are currently under investigation, as well as metalloproteinase inhibitors such as TNFα-converting enzyme (TACE). The use of these drugs, not surprisingly, is associated with a number of side effects. These include immunosuppresion, acute infusion reactions, delayed-type hypersensitivity reactions, autoimmune diseases, cardiovascular and neurologic adverse events, malignancies and lymphomas, and infectious complications.

Complement

The complement cascade is a major effector mechanism of the immune response. The cascade results in highly amplified events that interact with other physiologic cascades, including the coagulation pathway, kinin formation, and fibrinolysis.¹¹ Consequences of complement activation include opsonization, the release of biologically vasoactive peptides, and cellular lysis. Cell-mediated cytotoxicity is implemented by cytotoxic T lymphocytes, NK cells and antibody-dependent cell-mediated cytotoxicity (ADCC), mediated by a variety of cells that express surface Fc receptors. Effector cells of ADCC include monocytes, neutrophils, eosinophils, selected cytotoxic T cells, and NK cells.

Immunoglobulins

Five classes of Igs are recognized in animals. IgM is the largest, forming up to 15% of the total Ig present. IgM exists as a monomer or a large polymeric form. IgM is responsible for the primary Ig response; in animals, for some infections, it is the only defense.¹¹ The availability of five binding sites renders IgM efficient at antigen binding and agglutination, virus neutralization, and opsonization. IgM also is a potent activator of complement. Because it is such a large molecule, unless vascular permeability is altered, most IgM stays in circulation.

IgG (with multiple subclasses) makes up the majority of total Ig. It is the most soluble of the Igs and thus is able to reach extravascular spaces. Its primary biological functions are to facilitate the removal of microorganisms; neutralize toxins; and bind to microorganisms or infected cells, initiating effector mechanisms. IgG activates complement or initiates Fc-bearing effector cells (ADCC) and promotes removal of Ig-coated cells by ADCC.

IgE has a major role in the response to parasites and in the pathogenesis of allergic diseases in part because of its unique ability to bind by way of the Fc portion of the IgE molecule to specific receptors on mast cells and basophils. Cross-linkage of two IgE molecules results in calcium-mediated mast cell degranulation and the release of a number of preformed (e.g., histamine and serotonin) and synthesized (e.g., metabolites of arachidonic acid) mediators.

IgA is produced in submucosal lymphoid tissues and regional lymph nodes. After secretion outside of the cell, it travels to epithelial cells, where the secretory component of the IgA acts as a receptor, binding to IgA and stimulating its endocytosis. The two components are eventually exocytosed and attach to the mucosal surface, where they provide a protective component, neutralize toxins, adhere to bacteria and viruses, and interact with parasites.¹¹

Each Ig molecule monomer comprises two heavy chains and two light chains attached by covalent bonds. The number of bonds varies with the Ig; the number of dimers varies with the class. A number of fragments (generated by enzymatic cleavage) can be described, including Fab, the antigen-combining fragment, and Fc, the crystallizable fragment, which binds to Fc receptors found on cells of the innatue immune system (e.g., NK cells, macrophages, neutrophils and mast cells).¹¹

Calcineurin Inhibitors

Calcineurin is a protein phosphatase that dephosphorylates and thus activates the transcription factor nuclear factor of activated T cell (NFATc). Upon activation, NFATc translocates to the nucleus and upregulates IL-2 expression of regulatory proteins.

Chemistry–Structure Relationship

Cyclosporin A (CsA), now known as cyclosporine, is the most important immunosuppressive drug for human transplantation and the treatment of selective autoimmune disorders.^4,30 CsA is one of nine cyclosporins (A through I), each a cyclic peptide drug (Figure 31-3) isolated from the fungi Cylindrocarpon lucidum and Trichoderma polysporum. An M designation, when present, indicates a metabolite. The drug is both very lipophilic (hydrophobic) and must be solubilized before administration.⁴ The oral preparation is a soft gelatin capsule (Sandimmune) or a (newer) microemulsion formulation (Neoral). The intravenous preparation is an ethanol–polyoxyethylated castor oil mixture. Historically, CsA has been formulated in peanut oil (for treatment of ophthalmic ocular disorders in dogs); however, an approved product formulated for topical use is now available.

Figure 31-3 The chemical structure of selected immunomodulating drugs.

Mechanism of Action

CsA is a unique immunosuppressant in that it specifically inhibits T_h cells (both T_h1 and T_h2) early in their immune response to antigenic and regulatory stimuli⁴ without affecting suppressor cells. Suppression occurs as CsA binds to cyclophilin, a cytoplasmic receptor protein, forming a heterodimeric complex. This complex then binds to calcineurin. Binding of calcineurin inhibits calcium-stimulated phosphatase that dephosphorylates the regulatory protein. As such, CsA prevents transcription of T cell genes enhanced in response to T cell activation. Transcription mediated by IL-2, certain proto-oncogenes, and selected cytokine receptors are particularly affected.⁴ IL-2 production (and thus T cell proliferation and antigen-specific cytotoxic T lymphocyte generation) also is attenuated because the expression of TGF-β, a potent inhibitor of IL-2, is increased.⁴ B cells are not affected. The drug is most effective when administered before T cell proliferation has occurred. In addition to these immunomodulatory effects, CsA also affects other inflammatory cells. CsA inhibits skin mast cell numbers, survival, and response (secretory and histamine release) as well as secretion of IL-3, IL-4, IL-5, IL-8, and TNFα. Similarly, eosinophile response (release of granules and cytokines) and recruitment to allergic sites is impaired. CsA prevents TNFα-mediated late phase reactions, thus inhibiting IgE and mast cell–dependent cellular infiltration in the skin and bronchial mucosa. However, CsA does not inhibit IgA secretion or IgG and IgM formation in dogs and has no apparent effect on serum allergen-specific IgE levels, intradermal tests, or vaccination.

Surprisingly little information is available regarding immunomodulatory effects of CsA in dogs or cats. Using dermal microdialysis, Brazis and coworkers³¹ demonstrated that CsA at 5 mg/kg per day for 15 and 30 days decreased histamine, but not prostaglandin D₂, release in sensitized Beagles challenged with Ascaris suum.

Preparations

CsA is available in a variety of preparations, two of which are approved in the United States for use in animals. CsA was first formulated for oral use in humans as vegetable oil. Oral absorption in this preparation depends on emulsification by bile acids. Poor oral bioavailability led to the formulation of a microemulsion preparation (modified CsA, ME), which, on contact with gastrointestinal fluids, disperses into a homogeneous monophasic microemulsion that mimics the mixed micellar phase of the standard formulation. In dogs the ME formulation offers a 35% bioavailability (Novartis Animal Health data on file).

Atopica is the veterinary-approved microemulstion preparation of CsA intended for systemic use in both capsules and solutions. A 0.2% ophthalmic ointment (Optimmune) is also available. A number of human-approved drugs are available, including an injectable solution, an oral solution (100 mg/mL), an ophthalmic emulsion (0.05%), and a variety of capsule sizes for the standard and the microemulsion-modified preparation. Included are a number of generic-modified CsA products. However, the therapeutic equivalence that has been established for these products in humans should not be assumed to be therapeutically equivalent to Atopica in animals. Indeed, one preparation made by IVAX Pharmaceuticals and sold by selected chain pharmacies appears to result in much higher concentrations in dogs compared with other preparations on the basis of samples submitted through the author’s laboratory. Monitoring should be the basis for assessing the appropriate dose–concentration relationship for oral human CsA products used in dogs or cats; owners might need to be aware if and when a pharmacy switches from one human generic to another such that prophylactic monitoring might be implemented.

Clinical Pharmacology

The pharmacokinetic behavior of CsA is complex, resulting in marked variability in the relationship between dose and blood concentrations.³² Variability reflects not only differences in both hepatic and intestinal metabolism (by CYP3A4) but also differences in P-glycoprotein among various tissues.³² The disposition of CsA has been well reviewed in the dog.³³ Absorption after oral administration is slow and incomplete. The complex lipid nature of CsA complicates absorption by being dependent on bile acids, which generate a microemulsion. In humans oral bioavailability of the capsule ranges from 20% to 50% but is improved by 10% to 20% in the microemulsion form which is not dependent on bile acids.^4,34 Peak concentrations occur 1 to 4 hours after oral administration in human beings. When the capsule—but not the microemulsion—is administered with a fatty meal, absorption is slowed. Studies suggest that decreased bioavailability of CsA after oral administration may reflect activity of drug-metabolizing enzymes of the intestinal epithelium³⁵ or P-glycoprotein–mediated drug efflux.

The oral bioavailability of microemulsion in dogs is 35% compared with the 20% of the oral preparation.³³ Bioavailability of orally administered CsA is approximately 25% to 30% after multiple oral administration in cats (n = 6). Food may impair the absorption of CsA; peak concentrations in fasted dogs were 20% higher than in nonfasted dogs in one study, although time to peak (approximately 1.5 hours) was the same.³³ The drug is not predictably absorbed topically after transdermal administration (unpublished data, Boothe 2007). CsA is widely distributed, characterized by a large volume of distribution (13 L/kg in humans). The drug accumulates in erythrocytes (accounting for 50% or more of the drug in humans), and leukocytes (accounting for 10% to 20% of circulating drug in humans).⁴ Consequently, monitoring of whole blood rather than plasma or serum is recommended. Remaining circulating drug is bound to plasma lipoproteins. Further, concentrations in skin are up to tenfold higher than in blood, although this is based on homogenate data (as reviewed by Guaguère and coworkers³³). In contrast, largely because of the influence of adenosine triphosphate–binding transporters P-glycoproteins, especially the ABCB1 cassette (P-glycoprotein, MDR1 gene product), little CsA crosses the blood–brain barrier.

CsA is metabolized to a large number of metabolites predominantly by the liver, although sufficient metabolism occurs by intestinal enterocytes that oral bioavailability is affected. Microflorae also may contribute to metabolism.³⁷ CYP3A4 (commonly associated with P-glycoprotein or other efflux pumps) plays a major role in metabolism; many of the drug interactions involving CsA also involve CYP3A4 or associated glycoprotein. More than 25 to 30 metabolites have been documented in humans and dogs.^32,38,39 Metabolism is targeted primarily toward the side chains rather than the ring structure and reflects hydroxylation, demethylation, sulfation, and cyclization. The major hydroxylated metabolites (AM1 and AM9) are further metabolized, contributing to the complex metabolic profile. Both AM1 and AM9 may contribute 10 to 20% of CsA activity, with AM1 contributing 27% of trough activity.⁴⁰ In humans AM1 accumulates with chronic dosing and ultimately may surpass CsA, and monitoring assays might ideally detect the active compounds.³⁹ They are detected to variable degrees by selected immunoassays based on a monoclonal antibody (e.g., Abbott TdX, Architect systems, Seimens Dimension).^41,42 Selected laboratories may also offer a high-performance liquid chromatography (HPLC)–based system that, may or may not (generally not) quantitate the metabolites.³⁹ Ultimately metabolism continues until the drug is totally inactivate the drug, although this has not been proved conclusively.⁴ Metabolites are excreted in bile and feces, with less than 2% of unchanged drug eliminated in the kidneys of dogs. CYP3A4 is largely responsible for metabolism.

The half-life of CsA in dogs is quite variable, depending on the investigator and assay. In blood the half-life ranges from a low of 5 hours (HPLC) to a high of 18 hours (using fluorescent polarized immunoassay [FPIA]); 29 hours was reported for serum.⁴³ That reported for Atopica, the product approved for use in dogs, is 4.5 hours, a length more consistent with that measured in the author’s therapeutic drug monitoring laboratory using FPIA. In a manufacturer-sponsored affinity colony-mediated immunoassay (ACMIA) study, Steffan and coworkers⁴⁴ reported the disposition of CsA (5 mg/kg) after single-dose oral administration of either capsules or solution in fasting or fed conditions using a randomized crossover design with a 1-week washout between studies (Table 31-3); food decreased peak concentrations and area under the curve by 22%.

Table 31-3 Disposition of Cyclosporine Reported By Various Investigators

In cats elimination half-life of CsA is 8 hours, which was similar to that after intravenous administration. Liver disease will decrease clearance of CsA substantially. However, for the nonmicroemulsion form, decreased oral absorption in the face of decreased bile may balance decreased clearance. Monitoring is recommended in the presence of hepatic or gastrointestinal disease.

Mehl and coworkers⁴⁵ reported the disposition of CsA in cats (n = 6 male) after single-dose intravenous (1 mg/kg) and multiple-dose (14 days; 3 mg/kg twice daily) as Neoral (see Table 31-3). Variability in plasma drug concentrations among cats and across time underlines the importance of monitoring if treating life-threatening conditions. After multiple-day (7 to 14 days) oral administration (3 mg/kg), mean (peak) plasma concentrations at 2 hours were 740 ± 326 (7 days) and 655 ± 285 ng/mL (14 days), whereas trough concentrations were 332 ± 237 and 301.5 ± 250 ng/mL, respectively. Oral bioavailability was only 25% to 29%.

Because cats may find the oral preparation unpalatable, the oral solution can be given diluted in olive oil. The intravenous preparation (4 to 6 mg/kg as a 4-hour intravenous infusion) can be given to animals for which oral administration is not possible.⁴⁶ Ocular administration might serve as an alternative route for systemic delivery of CsA in cats.⁴⁷ After ocular administration of either an oral preparation or an ocular preparation of CsA in olive oil, (5 mg/kg in each eye as a 10% solution) peak concentrations of 450 to 1033 ng/mL (oral preparation) and 288 to 648 ng/mL (ocular) were achieved, with an absorption lag time ranging from 0 to 1.34 hours for the oral solution and 0.27 to 1.2 hours for ocular preparation. The elimination half-life ranged from 2.41 to 10.04 hours (oral), and 3.09 to 15.75 hours (ocular), respectively. Blood concentrations were sufficient to inhibit lymphocyte activity as measured in vitro, leading the authors to conclude that ocular administration of CsA in an olive oil vehicle might be a reasonable alternative to oral, or even intravenous, administration in cats intolerant to the latter.

Drug Interactions

Novartis⁴⁸ provides a transplant drug interactions monograph that cites more than 600 references and delineates cyclosporine interactions involving more than 300 drugs. The list of drugs that might interact with CsA is extensive. The manual is available on the Novartis website at no charge and should be consulted when treating patients receiving additional drugs. Selected interactions can be found in Table 31-4. This review will focus on some of the more common interactions, including those used intentionally.

Table 31-4 Cyclosporine Drug Interactions

The enzyme that metabolizes CsA (CYP3A4) is responsible (in humans) for approximately 30% of all drug metabolism; many of CsA drug interactions occur with this enzyme. Further, CsA is a target of P-glycoprotein, another site characterized by a substantial number of CsA–drug interactions.^4,49 The risk of drug interactions is another indication of the need for therapeutic drug monitoring as a guide to proper dosing regimens. CsA elimination is accelerated, probably in part because of the induction of drug-metabolizing enzymes, by phenytoin, phenobarbital, rifampin, and sulfamethoxazole–trimethoprim combinations, and others. Dexamethasone also is an inducer of CsA.³² Its elimination is decreased by amphotericin B, erythromycin, and ketoconazole.⁴ CsA also appears to alter the oral absorption of other drugs.³⁵ CsA use with other immunosuppressive drugs may benefit from these interactions, including glucocorticoids.⁴

The inhibitory effect of ketoconazole on intestinal epithelial and hepatic drug metabolism and on P-glycoprotein efflux may be of therapeutic benefit in patients receiving CsA by decreasing hepatic clearance and increasing oral bioavailability.^35,50–53 Ketoconazole may also decrease the lipoprotein that binds CsA, resulting in higher concentrations of free CsA.⁵¹ Studies with ketoconazole in humans found the dose of CsA to be reduced by approximately 70% to 85%.⁵⁴ The use of ketoconazole in conjunction with CsA as a means of decreasing drug cost has been well accepted in human transplant patients.⁵¹ The two drugs have been used safely for up to 47 months in one study reducing the CsA dose as much as 88%.⁵¹ Although the effects emerge rapidly, with 62% of the effect is apparent by day 7, the maximum inhibitory effect may not be present for 12 months. This has implications regarding monitoring and supports the need for collection of peak and trough samples such that the impact of ketoconazole on drug elimination half-life might be determined.

The effect of combining ketoconazole with CsA has been studied in dogs.⁵⁵ Ketoconazole was studied at doses ranging from 1.25 to 20 mg/kg per day, with the magnitude of inhibition increasing with the dose of ketoconazole above but not below 2.5 mg/kg.⁵⁵ Clearance was reduced by 85% at 10 mg/kg per day. Differences in clearance did not result in significant differences in oral bioavailability. In their review, McNaulty and Lensmeyer⁵⁶ indicated that in dogs, CsA half-life will increase over twofold and decrease the concentration of active metabolites in response to 2.5 to 10 mg/kg ketoconazole. Up to 75% of the CsA dose could be reduced experimentally in Beagles concurrently receiving a dose of ketoconazole of 13.6 mg/kg per day.⁵⁷ In a study in dogs with perianal fistulae, Mouatt⁵⁸ examined the impact of ketoconazole (10 mg/kg once daily) on CsA concentrations (1 mg/kg twice daily). Samples were collected 12 hours after the last dose (duration not clear). Data were not provided on all dogs, but the author noted that at 1.1 mg/kg twice daily of CsA, all dogs exceeded 200 ng/mL at through (12 hours); nine dogs exceeded 900 ng/mL, and two dogs exceeded 1500 ng/mL. Concentrations varied by 10% to 40% in the same dog despite no dose change. This may have reflected variability in time to steady state, which took 2 to 4 weeks. A trough concentration of 200 ng/mL was targeted. Although 8 dogs maintained concentrations of 220 to 520 ng/mL with CsA doses as little as 0.35 to 0.55 mg/kg twice daily, one dog required only 0.16 mg/kg twice daily to maintain 159 to 225 ng/mL, whereas three others required 0.95 to 1.1 mg/kg twice daily to maintain 120 to 235 ng/mL. This marked variability in response to ketaconozole appears to occur in clinical patients as is suggested by samples submitted to the author’s therapeutic drug monitoring laboratory. Marked variability occurs not only in concentrations, but in the time to steady-state, which in turn determines when monitoring should be implemented. For example, the author’s laboratory has demonstrated prolongation of the half-life of CsA in a patient from 4 hours (as reported in normal dogs) to over 150 hour. Steady state was not achieved in this patient until approximately 4 weeks, causing CsA concentrations to continue to increase despite a decrease in dose that was based on monitoring at 1 week. Yet, in other patients, half-life has been less than 12 hours, despite ketoconazole therapy. Detecting these diffrences requires collection of peak and trough samples such that half-life and time to steady-state can be determined in each patient.

The simultaneous administration of ketoconazole with CsA also has been studied in cats. McNaulty and Lensmeyer⁵⁶ prospectively studied the impact of a two doses of ketoconazole (10 mg/kg at 24 and 0.5 hr) before a single dose of CsA (4 mg/kg intravenously) in cats (n = 5) using a randomized crossover design with a 14-day washout. Concentrations of CsA were detected using HPLC. Clearance was reduced from 2.73 ± 0.3 to 1.22 ± 0.18 mL^∗kg/min, resulting in an elimination half-life prolongation from 10 ± 0.9 to 21 ± 3 hours.

Several studies have examined the impact of cimetidine, an inhibitor of CYP3A4, CYP2D6, and CYP1A2 on CsA concentrations. Cimetidine also is a substrate for P-glycoprotein. The results of the studies are contradictory, perhaps reflecting differences in duration of therapy and species. D’Souza and coworkers⁵⁹ found that 5 days of cimetidine therapy significantly decreased CsA clearance, increased volume of distribution (perhaps by impacting P-glycoprotein in distribution tissues) and prolonged elimination half-life in rabbits, whereas Bar-Meir and coworkers⁶⁰ found that short-term administration of cimetidine had no effect on CsA metabolism in rats. Shaefer and coworkers⁶¹ found that 7 days of dosing with cimetidine or famotidine did not affect CsA pharmacokinetics in healthy men. Daigle⁶² explored the impact of cimetidine (15 mg/kg orally every 8 hours for 8 days) on the disposition of CsA (5 mg/kg orally per day; the last 3 days of cimetidine administration) in dogs using a randomized crossover design with a 14-day washout. Significant differences could not be demonstrated for C_max or area under the curve the power to detect a significant change was not addressed. The author’s therapeutic drug monitoring laboratory has identified some patients for which a cimetidine–CsA interaction may be present, but, other patients for which no effect could be measured.

Among the other drugs that impair CsA elimination or compete with efflux pumps include itraconazole, the calcium channel blockers such as diltiazem, and the macrolide antibacterial erythromycin.⁵⁰ In humans, diltiazem decreases the CsA dose by approximately 30% to 50%.⁵⁴ Other drugs that influence CYP activity should be expected to potentially affect CsA. For example, in the author’s laboratory, a cat receiving azithromycin (5 mg/kg once daily) along with CsA (5 mg/kg twice daily), exhibited peak concentrations exceeded 4500 ng/mL, presumably in part resulting from an elimination half-life that exceeded 150 hours. Azithromycin also competes for P-glycoprotein. Other drugs that induce P-glycoprotein might decrease CsA concentrations. For example, P-glycoprotein is upregulated in the duodenum of dogs receiving glucocorticoids.^62a

Side Effects

CsA is characterized by a narrow therapeutic index in human patients, with renal toxicity the primary adverse effect. Renal tubular cells develop hyperuricemia (worsened by diuretics) and hyperkalemia (a renal tubular and erythrocyte ion channel effect).⁶³ Hepatic injury also occurs. Although less common than renal dysfunction, the risk of severe hepatic damage is markedly increased when CsA is used in combination with cytotoxic drugs. CsA also increases the incidence of gallstones in human patients. However, in contrast to humans, renal and hepatic toxicities do not appear to be in dogs and cats. Risk factors, such as concurrent administration of nephroactive or nephrotoxic drugs, or renal transplantation have not been addressed in dogs or cats. Hyperlipidemia also has been a reported side effect in humans, particularly in patients receiving glucocorticoids. Other side effects reported in humans include neurotoxicity, gastrointestinal upset, and hypertension.⁴ Development of B cell lymphoma also has been reported in humans; an incidence 10% has been reported in cats undergoing renal transplantation, with mean time to onset of 9 months. ^63a Side effects in dogs include gastrointestinal upset and dermatologic or mucosal abnormalities. Vomiting may occur in up to 40% of dogs, although it may be intermittent and short in duration. Diarrhea occurs less commonly (16% to 18%).Vomiting may be more likely when CsA is combined with ketoconazole, but this may reflect higher CsA concentrations. Dermatologic abnormalities reported in dogs include hair loss (possibly reflecting hair growth and pushing of hair from follicles), gingival hyperplasia, and gingivitis in up to 33% of dogs.⁵⁸ In one study,⁵⁸ hair loss resolved by 7 weeks, although hairy coats were thinner at study end (see Therapeutic Use). Hyperplasia may reflect an imbalance of fibroblast formation and collagen degradation by collagenase, although stimulation of TGF-β also has been suggested.³³ Stimulation of TGF-β also stimulates extracellular matrix and decreases degrading proteases. Treatment with antimicrobials (metronidazole, spiramycin) may be useful for treating hyperplasia.⁵⁸ Skin healing might be supported rather than inhibited, as occurs with glucocorticoids.⁶⁷

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