increadibly i could not find the chemical name of Gilead GS 9620 drug, so strange.....the name got to be somewhere because they sure patented this
i want to know the chemical because it is quite possible we are talking about similar stuff as Imiquimod and resiquimod, see the full article in the following post about: Imiquimod and resiquimod as novel immunomodulators, especially where they menthion viruses like hiv and so on
Augmenting the host's natural immune response to viruses by the administration of exogenous cytokines such as interferon-α (IFN-α) is a strategy increasingly employed in antiviral therapeutics. Enhancing the release of endogenous cytokines is, however, an alternative approach. The imidazoquinolinamines imiquimod and resiquimod have demonstrated potency as inducers of IFN-α and other cytokines both in vitro and in vivo. Cytokine gene activation is mediated via the signal transducer and activator of transcription 1 (STAT-1) and involves the transcription factors NFκB and α4F1. Antiviral activity has been demonstrated against a variety of viruses, and clinical efficacy has been demonstrated against genital warts, herpes genitalis and molluscum contagiosum. Imiquimod is administered as a 5% cream (Aldara) and has been licensed for the treatment of anogenital warts in immunocompetent patients. Complete clearance of warts has been observed in up to half of treated patients with only local side effects reported. Resiquimod can be administered topically but also exists as an oral formulation. The range of potential infections for which these agents may have clinical utility includes chronic hepatitis C virus infection and Kaposi's sarcoma. In addition, the imidazoquinolinamines may find roles in the therapy of cancers and as vaccine adjuvants.
Significant advances in antiviral therapeutics have occurred in recent years. A number of agents that inhibit viral replication in vitro have been developed, including agents active against human immunodeficiency virus (HIV), cytomegalovirus (CMV) and herpes simplex virus (HSV). The initial promise of antiviral agents has been offset by the development of antiviral resistance in specific populations, such as immunocompromised hosts.1 In addition, for many viruses effective antivirals are not available. An alternative strategy in antiviral therapeutics involves enhancing the host's natural immune response to viruses by the administration of exogenous cytokines. The cytokine that has demonstrated the greatest antiviral potential has been interferon-α (IFN-α), which is a component of therapy for chronic hepatitis C virus (HCV) hepatitis and shows efficacy against other viruses.2 Therapy with cytokines is, however, parenteral and is associated with unwanted side-effects.
Imiquimod (Aldara, R-837, S-26308) and resiquimod (R-848, S-28463) are members of a new group of low molecular weight compounds, the imidazoquinolinamines3 (Figure). These have been shown to have properties as immune response modifiers in vitro and in vivo, and demonstrate antiviral and anti-tumour activity via endogenous cytokine production.3,,4 In vitro studies using non-human or human monocytes treated with imiquimod or resiquimod have reported increased mRNA in cell lysates and/or cytokine levels in supernatants of IFN-α, interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α.3,5–,7 In comparison with lipopolysaccharide or viral stimulation, IFN-α fold induction was greater than that of other cytokines.3,5–,7 IL-1α, IL-1 receptor antagonist, IL-6, IL-8, IL-10, granulocyte-macrophage colony stimulating factor, granulocyte colony stimulating factor and macrophage inflammatory protein-1α were also upregulated.3 Resiquimod is more potent at inducing cytokine expression than imiquimod. The clinical significance of many of these cytokines is uncertain due to the variable experimental conditions employed. In vivo studies of humans and animals treated with topical 5% imiquimod cream or topical 0.1–1.0% resiquimod gel have, however, confirmed the induction of mRNA for IFN-α and TNF-α in treated but not untreated skin.8,,9 In addition to monocytes, keratinocytes in skin were stimulated to produce cytokines. Imiquimod upregulated IL-6 and IL-8 in vitro,3 while resiquimod induced mRNA for IL-1α, IL-8, TNF-α and transiently IFN-α.10
Peripheral blood mononuclear cell cytokine induction by imiquimod in vivo required tyrosine and protein kinase C activity, was independent of cellular protein synthesis and was mediated via the transcription factors NFκB and α4F1.11 Furthermore, mice lacking a component of the IFN-stimulated gene factor 3, termed the signal transducer and activator of transcription 1 (STAT-1), lacked imiquimod-mediated gene activation.12 Patients responding to topical imiquimod treatment of genital warts had higher constitutive pretreatment levels of STAT-1.13 Hence, imiquimod modulates IFN signal transduction to enhance transcription of IFN-α stimulated genes.
Langerhans' cells (LC), which are potent antigenpresenting cells in multiple locations including the skin, demonstrated functional activation and enhanced induction of T-lymphocyte proliferation in response to imiquimod or resiquimod treatment.14 LC migration to draining lymph nodes was also enhanced, which could facilitate antigen presentation to T-lymphocytes.15 A Th-1 cytokine profile, including IFN-γ, was preferentially induced in mitogen-stimulated T-lymphocytes exposed to imiquimod or resiquimod.16 This was mediated by upregulation of IFN-α and IL-12 in monocytes and macrophages, an effect seen to a greater extent with resiquimod than with imiquimod treatment.16 B-lymphocytes proliferated, became activated and were stimulated to produce immunoglobulin.17 In these studies resiquimod was more potent at inducing lymphocyte proliferation and was also capable of aiding immunoglobulin class switching, unlike imiquimod.17 These links between innate and acquired immune responses suggest the potential usefulness of imiquimod, and in particular, resiquimod, as agents that could enhance vaccine responses.
Imidazoquinolinamines demonstrate indirect antiviral activity in vivo owing to cytokine induction, which inhibits viral replication directly and stimulates innate and acquired antiviral immune responses. In patients treated with 5% imiquimod cream, human papillomavirus (HPV) DNA and mRNA for the L1 gene were significantly decreased in association with a clinical response to therapy.8 Animal models, case reports and open-label studies have variously demonstrated the antiviral effect of imiquimod against HSV, Rift Valley fever virus, Banzi virus and in the treatment of molluscum contagiosum.3,18,,19 In most circumstances the observed antiviral effect has been associated with topical administration. The pharmacokinetics of topical administration are incompletely delineated but systemic absorption has not been detected, so the effect is local.3 The cream is usually applied to clean dry skin and left for 6–10 h before being washed off.
Resiquimod has greater potency at inducing cytokine expression than imiquimod but whether this will increase its antiviral spectrum is presently unknown. It may, however, be more useful than imiquimod in treating HSV-2 and may also be used in HCV infection.20,,21 In a guinea-pig model of HSV-2 infection, resiquimod was effective when administered by dermal, subcutaneous or intravaginal routes before infection.20 Antiviral activity is related to induction of serum 2′,5′-oligoadenylate synthetase activity. Resiquimod was also found to decrease recurrence of HSV-2 when administered subcutaneously in this model. Unlike imiquimod, for which pre-systemic biotransformation has limited its oral bioavailability, resiquimod may be administered by the oral route and trials are under way to assess its use in anti-HCV therapy, for which IFN-α forms the cornerstone of therapy.
Imiquimod 5% cream (Aldara) is licensed for the treatment of anogenital warts in immunocompetent patients. The evidence supporting this license comes from three prospective, double-blind, randomized, vehicle-controlled trials.22–,24 In these trials 698 immunocompetent individuals were randomized to receive topical therapy with imiquimod 5% cream, 1% cream (22,,23 only) or vehicle control. The topical treatment was applied daily22 or three times a week23,,24 for 16 weeks or until lesions cleared. Complete clearance of warts was observed in 37–52% of those treated with 5% cream, 14–21% of those treated with 1% cream and 0–11% of those treated with vehicle control by intent-to-treat analyses.22–,24 For complete responders, relapse rates at 10–12 weeks were 13–19% for 5% cream, 0–17% for 1% cream and 0–10% for vehicle control. Response rates were higher in female as compared with male patients. Local skin effects, including erythema, excoriation, flaking and erosion, were common but usually well tolerated. Ulceration was also noted in a minority of patients. These side-effects were associated with itching, pain and burning but systemic side-effects were not reported as occurring with greater frequency in the treatment group.22 None of these studies analysed changes in HPV DNA. Subsequent clinical audit has demonstrated a similar response rate.
Therapy of anogenital warts in HIV-seropositive individuals has been less effective. In a randomized, double-blind, vehicle-controlled trial of imiquimod 5% cream administered three times a week in 100 HIV-seropositive individuals receiving antiretroviral therapy and with CD4 T-lymphocyte counts >100 × 106 cells/L, complete response rates were seen in only 11% of the imiquimod group, compared with 6% of the control group, after 16 weeks of therapy, a result that was not statistically significant.26 A ≥50% reduction in wart size was, however, demonstrated in 38% of those who received imiquimod as compared with 14% of controls (P = 0.01), and the therapy was well tolerated. The number of individuals in this study whose HIV RNA plasma copy number was undetectable was not stated. Further studies are needed to address how this response rate can be improved.
In a further, double-blind, randomized, vehicle-controlled trial, 100 immunocompetent patients with molluscum contagiosum were randomized to receive a control or 1% imiquimod cream three times daily, 5 days a week for 4 weeks.27 Clearance of lesions was demonstrated in 82% of the imiquimod-treated individuals but only 16% of controls. Relapse rates after 10 months of follow-up were very low.
Resiquimod may also find a role in the treatment of HPV or molluscum contagiosum infection. In addition, it may be particularly useful against HSV-2, either as an agent to prevent recurrence or as a vaccine adjuvant in the presence of HSV glycoproteins. In a randomized study involving 52 immunocompetent individuals with a history of six or more recurrences of herpes genitalis per year, resiquimod demonstrated clinical efficacy.28 Resiquimod gel at various concentrations, or vehicle control, was administered to lesions within 24 h of onset and treatment continued for 3 weeks. The median time to first recurrence was 169 days for the combined resiquimod treatment group as compared with 57 days for the control group
(P < 0.01). In the 6 months of follow-up 32% of the resiquimod but only 6% of the control group had no recurrences (P < 0.05). A European multicentre Phase III randomized double-blind study is currently determining the efficacy of 0.01% resiquimod gel at preventing recurrences of anogenital herpes.
It is likely that immune response modifiers similar to imiquimod and resiquimod will find other clinical indications but many questions remain to be answered. Imidazoquinolinamines may have efficacy in the treatment of conditions for which IFN-α is currently employed, such as Kaposi's sarcoma (KS) and chronic HCV infection. Cutaneous lesions such as HSV genital ulcers or KS lesions could be treated using the topical preparations already studied. However, conditions such as chronic HCV hepatitis would require an oral formulation and resiquimod may be better suited to these uses.21 Interestingly, Phase I trials of an oral formulation of imiquimod have already been conducted in HIV-seropositive individuals and patients with cancer.29 The potential role of oral imiquimod in the therapy of HIV infection is intriguing but caution is warranted; in this trial of oral imiquimod in HIV-seropositive individuals two of 10 (20%) individuals demonstrated dramatic increases in plasma HIV RNA copy number, while two individuals demonstrated significant decreases. Transcription factors critical for imiquimod-mediated cytokine induction, such as NFκB, also upregulate HIV replication, and the significance of LC migration to lymph nodes in HIV immunopathogenesis needs to be investigated. Imiquimod, and to a greater extent resiquimod, have also demonstrated leishmanicidal activity due to nitric oxide synthesis in macrophages in an animal model of cutaneous leishmaniasis, suggesting other potential uses of imidazoquinolinamines against infection.30
In addition to the therapy of established infection the imidazoquinolines may have activity in therapy of cancers such as basal cell carcinoma (BCC). Of 24 patients treated, at various dosing intervals, with topical 5% imiquimod cream, 20 (83%) lacked evidence of BCC on biopsy 6 weeks after therapy compared with only one of 11 (9%) of the group treated with vehicle control.31 It remains to be established whether oral formulations of imidazoquinolines will extend the range of potential cancers that could be treated.
Furthermore, the role of imidazoquinolines as vaccine adjuvants requires investigation. Adjuvants are essential to enhance the efficacy of vaccination with weak immunogens. The development of safe and effective adjuvants to boost cell-mediated immunity is a priority of human vaccine research. Imidazoquinolines induce Th-1-mediated immune responses as opposed to the Th-2 responses associated with the use of alum, which is currently used as an adjuvant in human vaccines.32 This is the result of IFN-α and IL-12 production, which enhances IFN-γ production. The potential advantages of inducing Th-1 responses in response to immunization could have far-reaching consequences in the management of infections and cancer.
Many more studies are urgently needed to determine the safety and applicability of these novel immunomodulating agents in the therapy of HIV infection, other infectious diseases, cancer and in the development of immunization protocols. However, they are already demonstrating clinical utility in the therapy of genital warts, molluscum contagiosum and, potentially, herpes genitalis
this is a very old article from 2001 J. Antimicrob. Chemother. (2001) 48 (6): 751-755.
as usual this stuff has been kept away even blocking Resiquimod trials......
Oral resiquimod in chronic HCV infection: safety and efficacy in 2 placebo-controlled, double-blind phase IIa studies.
Pockros PJ, Guyader D, Patton H, Tong MJ, Wright T, McHutchison JG, Meng TC.
Division of Gastroenterology/Hepatology, Scripps Clinic, La Jolla, CA, USA. pockros.***@****
To explore safety, pharmacokinetics, and pharmacodynamics of oral administration of resiquimod, a Toll-like receptor 7 and 8 agonist that induces endogenous interferon-alpha, in subjects with chronic hepatitis C virus infection.
Two randomized, double-blind phase IIa studies of resiquimod administered two times per week for 4 weeks. Multicenter study (U.S.): 12 subjects received resiquimod 0.01 mg/kg and 4 received placebo. Single center study (France): 6 subjects received 0.01 mg/kg, 11 received 0.02 mg/kg and 6 received placebo.
Resiquimod 0.01 mg/kg was tolerated; two 0.2 mg/kg subjects discontinued treatment. More subjects reported severe grade adverse events at 0.02 mg/kg; events were consistent with systemic cytokine induction, including fever, headache, shivering, and lymphopenia. Mean maximum serum resiquimod concentrations were 3.82+/-1.47 and 7.55+/-4.17 ng/mL for 0.01 mg/kg and 0.02 mg/kg, respectively. At 0.02 mg/kg, two, three and one subjects had maximal reductions in viral levels of at least 1-, 2- and 3-logs, respectively; reductions were generally transient. Interferon-alpha levels appeared correlated with decreases in viral titer and lymphocyte counts, as well as increase in neutrophil counts.
Oral administration of resiquimod 0.02 mg/kg transiently reduced viral levels but was associated with adverse effects similar to interferon-alpha.
Topical resiquimod promotes priming of CTL to parenteral antigens
Topical resiquimod is a potent adjuvant for locally administered subcutaneous vaccines, inducing clinically relevant CTL responses following single application at the time of subcutaneous vaccination.
what about using Topical resiquimod in hbv vaccine which is formulated with hbsag antgen?
Randomized, Single-Blind, Placebo-Controlled Study of Topical Application of the Immune Response Modulator Resiquimod in Healthy Adults
Topical resiquimod gel was well tolerated when it was applied to healthy human skin as multiple doses of 1 g of 0.01% resiquimod for 24 h three times per week for 3 weeks and as multiple doses of 0.05% resiquimod for 8 h two or three times per week for 3 weeks. A dose-response relationship for LSRs was observed when a cumulative scoring system was used. Although only one subject reported an LSR of moderate severity, overall assessment of the LSRs and the presence of systemic signs and symptoms consistent with systemic induction of cytokines in two subjects suggested that the 0.25% resiquimod gel might not be adequately tolerable for future studies. The local effects observed for 0.25% resiquimod in this multiple-dose study were markedly different from those observed in the single-dose study, in which 0.25% resiquimod was tolerated but which also resulted in minimal evidence of cytokine production (Sauder et al., 38th ICAAC). This may be a result of increased local concentrations of resiquimod, changes in local penetration, an influx of cells capable of responding to resiquimod, or the increased responsiveness of target cells after multiple doses. Systemic accumulation of resiquimod after topical dosing was not observed in this study. The systemic effects observed during multiple dosing of 0.25% resiquimod may be related to spillover into the systemic circulation of cytokines induced locally rather than to systemic induction. A resiquimod concentration of 5 to 6 ng/ml in serum is usually required to induce cytokines systemically (I. Soria, unpublished data). The transient decrease in circulating neutrophil levels observed in a few subjects after multiple applications of resiquimod may be related to cytokine induction in the skin. In contrast, an increase in circulating neutrophil levels with a decrease in lymphocyte counts has been observed after oral administration of resiquimod in humans (T. Meng, unpublished data). This suggests that the cells are adhering or migrating, depending on where the cytokines are being induced, rather than resiquimod having a direct effect on cell production or survival. Tumor necrosis factor induces endothelial cell-leukocyte adhesion molecule type 1 expression, which can result in neutrophil adherence, while IL-8 induces neutrophil transmigration across endothelial cells (1a, 17).
The changes in cytokine mRNA levels in treated skin are consistent with those observed with imiquimod in a placebo-controlled study of patients with anogenital warts, in which significant increases in the levels of mRNA for IFN-α, IFN-γ, and 2′,5′-AS and a decrease for CD1a were observed (1, 18). The dose-dependent increases in the levels of CD3-, CD4-, and CD8-positive cells are consistent with the influx of cells associated with cellular immunity into treated skin. The decrease in the levels of CD1a-positive cells is consistent with activation of Langerhans' cells, which are bone marrow-derived DCs, by resiquimod and their emigration from the skin. Emigration of Langerhans' cells from the skin to the regional lymph nodes has been observed in mice following imiquimod application (14). Langerhans' cells, along with other types of DCs, play a major role in both the innate and the acquired host immune responses. The DC lineage appears to affect the response to resiquimod. Resiquimod can activate NFκb via TLR7 and induce type I IFN production from plasmacytoid DCs, as well as induce maturation of these cells, as determined by measurement of the levels of cytokine production, costimulatory marker expression, and CCR7 expression and improved survival (6, 10). In contrast, IL-12 monocyte-derived DCs preferentially secrete IL-12 in response to resiquimod (10).
These studies suggest that resiquimod is a topically active immunomodulator that can activate local cytokine mRNA production and initiate a cutaneous immune response.
The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer
This is a good literature collection re Resiquimod and Imiquimod mechanisms etc.
The key point BTW is, that this TLR 7and 8 have as a natural agonist single stranded RNA and activate potent antiviral mechanisms in response. Thus these drugs act as if they were ssRNA, sending a powerful antiviral mechanisms acitivating signal to various components of the immunsystem and the hepatocytes.
Dosing has to be very careful, since potent proinflammatory responses are elicited. Chances that they can clear HBV on their own are still slim, but they might act more potent than IFNalpha alone, particularly when used in combo with antivirals or surface antigen blockers or entry inhibitors.
The use of these creams as an adjuvant to local intradermal HBV vaccine formulations/applications (surface or surface plus preS1, or a combo with core antigen) sounds very promising, but who will try this?
i was thinking to try imiquimod cream with carefull monitoring since my hbsag is already on the slow continuous decline since i started gcmaf
it used to go up and down between 5000 and 7000iu/ml but since gcmaf only decline of about 300iu/ml monthly, it was 4200iu/ml on feb.
just want to see if decline can get faster by adding the cream
i m also (among many things) on high dose epa,dha, vit d3, and heptech, i guess epa/dh and fibroguard might be not beneficial to imiquimod response
it could be etv+tdf+gcmaf+vit d3+epa/dha omega3+imiquimod and see hbsag kinetics without fibroguard during this