Aust. N.Z.. I . Surg. 1992,62,250-255

REVIEW ARTICLE METHYLXANTHINES IN SURGERY: A BRIGHT FUTURE? JOHN A. TUCKEY, BRYANR. PARRYAND JOHN L. MCCALL Department of Surgery, University of Otago, Dunedin, New Zealand

Introduction Even before Dr H. H. Salter's publication in the Edinburgh Medical Journal of 1859 advocating the use of strung black coffee in the treatment of asthma, methylxanthines were being mentioned in medical texts.' Now, over 100 years later, methylxanthines have gained acceptance for use in asthma therapy and their sphere of application is expanding rapidly, particularly in relation to surgical practice. Recent research in the pathogenesis of Gram-negative sepsis, the adult respiratory distress syndrome and cancerassociated cachexia, has identified methylxanthines as potential therapeutic agents of interest to surgeons, anaesthetists and intensivists alike. Their adjuvant use with established treatment regimens of these serious and often fatal conditions may provide patients with added hope for a successful outcome.

The methylxanthines Methylxanthines are a family of compounds, the most important of which are theophylline, caffeine and theobromine. Caffeine and theobromine are ingested in large amounts in society, being found in the coffee plant Coffea arabicu, tea leaves from Thea sinensis, cocoa from Theobroma cacao and soft drinks from the Cola acuminata tree.2 In surgical practice, the relevant members of this group are pentoxifylline and theophylline (Fig. 1). Since their introduction into the clinical arena, few new derivatives have been developed. One exception is pentoxifylline (Trental, Hoechst, Frankfurt, Germany), a derivative closely related to theobromine.

Current uses With the increasing understanding of the role that inflammation plays in the pathogenesis of asthma, the trend has been for topical steroids to relegate theophylline to third or fourth line therapy, depending on the clinical ~ituation.~ Nevertheless, theophylline Correspondence: MI B. R. Parry, D e p m e n t of Surgery, Po Box 913, Dunedin, New Zealand. Accepted for publication 4 September 1991.

CH3

CH3

Theophy IIi ne

Caffeine

CH3

Pentoxifylline

Fig. 1. Structure of common methylxanthines.

and other methylxanthines do have anti-inflammatory properties. They have been demonstrated to stabilize and inactivate a number of inflammatory cells,425 inhibit the accumulation of polymorphonuclearleucocytes in bacteria-challenged lungs: and attenuate the microvascular leakage observed in the lungs of animal models induced by allergens or inflammatory mediator^.'.^ In contrast to theophylline, pentoxifylline is advocated in a wide variety of clinical situations. These centre around its use as a rheologic agent. It can increase red cell deformability , decrease blood viscosity and increase tissue oxygen tension.' Although advocated for use in peripheral vascular disease, the lack of well designed trials has hampered the establishment of pentoxifylline in the treatment of this condition. lo Other applications include venous ulcer disease, diabetic retinopathy, improving soft compromised surgical flap s u r ~ i v a l , ' ~radiation .'~ tissue n e c r ~ s i s and ' ~ male infertility. l 6

''

'*

Mechanism of action Methylxanthines are competitive inhibitors of phosphodiesterases, a family of enzymes that degrade cyclic AMP (CAMP). Inhibition of these enzymes leads to elevated cellular levels of CAMP, an intracellular messenger that plays a key role in regulat-

METHYLXANTHINES IN SURGERY

25 1

ing many important functions and enzyme systems Table 1. Metabolic effects of methylxanthines within the cell (Fig. 2). In addition they antagonize Glucose metabolism the effects of adenosine, also a modulator of intraPotentiate the action of insulin6’ cellular cAMP levels, at adenosine receptors. Potentiate the glucose induced secretion of insulin34 Examples of the effect of such alterations in Potentiate the amino acid induced secretion of cAMP flux are seen in the metabolism of energy insulin”.68 substrates. A summary for glucose and lipid Smooth glucose fluctuations in diabetics6’ metabolism is set out in Table 1. Methylxanthines Lipid metabolism promote the more efficient utilization of carbohyStimulate lip01ysis~~ drate in diabetes and tend to reduce the insulin Elevate plasma free fatty acid levels69 resistance found in these patients. Furthermore, alterations in the synthesis and secretion of a number of hormones and chemicals have been recorded, Theophylline is known to competitively antagonize including insulin, free fatty acids and growth both Al and Az receptor subtypes at clinical conhormone.I8-*’ centrations and it is thought that many of the extraUntil recently it has been widely believed that the pulmonary effects of methylxanthines are due to bronchodilator effects of theophylline can be attribthis.* Enprofylline, a novel xanthine with minimal uted to the elevation of cAMP levels via phosphoactivity against adenosine receptors, is not able to diesterase inhibition.” However, both theophylline reproduce several of these effects.29 Pentoxifylline and caffeine are poor phosphodiesterase inhibitors has even less adenosine antagonistic activity than at therapeutic concentrations, these levels being enpr~fylline.~’ It appears likely that the bronchotwo orders of magnitude less than required for dilatation observed with methylxanthines is not due effective i n h i b i t i ~ n . ~ ~Persson, -’~ somewhat iconoto antagonism of these receptors, as enprofylline is clastically, stated that 20 years of research in the more potent in this regard than t h e ~ p h y l l i n e . ~ ~ area had not produced a phosphodiesterase inhibitor These mechanisms could explain most of the with an acceptable clinical response.” clinical effects observed with these agents. HowAdenosine receptors are widely spread throughever, experimental data have not confirmed this and out the body, being present on myocardial cells, the basis of several of their important actions reairway smooth muscle cells, adipocytes, coronary blood vessels, and in the central nervous s y ~ t e m . ~ ~ - ~ ’mains unknown.’’ Methylxanthines are able to relax airway smooth muscle induced by a wide variety of Two receptor subtypes have been identified, A, and proposed asthma mediators, including amines, pepA2 receptors, but there is experimental evidence to tides, prostaglandins and leukotrienes, making it suggest that others may exist.28 These receptors likely that methylxanthines are operating by other mediate an alteration in cAMP levels by a Guanomechanisms in the lung and probably elsewhere sine triphosphate (GTP)-dependent mechanism. a l ~ o .It~is, interesting ~~ to note that these mediators are also ‘bit’ players in inflammatory and immunological cascades. Extracellular fluid ormone

Methylxanthines and cytokine expression Plasma me

lntracellular lluid

u u

/?(

ATP

pnOspn~Wa+e

cAMP

5’-AMP

Enzyme amplification

1

Effects on Metabolism (lipid, glucose, protein) Hormone synthesis Gene expression

Fig. 2. The cAMP system, illustrating the pathway of cAMP generation following hormone activation, and the downstream effects of this ‘second messenger’ on cellular function. R is the stimulatory receptor, G the GTPregulatory unit and AC the adenylate cyclase enzyme.

Cytokines are a subgroup of peptide regulatory factors with prominent immunoregulatory functions.32 Their sphere of influence was initially thought to be. limited to the immune system. However it is now apparent that it also encompasses a wide range of inflammatory and metabolic processes. 32,33 Members of this group include tumour necrosis factoralpha (TNF-a), interferons and the interleukins. Recently, methylxanthines have been found to modify the production and action of several cytokines including tumour necrosis factor (TNF-a) and interleukin- 1 (IL-1).34-36 As there is strong evidence implicating TNF-a in the pathogenesis of septic shock, the adult respiratory distress syndrome and, to a lesser degree, cancer cachexia, it is logical to consider the potential benefits of methylxanthines in these conditions. Of the methylxanthines,

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pentoxifylline is the most effective inhibitor of firmed in humans and opens the door for further T N F - u . ~It blocks TNF-a mRNA accumulation, studies evaluating its role in the treatment of severe probably at the level of gene tran~cription.~~ In sepsis and its sequelae, including adult respiratory addition pentoxifylline is able to reverse the activadistress syndrome (ARDS). tion process once it has begun and counter some of the direct effects of TNF-a on ce11s.28,38,39 These Methylxanthines and ARDS effects include IL- 1 and TNF-a induced superoxide The adult respiratory distress syndrome (ARDS) is production, neutrophil lysozyme release and inhibia clinical diagnosis, loosely defined, but usually tion of neutrophil c h e m o t a x i ~ .The ~ ~ latter event encompassing the features listed in Table 2. Multiseems to occur by a novel CAMP-independent acple risk factors to the development of ARDS intion.28In patients with functional neutrophil defects, clude pulmonary aspiration, pneumonia, massive such as lazy leucocyte syndrome or myelodysplastransfusion, septicaemia, bums and cardiopulmotic syndromes, pentoxifylline has restored normal nary bypass.52 Sepsis with a deleterious systemic chemotactic capacity in vino.40 Dexamethasone also response is accompanied by ARDS in about a third inhibits TNF-a production, at the level of transcripof cases.53 Despite a wide diversity of illnesses that tion and translation, but unlike pentoxifylline it cannot halt TNF-a production once it has b e g ~ n . ~In ~ . ~ ’predispose a patient to ARDS , there is a uniformity in the clinical and pathological findings, suggesting contrast to dexamethasone, the application of pena common pathway in its pathogenesis that may be toxifylline is not limited to prophylaxis alone and amenable to intervention.” TNF-a produces a similar this important distinction makes it a potentially useful picture in animal studies, with alveolar oedema, therapeutic agent in clinical practice. haemorrhage, septal thickening and perivascular neutrophil infiltrate^.^^ This damage can be attributed to the vascular hyperpenneability, oxygen free Methylxanthines and sepsis radicals, arachadonic acid metabolites and the proTNF-a plays a pivotal role in the pathogenesis of coagulant surface on vascular endothelium which ~ e p s i s .Indeed ~ ~ , ~it~is now claimed to fulfil Koch’s are induced by TNF-a.55-58 TNF-a antiserum atpostulates as an aetiological agent.42 Animals extenuates these effects.59 Alveolar lavage fluid from posed to recombinant TNF-a (rTNF) display hypopatients with ARDS has revealed very high levels tension, metabolic acidosis, haemoconcentration, of TNF-a whereas circulating levels in the same hyperglycaemia, hyperkalaemia and a vascular leak patients were only modestly elevated, suggesting a syndrome - signs which are also found in septic substantial local production of this cytokine.60 Autopsy findings are similar to those Neutrophils are thought to play an important role observed in severe sepsis, with pulmonary inflamin the cause of endothelial and epithelial injury seen mation and haemorrhage, acute renal tubular necroin ARDS and are the focus of the action of pentoxisis, gastrointestinal ischaemia and n e c r o ~ i s . ~ ~ -f ~ ~l l i n e Pentoxifylline .~~ inhibits TNF-a induced Further, the infusion of antibodies to TNF-a protect neutrophil adherence and superoxide anion producagainst endotoxin-induced septic shock and organ tion in ~ i t r o . Survival ~ , ~ ~ rates have been signifidamage as well as improving It has cantly improved by pent~xifylline~~ and a new been suggested that the targeting of the cytokine derivative of pentoxifylline, HWA 138 (Hoechst), pathway may bring great advances in the treatment has also proven to be effective in acute lung injury of this ~ondition.~’Those readers interested in a models .61,62 more extensive account of the relationship between Recent evidence has implicated the inflammatory TNF-a and sepsis are directed to a number of excelcytokine network in the pathogenesis of ARDS. It lent articles published on the remains to be seen if TNF-a inhibitors such as penExperimental studies with pentoxifylline in septoxifylline can be shown in clinical trials to improve sis have been promising. Pentoxifylline in rats survival rates and gain a place in the treatment of inhibits lipopolysaccharide (LPS)-induced TNF-a this condition. production in a dose dependent fashion.48 In a rat peritonitis model, those animals given pentoxifylTable 2. Features of the adult respiratory distress line developed less adhesions, abscesses and had sianificantlv fewer deaths than the control g- r o-u ~ . ~ syndrome54 ~ S;rvival rates have been significantly improved and Acute respiratory impairment Organ injury prevented in mice* rats and Guinea Bilateral diffuse alveolar infiltrates on chest radiography pig^..^^-^' This protective effect is available whethHypoxaemia er pentoxifylhe is administered pre- or post-LPS Noncompliant lungs The abilitv of pentoxifylline to Prevent Absence of elevated uulmonarv, mew wedge Dressures an endotoxin-induced- TNF-a rise- has be& con-

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METHYLXANTHINES IN SURGERY

Methylxanthines and cancer There is some evidence to suggest that pentoxifylline may benefit cancer patients. Methylxanthines including pentoxifylline enhance the lethality of human tumour cells treated with alkylating agents and cisplatin in ~ i t r o . ~ ~ - " Various mechanisms have been suggested for this amplification of action, including the ability of xanthines to prevent the delays in the cell cycle produced by alkylating agents and thereby allowing inadequate time for cell repair.63 Phase I trials have been completed, and Phase II trials are underway using a dosage regimen of 1600mg/day of pentoxifylline, slightly more than the conventional regimen of 1200 mg/day . Further to, and independent of, such potential use as anti-cancer therapy, a recent publication has reported improved appetite, energy and well-being in a patient treated with pentoxifylline for metastatic lung cancer.% This was associated with a reduction in the TNF-a mRNA content of peripheral blood mononuclear cells. In v i m , pentoxifylline inhibits TNF-a protein production in the supernatant of cultured peripheral blood monocytes but not of IL-6, suggesting that it is acting as a selective immunomodulator of TNF-a , As cancer cachexia may be due to the effects of TNF-a or other cytokines, the use of methylxanthines to prevent or ameliorate the well known metabolic derangements seen in such patients is under active study. A more extensive review of this subject has been recently published.33

Summary Methylxanthines have been used in clinical practice for over 100 years, and although understanding of their mechanisms of action is growing their effects are not fully understood. Nevertheless the knowledge to date has brought about a general upsurge of interest in methylxanthines and the development of novel derivatives. Methylxanthines are poised to escape the confines of their traditional role as these agents are applied in novel ways to surgical illnesses such as septic shock, the adult respiratory distress syndrome, cancer cachexia and functional neutrophil disorders. Methylxanthines, alone or in combination with other compounds, may well become part of the surgeon's future stock-in-trade.

Acknowledgements This study was supported by the Cancer Society of New Zealand Incorporated. John Tuckey is the recipient of the Cancer Society's Todd Fellowship.

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Methylxanthines in surgery: a bright future?

Methylxanthines have been used in clinical practice for over 100 years, and although understanding of their mechanisms of action is growing their effe...
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