Cimetidine (H2 Antihistamines)

 [First gen histamine H2 receptor antagonist that inhibits stomach acid production. Has direct anti-proliferative effects on cancer cells, inhibits cell adhesion, reduces tumour angiogenesis (growth of blood vessels essential to a developing tumour) and also boosts anti-cancer immunity in various cancers.] (link)

Cimetidine Life Extension report (excellent!):

https://www.lifeextension.com/magazine/2007/5/report_cimetidine

Cimetidine Anti Cancer Drug Reverses Tumor Immunity

https://jeffreydachmd.com/cimetidine-anti-cancer-drug-reverses-tumor-immunity/

High-dose cimetidine for the treatment of metastatic renal cell carcinoma. A Hoosier Oncology Group study.

The Hoosier Oncology Group evaluated cimetidine in 42 patients with metastatic renal cell carcinoma. There were two complete remissions that lasted for 26 and 33+ months in 38 evaluable patients. There were no partial remissions. Toxicity was minimal. Patients with renal cell carcinoma can occasionally respond to cimetidine with long-term remission.

Treatment of metastatic renal cell carcinoma with coumarin (1,2-benzopyrone) and cimetidine: a pilot study.

Forty-five patients with metastatic renal cell carcinoma were treated with coumarin (1,2-benzopyrone) and cimetidine. Patients received coumarin, 100 mg orally daily; cimetidine administration, 300 mg orally four times daily, was initiated on day 15 of therapy, and treatment with both drugs was continued until progression of disease. Three patients are too early to evaluate (on study less than or equal to 2 months with no change in tumor status). Objective responses (greater than or equal to 50% reduction in measurable disease) occurred in 14 of 42 evaluable patients (33.3%) (the 95% confidence interval based on this rate is +/- 14.3%), with three complete responses and 11 partial responses (PR). Complete responses lasted 9.5, 4+, and 9.5+ months. The median duration of response for the PR group was 5 months (range, 4 to 21+ months). Twelve patients experienced stabilization of disease ranging from 4 to 16.5+ months. No response was seen in 16 patients. There was no symptomatic, hematologic, or chemical (organ dysfunction) toxicity among the 45 patients treated. Coumarin and cimetidine appear to be safe and active agents in the treatment of metastatic renal carcinoma. 

Histamine type 2 receptor antagonists (H(2)RAs) as adjuvant treatment for resected colorectal cancer. (link)

OBJECTIVES: To determine if H(2)RAs improve overall survival when used as pre- and/or postoperative therapy in colorectal cancer patients who have had surgical resection with curative intent. We also stratified the results to see if there was an improvement in overall survival in terms of the specific H(2)RA used.

MAIN RESULTS: Of the six identified trials, five used cimetidine as the experimental H(2)RA, whereas one used ranitidine. There was a trend towards improved survival when H(2)RAs were utilised as adjuvant therapy in patients having curative-intent surgery for colorectal cancer (HR 0.70; 95% CI 0.48-1.03, P = 0.07). Analysis of the five cimetidine trials (n = 421) revealed a statistically significant improvement in overall survival (HR 0.53; 95% CI 0.32 to 0.87).

AUTHORS' CONCLUSIONS: Of the H(2)RAs evaluated cimetidine appears to confer a survival benefit when given as an adjunct to curative surgical resection of colorectal cancers. 

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• Make sure you research drug interactions on this one as there are many. https://www.drugs.com/drug-interactions/cimetidine.html Must be taken 2 hours away from CBD oil. Cimetidine increases absorption for Fenbendazole and Menbendazole.

Drug facts (increases creatinine!): 

https://www.ncbi.nlm.nih.gov/books/NBK544255/ (general information)

https://www.ncbi.nlm.nih.gov/books/NBK548130/ (effects on liver)

• Cimetidine is metabolized by and can inhibit several isoforms of the hepatic cytochrome P450 system (CYP 1A2, 2C9 and 2D6), which can result in significant drug-drug interactions if administered with agents that rely upon their metabolism by these microsomal enzymes (such as digoxin, warfarin, oral contraceptives, isoniazid and phenytoin).

• Chronic therapy with cimetidine has been associated with minor elevations in serum aminotransferase levels in 1% to 4% of patients, but similar rates were reported in placebo recipients. The ALT elevations were usually asymptomatic and transient and usually resolved even without dose modification. Several instances of clinically apparent liver injury have been reported in patients receiving cimetidine, but the time to onset and pattern of injury has varied greatly. Onset can be as short as a few days to as long as 7 months, and the serum enzyme pattern varies from hepatocellular to cholestatic, most cases having a “mixed” hepatocellular-cholestatic pattern of injury (Cases 1 and 2). The injury is rarely severe and resolves within 4 to 12 weeks of stopping cimetidine.

• Cimetidine has been shown clinically to reduce the clearance of mirtazapine, imipramine, timolol, nebivolol, sparteine, loratadine, nortriptyline, gabapentin, and desipramine in humans.[28]

• Cimetidine inhibits the renal excretion of metformin and procainamide, resulting in increased circulating levels of these drugs.[19] - Lactic acidosis risk!

• Cimetidine may increase the blood levels of atorvastatin. This can increase the risk of side effects such as liver damage and a rare but serious condition called rhabdomyolysis that involves the breakdown of skeletal muscle tissue.

• Cimetidine affects the metabolism of methadone, sometimes resulting in higher blood levels and a higher incidence of side effects, and may interact with the antimalarial medication hydroxychloroquine.

• Cimetidine is a potent inhibitor of tubular creatinine secretion. Creatinine is a metabolic byproduct of creatine breakdown. Accumulation of creatinine is associated with uremia, but the symptoms of creatinine accumulation are unknown, as they are hard to separate from other nitrogenous waste buildups.[26]

Cimetine to treat herpes and shingles

https://www.lifeextension.com/magazine/2001/3/report_tagamet

Cimetidine: A Safe Treatment Option for Cutaneous Warts in Pediatric Heart Transplant Recipients

Cutaneous warts (verrucae) are caused by human papilloma virus (HPV), a double-stranded DNA papovavirus. The primary objective of our study is to determine if there are any adverse effects associated with high-dose cimetidine treatment. A secondary objective is to report our experience with cimetidine in the treatment of cutaneous warts in pediatric heart transplant recipients. Methods and Results: This was a retrospective observational study. A total of 8 pediatric heart transplant recipients diagnosed with multiple recalcitrant warts were the subject of the study. All patients were treated with cimetidine (30–40 mg/kg/day) in two divided doses for 3 to 6 month durations. All patients had complete resolution of their lesions except 1 patient who had no clinical improvement. Of these 8 patients, one had recurrence of warts at one year follow-up, which resolved with restarting cimetidine therapy. One patient who had only 3 months of cimetidine therapy had immediate relapse after cimetidine was stopped. None of them had significant change in their tacrolimus trough, serum creatinine, and alanine transaminase levels. No adverse events were reported except one patient experienced mild gynecomastia. Conclusion: Cimetidine can be a safe and alternative treatment option for multiple warts in pediatric heart transplant recipients.

* Cimetidine therapy for warts in children

In 1993–1994 we conducted an uncontrolled trial of cimetidine in children with multiple viral warts at our institution. Thirty-three patients, 5 to 17 years of age (mean age, 9 years; 19 male and 14 female patients), were enrolled in the trial. All patients had multiple warts (average number 18) with an average duration of 19 months. No adjuvant therapy was used. Our patients included those with common warts, plantar warts, plane warts, and filiform warts. The dose of cimetidine varied from 20 to 40 mg/kg per day in two to three divided doses. Twenty-seven patients (82%) were cured by this therapy, and none has had a recurrence. The time to clear varied from 2 to 20 weeks, averaging 7.6 weeks. Only one patient experienced side effects (nausea and diarrhea) and withdrew from the trial. Our results were similar to those of Orlow and Paller 1 who reported an uncontrolled series of 32 children (3 to 16 years of age) with multiple warts treated with cimetidine at dosages of 25 to 40 mg/kg per day. They achieved an 80% cure rate at 8 weeks with no recurrences experienced.

Reviews:

• I am actually using this as a treatment for warts on my fingers and not for heartburn! They HAVE decreased!

• After public swimming lessons, my son began to develop warts on his hands and feet. The OTC stuff purchased at the store sort of works but it's a slow and unpleasant process that doesn't kill the roots so the warts tend to come back. I read online that Cimetidine can kill the virus that causes the warts in the first place and that virus lives in the body and can be spread. So, anyway, I bought a bottle of this and began giving them to my son daily. Within a couple weeks, his warts all began to turn black. At the end of three weeks, they started falling off. One month later, you can barely tell where they were. Very happy about this!!!

Typical dosing for cimetidine (Tagamet HB)

Cimetidine (Tagamet HB) is available both over-the-counter (OTC) and by prescription. The OTC strength is 200 mg, and the prescription strengths include 200 mg, 300 mg, 400 mg, and 800 mg.

OTC dosing:

• Heartburn symptoms: The typical dose is 200 mg by mouth once a day.

• Heartburn prevention: The typical dose is 200 mg by mouth once a day right before or 30 minutes before eating food or drinking beverages that cause heartburn.

Prescription dosing:

• Duodenal ulcer: The typical dose is 800 mg once a day at bedtime for 4 to 6 weeks. After the ulcer has healed the dose usually goes down to 400 mg at bedtime.

• Gastric ulcer: The typical dose is 800 mg by mouth at bedtime or 300 mg four times a day (with meals and at bedtime).

• GERD: The typical dose is either 800 mg by mouth twice a day or 400 mg four times a day for 12 weeks.

• Hypersecretory conditions: The typical dose is 300 mg by mouth four times a day with meals and at bedtime.

The use of cimetidine for the treatment of pruritus in polycythemia vera

Thirty-four patients with polycythemia vera complicated by pruritus were treated with 900 mg of cimetidine daily for 30 days and their responses to treatment were evaluated. The conditions of 15 (44%) were improved, with 12 patients stating that pruritus completely disappeared.

Does Cimetidine Improve Prospects for Cancer Patients? 1999

https://www.karger.com/Article/Fulltext/7686

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.

cimetidine

https://www.cancer.gov/publications/dictionaries/cancer-drug/def/cimetidine

A histamine H(2)-receptor antagonist. Enhancing anti-tumor cell-mediated responses, cimetidine blocks histamine's ability to stimulate suppressor T lymphocyte activity and to inhibit natural killer (NK) cell activity and interleukin-2 production. Cimetidine also may inhibit tumor growth by suppressing histamine's growth-factor activity and blocking histamine-induced stimulation of vascular endothelial growth factor (VEGF), a pro-angiogenic growth factor.

Cimetidine

Cimetidine is excreted primarily in the urine. Half-life. Cimetidine's half-life is estimated to be around 2 hours. Clearance.

Cimetidine undergoes relatively little metabolism, with 56 to 85% excreted unchanged. It is metabolized in the liver into cimetidine sulfoxide, hydroxycimetidine, and guanyl urea cimetidine. The major metabolite of cimetidine is the sulfoxide, which accounts for about 30% of excreted material.

Interactions between your drugs

Moderate

cimetidine  metFORMIN

Applies to: Tagamet (cimetidine) and metformin

Using metFORMIN together with cimetidine may increase the effects of metFORMIN. You should monitor your blood glucose and contact your doctor if you experience weakness, increasing sleepiness, slow heart rate, cold feeling, muscle pain, shortness of breath, stomach pain, feeling light-headed, and fainting. You may need a dose adjustment and you may need to check your blood sugar more often to safely use both medications.

Cimetidine

Cimetidine is a potent inhibitor of Multidrug and toxin extruder 1 (MATE1) of proximal tubular epithelial cells and it is a broad-spectrum inhibitor of transporters including Organic Cation Transporter 2 (OCT 2).17,18 Concomitant use of Metformin and Cimetidine decrease the excretion of Metformin, resulting in increased exposure of Metformin and elevated risk of Metformin Associated Lactic Acidosis (MALA).19,20 It is recommended to reduce the dose of Metformin when Cimetidine is co-prescribed.21

Moderate

cimetidine  metFORMIN

Applies to: cimetidine, metformin

MONITOR: Cimetidine may significantly reduce the renal tubular secretion of metformin. The mechanism may involve cimetidine inhibition of the organic cation transporter 2 (OCT2), thereby increasing metformin plasma concentration. In one study, the area under the plasma concentration-time curve for metformin was increased by 50% and the plasma clearance was reduced by 27%. Increased metformin levels may increase the risk of lactic acidosis.

MANAGEMENT: Particularly slow and cautious titration of metformin dosage is recommended if these drugs must be used together. The maximal dose of metformin should also be reduced until further information about this interaction is available. Patients should be advised to monitor their blood glucose and to promptly notify their physician if they experience possible signs of lactic acidosis such as nausea, vomiting, malaise, myalgia, weakness, respiratory distress, slow or irregular heartbeat, dizziness, lightheadedness, or other unusual symptoms.

The use of cimetidine for the treatment of pruritus in polycythemia vera

Thirty-four patients with polycythemia vera complicated by pruritus were treated with 900 mg of cimetidine daily for 30 days and their responses to treatment were evaluated. The conditions of 15 (44%) were improved, with 12 patients stating that pruritus completely disappeared.

Does Cimetidine Improve Prospects for Cancer Patients? 1999

https://www.karger.com/Article/Fulltext/7686

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.

cimetidine

https://www.cancer.gov/publications/dictionaries/cancer-drug/def/cimetidine

A histamine H(2)-receptor antagonist. Enhancing anti-tumor cell-mediated responses, cimetidine blocks histamine's ability to stimulate suppressor T lymphocyte activity and to inhibit natural killer (NK) cell activity and interleukin-2 production. Cimetidine also may inhibit tumor growth by suppressing histamine's growth-factor activity and blocking histamine-induced stimulation of vascular endothelial growth factor (VEGF), a pro-angiogenic growth factor.

Cimetidine

Cimetidine is excreted primarily in the urine. Half-life. Cimetidine's half-life is estimated to be around 2 hours. Clearance.

Cimetidine undergoes relatively little metabolism, with 56 to 85% excreted unchanged. It is metabolized in the liver into cimetidine sulfoxide, hydroxycimetidine, and guanyl urea cimetidine. The major metabolite of cimetidine is the sulfoxide, which accounts for about 30% of excreted material.

Interactions between your drugs

Moderate

cimetidine  metFORMIN

Applies to: Tagamet (cimetidine) and metformin

Using metFORMIN together with cimetidine may increase the effects of metFORMIN. You should monitor your blood glucose and contact your doctor if you experience weakness, increasing sleepiness, slow heart rate, cold feeling, muscle pain, shortness of breath, stomach pain, feeling light-headed, and fainting. You may need a dose adjustment and you may need to check your blood sugar more often to safely use both medications.

Cimetidine

Cimetidine is a potent inhibitor of Multidrug and toxin extruder 1 (MATE1) of proximal tubular epithelial cells and it is a broad-spectrum inhibitor of transporters including Organic Cation Transporter 2 (OCT 2).17,18 Concomitant use of Metformin and Cimetidine decrease the excretion of Metformin, resulting in increased exposure of Metformin and elevated risk of Metformin Associated Lactic Acidosis (MALA).19,20 It is recommended to reduce the dose of Metformin when Cimetidine is co-prescribed.21

Moderate

cimetidine  metFORMIN

Applies to: cimetidine, metformin

MONITOR: Cimetidine may significantly reduce the renal tubular secretion of metformin. The mechanism may involve cimetidine inhibition of the organic cation transporter 2 (OCT2), thereby increasing metformin plasma concentration. In one study, the area under the plasma concentration-time curve for metformin was increased by 50% and the plasma clearance was reduced by 27%. Increased metformin levels may increase the risk of lactic acidosis.

MANAGEMENT: Particularly slow and cautious titration of metformin dosage is recommended if these drugs must be used together. The maximal dose of metformin should also be reduced until further information about this interaction is available. Patients should be advised to monitor their blood glucose and to promptly notify their physician if they experience possible signs of lactic acidosis such as nausea, vomiting, malaise, myalgia, weakness, respiratory distress, slow or irregular heartbeat, dizziness, lightheadedness, or other unusual symptoms.

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

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.

Complete remission in a patient with acute myelogenous leukemia treated with leukocyte alpha-interferon and cimetidine

A 76-year-old woman with acute myelogenous leukemia with approximately 65% myeloblasts on bone marrow examination was treated daily with a combination of 4 megaU of leukocyte interferon IM and 1,000 mg cimetidine PO. During therapy there was a gradual decrease of bone marrow myeloblasts down to 9% and a normalization of peripheral white blood cells. The treatment was discontinued after 6 weeks because of increasing fatigue and anorexia. The general condition improved greatly during the following weeks and the patient entered complete remission, which has continued for 6 months so far. In the course of therapy there was a gradual appearance of antibodies showing a selective binding capacity to autochthonous leukemic cells with no tendency to increased binding to remission cells. The aim of this report is to stimulate a further evaluation of this form of therapy in additional AML patients whenever this might be justified as an alternative to conventional chemotherapy.

Cimetidine-Induced Myelosuppression After Bone Marrow Transplantation

A strong temporal correlation was observed between cessation of cimetidine and a sustained increase in blood counts in two marrow transplant recipients. Both were receiving cimetidine from the day of transplantation for prophylaxis of stress ulceration and gastritis. The blood counts of both patients were not increasing satisfactorily 5–6 weeks after marrow transplantation without any obvious cause of marrow suppression. A similar observation has been made with the use of ranitidine after marrow transplantation suggesting that histamine H2-receptor antagonists should be used very cautiously, if at all, in the setting of bone marrow transplantation.

Cimetidine reduces metastases and increases survival times:

Cimetidine (CIM), or Tagamet, is an over-the-counted medicine which was approved by the FDA back in 1977 and so is now off patent. It is a 'histamine receptor antagonist', and is used to treat stomach and duodenal ulcers and heartburn and indigestion. Histamines cause the stomach to produce excess acid and cimetidine stops this. 

Research shows this cheap antihistamine can play an important role in preventing cancer cell walls becoming inflamed tamoxifen and therefore 'sticky'. One expert described this as 'like having velco patches'. The sticky cells survive in the blood stream by sticking to the blood and lymph vessel walls and then spreading; they also use the stickiness to clump together with other cancer cells and thus start a tumour. The stickiness also holds the tumour together.  

Cimetidine seems particularly useful in limiting cancer spread as a result of colorectal cancer surgery or biopsy - it greatly increased survival. Other successful studies have taken place with melanoma, renal cell carcinoma, gastric cancer and prostate cancer. For example, there is some evidence CIM helps restrict spread in cases of melanoma and might even boost white cell count and improve the effectiveness of cyclophospamide too.

In a 2002 study by Matsumoto, where 800 mg of cimetidine per day was given for 1 year to people who had undergone colorectal cancer surgery 2 weeks previously and were starting chemotherapy (5-FU), the 10 year survival rose from 49.8% in the control group to 84.6% in the cimetidine group. 

The velcro-like stickiness is caused by E-selectin. Cimetidine is proven to block E-selectin. As the research said,

"Thus Tagamet (Cimetidine) reduces the histamine-derived inflammation of cancer cells and reduces metastases and cancer spread, the main cause of cancer death."

Cimetidine consistently shows increases in cancer survival times

The first report of cimetidine's use with cancer was an article in The Lancet in 1979 (1: 882-883) which reported that it possessed anti-tumour abilities. It had been used with a lung cancer patient. Several studies with mice followed until another Lancet report showed it effective with melanoma patients, where it cleared up the ulceration of tumours.

A number of papers then appeared in the New England Journal of Medicine and The Lancet showing its effectiveness amongst patients after colorectal cancer operations, either used on its own or in conjunction with standard treatments. By 2002 the British Journal of Cancer reported a trial with 64 patients. The group without cimetidine showed a 10-year survival of 49.8, whereas the group also taking cimetidine had a 10-year survival of 84.6 per cent. In the group with the most aggressive cancers the figures were, without 23 per cent; with 85 per cent! The important conclusion was to give the drug before and during surgery.

This conclusion was reinforced by two studies one from Japan (Fujita Health University; Matsumoto; Lancet 1995; 346: 115) where the group taking cimetidine with the chemotherapy 5-FU had a 4-year survival of 96.3 per cent compared to the group on chemo only of 68.8 per cent. The cimetidine was given before the surgery. However, in a Danish study where it was started 3 weeks after surgery there was no benefit over the control group.

So, while the general evidence is clear and positive, there is some debate over whether you should take Cimetidine before or just after surgery.

Cimetidine may boost immune response too

In our article, Can Surgery Spread Cancer? we looked at various ways in which surgery might cause metastatic activity. Cimetidine may in fact help in two ways - not just by its histamine-preventing activity stopping cells clumping together, but it just may boost the immune system as well.

In 1997 the journal Cancer (80: 15-21) reported a study by Adams and Morris where again the cimetidine was given before and during colorectal surgery. They looked at white blood lymphocytes before and after the surgery. Those patients taking the cimetidine showed an improvement in lymphocyte levels in more than half the subjects, whereas the placebo boosted the levels in under a quarter of the control group. Equally important was the follow up where 3-year survival was in line with the findings at the time of surgery. It is possible that this immune response as an independent benefit. It is thought that antihistamines have a strong effect on cytokines. Other studies have looked at prostate cancer and found similar improved survival figures.

There is some concern that Cimetidine has estrogenic properties and should NOT be used with, say, ER+ breast cancer or prostate cancer.