Immunomodulatory Therapy (immunomodulatory + therapy)

Distribution by Scientific Domains
Distribution within Medical Sciences

Selected Abstracts

Immunomodulatory therapy for chronic hepatitis B virus infection

D. Sprengers
Abstract Hepatitis B virus (HBV) is one of the most prevalent viral pathogens of man with around 350 million chronically infected patients. It has been postulated that in persistently infected individuals the HBV-specific immune response is too weak to eliminate HBV from all infected hepatocytes, but sufficiently strong to continuously destroy HBV-infected hepatocytes and to induce chronic inflammatory liver disease. The primary aim in the treatment of chronic hepatitis B is to induce sustained disease remission and prevent serious complications like liver failure and/or hepatocellular carcinoma. The recent emergence of drug-resistant HBV mutants and post-treatment relapse as a consequence of nucleoside analogue monotherapy emphasizes that the principal goal should be to stimulate a successful immune response. In this paper we will focus on the immune response to HBV and we will review reported data on immunotherapeutic strategies like immunomodulatory drugs (cytokines and Thymic derivates) and vaccine therapies using currently available recombinant anti-HBV vaccines, lipopeptide-based T cell vaccine and newly developed genetic vaccines. [source]

Simvastatin regulates oligodendroglial process dynamics and survival

GLIA, Issue 2 2007
Veronique E. Miron
Abstract Simvastatin, a lipophilic statin that crosses the blood-brain barrier, is being evaluated as a potential therapy for multiple sclerosis (MS) due to its anti-inflammatory properties. We assessed the effects of simvastatin on cultures of rat newborn and human fetal oligodendrocyte progenitor cells (OPCs) and human adult mature oligodendrocytes (OLGs) with respect to cellular events pertaining to myelin maintenance and repair. Short-term simvastatin treatment of OPCs (1 day) induced robust process extension, enhanced differentiation to a mature phenotype, and decreased spontaneous migration. These effects were reversed by isoprenoid products and mimicked with an inhibitor of Rho kinase (ROCK), the downstream effector of the isoprenylated protein RhoA GTPase. Prolonged treatment (2 days) caused process retraction that was rescued by cholesterol, and increased cell death (4 days) partially rescued by either cholesterol or isoprenoid co-treatment. In comparison, simvastatin treatment of human mature OLGs required a longer initial time course (2 days) to induce significant process outgrowth, mimicked by inhibiting ROCK. Prolonged treatment of mature OLGs was associated with process retraction (6 days) and increased cell death (8 days). Human-derived OPCs and mature OLGs demonstrated an increased sensitivity to simvastatin relative to the rodent cells, responding to nanomolar versus micromolar concentrations. Our findings indicate the importance of considering the short- and long-term effects of systemic immunomodulatory therapies on neural cells affected by the MS disease process. © 2006 Wiley-Liss, Inc. [source]

Synthesis and receptor binding of IgG1 peptides derived from the IgG Fc region

Katalin Uray
Abstract The IgG binding Fc, receptors (Fc,Rs) play a key role in defence against pathogens by linking humoral and cell-mediated immune responses. Impaired expression and/or function of Fc,R may result in the development of pathological autoimmunity. Considering the functions of Fc,Rs, they are potential target molecules for drug design to aim at developing novel anti-inflammatory and immunomodulatory therapies. Previous data mostly obtained by X-ray analysis of ligand,receptor complexes indicate the profound role of the CH2 domain in binding to various Fc,Rs. Our aim was to localize linear segments, which are able to bind and also to modulate the function of the low affinity Fc,Rs, like Fc,RIIb and Fc,RIIIa. To this end a set of overlapping octapeptides was prepared corresponding to the 231,298 sequence of IgG1 CH2 domain and tested for binding to human recombinant soluble Fc,RIIb. Based on these results, a second group of peptides was synthesized and their binding properties to recombinant soluble Fc,RIIb, as well as to Fc,Rs expressed on the cell surface, was investigated. Here we report that peptide representing the Arg255,Ser267 sequence of IgG1 is implicated in the binding to Fc,RIIb. In addition we found that peptides corresponding to the Arg255,Ser267, Lys288,Ser298 or Pro230,Val240 when presented in a multimeric form conjugated to branched chain polypeptide in uniformly oriented copies induced the release of TNF,, a pro-inflammatory cytokine from MonoMac monocyte cell line. These findings indicate that these conjugated peptides are able to cluster the activating Fc,Rs, and mediate Fc,R dependent function. Peptide Arg255,Ser267 can also be considered as a lead for further functional studies. Copyright © 2004 John Wiley & Sons, Ltd. [source]

Idiopathic granulomatous and necrotising inflammatory disorders of the canine central nervous system: a review and future perspectives

Lauren R. Talarico
Granulomatous meningoencephalomyelitis, necrotizing meningoencephalitis, and necrotizing leukoencephalitis are common inflammatory conditions of the canine central nervous system. Although each disease has unique histopathological features, these canine disorders collectively seem to be aberrant immune responses directed against the central nervous system. A review of the neurological signs and general neurodiagnostic approach to canine meningoencephalitis is followed by an overview of the specific clinical and neuropathological features of granulomatous meningoencephalomyelitis, necrotizing meningoencephalitis, and necrotizing leukoencephalitis. The aetiopathogenesis of each disorder is explored including potential genetic, immunological, and environmental factors along with the current and prospective immunomodulatory therapies for meningoencephalitis. [source]

Novel pharmacological approaches in the treatment of psoriasis

V Schleyer
ABSTRACT Progress in the understanding of psoriasis as a T-cell mediated inflammatory disease has led to the development of new immunomodulatory therapies. Currently the main focus is on the so-called biologics (or biological agents), including fusion proteins, monoclonal antibodies, cytokines and selective receptors. They mainly target single steps in the complex cascade of humoral and cellular inflammatory immunomechanisms that finally lead to the accelerated growth of epidermal and vascular cells in the psoriatic lesions. The most promising and advanced biological agents are discussed along with their influence on the critical pathophysiological steps in psoriasis, including depletion of T cells, blockade of initial T-cell activation and T-cell receptor (TCR) stimulation, blockade of costimulatory signals and T-cell proliferative signals as well as restoration of the T helper type 1 (Th1)/Th2 balance by diminishing type 1 cytokines and administration of type 2 cytokines. In addition to the biological agents, further development of ,classical' dermatological therapies, such as retinoids, or the discovery of new indications for non-dermatological agents contribute to the novel pharmacological approaches in the treatment of psoriasis. [source]

HBV core sequence: definition of genotype-specific variability and correlation with geographical origin

M. Jazayeri
Summary., There are eight genotypes and nine subtypes of HBV. Small differences in geographical origin are associated with sequence changes in the surface gene. Here, we compared core gene sequences from different genotypes and geographical regions. Specific combinations of 24 amino acid substitutions at nine residues allowed allocation of a sequence to a subtype. Six of these nine residues were located in different T cell epitopes depending on HBV geographical area and/or genotype. Thirty-seven nucleotide changes were associated uniquely with specific genotypes and subtypes. Unique amino acid and nucleotide variants were found in a majority of sequences from specific countries as well as within subtype ayw2 and adr. Specific nucleotide motifs were defined for Korean, Indian, Chinese, Italian and Pacific region isolates. Finally, we observed amino acid motifs that were common to either South-east Asian or Western populations, irrespective of subtype. We believe that HBV strains spread within constrained ethnic groups, result in selection pressures that define sequence variability within each subtype. It suggests that particular T cell epitopes are specific for geographical regions, and thus ethnic groups; this may affect the design of immunomodulatory therapies. [source]

Progressive multifocal leukoencephalopathy: Can we reduce risk in patients receiving biological immunomodulatory therapies?

Kenneth L. Tyler MD
No abstract is available for this article. [source]

Opportunistic infections and other risks with newer multiple sclerosis therapies,

Joseph R. Berger MD
The introduction of newer therapies for the treatment of multiple sclerosis has generated considerable optimism. That optimism has been tempered by the potential risks of these therapies, such as the risk for progressive multifocal leukoencephalopathy. A review of the possible causes of reactivation of JC virus in this population has illustrated the need to better understand the untoward effects of monoclonal antibody therapies and other immunomodulatory therapies currently being contemplated for use in multiple sclerosis. These drugs alter the immune response at different sites, and most, if not all, affect more than one aspect of host immunity. Drawing from existing experience with the use of these immunomodulatory therapies in other conditions and that available from the limited experience with multiple sclerosis, we review their potential untoward effects. The latter include a predisposition to opportunistic and community-acquired infections, an altered response to vaccination, the development of cancers, and the appearance of autoimmune diseases. The identification of progressive multifocal leukoencephalopathy as a risk of therapy is relatively straightforward in light of its rarity and high morbidity and mortality, but a relatively slight increased risk for more common and less disabling disorders may be overlooked. Determining the actual risk frequency for many of these complications will likely require careful postmarketing surveillance. Ann Neurol 2009;65:367,377 [source]

Acquired haemophilia: management of bleeds and immune therapy to eradicate autoantibodies

HAEMOPHILIA, Issue 5 2005
P. A. Holme
Summary., Acquired haemophilia is a rare, but often severe bleeding disorder caused by autoantibodies against a coagulation factor, usually factor VIII (FVIII). Between 1997 and 2004 we observed 14 patients (mean age of 78 years) with acquired haemophilia. The aim of the present study was to investigate the effect of activated prothrombin complex concentrate (aPCC) for bleeds and the response to corticosteroids and cyclophosphamide to eradicate the offending autoantibodies. The most common clinical presentations were severe profuse bruising (12) and haematuria (5). Ten patients were classified as idiopathic. At the time of diagnosis all patients had a very low FVIII level, and one patient also showed factor IX < 1%. High levels of antibodies to FVIII varying from 10 to 1340 Bethesda units (BU) and prolonged activated partial thromboplastin time were disclosed in all patients. Eight severe bleeds were treated with aPCC (FEIBA®) at a dosage of 70 IU kg,1 every 8 h until haemostasis. Ten patients received corticosteroids and cyclophosphamide as immunomodulatory therapy. Effective haemostasis was achieved in all bleeds after aPCC. Ten of 11 patients responded either completely or partially to the immunomodulatory regime within 6 months. Five patients achieved complete response (CR) whereas partial responses were seen in five patients. The anti-CD20 monoclonal antibody rituximab was given to two patients in conventional doses and a CR was seen in one patient. aPCC is effective in treating acute bleeds in patients with acquired haemophilia with high inhibitor levels. The combination of oral corticosteroids and cyclophosphamide seems to be effective to eradicate the inhibitor. [source]

Improvement in orofacial granulomatosis on a cinnamon- and benzoate-free diet

Allison White RD
Abstract Background: Orofacial granulomatosis (OFG) is a chronic inflammatory disorder presenting characteristically with lip swelling but also affecting gingivae, buccal mucosa, floor of mouth, and a number of other sites in the oral cavity. Although the cause remains unknown, there is evidence for involvement of a dietary allergen. Patch testing has related responses to cinnamon and benzoate to the symptoms of OFG, with improvement obtained through exclusion diets. However, an objective assessment of the effect of a cinnamon- and benzoate-free diet (CB-free diet) as primary treatment for OFG has not previously been performed. Thus, this study was undertaken to investigate the benefits of a CB-free diet as first-line treatment of patients with OFG. Materials and Methods: Thirty-two patients with a confirmed diagnosis of OFG were identified from a combined oral medicine/gastroenterology clinic. All had received a CB-free diet as primary treatment for a period of 8 weeks. Each patient underwent a standardized assessment of the oral cavity to characterize the number of sites affected and the type of inflammation involved before and after diet. Results: There was a significant improvement in oral inflammation in patients on the diet after 8 weeks. Both global oral and lip inflammatory scores improved (P < 0.001), and there was significant improvement in both lip and oral site and activity involvement. However, improvement in lip activity was less marked than oral activity. Response to a CB-free diet did not appear to be site specific. A history of OFG-associated gut involvement did not predict a response to the diet. Conclusions: The impact of dietary manipulation in patients with OFG can be significant, particularly with regard to oral inflammation. With the disease most prevalent in the younger population, a CB-free diet can be recommended as primary treatment. Subsequent topical or systemic immunomodulatory therapy may then be avoided or used as second line. [source]

Cell-based immunotherapy with mesenchymal stem cells cures bisphosphonate-related osteonecrosis of the jaw,like disease in mice

Takashi Kikuiri
Abstract Patients on high-dose bisphosphonate and immunosuppressive therapy have an increased risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ); despite the disease severity, its pathophysiology remains unknown, and appropriate therapy is not established. Here we have developed a mouse model of BRONJ-like disease that recapitulates major clinical and radiographic manifestations of the human disease, including characteristic features of an open alveolar socket, exposed necrotic bone or sequestra, increased inflammatory infiltrates, osseous sclerosis, and radiopaque alveolar bone. We show that administration of zoledronate, a potent aminobisphosphonate, and dexamethasone, an immunosuppressant drug, causes BRONJ-like disease in mice in part by suppressing the adaptive regulatory T cells, Tregs, and activating the inflammatory T-helper-producing interleukin 17 cells, Th17. Most interestingly, we demonstrate that systemic infusion with mesenchymal stem cells (MSCs) prevents and cures BRONJ-like disease possibly via induction of peripheral tolerance, shown as an inhibition of Th17 and increase in Treg cells. The suppressed Tregs/Th17 ratio in zoledronate- and dexamethasone-treated mice is restored in mice undergoing salvage therapy with Tregs. These findings provide evidence of an immunity-based mechanism of BRONJ-like disease and support the rationale for in vivo immunomodulatory therapy using Tregs or MSCs to treat BRONJ. © 2010 American Society for Bone and Mineral Research [source]

Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 3

F Terenghi
Intravenous immunoglobulins (IVIg) are successfully used as immunomodulatory therapy in patients with multifocal motor neuropathy (MMN) but their mechanism of action remains unknown. An anti-idiotypic block of pathogenic autoantibodies has been often postulated even if other possible mechanisms, including a modulation of the release of various cytokines, have been proposed. To evaluate the expression of cytokines in patients with MMN and their possible modulation by IVIg, we determined circulating levels of TNF,, INF,, IL2, IL4, IL10, and IL12 by ELISA in serum samples of 17 patients with MMN and compared them with 12 patients with amyotrophic lateral sclerosis (ALS), 12 with multiple sclerosis (MS), 6 with chronic inflammatory demyelinating polyneuropathy (CIDP), 5 with myasthenia gravis (MG) and 12 healthy controls (NS). Comparable levels of INF,, IL2, IL4, IL10 and IL12 were detected in patients' sera and controls. Even if TNF, levels did not differ significantly among patients' groups, they were higher than in any healthy control (mean ± SD 1.2 ± 0.5 pg/ml, range 0.7,2.4 pg/ml), in 12 (70%) MMN patients (mean ± SD 3.6 ± 1.9 pg/ml; range 0.2,7.5 pg/ml), all ALS, 3 MS (25%), 2 CIDP (40%) and 2 MG (40%). We then measured the concentration of TNF, before and after IVIg therapy in 9 MMN and 2 ALS patients. In all but one MMN patients, circulating levels of TNF, slightly increased after treatment with IVIg (mean values 4.3 vs. 7.2 pg/ml) and decreased 3 weeks after therapy while in both ALS patients they decreased or remained unchanged. No detectable level of TNF, was found in IVIg preparation. This study shows that, similarly to what previously reported in other autoimmune neuropathy as GBS and CIDP, TNF, serum levels are slightly increased in MMN but, at odds with what reported in these disease, their concentration tend to increase parallel to clinical improvement after IVIg therapy. Further studies are necessary to clarify the pathogenetic implication of this finding and in particular whether a possible deviation from a presumably Th2 to a Th1 immune response may help explaining the effect of IVIg in MMN. [source]

Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis,

Steve Simpson Jr. MPH
Objective A protective association between higher vitamin D levels and the onset of multiple sclerosis (MS) has been demonstrated; however, its role in modulating MS clinical course has been little studied. We investigated whether higher levels of serum 25-hydroxyvitamin D (25-OH-D) were associated with a lower risk of relapses in people with MS. Methods We conducted a prospective cohort study of 145 participants with relapsing-remitting MS from 2002 to 2005. Serum 25-OH-D levels were measured biannually, and the hazard of relapse was assessed using survival analysis. Results There was an inverse linear relationship between 25-OH-D levels and the hazard of relapse over the subsequent 6 months, with hazard ratio (HR) 0.91 (95% confidence interval [CI]: 0.85,0.97) per 10nmol/l increase in 25-OH-D level (p = 0.006). When variation due to timing of blood collection was removed by estimating 25-OH-D at the start of each season, this association persisted, with HR 0.90 (95% CI, 0.83,0.98) per 10nmol/l increase (p = 0.016). Taking into account the biological half-life of 25-OH-D, we estimated 25-OH-D at monthly intervals, resulting in a slightly enhanced association, with HR 0.88 (95% CI, 0.82,0.95) per 10nmol/l increase (p = 0.001). Adjusting for potential confounders did not alter these findings. Interpretation In this prospective population-based cohort study, in a cohort largely on immunomodulatory therapy, higher 25-OH-D levels were associated with a reduced hazard of relapse. This occurred in a dose-dependent linear fashion, with each 10nmol/l increase in 25-OH-D resulting in up to a 12% reduction in risk of relapse. Clinically, raising 25-OH-D levels by 50nmol/l could halve the hazard of a relapse. ANN NEUROL 2010;68:193,203 [source]

The programmed death 1/programmed death ligand 1 inhibitory pathway is up-regulated in rheumatoid synovium and regulates peripheral T cell responses in human and murine arthritis

Amalia P. Raptopoulou
Objective T cells play a major role in the pathogenesis of rheumatoid arthritis (RA). The programmed death 1 (PD-1)/programmed death ligand 1 (PDL-1) pathway is involved in peripheral tolerance through inhibition of T cells at the level of synovial tissue. The aim of this study was to examine the role of PD-1/PDL-1 in the regulation of human and murine RA. Methods In synovial tissue and synovial fluid (SF) mononuclear cells from patients with RA, expression of PD-1/PDL-1 was examined by immunohistochemistry and flow cytometry, while PD-1 function was assessed in RA peripheral blood (PB) T cells after stimulation of the cells with anti-CD3 and PDL-1.Fc to crosslink PD-1. Collagen-induced arthritis (CIA) was induced in PD-1,/, C57BL/6 mice, and recombinant PDL-1.Fc was injected intraperitoneally to activate PD-1 in vivo. Results RA synovium and RA SF were enriched with PD-1+ T cells (mean ± SEM 24 ± 5% versus 4 ± 1% in osteoarthritis samples; P = 0.003) and enriched with PDL-1+ monocyte/macrophages. PD-1 crosslinking inhibited both T cell proliferation and production of interferon-, (IFN,) in RA patients; PB T cells incubated with RA SF, as well as SF T cells from patients with active RA, exhibited reduced PD-1,mediated inhibition of T cell proliferation at suboptimal, but not optimal, concentrations of PDL-1.Fc. PD-1,/, mice demonstrated increased incidence of CIA (73% versus 36% in wild-type mice; P < 0.05) and greater severity of CIA (mean maximum arthritis score 5.0 versus 2.3 in wild-type mice; P = 0.040), and this was associated with enhanced T cell proliferation and increased production of cytokines (IFN, and interleukin-17) in response to type II collagen. PDL-1.Fc treatment ameliorated the severity of CIA and reduced T cell responses. Conclusion The negative costimulatory PD-1/PDL-1 pathway regulates peripheral T cell responses in both human and murine RA. PD-1/PDL-1 in rheumatoid synovium may represent an additional target for immunomodulatory therapy in RA. [source]

18F-fluorodeoxyglucose,positron emission tomography scanning is more useful in followup than in the initial assessment of patients with Erdheim-Chester disease

Laurent Arnaud
Objective Erdheim-Chester disease (ECD) is a rare form of non,Langerhans' cell histiocytosis. The aim of this study was to assess the value of whole-body scanning with 18F-fluorodeoxyglucose,positron emission tomography (FDG-PET) in a large cohort of ECD patients from a single center. Methods We retrospectively reviewed all PET scans performed on 31 patients with ECD who were referred to our department between 2005 and 2008. PET images were reviewed by 2 independent nuclear medicine specialist physicians and were compared with other imaging modalities performed within 15 days of each PET scan. Results Thirty-one patients (10 women and 21 men; median age 59.5 years) underwent a total of 65 PET scans. Twenty-three patients (74%) were untreated at the time of the initial PET scan, whereas 30 of the 34 followup PET scans (88%) were performed in patients who were undergoing immunomodulatory therapy. Comparison of the initial and followup PET scans with other imaging modalities revealed that the sensitivity of PET scanning varied greatly among the different organs studied (range 4.3,100%), while the specificity remained high (range 69.2,100%). Followup PET scans were particularly helpful in assessing central nervous system (CNS) involvement, since the PET scan was able to detect an early therapeutic response of CNS lesions, even before magnetic resonance imaging showed a decrease in their size. PET scanning was also very helpful in evaluating the cardiovascular system, which is a major prognostic factor in ECD, by assessing the heart and the entire vascular tree during a single session. Conclusion The results of our large, single-center, retrospective study suggest that the findings of a FDG-PET scan may be interesting in the initial assessment of patients with ECD, but its greater contribution is in followup of these patients. [source]

Morbidity and mortality in rheumatoid arthritis patients with prolonged therapy-induced lymphopenia: Twelve-year outcomes

Alice R. Lorenzi
Objective To assess immunologically relevant outcomes in a cohort of rheumatoid arthritis (RA) patients with prolonged therapy-induced lymphopenia. Methods Morbidity (infection or malignancy) and mortality were assessed in 53 RA patients who were treated with the lymphocytotoxic monoclonal antibody alemtuzumab between 1991 and 1994. Data were obtained by interview, medical record review, and Office for National Statistics mortality monitoring. Lymphocyte subsets were enumerated by flow cytometry. A retrospective, matched-cohort study of mortality was performed with 102 control subjects selected from the European League Against Rheumatism database of patients with rheumatic disorders. Results Lymphopenia persisted in the patients: median CD3+CD4+, CD3+CD8+, CD19+, and CD56+ lymphocyte counts measured at a median followup of 11.8 years from the first administration of alemtuzumab were 0.50 × 109/liter, 0.26 × 109/liter, 0.11 × 109/liter, and 0.09 × 109/liter, respectively. Twenty-seven of 51 cases and 46 of 101 controls with available data had died, yielding a mortality rate ratio of 1.20 (95% confidence interval 0.72,1.98). Causes of death were similar to those that would be expected in a hospital-based RA cohort. No opportunistic infections were noted, and only 3 infections were documented following 36 elective orthopedic procedures. Conclusion Despite continued lymphopenia 11.8 years after therapy, our patient cohort did not exhibit excess mortality or unusual infection-related morbidity, and surgery was well tolerated. These data should be reassuring for clinicians and patients who are considering lymphocytotoxic or other immunomodulatory therapy for RA. [source]

Oxidoreductase macrophage migration inhibitory factor is simultaneously increased in leukocyte subsets of patients with severe sepsis

BIOFACTORS, Issue 4 2008
Lutz E. Lehmann M.D.
Abstract The oxidoreductase Macrophage Migration Inhibitory Factor (MIF) is discussed as a promising target for immunomodulatory therapy in patients with severe sepsis. Moreover, MIF expresses tautomerase as well as thiol-protein oxidore-ductase activities and has a potential role in cellular redox homeostasis, apoptosis inhibition, endotoxin responsiveness as well as regulation of nuclear transcription factors. To further elucidate a potential role of intracellular MIF in severe sepsis, we assessed alterations of intracellular MIF content in peripheral blood leukocytes of patients with severe sepsis in comparison to healthy controls and non-septic patients after major surgery. Intracellular MIF was significantly elevated simultaneously in lymphocytes, B-cells, macrophages and granulocytes of patients with severe sepsis when compared to healthy control individuals (p < 0.05) and increased when compared to non-septic patients after major surgery. In parallel, plasma MIF levels were elevated in severe sepsis (p < 0.05). There was no difference of intracellular MIF in lymphocytes, B-cells, macrophages or granulocytes between surviving and non-surviving patients with severe sepsis (p > 0.05). However, in survivors LPS ex vivo stimulation increased MIF secretion but not in non-survivors of sepsis (p < 0.05). This finding underlines the role of intracellular MIF in inflammatory diseases. It suggests monitoring of intracellular MIF in further clinical and non-clinical research valuable. [source]

Evaluation of imiquimod for the therapy of external genital and anal warts in comparison with destructive therapies

H. Schöfer
Summary External genital and anal warts (acuminate condyloma) were the first medical indication the topical immune response modifier imiquimod was approved for in 1997. Since then, many placebo controlled randomized clinical trials have demonstrated the efficacy and safety of this synthetic imidazoquinoline derivate for the treatment of different human papillomavirus infections and tumours. Treatment modalities for genital warts (5% cream, three times weekly, minimum duration 4 weeks, control of side-effects) have been optimized and assured by further clinical trials and meta-analyses. For a few years clinical studies focussed on the long-term efficacy of the immunomodulatory therapy (sustained clearance from warts) and most recent studies compared the efficacy of ablative, destructive and imiquimod monotherapy as well as combination therapies. [source]