2015 July-August; 36(4): 187–191. ISSN: 1971-145X
Published online 2015 December 28. doi: 10.11138/gchir/2015.36.4.187.

Drug-induced retroperitoneal fibrosis: short aetiopathogenetic note, from the past times of ergot-derivatives large use to currently applied bio-pharmacology

C. ALBERTI

LD of Surgical Semeiotics

Corresponding author: Contardo Alberti, e-mail address: eneide94@gmail.com

Abstract

Among the secondary forms of retroperitoneal fibrosis (RPF), that drug-induced shows very intriguing aspects given both the broad range of involved pharmaceuticals and the considerable interest arisen from the related pathogenetic mechanisms. The particular incidence, in the last four decades past century, of the RPF due to long-term use of ergot alkaloid derivatives (ergotamine, methysergide, pergolide, bromocriptine, cabergoline) and specific L-dopa derived agents, such as methyldopa, as well as to different analgesics, came progressively down given that their long-term use for either the prevention of migraine attacks or the therapy of chronic pathologies (Parkinson’s disease, prolactinoma, pain management, etc) has been, year after year, supplanted or even made unavailable in many countries. More recently, instead, the occurrence of the RPF has been sometimes identified with the use of antitumoral chemotherapeutics, such as carboplatin and methotrexate, and, just lately, as an unusual side-effect of certain biological agents, about which it is timely to go into specific pathogenetic problems in more depth.

Keywords: Retroperitoneal fibrosis, Urology, Ergot derivatives, Biological agents, Neuropharmacology, Electroceuticals

Introduction

Retroperitoneal fibrosis (RPF) is a rare chronic wooden fibroinflammatory process surrounding the infrarenal part of abdominal aorta and iliac vessels with frequent encasement of ureters – hence the arising obstructive uronephropathy – and, in addition, the inferior vena cava (1, 2). It includes both the idiopathic, likely autoimmune, form (Ormond’s disease), still accounting more than half (55–60%) of cases – at times linked with either the IgG4-related sclerosing disease or the profibrotic β-catenin/Wnt signalling hyperactivation as well as in systemic sclerosis expressions (3, 4) – and many secondary forms as the outcome of different known conditions, among which retroperitoneal accidental traumas, infections, malignancies (RPF as either desmoplastic local response to primary and metastatic retroperitoneal tumors or paraneoplastic form due to extra-retroperitoneal neoplasias), occupationally used materials as asbestos (silicate mineral also responsible for a pleural/peritoneal mesothelioma onset), medical procedures (interventional radiology, surgery, external beam radiation therapy, etc) and, just looking down here, long-term intake of certain drugs (57).

Charged drugs

The outlined list of charged drugs includes:

  • ergot alkaloid-derived agents, including both 6,8-methylergoline- and lysergic acid derivatives, mainly used as anti-migraine drugs (ergotamine, methysergide) and partly as dopaminergic agonists (pergolide, bromocriptine, cabergoline), besides the psychedelic LSD (lysergic acid diethylamide);
  • specific L-dopa-derivatives, such as methyldopa;
  • β-adrenergic blockers, either nonselective (propranolol, sotalol, oxyprenolol) or β1-selective agents (metoprolol, atenolol);
  • analgesics: particularly phenacetin, paracetamol and aspirin;
  • hydralazine;
  • antitumoral chemotherapeutics, among which carboplatin and methotrexate;
  • bio-pharmaceutical agents, such as the tumor necrosis factor-α (TNF-α) receptor blocker Etanercept and, questionably, the anti-TNF-α monoclonal antibody (Infliximab).

Ergot-derived anti-migraine drugs
A significant occurrence of RPF – sometimes together with pleuropulmonary fibrosis and fibrotic tickening of heart valves – has been found, during the ‘60–’70s last century, in patients long-term treated, for migraine relief, with either ergotamine tartrate or dihydroergotamine or, particularly, with methysergide.

Methysergide maleate (1-methyl-D-lysergic acid butanolamide-maleate, C21H27N3O2 · C4H4O4) is a specific serotonin 5-HT2A (collaterally also 5-HT2C) receptor antagonist meanwhile with 5HT1A receptor agonist effects. So, methysergide, as an antiserotoninergic drug acting against serotonin-induced brain vasodilatation – responsible, according to Wolff ‘s theory, for migraine attacks – has been used, on large scale, for prevention of both cluster and migraine headaches besides to treat the neuroendocrine syndromes, such as particularly that induced by carcinoid tumor.

Methysergide, in some ways, may be thought as pro-drug of its active derivative methyl-ergometrine that acts as relatively “dirty drug” even endowed, indeed, with additional dopaminergic properties (8).

The lenghty use of methysergide has led, with an estimated incidence of 1/5,000 treated patients, to RPF onset, sometimes together with mediastinal, pleural, pericardial and subendocardial fibrosis that implies a left-sided cardiac valve dysfunction (8, 9).

The pathogenetic mechanism of lysergic acid derivative-induced RPF could be identified partly with such drug-related profibrotic-reactive haptenic role or, alternatively, with a feed-back rebound release of serotonin resulting in TGF-β/Smads cascade-mediated enhancement of myofibroblast proliferation with following overproduction of extracellular matrix (ECM) components – such as collagen, fibronectin, tenascin, glycosaminoglycans – that, besides the retroperitoneal space, may involve pleura, lung, mediastinum, cardiac valves and pericardium (1, 57, 10).

To validate previous clinical findings (1115), early experimental endorsements have been achieved, about at the end of 60s last century – on my own initiative, with the collaboration of two Medicine undergraduates then (Potenzoni, Cortellini) and a veterinary medicine histologist (doctor Freddi) – by a research work in animal models (rats and rabbits), whose six related reports on pyeloureterographic and histological findings were then published in nonindexed medicine journals (16, 17). Among the researchers which took into consideration such articles, just only Wagenknecht disagreed on our reports (5). Nevertheless, a further study on this subject, again in an animal model, with like our results, has been elsewhere carried out (18).

Just considering that the long-term use of methysergide was responsible for a significant incidence of RPF, besides other fibrotic disorders, its administration in migraine, after the 70s–80s past century, has been supplanted or even made unavailable in many countries (8). Subsequently nonergot-derived anti-migraine drugs were used, among which particularly sumatriptan, as a serotonin 5-HT1-line receptor agonist together with 5-HT2A/5-HT2C receptor antagonism, it inducing a negative feedback regulation of brain serotonin synthesis, and topiramate, as a blocker of brain cell voltage-dependent sodium channels togheter with enhancing the GABA (γamino-butyric acid) activity at related receptors while antagonizing the glutamate pathway (1921).

Ergot-derived dopamine receptor agonists
Also other ergot-derived drugs – such as pergolide, cabergoline, bromocriptine – though used as dopamine D1/D2 receptor agonists particularly in the management of the Parkinson’s disease, besides the hyperprolactinemia and restless leg syndrome, can induce RPF and pleural, pericardial, cardiac valve fibrotic reactions.

Their possible fibrogenic mechanisms are quite same as that of methysergide, by inducing the serotonin rebound release-mediated activation of myofibroblasts to overproduce ECM fibrogenic components, as well as the reactive fibrotic process might be thought, in addition, as an immune response to such drugs acting as haptens (2224).

The pergolide long term use-related frequent heart valve fibrotic damage seems, indeed, to be due to drug action at 5-HT2B serotonin receptors of subendocardial myofibroblasts, with following fibrous valve thickening (2527).

Cabergoline and bromocriptine, as also inhibitors on pituitary both prolactinogenous and growth hormone secreting cells, are first-line drugs in the treatment of prolactinoma and acromegaly. Cabergoline, besides dopamine D2/D3/D4 receptor agonist, shows significant affinity, just as ergot-derived drug, particularly for 5-HT2B serotonin receptors, that’s why there is the eventuality of fibrotic disorders development. However a detailed study (28) shows that cabergoline, though administered for long-term treatment of hyperprolactinemia/acromegaly, wouldn’t seem to be linked with an enhanced risk of fibrotic events. Bromocriptine is used not only in the management of Parkinson’s disease, neuroleptic malignant syndrome and pituitary prolactinoma, but also at times in the treatment of type 2 diabetes, with possible RPF onset after its long-term administration (2224).

Lisuride, as an isoergoline (diethyl-methyl-hexahy-dro-indolo-quinoline-urea) class-related drug, can antagonize the 5-HT2B serotonin receptors while acting as agonist on 5-HT1A and 5-HT2A/5-HT2C serotonin receptors, that’s why it is used for prevention of migraine attacks. Moreover such drug, as displaying high affinity particularly for D2/D3/D4 dopamine receptors together with prolactin-reducing properties, is useful to treat the Parkinson’s disease and to lower the pituitary prolactin secretion. Though it is a lysergic acid-derivative, its use-linked development of RPF and other fibrotic forms (pleural, lung, heart valve) involves a very small number of cases, supporting the concept that the 5HT2B receptor activation role of other ergot-derivatives (particularly, pergolide and cabergoline) might be the crucial cause of the figrogenic mechanisms (29, 30). What has been recently highlighted even from Ema-Chmp (European medicines agency-Committee for medical products for human use) with properly authoritative precautional instructions (31).

Specific L-dopa derivatives
From L-dopa (L-3,4-dihydroxyphenilalanine) – as a precursor of cathecholamine neurotransmitters such as dopamine, norepinephrine, epinephrine – that is used to enhance dopamine brain levels in the management of Parkinson’s disease and to treat the dopamine-responsive dystonia, it is achieved, by methylation, the methyl-dopa (L-α-methyl-3,4-dihydroxyphenilalanine), endowed, as α2-adrenergic selective agonist, with sympatholytic-antihypertensive properties. Its various side-effects include sometimes, over an administration period of 4–5 years, the development of the RPF through likely autoimmunization-related retroperitoneal deposition of collagen (32).

β-adrenergic blockers, analgesics, hydralazine, antitumoral chemotherapeutics
In comparison with many reports on the RPF occurrence following the long term use of either nonselective (propranolol, oxprenolol, sotalol, labetalol) or β1-selective adrenergic blockers (atenolol, metoprolol) (3336), subsequent findings of a thorough study (37) led to suggest that such drugs do not cause RPF.

As regards the analgesics, the literature displays interesting articles on some RPF cases occurred during lenghty treatment with such drugs – particularly phenacetin, aspirin, paracetamol – where the retroperitoneal fibrous pathology was at times associated with analgesic-due nephropathy, particularly just with renal papillary necrosis (3842).

Hydralazine (1-hydrazinylphthalazine), though inducing arterial smooth muscle relaxation, isn’t used as a primary antihipertensive agent given that it, by eliciting heart sympathetic baroreceptor reflex stimulation, may lead to increase heart rate/cardiac output with following risk, in patients with coronaropathy, of angina pectoris or even miocardial infarction. Hence, to prevent such serious side effects, its prescription is often associated with -blockers and also diuretics given plasma renin increase-due water retention too. It has been reported that long-term use of such drug, in association whith hydrochlorothiazide, may induce RPF (43).

As far as the antitumoral drugs, some chemotherapeutics, such as carboplatin and methotrexate, would be assessed as possible inductive factors of RPF (4446), so that the withdrawal of such drugs could sometimes result in a spontaneous regression of fibrotic retroperitoneal damage (45). The extreme infrequency of reports concerning this chemo-induced RPF occurrence makes problematic to identify its pathogenetic mechanisms.

Bio-pharmaceutical agents
With reference to possible induction of RPF from the use of biological agents, there are so far few but significant reports concerning etanercept, a biotechnologically made TNF-α receptor blocker, and, more questionably, regarding the anti-TNF-α monoclonal antibody infliximab, both drugs used to mainly treat the autoimmune diseases, such as rheumatoid arthritis, psoriasis, Crohn’s disease, sarcoidosis.

Etanercept is a dimeric protein-based drug biotechnologically obtained by fusion of TNF-α receptor 2-related DNA gene sequence with IgG1 immunoglobulin-related DNA gene sequence, resulting in a final expression of DNA linked-derived chimeric protein that acts as a TNF-α decoy receptor, so opposing such factor effects and therefore inhibiting the evolution of autoimmune diseases. Quite recently it has been described the etanercept-induced development of RPF, that forced to give up, in such occasion, this therapeutic measure (47).

About the anti-TNF-α monoclonal antibody (infliximab, adalimumab, golimumab) there are not, up to now, particular reports regarding its direct implication in a de novo RPF onset. It would seem, indeed – as it results from a recent “personalized health information and FDA research report, May 2015” – that, among 85,107 people reported to have side effects when taking infliximab (Remicade) only two people (0.0016%) show RPF. The development, instead, of other autoimmune diseases – such as sarcoidosis, psoriasis, inflammatory bowel disease – has been significantly found, as paradoxical phenomenon, just during therapies with TNF-α antagonists (48, 49).

Conclusion

Taking into consideration the above detailed review of the literature on different drug use-linked RPF onset, it wouldn’t seem that emerge, over the last ten years, quite significant innovative knowledges in comparison to what has been formerly pointed out apart from recent data concerning the RPF occurrence related to novel biotherapies.

Just with reference to the past, a proper treatment of any theme – both in humanities and positive sciences – should include the pre-comprehension of its significant historical aspects without overlooking them because of either carelessness or supercilious attitude.

The most RPF secondary to use of either ergot- or L-dopa-derivatives or even analgesics, are dated at the 60s–80s of last century, given that furtherly their long-term use has been supplanted or kept under careful measures to prevent the RPF onset (8, 9, 1115, 2232). In this regard, to avoid, during the management of Parkinson’s disease, the reported ergot derivative-related fibrotic damages, many experimental studies are today in progress, among which the piece of research, in animal models –with the resort to optical/chemogenetic switches – to reach proper cell therapy measures fit for increasing the release of dopamine from midbrain neurons (50).

As regards the use of novel biological agents, both the TNF-α receptor blocker Etanercept and the anti-TNF-α antibody Infliximab may lead to extremely rare occurrence of RPF, what, however, implying next thorough studies to properly identify underlying pathogenetic mechanisms (4749).

To come up against the risk of RPF onset dependent on such anti-TNFα agents, other drugs, targeting particular molecules or pathways – among which the B-cell surface protein CD20, interleukin-6 cytokine or Janus kinase/Stat – may be used to treat patients seriously suffering from autoimmune disorders (5155). Moreover, regarding such diseases, the resort to anti-inflammatory nerve vagus-mediated electroceutical approaches could be a foreseeable alternative to drug use (56), as well as the administration of centrally(brain)-acting muscarinic acetylcholine receptor agonist cytokine-lowering xanomeline (57).

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