Recently, these drugs have been suggested for MS therapy (as have so many other therapies). This has stimulated the following search, currently only in the initial phase, on their mode of action in MS and a possible relation between MS and asthma.

Correlation between Asthma and MS

Luxurious epidemiological data should enable no doubt to the question, if asthma or other autoimmune diseases are found along with MS. Still, exactly here, a controversy is found. In an old study [1] MS seems to exclude bronchial asthma, rheumatoid arthritis and juvenile diabetes; case-reports can be found where the exceptions only seem to confirm this rule. However, in a big epidemiological study of 159,200 ptients [2], the association with asthma (among others) was confirmed. Also the title of some reports indicates a connection with asthma [3,4,5] (unknown while no abtract were published in my search).

MS-Therapy with beta₂-agonists?

Confirmation of an effect of beta₂-agonists upon MS was found in two studies only (Oct 9, 2001) but is still raising hopes among MS-patients. These two abstracts shall therefore be dealt with to a greater detail:

1. In an experimental study, published 1995, Wiegmann et al. [6] found that both pre-treatment and shortly delayed treatment with isopoterenol (a mixed beta-agonist) and terbutaline decreased the number of relapses in EAE. Generally, EAE caused an increased number of cellular beta.adrenergic receptors, but this pathological condition was normalized by terbutaline treatment.

2. In a small clinical study of 21 patients with SP-MS, Makhlouf et al.  [7] found that salbutamol induced a decrease in the amount of interleukin-12 [IL-12] producing monocytes and dendritic cells that lasted up to one week after treatment interruption. A lasting effect is not made with this study but an important start is made. The potential importance of this therapy must be conceived from knowledge of, what IL-12 may cause from studies where beta₂-agonists are commonly used: for treating or preventing asthmatic attacs.

Pharmacological properties of beta₂-agonists
of interest for MS research

In 1989, Hellstrand & Hermodsson [8] suggested a role for (endogenous) adrenaline (via lymphocyte beta₂-receptor activation) in the regulation of natural killer cells. The adverse effect of such stimulation was studied in leucocytes from leucaemia patients, which Talmadge et al. [9] found to contain beta-adrenergic receptors (type 1!) resulting in increased cAMP, in turn leading to down-regulation of TNF-alpha expression, which could be needed in that disease.

In the treatment (or prophylaxis) of asthmatic attacks, the sympathicomimetic effect of these drugs have been used for decades, but later years have given new evidence for a humoral and cellular effect as well (described as an antiinflammatory effect). Unfortunately, these effects are supposed to originate to an almost ridiculously amount of factors, with each study focussing on one or a few (not all candidates are cited here). In the following are given the results of a literature study concerning terbutaline and salbutamol (albuterol?) only, with other beta₂-agonists appearing incidentally.

T-lymphocyte chemokine receptor expression may be important in autoimmune and atopic disorders (to which asthma belongs, possibly also of autoimmune origin) which are believed to be influenced from inappropriate T helper cells type 1 [Th1]- and type 2 [Th2]-dominated responses [10]. Also in rheumatoid arthritis, beta₂-agonists delay the onset and reduce the severity of joint injury; simultaneously, these patients show increased cAMP production and inhibition of TNF-alpha production by beta₂-adrenergic stimulation [11]. Some of the lymphocytes are supplied with a beta₂-adrenergic receptor [beta2AR] and their activity considerably determined by stimulation of some adrenergic drugs on this. Sanders et al. [12] found that expression of the beta2AR binding site by Th1 cells, but not by Th2, establishes a physiologic mechanism for selective modulation of Th1 cell IFN-gamma production, in turn leading to TNF-alpha synthesis, provided that beta2AR stimulation occurs before cell activation by a B cell. In contrast to Th1 cells, terbutaline did not affect either IL-4 production by Th2 cells or subsequent IgG1 production by B cells. Although baseline levels of intracellular cAMP were similar in both subsets (Th1 and Th2 cells), terbutaline induced an increase in cAMP levels in Th1 cells only. The same study group [13] found that a detectable level of the beta 2AR is expressed on activated Th1 cells, but not activated Th2 cells. Moreover, IL-2 production is preferentially modulated by an endogenous and therapeutic ligand following Th1 cell activation [14].

The beta₂-agonists are known to decrease IL-12 production in monocytes of normal individuals through increased intracellular cAMP; thereby, they inhibit the development of Th1 cells, while promoting Th2 cell differentiation [15]. The role of this cytokine is described in the publication of Gately et al. [16], who also suggested that inhibition of IL-12 synthesis or activity may be beneficial in diseases associated with pathologic Th1 responses, such as MS, whereas recombinant IL-12 may have utility in the treatment of diseases associated with pathologic Th2 responses such as allergic disorders and asthma. That, in turn, leads to the cellular considerations.

In an experimental study, Malfait et al. [17] found that salbutamol not only reduced IL-12 and TNF-alpha release but also exerted a therapeutic action in collagen-induced arthritis. In another experimental study [18], the transient increase in cAMP levels caused by salbutamol was laid as basis for potentiating the effect of vaccinations.

Using allergen-specific T cells, Holen and Elsayed [19] tested four beta₂ agonists at therapeutically relevant doses. They found that these drugs could reduce a number of damaging cytokines (including IL-4 and IL-5) and thus suppress an underlying inflammatory process, dominated by TH2-like cytokine secretion. Salmeterol was more potent in this respect than feneterol, salbutamol and terbutaline, but differences occurred according to the property examined and can be assumed further differing in various cells and diseases. This inhibition of IL-4 was confirmed in another study [20].

In 1991, Mencia-Huerta et al. [21] suggested that beta₂-agonists, beside their bronchodilator effect, may regulate IgE-dependent processes. The same study group [22] found that beta₂-agonists potentiates the effect of IL-4. Moreover, they suggested that the effect of this drug could be explained by an increase of the production of Th2-type lymphokines [23]. Authors from the same study group [24] found that the beta₂-agonists both in vivo and in vitro potentiates the IL-4-induced IgE production and in a later study [25] showed that this was associated with an increase in intracellular cAMP levels. In (functional) contrast, Mohede et al. [26] found that all beta-agonists at low concentrations inhibit IL4 and IFN-gamma production by peripheral blood mononuclear cells, thus exlaining their use as anti-inflammatory drugs in asthma.

Various cytokines have been cited in the literature, making understanding of this mechanism further difficult to understand. One publication [27] incriminated IL-18 as a unique cytokine that enhances innate immunity and both Th1- and Th2-driven immune responses. Concidering renal cells, beta2AR activation downregulates TNFalpha and IL-6 production [28]. It sems to be a question, what is cause and what is caused by: considering renal macrophages; Nakamura et al. [29] also found a dose-dependant response to terbutaline (high doses increasing IL-6 production) and suggested that the (lower dose) terbutaline-induced down-regulation of IL-6 production was mediated by an inhibitory effect on TNF-alpha. Also in other experimental studies did terbutaline indirectly inhibit TNF-alpha production [30,31]. Also IL-8 is an important cytokine in inflammatory processes by functioning as a chemoattractant and as an activator of oxygen metabolism. Although Kavelaars et al. [32] found that beta₂-agonists potentiates certain steps in the production of IL-8, these agents also reduce their release with the net effect of enhancing production of IL-8 (and IL-10) by human monocytes. In contrast to this, Yoshimura et al. [33] found no effect of four beta-agonists on IL-8 production whereas they were found inhibit TNF-alpha and IL-1 beta production in a concentration-dependent manner. In vitro, Linden [34] found that beta-adrenoceptor stimulation, via an increase in intracellular cyclic AMP, adds to the IL-8 increase caused by the pro-inflammatory cytokine TNF-alpha.

Zetterlund et al. [35] found that four beta₂-agonists exhibited only minor effects on IL-1beta secretion from blood monocytes and no effect on leukotriene-B4 [LTB4, a granulocyte attactant, also increasing vascular permeability] secretion from either cell type. Earlier, Linden [36] had reported that these drugs inhibit both the release of eicosanoids and of IL-1 beta, but this effect is not mediated via beta2AR. Erlansson et al. [37] found that LTB4-secretion is reduced by terbutaline systemical and topical but not by topical administration alone. Ezeamuzie and al-Hage [38] compared two beta₂-agonists on various cytokines and found that unlike salbutamol, all the actions of salmeterol were independent of beta2AR. In particular, the inhibitory effects of salmetrol on human eosinophil functions are unlikely to be mediated via beta 2AR [39].

Without relating the effect to humoral factors, Bolton et al. [40] found that salmeterol pretreatment can reduce the plasma leakage and leukocyte adhesion to blood vessels through its action on beta2AR.

Old drugs for another old disease

The beta₂-agonists in general use are old, cheap drugs without patency protection and no firm is likely to pay for such an investigation of their possible beneficial effect in MS, nonwithstanding the cellular and humoral effects described above and, as concluded elsewhere, no money = no study. The clinical consequence of a longer therapy with these drugs remains obscure. Currently, the treatment of asthma with leukotriene receptor antagonists (montelukast, zafirlukast) is occupying the attention of asthma specialists. These drugs have been found superior in stress-induced asthma, but their effect in severe, chronical asthma seems to be inferior beta₂-agonists. Generally, studies are referring them as „superior to placebo,“ without considering the ethical consequences of such investigations.

Let us therefore continue the deductions, as far as this is possible without employing the pharmaceutical industry.

The use of inhaled salmeterol 4 weeks caused no clinically significant anti-inflammatory action as measured in cellular function and cytokine levels of asthmatic patients [41]. To criticize in this study is, however, the topical use and relatively short duration of therapy. In asthmatic patients, however, Calhoun et al. [42] found that salmeterol therapy alone does not meaningfully reduce inflammation but, on the other hand, neither cause amplified inflammation. Cho et al. [43] found that (S)-albuterol (identity with S-salbutamol presumed but not yet confirmed) may even have adverse effects in asthma control by activating mast cells to produce inflammatory mediators such as histamine and IL-4.
 What may be benificial in autoimmune diseases is easily damaging in neoplastical disorders. Due to the described differential effect on T helper cells, Huang et al. [44] concluded that „beta₂-agonists, despite their effect in symptomatic rescue in asthma, should not be used indiscriminately as long-term therapeutic agents.“

Unfortunately, chronic use of the beta₂-agonists results in the rapid desensitization of beta2AR and, therefore, the inhibitory effect of cyclic AMP on lymphocyte activation is attenuated [45,46]. Moreover, Kankaanranta et al. [47] found that eosinophil apoptosis is delayed in asthma under this treatment. Thus, beta₂-agonists might contribute to the prolonged eosinophil survival through inhibition of apoptosis and thus may worsen eosinophilia in asthmatic patients. In accordance with this observation, Coqueret and Lagente [48] found that beta₂-agonist potentiate the IgE production. Finally, in a study of leukotriene receptor antagonist, terbutaline was found to increase nitric oxide in exhaled air as indicative of inflammation [49]. Throughout the last century, incidence and mortality from asthma has increased and this has been related to the previous therapy [51] (as it was earlier related to the non-specific beta-agonists). There is, however, a tendency of making old drugs bad when new drugs are introduced. In contrast, Howarth et al. [50] found no indication that the chronic inflammatory process in asthma patients was affected by beta₂-agonists. Another mechanism for explaining a paradoxical increase in asthma morbidity and mortality associated with the chronic use of short-acting beta₂-agonists was suggested by Agarwal and Marshall [51]: these drugs induce a shift in the human type-1/type-2 cytokine balance toward a type-2 response (difference to Th1/Th2 not understood).

Competing agents with similar effects

A number of highly potent Phosphodiesterase (PDE) inhibitors are being developed for the treatment of various autoimmune diseases, among them MS [52,53,54]. Also these drugs have the potential of modulating the immune responses from the Th1 toward the Th2 phenotype, probably while similarly increasing intracellular cyclic AMP. Also these drugs have have complex (badly understood) inhibitory effects within in vivo achievable concentration ranges on Th1-mediated immunity, whereas Th2-mediated responses are mostly unaffected or enhanced. One of the drugs, Ibudilast, which has been used successfully against asthma and cerebrovascular disease in Japan, ameliorated the severity of acute EAE by prophylactic but did not modify the course of the disease when given after the onset of EAE [55]. PDE-IV-Inhibitors are more effective than their predecessors and their activity increased in the presence of beta-agonists [56]

Concerning the ability to inhibit IL-8 generation, considerable synergism between salbutamol and the PDE4 inhibitors has been reported [57]. T-cell chemotaxis induced by platelet-activating factor (PAF) and IL-8 can be attenuated by inhibition of phosphodiesterase activity and raised intracellular cAMP levels. Not only beta₂-agonists and PDE-4 inhibitors have this effect, but even theophylline, a nonselective PDE-inhibitor, is acting that way [58]. Where beta₂-agonists and theophylline are commonly considered as antiasthmatic drugs due to their bronchodilator effect, the anti-asthmatic effect has recently been suspected to be due to their anti-inflammatory actions [59].
 Also ‚very late antigen 4 antagonists‘ [60] have been suggested as anti-inflammatory agents, to be used against both asthma and MS.

In conclusion,

beta2-agonists may help ameliorate MS by increasing cAMP in Th1 cells, with reduction in TNF-alpha, other damaging humoral factors and their cellular consequences. The clinical basis for a beneficial effect is currently very weak, but research in this issue is being carried out. However, chronical therapy with short-acting beta₂-agonists may result in the opposite effect while newer, long-acting drugs do not resample the better investigated drugs salbutamol and terbutaline in a number of effects. Utilizing the cellular and humoral effect of beta₂-agonists may then be interesting if downregulation of the receptors can be prevented simultaneously.

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Inserted November 7, 2001
(further elaboration necessary!)