Shingles Vaccine for Recurrent Herpes Simplex
I have known Linda for about seven years now, treating her for Hashimotos’ thyroid disease. Linda has other problems. She takes daily acyclovir for recurrent attacks of oral-facial herpes simplex which can be quite debilitating. Recently, we were chatting and Linda brought up the idea of Shingles vaccination to prevent the oral-facial herpes attacks. Above header image: Shingles commonly affected areas courtesy of Sonapharmacy.com
I immediately volunteered my opinion that this is a bad idea. This is a Chickenpox vaccine, not a herpes simplex vaccine. How do we know it would work? The shingles vaccine is a live attenuated chicken pox (varicells) virus cultured on aborted human fetal cells. (MRC5 line), so the vaccine contains human DNA fragments.
Information about the Shingles Vaccine:
“The live virus shingles vaccine is actually a very strong booster dose of the Varicella Zoster (chickenpox) vaccine. Zostavax vaccine for shingles and Varivax vaccine for chickenpox are both manufactured by Merck and are the only licensed vaccines to prevent chickenpox and shingles in the U.S.”
In the Zostavax product information insert, Merck describes the ingredients of shingles vaccine:
“ZOSTAVAX is a lyophilized preparation of the Oka/Merck strain of live, attenuated varicella-zoster virus (VZV). ZOSTAVAX, when reconstituted as directed, is a sterile suspension for subcutaneous administration. Each 0.65-mL dose contains a minimum of 19,400 PFU (plaque-forming units) of Oka/Merck strain of VZV when reconstituted and stored at room temperature for up to 30 minutes. Each dose contains 31.16 mg of sucrose, 15.58 mg of hydrolyzed porcine gelatin, 3.99 mg of sodium chloride, 0.62 mg of monosodium L-glutamate, 0.57 mg of sodium phosphate dibasic, 0.10 mg of potassium phosphate monobasic, 0.10 mg of potassium chloride; residual components of MRC-5 cells including DNA and protein; and trace quantities of neomycin and bovine calf serum. The product contains no preservatives.”
Serious Adverse Events
“By August 2011, the federal Vaccine Adverse Event Reporting System (VAERS) had received 442 serious vaccine adverse reports following Zostavax vaccination, including 36 reported deaths . Serious shingles vaccine reaction symptoms reported to VAERS include rash, joint pain (arthralgia), muscle pain (myalgia), fever, abnormally swollen glands (lymphadenopathy) and hypersensitivity reactions including anaphylaxis (shock).”(reference)
Paris Hospital Does Study Using Zostivax for Recurrent Oral Herpes.
After a few minutes I thought well, maybe somebody else has done a study and tried the Shingles Vaccine for recurrent oral herpes. Maybe it does work, Let’s look it up.
We found a 2012 study France (14): Efficacy of antiVZV antiHSV3 vaccine HSV1 HSV2 recurrent herpes simplex Jacqueline Le Goaster 2012.
In a hospital in Paris a prospective study was done in 2012 using shingles vaccine for 24 patients with recurrent oral-facial herpes, uncontrolled by acyclovir. Another 25 patient serves as controls. Remarkably, the shingles vaccine group had zero recurrence of herpes over 6 years of follow up, while the control group continued to have 4-5 outbreaks per year as before.(14)
I turned to Linda and said I would have to change my opinion, as this actually looks pretty good for preventing attacks of oral herpes. So, if you notice a piece of my hat missing, that’s where I had to take a large bite and “Eat My Hat”.
2017 Update one year later: Linda called in to give me an update. I asked Linda if she decided to go ahead with the shingles vaccine. No she said. She came down with a case of shingles about 6 months ago, and after that, the recurrent Oral-Facial Herpes went away. I thought about it for a minute, and said: Very good, Apparently, your case of Shingles served as a Self-Vaccination, stimulating the immune system. The oral-facial Herpes is now cured. Oct. 2017: FDA Approves New Shingles (Shingrix) Vaccine as More Effective and will Replace Older Zostavax (3-10)
Many people have asked me, should I take the new Shingles Vaccine? Shingrix? My answer is: on paper Shingrix looks more effective and better in some ways than the older vaccine Zostavax which was a live virus. The Shingrix does not contain a live virus, which I consider a safer feature.
The problem with a live virus vaccine:
Live Virus Can itself Cause Disease
The Zostavax manufacturer product insert states that “transmission of vaccine virus may occur between vaccines and susceptible contacts.” Zostavax Manufacturer Merck is now involved in class action suit related to the ability of the live virus in the vaccine itself to cause disease .(10)
Unlike the Zostavax which is a live virus, the Shingrix combines an antigen, glycoprotein E, and an adjuvant system, AS01B.(11) These two items are new. Like any new drug, it may take a few years of use before we really know about the adverse side effects. So ask me again 5 years from now. In the mean time, consider the new vaccine a population wide experiment with you and me as the guinea pigs. Adverse reactions to the new vaccine may be severe.(15)
” About one in six people experienced side effects so severe that it actually prevented their normal activities.” (15)
Burning Mouth Syndrome
The syndrome of “burning mouth” can be a diagnostic dilemma. However, this is probably just another presentation for oral facial herpes. Elevated blood and saliva Herpes antiviral antibody titers may be found. Resolution of symptoms with anti-viral drug acyclovir was reported.(12,13) One might expect benefit from Shingles vaccination, similar to efficacy in oro-facial herpes.
Update 2018: “necrotizing retinitis” from Shingles Vaccine Eye Damage, This article Link courtesy of Matthews and Associates 2905 Sackett Street Houston, Texas 77098. Quote:“The shingles Zostovax vaccine Merck Pharmaceuticals has been marketing since 2006 now comes with a warning that it could cause eye damage. February 17, 2016, the FDA approved a label change to Merck’s Zostamax vaccine prescribing information. The change to the label added “Eye Disorders: necrotizing retinitis.” Merck consequently faces Shingles Vaccine Lawsuits over this dubious vaccine.Endquote.
July 2018 Update: Video on Shingles Vaccine Shingrix-Connection with Chickenpox
The HighWire with Del Bigtree Published on Jun 27, 2018
How the chickenpox vaccine is creating a shingles epidemic.
Cimetidine for Herpes Zoster (Shingles) (20-26)
Cimetidine (Tagamet) is an old anti-acid drug that is off patent, having been replaced by the newer PPI drugs (proton pump inhibitors). Cimetidine is now available OTC (over the counter). Cimetidine functions as an immune modulator, a competitive inhibitor of the H2 class histamine receptor, present on a subclass of suppressor T lymphocytes cells. The anti-viral effect of Cimetidine is due to this augmentation of the host immune system.
Cimetidine is useful for Herpes Zoster (Shingles) with shortened active phase and prompt reductionin pain symptoms as reported by Dr Van Der Spuy, Levy and Levin in the Jul 1980 S African Med .(18) They recommended 1600 mg per day for two days to abort a crop of blisters. In 1985, Dr Levy reported Shingles treatment with Cimetidine showed excellent clinical response.(23) In 1996, Dr Kapinska-Mrowiecka treated 221 Shingles patients with Cimetidine 1,000 mg per day, finding most effective when used early in the course of the disease.(20) Dr Hayne reported shortening of the active phase of Shingles from 35 days to 10 days in 61 yr old male with reduction of pain and erythema.(24)
Conventional Treatment for Shingles Herpes Zoster: Zovirax (Acyclovir) 800 mg tab, one PO QID x 7-10 Days.
Jeffrey Dach MD
7450 Griffin Road Suite 180/190
Davie, Fl 33314
This article is part two of a series, for part one, click here.
Article with related interest:
Links and References
3) Oxman, Michael N., Ruth Harbecke, and David M. Koelle. “Clinical Usage of the Candidate Adjuvanted HZ/su Zoster Vaccine: re-vaccination of recipients of live attenuated zoster vaccine and co-administration with a seasonal influenza vaccine.” The Journal of Infectious Diseases (2017). Clinical Usage Adjuvanted HZ su Zoster Vaccine Oxman J Infectious Dis 2017
4) Retamal-Díaz, Angello R., et al. “A Herpes Simplex Virus Type 2 Deleted for Glycoprotein D Enables Dendritic Cells to Activate CD4+ and CD8+ T Cells.” Frontiers in Immunology 8 (2017): 904.
5) Cunningham, Anthony L. “The herpes zoster subunit vaccine.” Expert opinion on biological therapy 16.2 (2016): 265-271.
Introduction: Herpes zoster (HZ) causes severe pain and rash in older people and may be complicated by prolonged pain (postherpetic neuralgia; PHN).
Areas covered: HZ results from reactivation of latent varicella-zoster virus (VZV) infection, often associated with age related or other causes of decreased T cell immunity. A concentrated live attenuated vaccine boosts this immunity and provides partial protection against HZ, but this decreases with age and declines over 5-8 years. The new HZ subunit (HZ/su or Shingrix) vaccine combines a key surface VZV glycoprotein (E) with T cell boosting adjuvant (AS01B). It is highly efficacious in protection (97%) against HZ in immunocompetent subjects, with no decline in advancing age and protection maintained for >3 years. Phase I-II trials showed safety and similar immunogenicity in severely immunocompromised patients. Local injection site pain and swelling can be severe in a minority (9.5%) but is transient (2 days).
Expert Opinion: The HZ/su vaccine appears very promising in immunocompetent patients in the ZoE-50 controlled trial. The unblinding of the current ZoE-50 trial and publication of results from the accompanying ZoE-70 trial will reveal more about its mechanism of action and its efficacy against PHN, particularly in subjects >70 years. Phase III trial results in immunocompromised patients are eagerly awaited.
6) CDC recommends new shingles vaccine to replace older one By Susan Scutti, CNN October 26, 2017
7) Shingrix Vs. Zostavax: What Is The Difference Between Shingles Vaccines? By Dr. Brian Staiger
Six people out of 7,344 who received the two doses of Shingrix developed shingles—that is 0.08%. 210 out of 7,415 people who received the placebo became ill with shingles—that is 3%.
8) This New Vaccine Has a Secret Benefit
For older adults, who are often the most vulnerable to severe and occasionally fatal infections, this kind of immune-boosting strategy will be a godsend.Paul Offit 11.07.17 12:00 AM ET
9) Zostavax Just Say No to the Shingles Vaccination! Dr. Julian Whitaker Shingles Vaccination Trial Results Unimpressive
The primary clinical trial prior to Zostavax’s approval showed that it reduced risk of developing shingles by about 50 percent, but this isn’t as impressive as it sounds. In the placebo group, 3.3 percent of the study participants developed shingles, compared to 1.6 percent in the vaccine group. Yes, that’s a 50 percent difference, but the real, absolute risk reduction is just 1.7 percentage points.
Another way of looking at it is 175 people would have to be vaccinated to prevent one case of shingles, and 1,087 would need to be treated to prevent one case of postherpetic neuralgia (lingering nerve pain after an initial attack)—at a cost of $150–$300 per shingles vaccination.
10) Merck’s Zostavax Drug Hit With Lawsuits (MRK, GSK) By Shobhit Seth | March 15, 2017 — 3:05 PM EDT
11) Chlibek, Roman, et al. “Safety and immunogenicity of an AS01-adjuvanted varicella-zoster virus subunit candidate vaccine against herpes zoster in adults≥ 50 years of age.” The Journal of infectious diseases 208.12 (2013): 1953-1961.
Background. An adjuvanted varicella-zoster virus glycoprotein E (gE) subunit vaccine candidate for herpes zoster is in development. In this trial we compared the safety, reactogenicity, and immunogenicity of the vaccine antigen combined with different adjuvant doses.
Methods. This was a phase II, observer-blind, randomized, multinational study. Adults ≥50 years old were randomized 4:4:2:1 to be vaccinated at months 0 and 2 with gE combined with a higher (AS01B) or lower (AS01E) dose adjuvant, unadjuvanted gE, or saline. Following each dose, solicited events were recorded for 7 days and unsolicited adverse events for 30 days. Serious adverse events were collected for 1 year. Cell-mediated and humoral immune responses were assessed at baseline and following each dose.
Results. No vaccine-related severe adverse events were reported. Solicited adverse events were generally mild to moderate and transient. For all gE-based vaccines, pain was the most common local symptom and fatigue the most common general symptom. Immune responses were significantly enhanced by AS01B and AS01E compared to unadjuvanted gE and were significantly stronger for gE/AS01B than for gE/AS01E.
Conclusions. AS01 improved the immunogenicity of gE while retaining acceptable safety and reactogenicity profiles. The enhancement of gE-specific cellular and humoral responses was adjuvant dose dependent.
Burning Mouth Syndrome
12) Nagel, Maria A., et al. “Burning mouth syndrome due to herpes simplex virus type 1.” BMJ case reports 2015 (2015): bcr2015209488.
Burning mouth syndrome is characterised by chronic orofacial burning pain. No dental or medical cause has been found. We present a case of burning mouth syndrome of 6 months duration in a healthy 65-year-old woman, which was associated with high copy numbers of herpes simplex virus type 1 (HSV-1) DNA in the saliva. Her pain resolved completely after antiviral treatment with a corresponding absence of salivary HSV-1 DNA 4 weeks and 6 months later. The patient was treated with oral valacyclovir, 1 g three times a day for 10 days, followed by valacyclovir, 1 g daily for 1 year.
13) Nagel, Maria A., and Don Gilden. “Burning mouth syndrome associated with varicella zoster virus.” BMJ case reports 2016 (2016): bcr2016215953.
We present two cases of burning mouth syndrome (BMS) —of 8-month duration in a 61-year-old woman and of 2-year duration in a 63-year-old woman—both associated with increased levels of antivaricella zoster virus (VZV) IgM antibodies in serum and with pain that improved with antiviral treatment. Combined with our previous finding of BMS due to herpes simplex virus type 1 (HSV-1) infection, we recommend evaluation of patients with BMS not only for VZV or HSV-1 DNA in the saliva, but also for serum anti-VZV and anti-HSV-1 IgM antibodies. Both infections are treatable with oral antiviral agents.
14) Le Goaster, Jacqueline, et al. “Efficacy of the anti-VZV (anti-HSV3) vaccine in HSV1 and HSV2 recurrent herpes simplex disease: a prospective study.” J Clin Trials 4 (2012): 51-58. Efficacy of antiVZV antiHSV3 vaccine HSV1 HSV2 recurrent herpes simplex Jacqueline Le Goaster 2012
15) New Supercharged Shingles Vaccine Has Serious Problems by Kate Raines. Published September 4, 2018
Cimetidine for Shingles
Cimetidine for herpes simplex
16) Cohen, Philip R., and Razelle Kurzrock. “Herpes simplex virus infections and cimetidine therapy.” Journal of the American Academy of Dermatology 19.4 (1988): 762-763.Herpes simplex and cimetidine Cohen Philip Razelle Kurzrock J Amer Acad Derm 1988
17) Kurzrock, R., M. Auber, and G. M. Mavligit. “Cimetidine therapy of herpes simplex virus infections in immunocompromised patients.” Clinical and experimental dermatology 12.5 (1987): 326-331.
Five severely immunocompromised patients with progressive mucocutaneous manifestations of culture‐proven herpes simplex virus infection were treated with cimetidine—1200 mg per day by mouth (four patients) or by i.v. infusion (one patient). Treatment resulted in rapid improvement as evidenced by decreased local pain and crusting of lesions within 24–48 h. Complete resolution was observed within 3–13 days. These encouraging, albeit preliminary, findings suggest that cimetidine warrants further, large‐scale trials in patients with herpes virus infections.
18) Levy, D. W., and W. Levin. “Cimetidine in the treatment of herpesvirus infections.” South African medical journal= Suid-Afrikaanse tydskrif vir geneeskunde 58.3 (1980): 112-116. Cimetidine treatment of herpes virus Levy D W Levin S African med J 1980
19) WAKEFIELD, DENIS. “Cimetidine in recurrent genital herpes simplex infection.” Annals of internal medicine 101.6 (1984): 882-882.
Cimetidine for herpes zoster
20) Kapinska-Mrowiecka, M., and G. Turowski. “Efficacy of cimetidine in treatment of Herpes zoster in the first 5 days from the moment of disease manifestation.” Polski tygodnik lekarski (Warsaw, Poland: 1960) 51.23-26 (1996): 338-339.
21) Komlos, Luise, et al. “In vitro cell-mediated immune reactions in herpes zoster patients treated with cimetidine.” Asian Pacific journal of allergy and immunology 12 (1994): 51-51.
22) Miller, Ariel, et al. “Cimetidine as an immunomodulator in the treatment of herpes zoster.” Journal of neuroimmunology 22.1 (1989): 69-76.
23) Levy, D. W., A. K. Banerjee, and Helen P. Glenny. “Cimetidine in the treatment of herpes zoster.” Journal of the Royal College of Physicians of London 19.2 (1985): 96. Cimetidine in the treatment of herpes zoster Levy D W J Royal College Physicians London 1985
24) Hayne, S. T., and J. B. Mercer. “Herpes zoster: treatment with cimetidine.” Canadian Medical Association Journal 129.12 (1983): 1284.Herpes zoster treatment with cimetidine Hayne Canadian Med Assoc J 1983
25) Kumar A, 1990. Cimetidine: an immunomodulator. DICP Mar;24(3):289-95.
26) Kelly MD, King J, Cherian M, Dwerryhouse SJ, Finlay IG, Adams WJ, King DW, Lubowski D, Morris DL. 1999. Randomized Trial of Preoperative Cimetidine in Patients with Colorectal Carcinoma with Quantitative Assessment of Tumor-Associated Lymphocytes. Cancer Journal 85: 1658-63.
27) Yilmaz, E, Alpsoy E, Basaran E. 1996. Cimetidine therapy for warts: a placebo-controlled, double-blind study. J Am Acad Dermatol Jun; 34(6):1005-7.
28) Franco I 2000. Oral cemetidine for the management of genital and perigenital warts in children. J Urol Sep;164(3 Pt 2):1074-5.
29) Devine SM, Wingard JR 1994, Viral infections in severely immunocompromised cancer patients. Support Care Cancer 1994 Nov;2(6):355-68.
30) Jafarzadeh, Abdollah, et al. “Immunomodulatory properties of cimetidine: Its therapeutic potentials for treatment of immune-related diseases.” International immunopharmacology 70 (2019): 156-166.
Histamine exerts potent modulatory impacts on the cells of innate- [including neutrophils, monocytes, macrophages, dendritic cells (DCs), natural killer (NK) cells and NKT cells] and adaptive immunity (such as Th1-, Th2-, Th17-, regulatory T-, CD8+ cytotoxic T cells, and B cells) through binding to histamine receptor 2 (H2R). Cimetidine, as an H2R antagonist, reverses the histamine-mediated immunosuppression, as it has powerful stimulatory effects on the effector functions of neutrophils, monocytes, macrophages, DCs, NK cells, NKT cells, Th1-, Th2-, Th17-, and CD8+ cytotoxic T cells. However, cimetidine reduces the regulatory/suppressor T cell-mediated immunosuppression.
31) Zhang, Yizhi, et al. “Cimetidine down-regulates stability of Foxp3 protein via Stub1 in Treg cells.” Human vaccines & immunotherapeutics 12.10 (2016): 2512-2518.
Cimetidine (CIM) modulates immunity, at least in part, by reducing regulatory T cell (Treg) levels1
Foxp3-expressing Treg cells have been well documented to provide immune regulation by promoting immune tolerance and suppressing immune over-reaction. Cimetidine (CIM), used to inhibit stomach acid secretion, has been reported to promote immune responses and suppress Treg cell function in several studies. However, the underlying mechanism is unknown. To investigate CIM effects on the suppressive function of Treg and Foxp3, here we used CIM to stimulate human CD4+CD25+ Treg cells and Jurkat T cells and evaluated changes of Foxp3 expression and stability. Our data showed that CIM leads to a reduction of Foxp3 via E3 ligase Stub1-mediated proteosomal degradation, which is dependent on an activated PI3K-AKT-mTOR pathway. Thus, CIM affects the suppressive function of Treg cells by destabilizing their Foxp3 expression.
32) Xie, Xiaoping, et al. “Cimetidine synergizes with Praziquantel to enhance the immune response of HBV DNA vaccine via activating cytotoxic CD8+ T cell.” Human vaccines & immunotherapeutics 10.6 (2014): 1688-1699.
Previously, we have reported that either CIM or PZQ, 2 clinical drugs, could be used to develop as adjuvants on HBV DNA vaccine to elicit both humoral and cellular immune responses. Here, we demonstrate that combinations of CIM and PZQ as adjuvants for a HBV DNA vaccine, could induce much stronger antigen specific CD4(+) and CD8(+) T cell responses compared either with CIM or PZQ alone. The synergistic effects of CIM plus PZQ to HBV DNA vaccine were observed on a higher IgG2a/IgG1 ratio, an increase of HBsAg-specific CD4(+) T cells capable of producing IFN-? or IL-17A and a robust IFN-?-, IL-17A-, or TNF-a-producing CD8(+) T cells to HBsAg. Most importantly, the antigen-specific CTL response was also elevated significantly, which is critical for the eradication of hepatitis B virus (HBV) infected cells. Using an HBsAg transgenic mouse model, the expression of HBsAg in the hepatic cells was also significantly reduced after immunized with pCD-S 2 in the presence of 0.5% CIM and 0.25% PZQ. Further investigations demonstrated that the synergistic effects of combination of CIM and PZQ were dependent on enhanced cytotoxic CD8(+) T cells, which was correlated with impaired activities of regulatory T cells. Therefore, combinations of CIM and PZQ have great potential to be used as effective adjuvants on DNA-based vaccinations for the treatment of chronic hepatitis B.
Cimetidine Adverse Effects
33) Pino, Maria A., and Samy A. Azer. “Cimetidine.” StatPearls [Internet]. StatPearls Publishing, 2019.
High doses of cimetidine (over 5 g/day) can cause reversible impotence or gynecomastia. This effect appears to be the result of the antiandrogenic potential of cimetidine, which depends on an increase in prolactin levels secondary to histamine H2 receptor blockade. Also, cimetidine has non-specific actions that stimulate prolactin secretion, causing galactorrhea in men in a dose-related pattern. The effects could also be related to a blockade of the 2-hydroxylation of estradiol. However, gynecomastia in men is not an adverse effect with the other H2 receptor blockers (ranitidine, famotidine, and nizatidine).
Patients receiving treatment with drugs metabolized through the cytochrome P450 enzymatic pathway may experience enhanced drug effects resulting from pharmacokinetic interaction when treated concomitantly with cimetidine, as it is a well-known enzyme inhibitor of several CYP isoforms including 1A2, 2C9, 2D6, 3A4 P450 isoforms. Clinically relevant is inhibition of cytochrome 3A4 and 1A2.. Inhibition of these enzymes can lead to increased plasma levels of certain drugs including warfarin, tricyclic antidepressants, lidocaine, calcium channel blockers, quinidine, oral sulfonylureas, phenytoin, theophylline, benzodiazepines, and beta-blockers (metoprolol and propranolol).
Drug Repurposing for Colorectal Cancer: Redesigning a House Into a Bookstore
Tumours have defensive mechanisms (the Empire’s TIE fighters, or in this case myeloid-derived suppressor cells and regulatory T cells) to stop immune cells from attacking it. This allows the tumour to continue to grow without surveillance.
Several studies have shown that cimetidine targets and shuts down the suppressor cells (Empire TIE fighters) [2,3]. By shutting down suppressor cells, the immune cells are free to attack the tumour with the ultimate goal of destroying that Death Star.
To?nnesen H, Bulow S, Fischerman K, Hjortrup A, Pedersen V.M, Svendsen L, et al. Effect of cimetidine on survival after gastric cancer. The Lancet. 1988;332(8618):990-992.
Zheng Y, Xu M, Li X, Jia J, Fan K, Lai G. Cimetidine suppresses lung tumor growth in mice through proapoptosis of myeloid-derived suppressor cells. Molecular Immunology. 2013;54(1):74-83.
Zhang Y, Chen Z, Luo X, Wu B, Li B, Wang B. Cimetidine down-regulates stability of Foxp3 protein via Stub1 in Treg cells. Human Vaccines & Immunotherapeutics. 2016;12(10):2512-2518.
Matsumoto S, Imaeda Y, Umemoto S, Kobayashi K, Suzuki H, Okamoto T. Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells. British Journal of Cancer. 2002;86(2):161-167.
Deva S, Jameson M. Histamine type 2 receptor antagonists as adjuvant treatment for resected colorectal cancer. [Internet]. 2012 [cited 8 February 2017]. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD007814.pub2/full
Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme V.P. Repurposing drugs in oncology (ReDO)—Cimetidine as an anti-cancer agent. ecancermedicalscience. 2014;8.
Moreno Ayala, Mariela A., Zehui Li, and Michel DuPage. “Treg programming and therapeutic reprogramming in cancer.” Immunology 157.3 (2019): 198-209.
Overcoming the immunosuppressive tumour microenvironment is the major challenge impeding cancer immunotherapy today. Regulatory T-cells (Tregs) are prevalent in nearly all cancers and, as immunosuppressive regulators of immune responses, they are the principal opponents of cancer immunotherapy. However, disabling Tregs systemically causes severe autoimmune toxicity, hastening the need for more selective methods to target intratumoural Tregs. In this review, we discuss a burgeoning new modality to specifically target tumour-infiltrating Tregs (TI-Tregs) by reprogramming their functionality from immunosuppressive to immune stimulatory within tumours. As the basis for therapeutic selectivity of TI-Tregs, we will focus on the defining features of Tregs within cancer: their highly activated state controlled by the engagement of key surface receptors, their distinct metabolic programme, and their unique transcriptional programme. By identifying proteins and pathways that distinguish TI-Tregs from other Tregs in the body, as well as from the beneficial antitumour effector T-cells within tumours, we highlight mechanisms to selectively reprogramme TI-Tregs for the treatment of cancer.
he selective reprogramming of Tregs within cancers represents a singular methodology
to overcome the last barriers that impede the broad suc-cess of
cancer immunotherapy in patients by both over-coming immunosuppression in the TME and limiting autoimmune toxicity.
Munn, David H., Madhav D. Sharma, and Theodore S. Johnson. “Treg destabilization and reprogramming: implications for cancer immunotherapy.” Cancer research 78.18 (2018): 5191-5199.
Regulatory T cells (Tregs) are an important contributor to the immunosuppressive tumor microenvironment. To date, however, they have been difficult to target for therapy. One emerging new aspect of Treg biology is their apparent functional instability in the face of certain acute proinflammatory signals such as IL6 and IFN?. Under the right conditions, these signals can cause a rapid loss of suppressor activity and reprogramming of the Tregs into a proinflammatory phenotype. In this review, we propose the hypothesis that this phenotypic modulation does not reflect infidelity to the Treg lineage, but rather represents a natural, physiologic response of Tregs during beneficial inflammation. In tumors, however, this inflammation-induced Treg destabilization is actively opposed by dominant stabilizing factors such as indoleamine 2,3-dioxygenase and the PTEN phosphatase pathway in Tregs. Under such conditions, tumor-associated Tregs remain highly suppressive and inhibit cross-presentation of tumor antigens released by dying tumor cells. Interrupting these Treg stabilizing pathways can render tumor-associated Tregs sensitive to rapid destabilization during immunotherapy, or during the wave of cell death following chemotherapy or radiation, thus enhancing antitumor immune responses. Understanding the emerging pathways of Treg stabilization and destabilization may reveal new molecular targets for therapy. Cancer Res; 78(18); 5191–9
Aldinucci, Donatella, Cinzia Borghese, and Naike Casagrande. “Formation of the immunosuppressive microenvironment of classic Hodgkin lymphoma and therapeutic approaches to counter it.” International journal of molecular sciences 20.10 (2019): 2416.
Classic Hodgkin lymphoma (cHL) is characterized by a few tumor cells surrounded by a protective, immunosuppressive tumor microenvironment composed of normal cells that are an active part of the disease. Hodgkin and Reed–Sternberg (HRS) cells evade the immune system through a variety of different mechanisms. They evade antitumor effector T cells and natural killer cells and promote T cell exhaustion. Using cytokines and extracellular vesicles, they recruit normal cells, induce their proliferation and “educate” (i.e. reprogram) them to become immunosuppressive and protumorigenic. Therefore, alternative treatment strategies are being developed to target not only tumor cells but also the tumor microenvironment. Here we summarize current knowledge on the ability of HRS cells to build their microenvironment and to educate normal cells to become immunosuppressive. We also describe therapeutic strategies to counteract formation of the tumor microenvironment and related processes leading to T cell exhaustion and repolarization of immunosuppressive tumor-associated macrophages.
Checkpoint Inhibitors and Adjuvants: Nivolumab, Pembrolizumab, and Indoximod
Nivolumab and pembrolizumab are human IgG4 (S228P) monoclonal antibodies that target PD-1, which is expressed on activated T cells, B cells, and myeloid cells. Both nivolumab and pembrolizumab bind and block engagement of PD-1, thereby activating T cells and cell-mediated immune responses.
Despite a great inflammatory infiltrate, patients with cHL have an impaired cellular immune response [107,142]. This is mediated by several factors
including the high expression of PD-L1 and PD-L2 ligands by HRS cells, since PD-1 engagement by PD-L1 leads to T cell exhaustion, that is reduced T cell activation and proliferation
Idelalisib is the first PI3K-d inhibitor to be approved for follicular lymphoma  and chronic lymphocytic leukemia . Recently, it has been demonstrated that the selective targeting of the ? isoform of PI3K in TAMs modulates the immunosuppressive TME, resulting in tumor regression . Hyperactivation of the PI3K/AKT pathway is involved in the pathogenesis of cHL
Hair Growth in WOmen
Int J Dermatol. 1987 Mar;26(2):128-30.
Treatment of female androgenetic alopecia with cimetidine.
Ten white women with moderate to severe androgenetic alopecia were treated with cimetidine 300 mg by mouth five times a day. Duration of therapy ranged from 1.5-9 months, with a median of 5 months. Seven patients (70%) showed good to excellent regrowth of hair. No major side effects were noted. The patients were followed up for 5 months. Cimetidine presumably has the ability to block androgen action. Cimetidine is not a first-line drug for the treatment of androgenetic alopecia in women and should be used only in selected cases.
Cimetidine for WARTS HPV No Better Than Placebo
J Am Acad Dermatol. 1999 Jul;41(1):123-7.
Cimetidine therapy for recalcitrant warts in adults: is it any better than placebo?
Rogers CJ1, Gibney MD, Siegfried EC, Harrison BR, Glaser DA.
Saint Louis University School of Medicine, Missouri, USA.
Three open-label, uncontrolled studies have documented successful treatment of warts with cimetidine, whereas two placebo-controlled, double-blind studies and two open-label comparative trials have failed to demonstrate efficacy. This double-blind, placebo-controlled study was designed with stringent enrollment and outcome criteria to minimize the confounding issue of spontaneous remission. Efficacy was not statistically superior to that of placebo, but a trend toward efficacy was suggested for younger subjects.
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Fl 33314
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