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Cimetidine: immunomodulatory effects Re viruses

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  • Cimetidine: immunomodulatory effects Re viruses

    Cimetidine: A review of the recent developments and reports in cutaneous medicine

    Dermatology Online Journal
    Noah Scheinfeld, MD
    Dermatology Online Journal 9(2): 4

    Department of Dermatology, St. Luke's-Roosevelt Hospital Center, New York.


    Cimetidine, approved by the FDA for inhibition of gastric acid secretion, has been advocated for a number of dermatological diseases. The cutaneous uses and immunological effects of cimetidine have been actively studied over the past few years, and this review summarizes the literature accumulated since 1997.


    Several reviews have assessed the use of cimetidine in dermatology in the last decade.[1] Since the last review was published in 2000,[2] over 500 articles have been published on cimetidine. In fact, cimetidine is a most actively researched medication, and more than 1,000 articles concerning it have been published in the last 5 years. To allow dermatologists to keep abreast of developments in the use of this medication, this review summarizes the literature since 1997 on the cutaneous benefits and side effects of cimetidine and its immunological effects.


    Cimetidine has immunomodulatory effects that include blocking suppressor T cells and facilitating cell-mediated immunity (CMI). The histamine-induced upregulation of IL-6 and IL-8 production, however, may be completely abrogated by a combination of pyrilamine and cimetidine.[11] In patients with allergic rhinitis, cimetidine decreases the number of CD4+ and increases the number of CD8+ lymphocytes.[12] Cimetidine and famotidine slightly reduce the O2- or H2O2 production of neutrophils in a dose-dependent manner, although ranitidine fails to do so.[13] Cimetidine inhibits nitric-oxide-associated nitrate production in a horse soft-tissue inflammation model.[14] It decreases interleukin 6 production by human keratinocytes.[15] It can block cell proliferation and c-fox gene transcription.[16] It also might have a role in suppressing delayed hypersensitivity reactions.[17] The exact role that these immunological effects play in the treatment of clinical disease has yet to be defined.

    Common warts in adults
    In the last 5 years, double-blind, placebo-controlled studies have finally been performed on cimetidine in the treatment of common warts. These studies have shown it to be ineffective; this ineffectiveness is shown most clearly in adults.[18] Some still advocate consideration of its use at a dose of 40 mg/kg/day,[19] but most reviewers do not.[20]

    The role of cimetidine in children is a more open question.[21] In a 3-month open-label study of 47 patients with multiple, nongenital, viral warts who were treated with oral cimetidine, 56% of children cleared and 44% of adults cleared.[22] However, in a placebo-controlled study, its efficacy was not statistically superior to that of placebo, although a trend toward efficacy was suggested for younger subjects.[23] Moreover, a prospective, randomized, controlled trial of 40 patients (62% less than 15 years old) yielded negative results.[24] Thus, in cases where the use of topical medications is not possible, cimetidine might still have a role in the treatment of warts in children. Interestingly, however, a recently reported case described marked improvement in a 16 year old boy with epidermodysplasia after three months of oral cimetidine at 40mg/kg/day.[25] No relapse occurred over a six month follow up period.

    One promising avenue for the use of cimetidine for treating warts is in conjunction with other therapies. Parsad et al. have reported that a combination regimen of cimetidine and levamisole is superior to cimetidine alone in treating warts in adults[26] and in children.[27] Levamisole is an immunomodulator that is approved by the FDA for use with 5-fluorouracil in the treatment of colon cancer. The original use of levamisole was as an antihelminthic.

    Genital warts and papillomatosis
    Cimetidine has been shown to be useful in the treatment of condylomata acuminata and papillomatosis. Four children treated with extensive condylomata acuminata of the genital and perigenital areas were treated with cimetidine 30–40 mg/kg; clearing of their condylomata was noted at 24 months following treatment.[28] Cimetidine was effective in the treatment of recurrent respiratory papillomatosis[29] and recalcitrant, diffuse conjunctival papillomatosis.[30]

    Molluscum contagiosum
    Molluscum contagiosum, a common illness in children, caused by a pox virus, has been treated with cimetidine. At a dose of 30–40 mg/kg/day, it has been used as a treatment for children[31] and adults.[32] In two patients, one with 60 lesions and the other with 200 lesions, cimetidine at 40 mg/kg/day in four divided doses for six weeks cleared all lesions.[33] However, other studies find it ineffective.[34] There is no evidence from double-blind, placebo-controlled studies that cimetidine clears molluscum contagiosum.

    Urticaria and other mast-cell-mediated diseases
    Cimetidine appears to have a role in the treatment of chronic idopathic urticaria and some other types of urticaria when used in combination with various H1 blockers.[35,36] For symptomatic dermatographism, the combination of an antihistamine and an H2 antagonist, such as chlorpheniramine and cimetidine, appears to be effective.[37] Cimetidine might also increase the latency time of heat-induced urticaria.[38] It appears that a combination regimen of H1 blockers, H2 blockers, and mast-cell stabilizers gives partial relief to the patients with mastocytosis.[39] Scombroid fish poisoning has been successfully treated with cimetidine.[40]

    Because of its function as an immunomodulator, researchers have used cimetidine in research on melanoma. In horses, it has been used to treat melanoma, although no benefit has been found.[41] In immunodeficient mice with transplanted melanoma cell lines, administration of cimetidine combined with tamoxifen seems to decrease melanoma growth.[42] It should be noted that levamisole, mentioned above, has been extensively evaluated as an immunomodulator to ameliorate melanoma without significant effect.

    Eosinophilic dermatoses
    Several eosinophilic dermatoses have responded to cimeditine. It was successful when used for eosinophilic fascitis (however, after a 5-month course it was discontinued because of side effects).[43] It has been used to treat eosinophilic pustular folliculitis in children.[44] The beneficial effects might be a result of the interrelation of histamine, mast cells and eosinophils in allergy and allergic disease.

    Cutaneous effects: pruritus and skin integrity
    Cimetidine was useful in treating pruritus after a burn injury. In a study controlling for the effect of topical medications, a cetirizine-cimetidine combination demonstrated a dramatic improvement at 1 and 6 hours, and a moderate improvement at 12 hours after the initial administration of the medication when compared with a diphenhydramine-placebo combination.[45] Oral cimetidine accelerated the recovery of skin barrier function after disruption in a dry environment, but histamine and the histamine H2 receptor agonist, dimaprit, delayed barrier repair.[46]

    Periodic fever, apthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome
    Cimetidine has a valuable role in treating of PFAPA syndrome.[47] In one study, it was as an effective first-line therapy for PFAPA at 20 mg/kg/day, curing 49 of 83 patients.[48] Alternatively, other authorities state that glucocorticoids are the most highly effective in controlling symptoms. Tonsillectomy and cimetidine treatment were associated with remission in a small number of patients.[49] In another study of 8 children, cimetidine was effective with no side effects.[50]

    Acute intermittent porphyria
    Cimetidine has been suggested as a treatment for acute intermittent porphyria.[51] Its role seems to be as a second-line treatment to intravenous hemin, which is expensive but appears to be more effective than increased carbohydrate intake. At a dose of 800 mg/day, cimetidine may also have a role in the prophylaxis of acute episodes by maintaining a baseline suppression of ALA-synthase activity.[52]

    Inhibition of Dapsone Toxicity
    One of the most important uses of cimetidine in dermatological therapy is to reduce the dapsone induction of methemoglobinemia.[53] Cimetidine reduces the hepatic oxidation of dapsone to the hydroxylamine, thereby limiting methemoglobinemia formation. This strategy allows maintenance of higher daily dosages of dapsone, sometimes even in excess of 200 mg.[54] In one study, co-administration of cimetidine with dapsone kept methemoglobin levels at 30% below the control values for nearly three months. Eight patients with dermatitis herpetiformis, linear IgA disease, or folliculitis decalvans, who were on long term dapsone therapy (50-100 mg daily), added cimetidine, 1.6 g daily, for three months.[55] Their mean methemoglobin level fell from a baseline of 5.5 g/dl to 3.9 g/dl in the third week. The values remained low until week 12 when there was a return to baseline. There was no alteration in hemoglobin level from baseline (mean 12.7 g/dl) during the cimetidine therapy. However, there was a significant fall in the visual analogue score for headache. The patients also reported a significant decrease in lethargy. These improvements were not associated with any deterioration in the control of the various skin disorders. Similar findings were obtained in an earlier study in dermatitis herpetiformis patients.[56]

    In rats, cimetidine has been shown to be more effective than ranitidine or famotidine in the reversible inhibition of the toxic metabolic pathway which produces dapsone's hydroxylamine metabolite.[57] Cimetidine also did not appear to inhibit the detoxification pathways of dapsone or cytosolic acetylation because of its greater affinity for cytochrome P-450.

    Cutaneous side effects
    Despite its common use, cimetidine has few cutaneous side effects. It can cause a delayed hypersensitivy reaction[58] and fixed drug eruption.[59] It has been reported to precipitate erythema multiforme and toxic epidermal necrolysis.[60] Cross-reaction with famotidine to induce erythema multiforme has been reported in cases where cimetidine-related erythema multiforme has already occurred.[61]

    Cimetidine has yet to be proven to be an effective monotherapy for dermatological diseases. It seems that cimetidine is probably most effective when used in conjunction with other medications. In the same fashion that levamisole eventually was proven to be an effective secondary medication along with 5-fluorouracil in the treatment of cancer of the colon, cimetidine will probably be proven useful outside of its use as an antacid. Promising uses include treating urticaria in conjunction with other antihistamines, and treating warts in conjunction with levamisole. In addition, cimetidine's inhibitory effect on the metabolism of dapsone, chloroquine, and pyrimethamine can aid dermatological therapy by maintaining medication levels and decreasing toxicity. The multiple immunomodulating effects of cimetidine are significant but poorly understood. As its immunological effects are elucidated, new uses will emerge.
    Last edited by St Michael; June 5th, 2006, 07:36 PM.

  • #2
    Re: Cimetidine: immunomodulatory effects Re viruses

    Tagemet To Treat Herpes And Shingles

    Herpes simplex and herpes zoster are viral diseases that can be kept in remission by a healthy immune system. Direct evidence for this can be seen in cancer patients who undergo immune-suppressing chemotherapy and experience severe herpes outbreaks as a result.1 Similar herpes flare-ups occur in other immune-comprising situations such as normal aging, where a latent herpes zoster virus can reemerge to cause painful shingles.

    While pharmaceutical companies promote expensive and only partially effective anti-viral drugs, there is evidence dating back more than 20 years that the drug cimetidine (sold over-the-counter as Tagamet) is highly effective in shortening the duration or preventing the outbreaks of herpes and shingles. The problem is that virtually no physicians are prescribing cimetidine to their herpes (or shingles) patients, despite persuasive findings in peer-reviewed scientific journals.

    When it comes to treating herpes infections, conventional doctors seem to only pay attention to drug company propaganda, while failing to recommend lower cost drugs (like cimetidine) that have been shown to work especially well in herpes patients.

    In 1988, The Life Extension Foundation recommended that certain cancer patients take the drug cimetidine (Tagamet) for the purpose of enhancing immune function. Cimetidine favorably modulates immune function via several mechanisms, but its best documented property is its inhibitory effect on T-suppressor cell function. The immune system is weakened when T-suppressor cells prematurely shut down immune function. Since cimetidine inhibits T-suppressor cell function, it can significantly enhance immune surveillance in some people.

    Cimetidine (Tagamet) is a histamine2 (H2) receptor antagonist and, as such, can contribute to the enhancement of immune function. Various studies indicate cimetidine's effectiveness in suppressing herpes infections.

    The first case observation occurred in August 1977 when a patient developed shingles just before commencing a course of cimetidine for a chronic stomach ulcer. The patient experienced dramatic relief of the shingles pain and rapid disappearance of the eruption. On the basis of this observation, cimetidine was prescribed to 21 patients with herpes zoster (shingles). The results were encouraging in 18 out of these 21 patients. The trial was then extended to other herpes virus infections. In six out of seven patients with herpes labialis (lip), the blisters were aborted, and in one patient with herpes keratitis the result was also encouraging, with the attacks being markedly shortened in duration and reduced in frequency. The results of these preliminary trials showed the potential role of cimetidine in the treatment of herpes virus infection.(2)

    In 1996, a clinical trial was conducted on 221 patients with herpes zoster who were treated daily with cimetidine at 3 x 200 mg during the day and 1 x 400 mg at night. The results showed that cimetidine shortened the period of disease duration. The authors suggested using cimetidine in the treatment of shingles during the earliest stages of the disease.(3)

    A case reported in Canada resulted in the statement that cimetidine therapy appeared to reduce the expected length of the active phase of herpes zoster from 35 days or more to just 10 days.(4)

    At the Golda Medical Center in Israel, in 1994, a double-blind placebo-control study of cimetidine treatment versus placebo was conducted for one week in 22 patients with herpes zoster (shingles). Those who were treated with cimetidine were found to recover much more quickly from skin rash and pain than those who were given the placebo.(5)

    At the Department of Neurology at Lady Davis Carmel Hospital in Israel, a randomized study evaluated the effect of cimetidine in the treatment of herpes zoster virus. The conclusion was that cimetidine treatment “shortened the median interval until the first decrease in pain, shortened the median interval until the complete resolution of pain and promoted faster complete healing of skin lesions….”(6)

    A paper presented by a researcher at Michigan State University in the Department of Pediatrics and Human Development (1990) stated7)

    “Suppressor T lymphocytes possess histamine2 (H2) receptors and contribute significantly to the function of the immune system. Cimetidine has been shown to enhance a variety of immunologic functions both in vivo and in vitro because of its inhibitory effects on suppressor-cell function. Successful tumor immunotherapy has been reported in experimental animals. Patients who received cimetidine were shown to exhibit enhanced cell-mediated immunity as evaluated by increased response to skin-test antigens, restoration of sensitivity following development of acquired tolerance, and increased responses of lymphocytes to mitogen stimulation. Patients also demonstrated that patients with herpes zoster and herpes simplex who were given cimetidine may have benefitted therapeutically from the drug.”

    The consensus from these studies is that when cimetidine is administered to those with herpes simplex or shingles, the result is a dramatic relief of the herpetic pain as well as rapid disappearance of the blisters.

    Novel approach overlooked

    Cimetidine is the generic equivalent of the popular OTC drug better known by the brand name Tagamet. It is used primarily to relieve symptoms of esophageal reflux such as heartburn. Tagamet functions as a histamine (H2) receptor antagonist. What most doctors don't know is that T-lymphocyte suppressor cells have the H2 receptor. By blocking this receptor (using an H2 receptor antagonist such as Tagamet), the immune system can be temporarily turned up to help combat certain cancers and herpes viral infections.

    Tagamet is manufactured by SmithKline Pharmaceuticals, headquartered in Philadelphia. When Life Extension asked about Tagamet's potential use in herpes treatment and quizzed about the lack of promotion for same, Carl Friedman from SmithKline's Research and Development Department said, “It [cimetidine] went off patent in 1994. We aren't vested in it anymore, so there's nothing to gain from it.” Echoing his sentiments, Deborah Frutos, from the pharmaceutical company's Corporate Finance and Administration Department said, “There's no incentive for us to promote our less expensive generic [cimetidine]. If we were to do any study for that, it would take lots of time and money. Even if it proved to be a good study, most physicians have other products they'd rather prescribe.” She added, “A grant guarantees that if we prove the drug is indicated for that [treating herpes], the generic would be manufactured and once the patent is protected, anyone can manufacture it. Let's just say we're not going to do it.”

    Cimetidine is the generic equivalent of the popular OTC drug better known by the brand name Tagamet. Pictured above is a microscopic view of cimetidine.

    The unwillingness of drug companies to promote their own products unless a patent guarantees them a fat profit margin is one reason why many promising therapies are overlooked. A person suffering from a herpes simplex or shingles outbreak can obtain Tagamet (cimetidine) over-the-counter for $38 a month as opposed to over $200 a month for the new anti-viral drugs being promoted to doctors. While there are no side-by-side comparisons, published studies indicate that Tagamet (cimetidine) may be more effective than FDA-approved anti-viral drugs.

    Here we have cimetidine right under our noses and offered at a fraction of the cost of anti-viral drug therapy. Why is the majority of the medical community ignoring it? When we asked three practicing pharmacists if physicians ever recommend cimetidine to herpes patients, all three responded in the negative: 1) “rarely,” 2) “not much” and 3) “uh…sometimes, but not very often.” Asking the same question of three physicians, the answers were equally noncommittal and nondescript.

    Cimetidine functions as an immunomodulator. In a collaborative study by several universities worldwide, 125 patients who were scheduled to undergo surgical procedures for colon or rectal cancer were randomized to receive either placebo or cimetidine preoperatively during a five day regimen. The conclusion was that a short course of cimetidine appeared to effect patient survival.8 Their hypothesis was based on their knowledge of previous studies that showed cimetidine to be effective as an immunostimulant.

    Herpes simplex

    The herpes simplex (HSV) is sexually transmitted by direct contact. HSV1 causes fever blisters on the mouth, sometimes on the face. HSV2 affects the genital area and is more commonly known as genital herpes. Once a person is infected with herpes simplex, they can spend a lifetime waiting for an outbreak, or they may experience several outbreaks a year. There is no known cure. The virus may lie dormant for months or years. Some people don't even know they have it until they have their first outbreak that manifests itself by an itchy and painful irritating rash, which then erupts as unsightly blisters.

    The Centers for Disease Control in Atlanta recently reported that 45 million adolescents (age 12-plus) and adults in the United States are infected with genital herpes. Slightly more prevalent in women, this disease lays its claim on one of every four women and one of every five men in the U.S.

    In the past 20 years, the number of Americans with genital herpes has increased 30%, especially among white adolescents.

    The infection becomes more pronounced in severity in people whose immune systems are compromised, e.g., in patients who have AIDS, cancer or other diseases, or who have undergone an organ transplant. HSV2 can be fatal to infants born to mothers who test positive for the disease and are experiencing an outbreak during delivery. (Physicians who are informed ahead of time normally perform a Caesarian section to prevent the mother from shedding the virus onto her baby.)

    Herpes zoster (shingles)

    The most common neurologic condition known is herpes zoster, usually referred to as shingles. The CDC says that up to one million people in the United States contract herpes zoster each year. David Cooper, M.D., a contributing editor to JAMA, stated in 1998 that shingles afflicts more than one million people every year.

    Herpes zoster is a reactivation of the virus that causes chicken pox. Once a person has recovered from chicken pox, the virus (varicella) remains dormant, hiding among the connective nerve tissue in the body. No one seems to know why it occurs, although stress and/or a compromised immune system is thought to exacerbate the condition, but it usually activates in people over the age of 50. Traveling through the ganglia, it causes a tingling, stinging or burning sensation. A couple days later, once the virus has completed its journey to the skin, an irritating and painful rash and accompanying blisters may erupt. The resulting condition can be so painful, the patient may be unable to tolerate clothing or anything that touches the affected area.

    Raising public awareness

    Shortly before his death this year, Steve Allen appeared with his lovely wife Jayne Meadows on NBC's “The Today Show”. They wanted to bring to light this illness that many would prefer not to discuss in public. Both of their mothers had suffered with the painful virus and in 1999, Meadows had undergone a similar experience, causing her to cancel an appearance with her husband on another popular television talk show.

    Following their appearance on “The Today Show” with Matt Lauer, 8,000 telephone calls were received at the Varicella Zoster Virus Research Foundation and nearly 3,000 visits were logged on the Foundation's website. Shingles had come out of the closet and the public wanted to know what to do about it.

    With so much public interest in such a painfully debilitating, often embarrassing illness, you would think physicians would make every effort to inform the general public that an OTC drug is available to them. Yet cimetidine (Tagamet), a drug proven in study after study over the past 20 years to be effective in boosting the immune system, is still a common sense, low-cost medication that is virtually ignored by the medical community.

    Standard treatment for herpes

    Anti-viral drugs are commonly used to treat herpes simplex and herpes zoster. Due to varying intensities of pain and other symptoms associated with herpes zoster, analgesics and various other medications are prescribed. The most popular drug of choice has been Zovirax. Retail cost: Zovirax can cost $ 112 for a month's supply (150 capsules of 200 mg dosage, five times a day). A stronger dosage, 400 mg, five times a day would be $206 for a month's supply. And there is yet a stronger dose, which naturally costs even more. (Some patients may only be required to undergo a two-week course of medication while others take it chronically to prevent outbreaks). More modern versions of acyclovir, such as desciclovir, famciclovir, valaciclovir and penciclovir, cost even more.

    Cimetidine may not work against warts

    It is important to understand that cimetidine is not a panacea for every disease that might be helped by improving immune function.

    One study used cimetidine for three months to evaluate its effects on 54 people with warts. Cure rates obtained were 32% in the cimetidine-treated group and 30.7% in the placebo-treated group. Thus, no significant difference was found between cimetidine and placebo in effectiveness in the treatment of patients with common warts.(9)

    In a much smaller study, the effect of cimetidine was investigated in the management of genital and perigenital warts in children. Four had extensive condylomata acuminata of the genital and perigenital areas. They were treated with high doses (30 to 40 mg./kg of cimetidine) in an attempt to eradicate the condyloma (in two patients) and avoid recurrence in the other two. Cimetidine was administered daily in three divided doses during a three-month period. At the 24-month evaluation, all four patients were free of condyloma. The conclusion of the authors was that cimetidine is effective for primary and adjunctive treatment of condyloma in young children. It also seems to be effective as first-line therapy.(10)


    Studies indicate that viruses like herpes simplex and herpes zoster can be put into quick remission, or the breakouts prevented altogether, when T-lymphocyte suppressor cell function is inhibited. The best way of accomplishing this is to take 200 mg of cimetidine (Tagamet) three times a day and then 400 mg at bedtime. Tagamet is available in pharmacies over-the-counter.

    Herpes simplex outbreaks have been shown to go into remission in response to the proper dose of cimetidine. In cases of herpes zoster (shingles), which targets the older population, cimetidine has been successfully used to lessen the debilitating pain and intensity of the skin rash and eruptions.

    Published studies indicate that viruses like herpes simplex and herpes zoster can be put into quick remission, or the breakouts prevented altogether, when T-lymphocyte suppressor cell function is inhibited. The best way of accomplishing this is to take 200 mg of cimetidine (Tagamet) three times a day and then 400 mg a bedtime. Tagamet is available in pharmacies over-the-counter. Suggested use is to initiate Tagamet as soon as symptoms of a herpes-related virus infection appear. Continue to take it for one to two weeks after all symptoms of the outbreak have abated.

    One precautionary note, even though Tagamet (cimetidine) is sold over-the-counter, refer to the package insert to make sure it does not interact with prescription drugs you may already be taking.

    Please note that if your doctor prescribes generic cimetidine, it may cost less to obtain it as a prescription drug (especially if you have prescription drug insurance) rather than buying the Tagamet name brand that is available without a prescription.
    Last edited by St Michael; June 5th, 2006, 07:37 PM.


    • #3
      Re: Cimetidine: immunomodulatory effects Re viruses

      Successful treatment of adult respiratory distress syndrome by histamine and prostaglandin blockade in a porcine Pseudomonas model.

      Sielaff TD, Sugerman HJ, Tatum JL, Blocher CR.

      Porcine Pseudomonas adult respiratory distress syndrome (ARDS) has been shown to respond to combination therapy of 150 mg of cimetidine, 12.5 mg/kg of ibuprofen, 10 mg/kg of diphenhydramine, 0.2 mg/kg of ketanserin, and 30 mg/kg of methylprednisolone (CIDKM or Poly-5) given at 20 and 120 minutes after the onset of a continuous infusion of liver Pseudomonas aeruginosa, 5 X 10(8) colony-forming units (CFU) ml at 0.3 ml/20 kg/min. The present study was designed to determine the minimal, effective therapy by selective deletion of individual agents from CIDKM. Eight groups were studied: saline control (S, n = 9), Pseudomonas control (P, n = 8), and the following Pseudomonas plus treatment groups (each n = 5): CIDKM (cimetidine, ibuprofen, diphenhydramine, and ketanserin), CID (cimetidine, ibuprofen, and diphenhydramine), IC (ibuprofen and cimetidine), ID (ibuprofen and diphenhydramine), and CD (cimetidine and diphenhydramine). Pseudomonas alone produced severe ARDS with significant (p less than .05) decreases in PAO2 cardiac index, and systemic arterial pressure and significant increases in pulmonary artery pressure, extravascular lung water (EVLW) and scintigraphically determined pulmonary albumin flux measured as slope index (SI). Full therapy, CIDKM or Poly-5, showed significant improvement in all parameters. Deletion of methylprednisolone did not significantly effect any parameter measured. The deletion of ketanserin, leaving CID, did not alter treatment efficacy, except for a significant decline in cardiac index at 3 hours. Deletion of ibuprofen from CID resulted in a failure to reverse pulmonary arterial hypertension, hypoxemia, elevated EVLW, and increased SI. Removal of either cimetidine or diphenhydramine from CID resulted in significant increases in EVLW compared with control levels and SI compared with both control levels and CID. These results indicate that a combination of both histamine H1 and H2 receptor blockers and the cyclooxygenase inhibitor, ibuprofen, is effective and essential in the treatment of hypoxemia, early pulmonary hypertension, and pulmonary microvascular injury in this fulminant model of porcine Pseudomonas ARDS.

      PMID: 3112984 [PubMed - indexed for MEDLINE]
      Last edited by St Michael; June 5th, 2006, 07:38 PM.


      • #4
        Re: Cimetidine: immunomodulatory effects Re viruses

        Improving the Efficiency of Vaccinations

        Are there things we can do improve the efficiency of vaccinations in CLL patients? This is still an open subject, but there are good leads that you might want to explore. Some experts (including our own Dr. Terry Hamblin) think vaccination efficiency in CLL patients may be improved by taking cimetidine at the same time. Cimetidine (brand name Tagamet) is a histamine receptor blocker. It has been around for ages, one of the early drugs that came on the scene for controlling heartburn and hyperacidity in the stomach. In addition to reducing stomach acid, cimetidine also works on blocking histamine-2 receptors. Another drug similar to cimetidine is ranitidine (Zantac), named in the second abstract below.

        The first abstract below (from Dr. Neil Kay of Mayo and Project Alpha fame) suggests that the effect of cimetidine is to increase the activity of NK cells (Natural Killer cells). NK cells are frontline troops in defending against invading viruses. This may be mechanism for the improved vaccination efficiency noted by practicing physicians in the field. I wish I could point to larger scale studies with all the appropriate bells and whistles, but I am afraid such studies have not been done. As things stand, since cimetidine has a well-deserved reputation for low adverse effects, you may want to discuss taking this vaccination booster with your doctor. Be aware that you may need to take the cimetidine before, during and after vaccination, for a period of time. You may also need more than the dosage of cimetidine in the over-the-counter version for dealing with acid stomach. Since it is not my intention to practice medicine without a license, I am not going to tell you the dose of cimetidine you should take, or the length of time you should be on it. That is a topic of discussion between you and your doctor.


        J Lab Clin Med. 1987 Apr;109(4):396-401.

        Cimetidine modulates natural killer cell function of patients with chronic lymphocytic leukemia.

        Allen JI, Syropoulos HJ, Grant B, Eagon JC, Kay NE.

        Peripheral blood natural killer (NK) activity in patients with B-cell chronic lymphocytic leukemia (B-CLL) is frequently low or absent. Because cimetidine (a histamine-2 antagonist) has been shown to alter human lymphocyte function in vitro, we decided to study cimetidine's effect on peripheral blood NK activity of patients with B-CLL and controls. We administered cimetidine orally (1.2 gm per day) to seven patients with B-CLL and 12 controls for up to 28 days. Peripheral blood NK activity of patients with B-CLL rose from a pretreatment level of 0.7 +/- 0.5 (mean +/- SEM) lytic units/10(6) cells (LU) to 8.7 +/- 2.4 LU (P less than 0.05) at day 28. Peripheral blood NK activity of controls decreased after 14 days of cimetidine treatment but returned to pretreatment levels by day 28. When peripheral blood cells from controls were exposed to cimetidine during in vitro incubation (10 micrograms/ml), mean NK activity was increased at 48 hours (54% +/- 22% increase over controls, n = 5, P less than 0.05). Single cell cytotoxicity assays revealed increased killing of target cells (but not effector-target conjugation) with cimetidine-exposed effector cells. These data suggest that cimetidine may be useful to augment peripheral blood NK activity for patients with B-CLL.

        PMID: 3493314

        Leukemia. 1995 Nov;9(11):1902-9.

        Improved vaccination response during ranitidine treatment, and increased plasma histamine concentrations, in patients with B cell chronic lymphocytic leukemia.

        Jurlander J, de Nully Brown P, Skov PS, Henrichsen J, Heron I, Obel N, Mortensen BT, Hansen MM, Geisler CH, Nielsen HJ.

        Department of Hematology, University Hospital Rigshospitalet, Copenhagen, Denmark.

        Patients with B cell chronic lymphocytic leukemia (B-CLL) have decreased capacity to mount relevant antibody responses upon immunization, and development of hypogammaglobulinemia is part of the natural history of the disease. We investigated the influence of histamine type-2 (H2) receptor blockade by ranitidine on the in vivo antibody production in B-CLL patients following vaccination. Anti-polysaccharide antibodies in B-CLL patients, vaccinated with a tetanus-toxoid conjugated vaccine against Haemophilus influenzae type-B (Hib), reached long-term protective levels in more than 90% of B-CLL patients randomized to ranitidine treatment, as compared to 43% of the untreated patients (P = 0.024). No difference in the response to vaccination against influenza virus types A and B protein could be detected between the two groups. Plasma histamine levels were 2-fold to 20-fold higher in 23 out of 31 B-CLL patients, compared to normal controls, and these levels showed a significant positive correlation to disease duration. These findings indicate the possibility of improving in vivo antibody production against a highly relevant pathogen in B-CLL patients by histamine type-2 receptor blockade, and the combined finding of an immune-stimulatory effect of ranitidine and increased plasma histamine levels, strongly suggests the involvement of histamine in the pathogenesis of B-CLL immunodeficiency.

        PMID: 7475282

        Digestion. 1999 Sep-Oct;60(5):415-21.

        Does cimetidine improve prospects for cancer patients?. A reappraisal of the evidence to date.

        Siegers CP, Andresen S, Keogh JP.

        Department of Experimental and Clinical Pharmacology and Toxicology, Medical University of Lubeck, Germany.

        BACKGROUND: Evidence first appeared in 1988 that cimetidine as an adjuvant may improve the survival of severely ill gastro-intestinal cancer patients when given peri- or postoperatively. Since then, several studies have appeared which suggest an anticancer activity for cimetidine, although few attempts have been made to corroborate their findings in large, placebo-controlled, double-blind studies.
        METHOD: We reviewed the literature concerning cimetidine's potential anticancer activity, particularly with regard to gastro-intestinal cancers.
        RESULTS: Most studies suggest that cimetidine may improve the outcome in cancer patients by a three-pronged mechanism involving (1) inhibition of cancer cell proliferation; (2) stimulation of the lymphocyte activity by inhibition of T cell suppressor function, and (3) inhibition of histamine's activity as a growth factor in tumours.
        CONCLUSION: Bearing in mind the experimental evidence, as well as the potential and excellent safety profile of cimetidine, more studies are required and justified to clarify cimetidine's protherapeutic activity.

        PMID: 10473965

        J Thorac Cardiovasc Surg. 1998 Aug;116(2):312-8.

        Cimetidine reduces impairment of cellular immunity after cardiac operations with cardiopulmonary bypass.

        Katoh J, Tsuchiya K, Osawa H, Sato W, Matsumura G, Iida Y, Suzuki S, Hosaka S, Yoshii S, Tada Y.

        Second Department of Surgery, Yamanashi Medical University, Japan.

        OBJECTIVE: Depressive effects of cardiopulmonary bypass on cell-mediated immune responses may lead to postoperative infectious complications. We previously reported that cimetidine reduced postbypass depression of the cytotoxic activity of natural killer cells. This study evaluated cimetidine as an agent to preserve cellular immunity after cardiac operations.
        METHODS: In a prospective randomized study, 20 patients were divided into two groups of equal size. Cimetidine-group patients received 400 mg of cimetidine intravenously before bypass and a 33 mg/hr intravenous infusion of cimetidine after the operation, continuing until the fifth postoperative day. Control-group patients received conventional perioperative therapy. Lymphocyte subsets, natural killer cell activity, percentage of CD56+CD16+ (percentage of natural killer cells), and percentage of CD11b+CD8+ (percentage of suppressor T lymphocytes) were measured perioperatively.
        RESULTS: Although temporary postoperative reductions in percentages of CD3+, CD4+, and CD56+CD16+ cells were observed in both groups, CD8+ percentages on postoperative day 1 and CD11b+CD8+ percentages on postoperative days 1 and 3 in the cimetidine group were significantly lower compared with those in the control group (p = 0.01,p = 0.004, andp = 0.02, respectively). Temporary postoperative reduction of natural killer cell activity was also observed in both groups, but the natural killer cell activity on postoperative day 1 in the cimetidine group (17.1%) was significantly higher (p = 0.02) than that in the control group (8.20%).
        CONCLUSIONS: Cimetidine counteracts depressive effects of cardiopulmonary bypass on cell-mediated immunity and may possibly reduce postoperative susceptibility to infection.

        PMID: 9699585
        Last edited by St Michael; June 5th, 2006, 07:40 PM.


        • #5
          Re: Cimetidine: immunomodulatory effects Re viruses

          St. Michael-

          I want to thank you, this is some awesome info, it ties in with some early research we did, but that I personally forgot. This highlights it and expands on it greatly.

          The comments about H1, H2 and ibuprofen are especially excellent.

          Has any one got a good link to an easy to read flowchart of immune system activation/function? I think that would be very complementary to this and other threads in the same vein. It would help us see the steps at which these and other interventions affect the immune system and cytokine activation. We could then "plug in" our interventions into that, in a way that helps it all make sense- and just might help us see where a possible intervention might instead be problematic.

          I need to tie some things together, and I cant visualize what I want without that or something similar. I'm afraid I'll miss steps or get it too confused. The goal is to prevent "exhuberant response" without decereasing (and hopefully enhancing) the ability of the immune system to react appropriately. I think flowing it out will help us see it better.
          Upon this gifted age, in its dark hour,
          Rains from the sky a meteoric shower
          Of facts....They lie unquestioned, uncombined.
          Wisdom enough to leech us of our ill
          Is daily spun, but there exists no loom
          To weave it into fabric..
          Edna St. Vincent Millay "Huntsman, What Quarry"
          All my posts to this forum are for fair use and educational purposes only.


          • #6
            Re: Cimetidine: immunomodulatory effects Re virii

            Yes, a flowchart would be one of the most important pieces of information we could use to add to our knowledge base.
            Please do not ask me for medical advice, I am not a medical doctor.

            Avatar is a painting by Alan Pollack, titled, "Plague". I'm sure it was an accident that the plague girl happened to look almost like my twin.
            Thank you,
            Shannon Bennett


            • #7
              Re: Cimetidine: immunomodulatory effects Re virii

              I don't have a flowchart handy, but I did post a new thread pulling together these various concepts:

              H5N1 Rx: ACE2 blocker + Tagamet + Advil + Benadryl (?)