A Common Virus

A major reason why our immune system fails with aging is that we lose vital naïve (virgin) immune cells while we accumulate excess levels of senile memory cells.^1,2

Naïve immune cells are needed to respond to new malignancies and infectious agents,³ whereas memory immune cells only respond to the original antigen, i.e. bacteria, virus, or cancer cell.⁴

Once our reserve of naïve immune cells is depleted, we become vulnerable to diseases that were fought off in our youth.

Some people suffer accelerated immune senescence that wreaks havoc throughout their body. These individuals are unable to fend off new invaders because of naïve cell depletion. They may also suffer systemic damage caused by inflammatory signals emitted from senescent memory cells.¹

A growing body of evidence has identified a virus (cytomegalovirus) that causes us to more rapidly deplete vital naïve immune cells with the consequential buildup of excessive memory cells.¹

A disconcerting 60 to 90% of us are estimated to harbor this insidious virus.⁵ Fortunately, there are steps one can take to help offset the age-accelerating effects inflicted by the cytomegalovirus (CMV) and thus retain more youthful immune function.

There is a limit as to how many naïve immune cells our bodies normally produce and this number declines with age.^6-9 Once a naïve cell is exposed to an antigen, it converts to a memory type immune cell that only responds to the same virus, bacteria, or other foreign agent.^4,10

When we develop certain chronic viral infections, our immune system goes into constant overdrive, producing high levels of naïve cells that convert into memory cells upon exposure to new copies and strains of the virus replicating in our cells. Unfortunately, there are only limited numbers of these vital naïve immune cells our bodies can naturally make.

Those inflicted with HIV suffer an accelerated form of aging as their immune system works to fight the virus, despite the advent of anti-HIV drugs.^11,12 Hepatitis C infection creates this same problem.¹³ The breakthrough news about hepatitis C is that new drugs are curing up to 90% of those infected.¹⁴

Most of us, however, are not infected with hepatitis C or HIV. What the vast majority of us do harbor in our bodies is the cytomegalovirus. Lab tests revealed that it is present in approximately 60% of the general population, and in 90% of those over the age of 80.⁵

The insidious property of cytomegalovirus (CMV) is that it leads to the continuous production of viral proteins that have the ability to establish secondary infections with differing CMV strains.^15-17 The deadly consequence that has been observed is continuous stimulation (and subsequent depletion) of naïve cells and excess accumulation of dysfunctional memory cells leading to the development of accelerated immune senescence.^18-20

Unless one is immune compromised, most of us infected with CMV are asymptomatic—or so we think.²¹ The harsh reality is that chronic CMV infection is associated with frailty, cognitive decline, and arterial occlusion—hallmark pathologies of “normal” aging processes.^22,23

CMV Shown To Shorten Life Span

 

CMV infection can increase mortality (death) rate in otherwise healthy, older individuals. This is most clearly seen by an increase in vascular deaths and immune senescence.^22,24

One study found that high CMV antibody levels (associated with CMV exposure) were independently associated with a 179% greater mortality rate over a five-year period.²² Another study showed a 35% increase in cardiovascular disease mortality in those with elevated CMV indicators.²⁵ In still another study, CMV reduced life expectancy by 3.7 years after adjusting for other factors.²⁴

What scientists are finding is that chronic CMV infection “exhausts” the immune system. It does this by depleting naïve cells needed to ward off new CMV strains and leaving behind a large population of pro-inflammatory senile memory cells.^18,26

Of interest, however, was a study on long-lived family members whose offspring enjoy a 30% reduced mortality rate.²⁷ These rare individuals, genetically enriched for longevity, were less susceptible to the characteristic CMV-driven impairments of immune function. This study showed that CMV infection was strongly associated with an age-related reduction in vital naïve T-cells and accumulation of memory T-cells in the general population, but not in members of long-lived families.²⁷ These long-lived individuals also showed lower pro-inflammatory status as measured by C-reactive protein. This study implies that by initiating strategies to boost naïve T-cell populations and suppress excess memory cells, one might derive some of the enhanced longevity benefits enjoyed by genetically programmed long-lived individuals.

CMV Adversely Affects Cognitive Thinking

T-helper cells are needed to help initiate an immune attack against foreign invaders. Regulatory T-cells (also known as suppressor T-cells) turn down immune responses, preferably after the pathogen has been brought under control.²⁸

For optimal immune health, one should have approximately one to four T-helper cells for every one regulatory T-cell.^29,30 As a result of normal aging, regulatory T-cell counts elevate,^31,32 while T-helper counts decline.³³ Certain cancers appear able to boost regulatory T-cell counts in order to protect themselves against an immune attack.^34-36

A study published in 2014 evaluated 360 adults (aged 60-103) and found that those with higher CMV activity had an 8-fold increased risk of an inverted T-helper/regulatory T-cell ratio, meaning they had more regulatory T-cells than T-helpers.³⁷

These human study subjects with inverted T-helper/regulatory T-cell ratios had impairments in some cognitive dimensions and more functional disability and dependency compared to subjects with higher T-helper counts and lower regulatory T-cell counts.

Humans with lower T-helper counts and higher regulatory T-cell counts die sooner.³⁸ It is thus important for aging individuals and certain cancer patients to take aggressive steps to maintain higher youthful levels of T-helper cells and keep regulatory T-cell counts from increasing too much.

CMV May Speed Up Immune Senescence

• An aging immune system fails because, as we age, the body loses vital naïve immune cells and accumulates excess levels of senescent memory cells.
• This makes us vulnerable to diseases that were easily overcome in youth.
• Growing evidence shows that a virus called cytomegalovirus (CMV) depletes naïve immune cells and infects approximately 60 to 90% of people.
• CMV infection can shorten the life span of otherwise healthy older adults. Bolstering natural killer cell (NK) activity may suppress CMV.
• A four-month course of a compound called enzymatically modified rice bran, along with a 60-day course (800 mg/day) of an over-the-counter drug called cimetidine, can help reduce the CMV burden in the body and boost antiviral activity.
• A commonly used Chinese herbal extract called cistanche can also influence antiviral components and help increase naïve T-cells and NK cells.

How CMV Inflicts So Much Damage

CMV attacks the endothelial lining of our arteries, which explains the high prevalence of vascular death seen in those with active CMV infection.^39-45

Immune cells are highly dependent on telomerase activity in order to maintain youthful function.⁴⁶ CMV causes immune cells to lose telomerase activity.^47-49

CMV also forces vital naïve immune cells to be used to suppress active infection. The result is accelerated immune senescence.^50-52 As naïve immune cells decline, aging humans lose their natural protection against bacteria, viruses, and cancer.

Naïve cells are lost to normal aging, making CMV infection particularly deadly in the elderly.^24,53

Active CMV infection is present in virtually all glioblastoma (fatal brain tumor) patients.⁵⁴ As we reported in 2013, administering an anti-CMV drug (valganciclovir) to glioblastoma patients improves two-year survival rates by more than 3-fold.⁵⁵ However, this drug has side effects^56,57 and costs about $50,000 annually. It is thus, not yet suitable for most normal aging people.

Another way to suppress CMV may be to bolster natural killer cell activity. An important function of natural killer (NK) immune cells is to destroy virus-infected cells throughout our body.⁵⁸

“An effective defense against CMV in immune competent subjects requires the participation of NK cells and T-lymphocytes… It has been shown that CMV chronic infection in old individuals is associated with accumulations of late-differentiated CD8 T-cells, characteristic of CD8 T-cell immunosenescence, and with the development of an ‘Immune Risk Phenotype’ (IRP), predictive of early mortality in the elderly indicating that this virus is a major driving force of T-cell immunosenescence.”⁸²

Reference: Current Opinion In Immunology—January 2014, “Shaping Of NK Cell Subsets By Aging.”

CMV-Induced Immune Cell Exhaustion

Immune cells used to suppress chronic infections like cytomegalovirus (CMV) become senile or “exhausted” over time.^18,50,59,60

As people accumulate exhausted T-cells, an adverse consequence is that the senile cells emit pro-inflammatory cytokines that exacerbate the chronic inflammation observed in elderly persons.^61,62 These individuals suffer higher mortality.^63,64

The deficit of naïve immune cells combined with over accumulation of exhausted T-cells decreases the efficacy (antibody response) of vaccinations.^65-67

Persistent CMV infection and the consequent accumulation of pro-inflammatory exhausted T-cells are associated with increased risk of coronary heart disease, impaired vascular function, vascular inflammation, and endothelial dysfunction.^39,41,68-72 This all leads to increased blood pressure and contributes to atherosclerosis.⁷³

An accumulation of exhausted T-cells has been seen in persons suffering from rheumatoid arthritis and other chronic inflammatory conditions.^74,75

A strong body of evidence, mostly published over the past few years, indicates that persistent CMV infection and the accumulation of senile (exhausted) T-cells initiates and accelerates a broad array of age-associated and inflammatory diseases.^76-81

An Immune Cell That Destroys CMV

Cytomegalovirus (CMV) invades cells throughout the body and spews out copies that infect other cells.⁸³

The first line of defense against virus-infected and malignant cells is our natural killer (NK) cells.^84-87 Young individuals have high levels of functional natural killer immune cells, but this declines with aging.^88-90

In elderly subjects, decreased NK cell activity is associated with an increased incidence and severity of viral infections, which explains why 90% of older people show CMV infection compared to about 60% of the general population.⁵

Healthy NK function is critical in eliminating transformed cells before a viral infection or malignancy develops.^59,91,92 NK cells are involved in immune regulation, antimicrobial immune responses, and elimination of senescent cells that otherwise cause chronic inflammation.⁵⁹

The age-related decrease in healthy NK cell function is likely to have wider implications for the health of older adults than currently understood by the mainstream. If an aging person is to control debilitating and deadly CMV replication, maintaining more youthful NK function would appear to play a critical role, as would restoration of the naïve immune cell population.

 

“…several features of the aging process, such as the reduced efficacy of vaccination, the appearance of senescent cells, and the higher rates of fungal infection may be attributable in part to the decline in NK cell function that accompanies human aging. If true, then developing strategies to prevent, delay, or reverse NK cell immunesenescence may be one way by which to improve the health of older adults.”⁵⁹

Reference: Ageing Research Reviews—September 2013

“The Impact Of Aging On Natural Killer Cell Function And Potential Consequences For Health In Older Adults.”

Suppressing CMV Infection

Immune compromised people, such as HIV patients, organ transplant recipients given immune-suppressing drugs, and certain cancer chemotherapy patients are particularly vulnerable to acute CMV infection.^93-96 These individuals facing blindness,⁹⁷ pneumonia,⁹⁸ and possible death from an uncontrolled CMV infection are prescribed a drug like valganciclovir that is highly effective in controlling viral replication.^99-101

One of the side effects of this drug is bone marrow suppression, which can hasten immune senescence.¹⁰² That’s because immune cells are formed in our bone marrow where they are released into the bloodstream for further differentiation into specific disease-fighting cells like macrophages and NK cells. Valganciclovir is therefore not recommended for most CMV-infected individuals who are asymptomatic.

Since we know that NK cells hunt down virus-infected cells and eliminate them, it makes sense to take steps to boost the functionality of our aging NK cells to suppress CMV activity.

Enhanced NK cell function alone will not likely eradicate CMV, but it can downregulate active CMV infection to reduce the damage inflicted on the body and theoretically reduce the number of naïve immune cells that will be used up fighting it.¹⁰³

In as much as aging itself causes a decline in functional NK activity, initiating a four-month course of an NK-boosting compound like enzymatically modified rice bran offers an intriguing approach to reducing the CMV burden in an aging body.^104-106

To further boost antiviral activity, consider taking 800 mg each night of the over-the-counter drug cimetidine for 60 continuous days. This drug is approved for relieving heartburn, but a side benefit is that it boosts the number of T-helper immune cells while suppressing excess regulatory T-cells.^107-110

As people age, and/or contract an illness such as cancer, they often produce too many regulatory T-cells^111,112 that prematurely shut down needed immune activity.^113-118 Aging also results in a decline of T-helper cells that initiate immune responses to virus-infected and cancer cells.¹¹⁹ Cimetidine can be obtained without a prescription at your local pharmacy at low cost.

T-helper cells are required for the immune system to react to new infections and malignancies.^120,121 They help activate the secretion of antibodies and macrophages to destroy ingested microbes and help activate cytotoxic T-cells to kill virus-infected target cells. To fully appreciate the importance of T-helper cells, you may know that HIV invades and destroys T-helper cells.¹²² As T-helper cell counts decline, AIDS patients become vulnerable to a host of opportunistic infections.^123,124

A four-month course of enzymatically modified rice bran combined with a 60-day regimen of cimetidine makes sense to reduce CMV activity and reverse markers of immune senescence such as dysfunctional NK cell activity, reduced T-helper counts, and excess numbers of regulatory T-cells.^104-107

A commonly used herbal extract in China called cistanche has been recently shown to favorably influence multiple antiviral immune components, including increasing the number of naïve T-cells and NK-cells.¹²⁵ Cistanche is a low-cost nutrient that should be taken daily in the dose of 210 mg, preferably with 1,000 mg of Reishi mushroom extract, to provide broad spectrum protection against the many factors involved in immune senescence.

There Is Not Yet Universal Consensus On CMV And Immune Senescence

 

Not all published scientific papers agree that CMV infection accelerates immune senescence. The topic is currently being debated by immunologists around the world.¹²⁶ The studies supporting the pathologic impact of CMV on immune status are compelling, as is the data associating active CMV infection with shortened human life spans. But as critics accurately point out, “association” is not always the same as “causation.”

For an aging human concerned about their health and longevity, it does not necessarily matter if CMV is accelerating immune senescence. That’s because maturing individuals are already suffering a decline of naïve T-cells, reduced T-helper cells, loss of NK cell activity, accumulation of worn out memory cells (that emit chronic inflammatory signals), and an increase in regulatory T-cells. So initiating daily supplementation with 210 mg of cistanche, a 60-day course using 800 mg daily of cimetidine, and a four-month course using 500 mg daily of enzymatically modified rice bran makes sense for anyone over age 35 (and sometimes younger individuals with certain immune deficits).

I’m ending this article with information about cimetidine side effects. I know Life Extension^® members have historically shied away from drugs because of side-effect concerns. When it comes to the 60-day course of 800 mg/day of cimetidine, I hope eligible members will take into account the many rewards that a strong immune boost provides and view drug interaction risk only as it relates to their individual status.

Aging humans who choose not to take cimetidine should still consider initiating low-cost cistanche daily, along with a four-month regimen of enzymatically modified rice bran.

Cimetidine: Drug Interactions And Side Effects

We describe here potential side effects for certain individuals taking cimetidine.

From past experience, I know the risk of any side effect will preclude some Life Extension members from considering even a 60-day course of cimetidine at the moderate dose of 800 mg at bedtime.

By way of analogy, I have dealt with aging men who have stubbornly high levels of C-reactive protein, which is an inflammatory factor associated with greater incidence of vascular disease, dementia, and certain cancers.^127-132

Low testosterone levels are associated with higher C-reactive protein levels.^133-136 An unwarranted fear of prostate cancer caused many of these men to not elevate their testosterone levels. The outcomes in some cases were tragic.

When it comes to cimetidine, the benefit is boosting T-helper immune cell counts and lowering excess regulatory T-cell levels.^107-110 Aging people often have elevated regulatory T-cells that interfere with optimal immune defenses. Mortality rates are higher in those with surplus regulatory T-cells in relation to T-helper cell counts.

I hope members who could benefit from a 60-day course of cimetidine (800 mg a night) will not be dissuaded by side effect risks that are usually manageable if they occur at all.

Significant Drug Interactions^137,138

Cimetidine is a known inhibitor of many isozymes of the cytochrome P450 enzyme system, including but not limited to CYP2D6, 3A4 and 1A2 isoenzymes, which can cause increases in plasma concentrations of certain drugs when cimetidine is ingested.^137,139

A short list of important, clinically relevant drug interactions include:¹⁰²

• Warfarin (Coumadin^®), an anticoagulant;
• Sildenafil (Viagra^®), a PDE5 inhibitor for erectile dysfunction;¹⁴⁰
• Phenytoin (Dilantin^®), an anticonvulsant;
• Propranolol (Inderal^®),a beta-blocker used to reduce blood pressure and heart rate);¹⁴¹
• Nifedipine (Procardia^®), a Ca²⁺-channel blocker primarily used to reduce blood pressure);
• Diazepam (Valium^®), an anti-anxiety medication;¹⁴²
• Several tricyclic antidepressant drugs, lidocaine, theophylline (anti-asthmatic) and metronidazole (antifungal).¹⁴¹

Dosage of these drugs and other similarly metabolized drugs, particularly in patients with significant renal (kidney) and/or hepatic (liver) disease, may require adjustment when starting/stopping cimetidine to maintain therapeutic blood levels.

In patients with poor liver¹⁴³ or kidney function,¹⁴⁴ as well as elderly patients at risk for neuropsychiatric illness,¹⁴⁵ cimetidine dosage should be reduced to 300 mg every 12 hours, and further reduction may be necessary depending upon patient tolerability.

Close monitoring of prothrombin time (PT)¹⁴⁶ is recommended with the anticoagulant warfarin (Coumadin^®), and careful adjustment of the anticoagulant dose may be necessary with cimetidine treatment.

Aging men with pre-existing erectile dysfunction using sildenafil (Viagra^®) should be aware that cimetidine boosts drug exposure by almost 60%,¹⁴⁷ so men should strongly consider using a reduced dose of sildenafil (Viagra^®) if concomitantly using cimetidine.

Sexual Side Effects In Men

Starting at the time of prescription use of cimetidine in the 1970s, multiple case reports began to appear in the peer-reviewed literature concerning sexual side effects, including loss of libido and erectile dysfunction.^148,149 In addition, many reports of breast tenderness and tissue growth in men, known as gynecomastia,¹⁵⁰ were published.^151,152 Conservative post-marketing surveillance data suggests that the incidence of gynecomastia may be as high as one out of every 25 male patients treated with cimetidine for high stomach acid.¹⁵³

These sexual side effects are not surprising since cimetidine is known to interfere with sex hormone binding sites in androgen responsive tissues,¹⁵⁴ as well as increase prolactin levels and interfere with the peripheral activity of sex hormones like dihydrotestosterone (DHT).¹⁵⁵

Since the risks for male sexual side effects and gynecomastia appear to increase with cimetidine dosages of 1,000 mg daily in men over the age of 40 years (though some men may experience sexual dysfunction within a short time of starting cimetidine at lower doses),^149,152 older men should avoid doses of cimetidine in excess of 800 mg daily and treatment regimens longer than 60 days.

Summary

The immune system begins to shut down as we age due to the loss of vital naïve immune cells and an accumulation of excess levels of older memory cells, which makes us vulnerable to disease. Research shows that about 60 to 90% of adults harbor a virus called cytomegalovirus (CMV), which depletes naïve immune cells. CMV may increase mortality in healthy older adults.

Enzymatically modified rice bran, taken over the course of four months, along with a 60-day course of cimetidine, may reduce CMV and boost antiviral activity. Cistanche, a common Chinese botanical extract, can also influence antiviral components and help increase naïve T-cells and NK cells.

If you have any questions on the scientific content of this article, please call a Life Extension^® Health Advisor at 1-866-864-3027.

References

1. Montecino-Rodriguez E, Barent-Maoz B, Dorshkind K. Causes, consequences, and reversal of immune system aging. J Clin Invest. 2013;123(3):958-65.
2. Prlic M, Sacks JA, Bevan MJ. Dissociating markers of senescence and protective ability in memory T cells. PLoS One. 2012;7(3):e32576.
3. Castellino F, Huang AY, Altan-Bonnet G, Stoll S, Scheinecker C, Germain RN. Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction. Nature. 2006 Apr 13;440(7086):890-5.
4. Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. “T Cell-Mediated Immunity.”
5. Staras SA, Dollard SC, Radford KW, Flanders WD, Pass RF, Cannon MJ. Seroprevalence of cytomegalovirus infection in the United States, 1988-1994. Clin Infect Dis. 2006 Nov 1;43(9):1143-51.
6. Park JH, Yu Q, Erman B, et al. Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. Immunity. 2004 Aug;21(2):289-302.
7. Takada K, Jameson SC. Naive T cell homeostasis: from awareness of space to a sense of place. Nat Rev Imunol.2009 Dec;9:823-32.
8. Surh CD, Sprent J. Homeostasis of naive and memory T cells. Immunity. 2008 Dec 19;29(6):848-62.
9. Weng N. Aging of the immune system: How much can the adaptive immune system adapt? Immunity. 2006 May;24(5):495-9.
10. Berard M, Tough DF. Qualitative differences between naive and memory T cells. Immunology. Jun 2002; 106(2):127-38.
11. Appay V, Almeida JR, Sauce D, Autran B, Papagno L. Accelerated immune senescence and HIV-1 infection. Exp Gerontol. 2007 May;42(5):432-7.
12. Desai S, Landay A. Early immune senescence in HIV disease. Curr HIV/AIDS Rep. 2010 Feb;7(1):4-10.
13. Schurich A, Henson SM. The many unknowns concerning the bioenergetics of exhaustion and senescence during chronic viral infection. Front Immunol. 2014 Sep 25;5:468.
14. Available at: http://www.medicalnewstoday.com/articles/280187.php. Accessed October 20, 2014.
15. Novak Z, Ross SA, Patro RK, et al. Cytomegalovirus strain diversity in seropositive women. J Clin Microbiol. 2008 Mar;46(3):882-6.
16. Chou SW. Reactivation and recombination of multiple cytomegalovirus strains from individual organ donors. J Infect Dis. 1989 Jul;160(1):11-5.
17. Chandler SH, Handsfield HH, McDougall JK. Isolation of multiple strains of cytomegalovirus from women attending a clinic for sexually transmitted disease. J Infect Dis. 1987 Apr;155(4):655-60.
18. Brunner S, Herndler-Brandstetter D, Weinberger B, Grubeck-Loebenstein B. Persistent viral infections and immune aging. Ageing Res Rev. 2011 Jul;10(3):362-9.
19. Ferrando-Martínez S, Ruiz-Mateos E, Hernández A, et al. Age-related deregulation of naive T-cell homeostasis in elderly humans. Age (Dordr). 2011 Jun;33(2):197-207.
20. Kovaiou RD, Weiskirchner I, Keller M, Pfister G, Cioca DP, Grubeck-Loebenstein B. Age-related differences in phenotype and function of CD4+ T cells are due to a phenotypic shift from naive to memory effector CD4+ T cells. Int Immunol. 2005 Oct;17(10):1359-66.
21. Available at: http://emedicine.medscape.com/article/215702-overview. Accessed October 28, 2014.
22. Wang GC, Kao WH, Murakami P, et al. Cytomegalovirus infection and the risk of mortality and frailty in older women: a prospective observational cohort study. Am J Epidemiol. 2010 May 15;171(10):1144-52.
23. Atzmony L, Halutz O, Avidor B, et al. Incidence of cytomegalovirus-associated thrombosis and its risk factors: a case-control study. Thromb Res. 2010 Dec;126(6):e439-43.
24. Savva GM, Pachnio A, Kaul B, et al. Cytomegalovirus infection is associated with increased mortality in the older population. Aging Cell. 2013 Jun;12(3):381-7.
25. Roberts ET, Haan MN, Dowd JB, Aiello AE. Cytomegalovirus antibody levels, inflammation, and mortality among elderly Latinos over 9 years of follow-up. Am J Epidemiol. 2010 Aug 15;172(4): 363-71.
26. Tatum A, Hill AB. Chronic viral infections and immunosenescence, with a focus on CMV. Open Longevity Science. 2012;6:33-8.
27. Derhovanessian E, Maier AB, Beck R, et al. Hallmark features of immunosenescence are absent in familial longevity. J Immunol. 2010 Oct 15;185(8):4618-24.
28. Voo KS, Peng G, Guo Z, et al. Functional characterization of EBV-encoded nuclear antigen 1-specific CD4+ helper and regulatory T cells elicited by in vitro peptide stimulation. Cancer Res. 2005 Feb 15;65(4):1577-86.
29. Available at: http://labmed.ucsf.edu/sfghlab/data/tests/63.html. Accessed October 28, 2014.
30. Available at: https://www.labcorp.com/wps/portal/!ut/p/c1/hY1ZDoIwFADP4gFIHwUqfLoAAqVYq2w_hMUQDJtLNHJ6uYCa-ZxMBqVopsfTZ0_mqHPWxSjlGRcJ4xjhkH3sQVYIWvQNqYMNpl98t0D_KnZbujOKEHpMjuZqpAdQ4HAFhgcoQQqw4w HdARxaBm4gKjT--9PxnBnpoaoYtKL0bHK9wn96GB7zy3EPVtlce1VFIra0rytcomuww0XIIV5FeSMWwmH_Jz9_YxS9Z4osPp95pZQ!!/dl2/d1/ L0lJS2FZQSEhL3dMRUJGcUFFQWpNQy9ZSTV5bHchIS83X1VFNFMxSTkzME9HUzIwSVMzTzROMk42NjgwL3Zp ZXdUZXN0/?testId=407414. Accessed October 28, 2014.
31. Fessler J, Ficjan A, Duftner C,Dejaco C. The impact of aging on regulatory T-cells. Front Immunol. 2013 Aug 6;4:231.
32. Raynor J, Lages CS, Shehata H, Hildeman DA, Chougnet CA. Homeostasis and function of regulatory T-cells in aging. Curr Opin Immunol. 2012 Aug;24(4):482-7.
33. Swain S, Clise-Dwyer K, Haynes L. Homeostasis and the age-associated defect of CD4 T cells. Semin Immunol. 2005 Oct;17(5):370-7.
34. Poggi A, Zocchi MR. Mechanisms of tumor escape: role of tumor microenvironment in inducing apoptosis of cytolytic effector cells. Arch Immunol Ther Exp (Warsz). 2006 Sep-Oct;54(5):323-33.
35. Kim R, Emi M, Tanabe K. Cancer cell immune escape and tumor progression by exploitation of anti-inflammatory and pro-inflammatory responses. Cancer Biol Ther. 2005 Sep;4(9):924-33.
36. Montes CL, Chapoval AI, Nelson J, et al. Tumor-induced senescent T cells with regulatory function: a potential form of tumor immune evasion. Cancer Res. 2008 Feb 1;68(3):870-9.
37. Luz Correa B, Ornaghi AP, Cerutti Muller G, et al. The inverted CD4:CD8 ratio is associated with cytomegalovirus, poor cognitive and functional states in older adults. Neuroimmunomodulat. 2014 21(4):206-12.
38. Serrano-Villar S, Pérez-Elías MJ, Dronda F, et al. Increased risk of serious non-AIDS-related events in HIV-infected subjects on antiretroviral therapy associated with a low CD4/CD8 ratio. PLoS One. 2014 Jan 30;9(1):e85798.
39. Blankenberg S, Rupprecht HJ, Bickel C, et al. Cytomegalovirus infection with interleukin-6 response predicts cardiac mortality in patients with coronary artery disease. Circulation. 2001 Jun 19;103(24):2915-21.
40. Grattan MT, Moreno-Cabral CE, Starnes VA, Oyer PE, Stinson EB, Shumway NE. Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis. JAMA. 1989 Jun 23-30;261(24):3561-6.
41. Hendrix MG, Dormans PH, Kitslaar P, Bosman F, Bruggeman CA. The presence of cytomegalovirus nucleic acids in arterial walls of atherosclerotic and nonatherosclerotic patients. Am J Pathol. 1989 May;134(5):1151-7.
42. Bentz GL, Yurochko AD. Human CMV infection of endothelial cells induces an angiogeniv response through viral binding to EGF receptor and beta 1 and beta 3 integrins. Proc Natl Acad Sci USA. 2008 Apr 8;105(14):5531-6.
43. Bolovan-Fritts CA, Trout RN, Spector SA. High T-cell response to human cytomegalovirus induces chemokine-mediated endothelial cell damage. Blood. 2007 Sep 15;110(6):1857-63.
44. Rahbar A, Söderberg-Nauclér C. Human cytomegalovirus infection of endothelial cells triggers platelet adhesion and aggregation. J Virol. 2005 Feb;79(4):2211-20.
45. Hendrix MG, Salimans MM, van Boven CP, Bruggeman CA. High prevalence of latently present cytomegalovirus in arterial walls of patients suffering from grade III atherosclerosis. Am J Pathol. 1990 Jan;136(1):23-8.
46. Adam E, Melnick JL, Probtsfield JL, et al. High levels of cytomegalovirus antibody in patients requiring vascular surgery for atherosclerosis. Lancet. 1987 Aug 8;2(8554):291-3.
47. Harley CB, Liu W, Blasco M, et al. A natural product telomerase activator as part of a health maintenance program. Rejuvenation Res. 2011 Feb;14(1):45-56.
48. Dowd JB, Bosch JA, Steptoe A, et al. Cytomegalovirus is associated with reduced telomerase activity in the Whitehall II cohort. Exp Gerontol. 2013 Apr;48(4):385-90.
49. Valenzuela HF, Effros RB. Divergent telomerase and CD28 expression patterns in human CD4 and CD8 T cells following repeated encounters with the same antigenic stimulus. Clin Immunol. 2002 Nov;105(2):117-25.
50. van de Berg PJ, Griffiths SJ, Yong SL, et al. Cytomegalovirus infection reduces telomere length of the circulating T cell pool. J Immunol. 2010 Apr 1;184(7):3417-23.
51. Fletcher JM, Vukmanovic-Stejic M, Dunne PJ, et al. Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion. J Immunol. 2005 Dec 15;175(12):8218-25.
52. Meijers RW, Litjens NH, de Wit EA, et al. Cytomegalovirus contributes partly to uraemia-associated premature immunological ageing of the T cell compartment. Clin Exp Immunol. 2013 Dec;174(3):424-32.
53. Sansoni P, Vescovini R, Fagnoni F, et al. The immune system in extreme longevity. Exp Gerontol. 2008 Feb;43(2):61-5.
54. Mekker A, Tchang VS, Haeberli L, Oxenius A, Trkola A, Karrer U. Immune senescence: relative contributions of age and cytomegalovirus infection. PLoS Pathog. 2012 8(8): e1002850.
55. Rahbar A, Orrego A, Peredo I, et al. Human cytomegalovirus infection levels in glioblastoma multiforme are of prognostic value for survival. J Clin Virol. 2013 May;57(1):36-42.
56. Rahbar A, Stragliotto G. Survival in patients with glioblastoma receiving valganciclovir. NEJM. 2013 Sep;369(10):985-6.
57. Brum S, Nolasco F, Sousa J, et al. Leukopenia in kidney transplant patients with the association of valganciclovir and mycophenolate mofetil. Transplant Proc. 2008 Apr;40(3):752-4.
58. Ar MC, Ozbalak M, Tuzuner N, et al. Severe bone marrow failure due to valganciclovir overdose after renal transplantation from cadaveric donors: four consecutive cases. Transplant Proc. 2009 Jun;41(5):1648-53.
59. Hazeldine J, Lord JM. The impact of ageing on natural killer cell function and potential consequences for health in older adults. Ageing Res Rev. 2013 Sep;12(4):1069-78.
60. van Baarle D, Tsegaye A, Miedema F, Akbar A. Significance of senescence for virus-specific memory T cell responses: rapid ageing during chronic stimulation of the immune system. Immunol Lett. 2005 Feb 15;97(1):19-29.
61. Effros RB, Pawelec G. Replicative senescence of T cells: does the Hayflick Limit lead to immune exhaustion? Immunol Today. 1997 Sep;18(9):450-4.
62. Franceschi C, Bonafè M, Valensin S, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000 Jun;908:244-54.
63. Chou JP, Effros RB. T cell replicative senescence in human aging. Curr Pharm Des. 2013;19(9):1680-98.
64. Wikby A, Maxson P, Olsson J, Johansson B, Ferguson FG. Changes in CD8 and CD4 lymphocyte subsets, T cell proliferation responses and non-survival in the very old: the Swedish longitudinal OCTO-immune study. Mech Ageing Dev. 1998 May 15;102(2-3):187-98.
65. Ferguson FG, Wikby A, Maxson P, Olsson J, Johansson B. Immune parameters in a longitudinal study of a very old population of Swedish people: a comparison between survivors and nonsurvivors. J Gerontol A Biol Sci Med Sci. 1995 Nov;50(6):B378-82.
66. Kang I, Hong MS, Nolasco H, et al. Age-associated change in the frequency of memory CD4+ T cells impairs long term CD4+ T cell responses to influenza vaccine. J Immunol. 2004 Jul 1;173(1): 673-81.
67. Grubeck-Loebenstein B, Della Bella S, Iorio AM, Michel JP, Pawelec G, Solana R. Immunosenescence and vaccine failure in the elderly. Aging Clin Exp Res. 2009 Jun;21(3):201-9.
68. Saurwein-Teissl M, Lung TL, Marx F, et al. Lack of antibody production following immunization in old age: association with CD8(+)CD28(-) T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines. J Immunol. 2002 Jun 1;168(11):5893-9.
69. Koskinen P, Lemström K, Bruggeman C, Lautenschlager I, Häyry P. Acute cytomegalovirus infection induces a subendothelial inflammation (endothelialitis) in the allograft vascular wall. A possible linkage with enhanced allograft arteriosclerosis. Am J Pathol. 1994 Jan;144(1):41-50.
70. Safaie N, Ghotaslou R, Montazer Ghaem H. Seroprevalence of cytomegalovirus in patients with and without coronary artery diseases at Madani Heart Center, Iran. Acta Med Iran. 2010 Nov-Dec;48(6):403-6.
71. Grahame-Clarke C, Chan NN, Andrew D, et al. Human cytomegalovirus seropositivity is associated with impaired vascular function. Circulation. 2003 Aug 12;108(6):678-83.
72. Crumpacker CS. Invited commentary: human cytomegalovirus, inflammation, cardiovascular disease, and mortality. Am J Epidemiol. 2010 Aug 15;172(4):372-4.
73. Cheng J, Ke Q, Jin Z, et al. Cytomegalovirus infection causes an increase of arterial blood pressure. PLoS Pathog. 2009 May;5(5):e1000427.
74. Schmidt D, Martens PB, Weyand CM, Goronzy JJ. The repertoire of CD4+ CD28 T cells in rheumatoid arthritis. Mol Med. 1996 Sep;2(5):608-18.
75. Schirmer M, Goldberger C, Würzner R, et al. Circulating cytotoxic CD8(+) CD28(-) T cells in ankylosing spondylitis. Arthritis Res. 2002 4(1):71-6.
76. Terrazzini N, Bajwa M, Vita S, et al. A novel cytomegalovirus-induced regulatory-type T-cell subset increases in size during older life and links virus-specific immunity to vascular pathology. J Infect Dis. 2014 May 1;209(9):1382-92.
77. Barnes LL, Capuano AW, Aiello AE, et al. Cytomegalovirus infection and risk of Alzheimer’s disease in older blacks and whites. J Infect Dis. 2014 Aug 8.
78. Jones A, McCurdy JD, Loftus EV Jr, et al. Effects of antiviral therapy for patients with inflammatory bowel disease and a positive intestinal biopsy for cytomegalovirus. Clin Gastroenterol Hepatol. 2014 Oct 2.
79. Chiba M, Abe T, Tsuda S, Ono I. Cytomegalovirus infection associated with onset of ulcerative colitis. BMC Res Notes. 2013 Feb 2;6:40.
80. Kedhar SR, Jabs DA. Cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Herpes. 2007 Dec;14(3):66-71.
81. Riddell SR. Pathogenesis of cytomegalovirus pneumonia in immunocompromised hosts. Semin Respir Infect. 1995 Dec;10(4):199-208.
82. Solana R, Campos C, Pera A, Tarazona R. Shaping of NK cell subsets by aging. Curr Opin Immunol. 2014 Aug;29:56-61.
83. Sinzger C, Digel M, Jahn G. Cytomegalovirus cell tropism. Curr Top Microbiol Immunol. 2008;325:63-83.
84. Wang D, Ma Y, Wang J, Liu X, Fang M. Natural killer cells in innate defense against infective pathogens. J Clin Cell Immunol. 2013; S13:006.
85. Brandstadter JD, Yang Y. Natural killer cell responses to viral infection. J Innate Immun. 2011 3(3):274-9.
86. Orange JS. Human natural killer cell deficiencies and susceptibility to infection. Microbes Infect. 2002 Dec;4(15):1545-58.
87. Terunuma H, Deng X, Dewan Z, Fujimoto S, Yamamoto N. Potential role of NK cells in the induction of immune responses: implications for NK cell-based immunotherapy for cancers and viral infections. Int Rev Immunol. 2008 27(3):93-110.
88. Tarazona R, Gayoso I, Alonso C, et al. NK cells in human ageing. In Handbook on Immunosenescence. Netherlands: Springer;2009:531-44.
89. Albright JW, Albright JF. Age-associated decline in natural killer (NK) activity reflects primarily a defect in function of NK cells. Mech Ageing Dev. 1985 Sep;31(3):295-306.
90. Hazeldine J, Hampson P, Lord JM. Reduced release and binding of perforin at the immunological synapse underlies the age-related decline in natural killer cell cytotoxicity. Aging Cell. 2012 Oct;11(5):751-9.
91. Smyth MJ, Wallace ME, Nutt SL, Yagita H, Godfrey DI, Hayakawa Y. Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer. J Exp Med. 2005 Jun 20;201(12):1973-85.
92. Sanchez-Correa B, Morgado S, Gayoso I, et al. Human NK cells in acute myeloid leukaemia patients: analysis of NK cell-activating receptors and their ligands. Cancer Immunol Immunother. 2011 Aug;60(8):1195-205.
93. Bruminhent J , Razonable RR. Management of cytomegalovirus infection and disease in liver transplant recipients. World J Hepatol. 2014 Jun 27;6(6):370-83.
94. Pourgheysari B, Bruton R, Parry H, et al. The number of cytomegalovirus-specific CD4+ T cells is markedly expanded in patients with B-cell chronic lymphocytic leukemia and determines the total CD4+ T-cell repertoire. Blood . 2010 Oct 21;116(16):2968-74.
95. Schütt P, Brandhorst D, Stellberg W, et al. Immune parameters in multiple myeloma patients: influence of treatment and correlation with opportunistic infections. Leuk Lymphoma. 2006 Aug;47(8):1570-82.
96. Dodd CL, Winkler JR, Heinic GS, Daniels TE, Yee K, Greenspan D. Cytomegalovirus infection presenting as acute periodontal infection in a patient infected with the human immunodeficiency virus. J Clin Periodontol. 1993 Apr;20(4):282-5.
97. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/000665.htm. Accessed October 28, 2014.
98. Rodriguez-Barradas MC, Stool E, Musher DM, et al. Diagnosing and treating cytomegalovirus pneumonia in patients with AIDS. Clin Infect Dis. 1996 Jul;23(1):76-81.
99. Rosa C , Limaye AP,Krishnan A,Blumstein G,Longmate J, Diamond DJ. Primary response against cytomegalovirus during antiviral prophylaxis with valganciclovir, in solid organ transplant recipients. Transpl Int. 2011 Sep;24(9):920-31.
100. Baryawno N, Rahbar A, Wolmer-Solberg N, et al. Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target. J Clin Invest. 2011 Oct;121(10):4043-55.
101. Stragliotto G, Rahbar A, Solberg NW, et al. Effects of valganciclovir as an add-on therapy in patients with cytomegalovirus-positive glioblastoma: a randomized, double-blind, hypothesis-generating study. Int J Cancer. 2013 Sep 1;133(5):1204-13.
102. Yasuoka A. Anti-cytomegaloviral drugsNihon Rinsho. 2012 Apr;70(4):564-7.
103. Iversen AC, Norris PS, Ware CF, Benedict CA. Human NK cells inhibit cytomegalovirus replication through a noncytolytic mechanism involving lymphotoxin-dependent induction of IFN-beta. J Immunol. 2005 Dec 1;175(11):7568-74.
104. Daiwa Pharmaceutical. NK cell immunomodulatory function by modified arabinoxylan rice bran (MGN-3/Biobran) at low concentration (500 mg/day = 7 mg/kg/day). 2012. Supplier unpublished or internal study.
105. Cholujova D, Jakubikova J, Czako B, et al. MGN-3 arabinoxylan rice bran modulates innate immunity in multiple myeloma patients. Cancer Immunol Immunother. 2013 Mar;62(3):437-45.
106. Bang MH, Van Riep T, Thinh NT, et al. Arabinoxylan rice bran (MGN-3) enhances the effects of interventional therapies for the treatment of hepatocellular carcinoma: a three-year randomized clinical trial. Anticancer Res. 2010 Dec;30(12):5145-51.
107. Brockmeyer NH, Kreuzfelder E, Guttmann W, Mertins L, Goos M, Ohnhaus EE. Cimetidine and the immuno-response in healthy volunteers. J Invest Dermatol. 1989 Dec;93(6):757-61.
108. Horvath J, Sinkovics JG. Adoptive immunotherapy with activated peripheral blood lymphocytes. Leukemia. 1994 Apr;8 Suppl 1:S121-6.
109. Zeng P, Xiao J, Lei Y. Cell-mediated immune function in NPC patients treated with cimetidine. Zhonghua Zhong Liu Za Zhi. 1995 May;17(3):223-5.
110. Kikuchi Y, Kizawa I, Oomori K, et al. Effects of cimetidine on interleukin-2 production by peripheral blood lymphocytes in advanced ovarian carcinoma. Eur J Cancer Clin Oncol. 1988 Jul;24(7):1185-90.
111. Shen Y, Qu QX, Zhu YB, Zhang XG. Analysis of CD8+CD28- T-regulatory cells in gastric cancer patients. J Immunoassay Immunochem. 2012;33(2):149-55.
112. Ha TY. The role of regulatory T cells in cancer. Immune Netw. 2009 Dec;9(6):209-35.
113. Kim R, Emi M, Tanabe K, Arihiro K. Tumor-driven evolution of immunosuppressive networks during malignant progression. Cancer Res. 2006 Jun 1;66(11):5527-36.
114. Wikby A, Månsson IA, Johansson B, Strindhall J, Nilsson SE. The immune risk profile is associated with age and gender: findings from three Swedish population studies of individuals 20-100 years of age. Biogerontology. 2008 Oct;9(5):299-308.
115. Strindhall J, Skog M, Ernerudh J, et al. The inverted CD4/CD8 ratio and associated parameters in 66-year-old individuals: the Swedish HEXA immune study. Age (Dordr). 2013 Jun;35(3):985-91.
116. Serrano-Villar S, Moreno S, Fuentes-Ferrer M, et al. The CD4:CD8 ratio is associated with markers of age-associated disease in virally suppressed HIV-infected patients with immunological recovery. HIV Med. 2014 Jan;15(1):40-9.
117. Ohara T, Takahashi M, Yamanaka H, Yamamoto Y, Shimada A, Nakaho T. Serum lactate dehydrogenase and CD4+/CD8+ lymphocyte ratio predict survival in terminally ill cancer patients. Gan To Kagaku Ryoho. 2002 Oct;29(10):1779-83.
118. Sevcíková L, Hunáková L, Chorváth B, Turzová M, Boljesíková E. T-lymphocyte subsets (CD4/CD8 ratio) in breast cancer patients. Neoplasma. 1992 39(4):219-22.
119. Yager EJ, Ahmed M, Lanzer K, Randall TD, Woodland DL, Blackman MA. Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J Exp Med. 2008 Mar 17;205(3):711-23.
120. Cosmi L, Maggi L, Santarlasci V, Liotta F, Annunziato F. T helper cells plasticity in inflammation. Cytometry A. 2014 Jan;85(1):36-42.
121. Krüger S, Schroers R, Rooney CM, Gahn B, Chen SY. Identification of a naturally processed HLA-DR-restricted T-helper epitope in Epstein-Barr virus nuclear antigen type 1. J Immunother. 2003 May-Jun;26(3):212-21.
122. Scriba TJ, Zhang HT, Brown HL, et al. HIV-1-specific CD4+ T lymphocyte turnover and activation increase upon viral rebound. J Clin Invest. 2005 Feb;115(2):443-50.
123. Fahey JL, Prince H, Weaver M, et al. Quantitative changes in T helper or T regulatory/cytotoxic lymphocyte subsets that distinguish acquired immune deficiency syndrome from other immune subset disorders. Am J Med. 1984 Jan;76(1):95-100.
124. Holmes CB, Wood R, Badri M, Zilber S, Wang B, Maartens G, Zheng H, Lu Z, Freedberg KA, Losina E. CD4 decline and incidence of opportunistic infections in Cape Town, South Africa: implications for prophylaxis and treatment. J Acquir Immune Defic Syndr. 2006 Aug 1;42(4):464-9.
125. Zhang K, Ma X, He W, et al. Extracts of Cistanche deserticola Can Antagonize Immunosenescence and Extend Life Span in Senescence-Accelerated Mouse Prone 8 (SAM-P8) Mice. Evid Based Complement Alternat Med. 2014 601383.
126. Kilgour AH, Firth C, Harrison R, et al. Seropositivity for CMV and IL-6 levels are associated with grip strength and muscle size in the elderly. Immun Ageing. 2013 Aug 13;10(1):33.
127. Abdellaoui A, Al-Khaffaf H. C-reactive protein (CRP) as a marker in peripheral vascular disease. Eur J Vasc Endovasc Surg. 2007 Jul;34(1):18-22.
128. Strandberg TE, Tilvis RS. C-reactive protein, cardiovascular risk factors, and mortality in a prospective study in the elderly. Arterioscler Thromb Vasc Biol. 2000 Apr;20(4):1057-60.
129. Engelhart MJ, Geerlings MI, Meijer J, et al. Inflammatory proteins in plasma and the risk of dementia: the Rotterdam study. Arch Neurol. 2004 May;61(5):668-72.
130. Kravitz BA, Corrada MM, Kawas CH. Elevated C-reactive protein levels are associated with prevalent dementia in the oldest-old. Alzheimers Dement. 2009 Jul;5(4):318-23.
131. Allin KH, Bojesen SE, Nordestgaard BG. Baseline C-reactive protein is associated with incident cancer and survival in patients with cancer. J Clin Oncol. 2009 May 1;27(13):2217-24.
132. Erlinger TP, Platz EA, Rifai N, Helzlsouer KJ. C-reactive protein and the risk of incident colorectal cancer. JAMA. 2004 Feb 4;291(5):585-90.
133. Giltay EJ, Haider A, Saad F, Gooren LJ. C-reactive protein levels and ageing male symptoms in hypogonadal men treated with testosterone supplementation. Andrologia. 2008 Dec;40(6):398-400.
134. Wickramatilake CM, Mohideen MR, Withanawasam BP, Pathirana C. Testosterone and high-sensitive C-reactive protein in coronary artery disease patients awaiting coronary artery bypass graft. Andrologia. 2014 May 9.
135. Helaly MA, Daoud E, El-Mashad N. Does the serum testosterone level have a relation to coronary artery disease in elderly men? Curr Gerontol Geriatr Res. 2011 791765.
136. Kalinchenko SY, Tishova YA, Mskhalaya GJ, Gooren LJ, Giltay EJ, Saad F. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study. Clin Endocrinol (Oxf). 2010 Nov;73(5):602-12.
137. Available at: http://www.gsk.com.au/resources.ashx/prescriptionmedicinesproductschilddataproinfo/843/FileName/1BF361428971B19DA2CEF 2E3EAD3BE09/PI_Tagamet.pdf. Accessed October 21, 2014.
138. Available at: http://www.rxlist.com/tagamet-drug/side-effects-interactions.htm. Accessed October 21, 2014.
139. Knodell RG, Browne DG, Gwozdz GP, Brian WR, Guengerich FP. Differential inhibition of individual human liver cytochromes P-450 by cimetidine. Gastroenterology. 1991 Dec;101(6):1680-91.
140. Krenzelok EP. Sildenafil: clinical toxicology profile. J Toxicol Clin Toxicol. 2000;38(6):645-51.
141. Greene W. Drug interactions involving cimetidine--mechanisms, documentation, implications. Q Rev Drug Metab Drug Interact. 1984;5(1):25-51.
142. Ruffalo RL, Thompson JF, Segal JL. Diazepam-cimetidine drug interaction: a clinically significant effect. South Med J. 1981 Sep;74(9):1075-8.
143. Villeneuve JP, Fortunet-Fouin H, Arsène D. Cimetidine kinetics and dynamics in patients with severe liver disease. Hepatology. 1983 Nov-Dec;3(6):923-7.
144. Ben-Joseph R, Segal R, Russell WL. Risk for adverse events among patients receiving intravenous histamine2-receptor antagonists. Ann Pharmacother. 1993 Dec;27(12):1532-7.
145. Jenike MA. Cimetidine in elderly patients: review of uses and risks. J Am Geriatr Soc. 1982 Mar;30(3):170-3.
146. Bell WR, Anderson KC, Noe DA, Silver BA. Reduction in the plasma clearance rate of warfarin induced by cimetidine. Arch Intern Med. 1986 Dec;146(12):2325-8.
147. Wilner K, Laboy L, LeBel M. The effects of cimetidine and antacid on the pharmacokinetic profile of sildenafil citrate in healthy male volunteers. Br J Clin Pharmacol. 2002;Suppl 1:31S-36S.
148. Barber SG. Male sexual dysfunction and cimetidine. Br Med J. 1979 Apr 28;1(6171):1147.
149. Peden NR, Cargill JM, Browning MC, Saunders JH, Wormsley KG. Male sexual dysfunction during treatment with cimetidine. Br Med J. 1979 Mar 10;1(6164):659.
150. Deepinder F, Braunstein GD. Drug-induced gynecomastia: an evidence-based review. Expert Opin Drug Saf. 2012 Sep;11(5): 779-95.
151. Jensen RT, Collen MJ, Pandol SJ, et al. Cimetidine-induced impotence and breast changes in patients with gastric hypersecretory states. N Engl J Med. 1983 Apr 14;308(15):883-7.
152. Spence RW, Celestin. Gynaecomastia associated with cimetidine. Gut. 1979; 20(2):154-7.
153. Available at: http://www.rxlist.com/tagamet-drug/side-effects-interactions.htm. Accessed October 21, 2014.
154. Sivelle PC, Underwood AH, Jelly JA. The effects of histamine H2 receptor antagonists on androgen action in vivo and dihydrotestosterone binding to the rat prostate androgen receptor in vitro. Biochem Pharmacol. 1982 Mar 1;31(5):677-84.
155. Barbara L, Corinaldesi R, Pasquali R, Raiti C, Zurita J, Stanghellini V. Endocrine effects of the H2-receptor antagonists cimetidine and ranitidine. Int J Tissue React. 1983 5(4):387-92.