High Doses Of Cimetidine Research Articles

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

Background and Objectives: Immunosuppressed individuals are at particularly increased risk for human papilloma virus-related infections. 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.

Perioperative Cimetidine Administration Improves Systematic Immune Response and Tumor Infiltrating Lymphocytes in Patients with Colorectal Cancer

Cimetidine has been shown to play an important role in the treatment of cancer and the regulation of the immune system. Therefore, we aimed to observe the effects of cimetidine on the systematic immune response in the perioperative period. Sixty patients with colorectal cancer were enrolled from Jan 2005 to Dec 2005 from Taizhou Hospital. The patients were administrated with cimetidine (0.8 g.d-1 or 1.2 g.d-1) or saline from the day of admission to the 10th POD. Venous blood sample was collected and the T-, B- and NK-lymphocyte subsets were determined by flow cytometry. The specimens were subjected to tumor-infiltrating lymphocytes (TILs) response examination. The levels of CD3 and CD4 T-lymphocytes were increased significantly in both low and high dose cimetidine groups 10 days after operation. The number of CD19 B cells was also elevated by cimetidine. However, no significant changes were observed in the CD8, CD4/CD8 value. TIL responses in the cimetidine groups were also enhanced significantly. Cimetidine can alleviate systematic immunosuppression and improve the local immune function of the colorectal cancer patients in the perioperative period.

Gastroprokinetic Activity of Nizatidine during the Digestive State in the Dog and Rat

The present study was undertaken to clarify a prokinetic activity of nizatidine (CAS 76963-41-2) during the digestive state as well as gastric emptying of a solid test meal in comparison with cimetidine (CAS 51481-61-9), famotidine (CAS 76842-35-6) and cisapride (CAS 81098-60-4). Intravenous administration of nizatidine (0.3-3 mg/kg) enhanced the motility of the gastric antrum and duodenum during the digestive state. With cimetidine (1-10 mg/kg) and famotidine (0.1-1 mg/kg) enhancement of gastric motility was observed only with the highest dose of cimetidine, and famotidine had no effect. Marked enhancement of gastric motility was observed with cisapride (0.1-0.5 mg/kg). After intraduodenal administration of nizatidine (10 and 20 mg/kg) and cisapride (0.25 and 0.5 mg/kg), they also amplified the contractile activity of the gastric antrum. Gastric emptying of a solid test meal was accelerated by intraperitoneal administration of nizatidine (1-10 mg/kg) to the same extent as cisapride (0.1-1 mg/kg). In addition, even in a model of delayed gastric emptying induced by clonidine, nizatidine, like cisapride, improved the rate of gastric emptying. Neither cimetidine (3-30 mg/kg) nor famotidine (0.3-3 mg/kg) affected the gastric emptying of a solid meal or delayed gastric emptying. These results suggest that nizatidine enhanced gastric motility even during the digestive state, and accelerated gastric emptying of a solid meal, similar to cisapride. Furthermore, nizatidine improved clonidine-induced delayed gastric emptying. These prokinetic activities of nizatidine may by useful for the treatment of abdominal symptoms due to dysmotility and delayed gastric emptying in patients with gastritis and non-ulcer dyspepsia (NUD). In comparison with famotidine and cimetidine, nizatidine may be different from other histamine H2-receptor antagonists and has unique properties other than its gastric antisecretory activity.

Effect of Histamine H2-Receptor Antagonists on Acute Inflammatory of the Rat Paw Oedema

The effect of three histamine H2-antagonists, cimetidine, ranitidine, and loxtidine, on acute rat paw oedema induced by histamine, carrageenan or complete Freund's adjuvant, have been examined. Administered intraperitoneally, all three antagonists inhibited histamine-induced paw oedema dose-dependently in the range 0.5-15 mumol kg-1. The highest dose of cimetidine produced an inhibition of 92% as against 38% with the same dose of mepyramine. Analysis of the concentration-effect curves produced IC50 values of 1.66, 5.12 and 12.30 mumol kg-1 for cimetidine, loxtidine, and ranitidine, respectively, on histamine-induced oedema. In carrageenan-induced inflammation 12.3 mumol kg-1 of each of the three drugs produced significant inhibition, whereas in adjuvant-induced inflammation, (acute phase), cimetidine was very active, loxtidine less so and ranitidine inactive. Thus the relative effectiveness of the antagonists (cimetidine greater than loxtidine greater than ranitidine) appears to differ from their known potency relationship (loxtidine greater than ranitidine greater than cimetidine) on H2-mediated effects. We conclude that H2-receptors are involved in the induction of rat paw oedema, especially those induced by histamine and carrageenan, but that their relative effectiveness appears atypical.

Do the H2-receptor antagonists, cimetidine and famotidine, modify the degree of renal recovery following renal insult?

The effects of two different H2-receptor antagonists, cimetidine and famotidine, on the acute renal failure induced by 20 min of renal artery occlusion and gentamicin (240mg/kg BW, s. c., for 3 days) were investigated in Sprague-Dawley rats. The animals were treated with either cimetidine (80 or 160 mg/kg BW) or famotidine (4 or 8 mg/kg BW) mixed in the drinking water for 7 days. The low dose of cimetidine and famotidine did not alter the renal function in the absence of renal trauma. However, the high dose of cimetidine or famotidine decreased the GFR by 32% and 22%, whereas RPFR increased by 46% and 62%, and % FENa by 92% and 558%, respectively. The data for the renal function obtained 24 hrs after 20 min of renal ischemia demonstrated a decrease of 54% in GFR, a decrease of 47% in RPFR and an increase of 370% in %FENa over the non-ischemic control values (p less than 0.05). Cimetidine (80 mg/kg BW) or famotidine (4 mg/kg BW) did not modify the recovery of renal function following the ischemic insult, showing 55% and 539% decreases in GFR, 74% and 101% increases in RPFR, and 393% and 461% increases in %FENa over the non-ischemic control rats, respectively. Famotidine reduced the decrease in RPFR significantly during the recovery period following ischemia. In the gentamicin study, gentamicin treatment was found to lower the renal function significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the prenatal administration of cimetidine on testicular descent and genital differentiation in rats

Cimetidine has been shown to induce gonadal and sexual dysfunction in men. This study aimed to clarify the effect of cimetidine on testicular descent and genital development in utero. Pregnant rats (280 to 330 g) were separated into 4 groups. In group 1, the rats were injected subcutaneously with a dose of 600 mg/kg of cimetidine twice on days 15, 16, 17, and 18 of gestation. In group 2, the rats were injected with a dose of 300 mg/kg of cimetidine twice in the same way as in group 1. In group 3, the rats were injected with a dose of 150 mg/kg of ranitidine twice in the same manner as in the above groups. In group 4, the rats were injected with the same volume of saline. At birth the anogenital distance was measured, and the incidence of testicular descent was examined in male offspring at 90 days of age. Next, the testes were weighed and histologically examined. The chi-square test and Student t test were used to perform statistical analyses of the results. At birth, the anogenital distance (AGD) index in male offspring decreased significantly in groups 1 and 2 in comparison with groups 3 or 4. However, there was no significant difference in the AGD index between groups 3 and 4. At 90 days of age, the incidence of cryptorchidism was 55.3% in group 1 and 25.9% in group 2. In contrast, all testes descended into the scrotum in both groups 3 and 4. The incidence of cryptorchidism was significantly higher in group 1 than in groups 2 (P <.05), 3, or 4 (P <.01), while the incidence of cryptorchidism was also significantly higher in group 2 than in groups 3 or 4 (P <.01). The weight of the testis decreased significantly more in the undescended testis than in the scrotal testis (P <.01); however, there was no significant difference in the weight of the scrotal testes among the 4 groups. The histologic development of the undescended testes showed an absence of germ cells and smaller tubes in comparison with those of scrotal testes, which showed an advanced differentiation of germ cells and larger tubes in all 4 groups. These findings suggest that the antiandrogenic effect of cimetidine inhibits both the testicular descent and genital differentiation in fetuses and also causes cryptorchidism in postnatal rats. These same events might also occur in human fetuses when high doses of cimetidine are administered to pregnant women around the end of the first trimester.

High-dose cimetidine reduces proinflammatory reaction after cardiac surgery with cardiopulmonary bypass

Background. Cimetidine, which is usually used for gastric ulcer, enhances cellular immunity. The effect of cimetidine on perioperative proinflammatory response after cardiac surgery with cardiopulmonary bypass was investigated. Methods. Elective coronary artery bypass graft cases in which CPB was performed were placed randomly in a cimetidine (C) group (n = 20) or a no-treatment (N) group (n = 20). The time course of plasma levels of neutrophil elastase, interleukin (IL)-6 and IL-8, leukocyte counts, lymphocyte recovery ratio, C-reactive protein, creatine-kinase-MB, and oxygenation index were analyzed. Results. The plasma levels of neutrophil elastase and IL-8 were inhibited in the C groups at 2 hours after CPB termination. In a comparison of the two groups, the C group demonstrated higher lymphocyte recovery ratio and lower C-reactive protein on postoperative day 5 and shorter intubation time. No intergroup differences were observed in IL-6, leukocyte counts, creatine-kinase-MB levels, or oxygenation index. Conclusions. Cimetidine may reduce surgical stress and augment the immune system after cardiac surgery with cardiopulmonary bypass.

Immunotherapy for renal carcinoma: theoretical basis and current standard of care.

Carcinoma of the kidney (a.k.a. ‘hypernephroma’ or renal cell cancer) accounts for 2–3% of all adult cancers, and over 4000 new cases are reported in the UK every year [1]. It occurs more commonly in men, and has a peak incidence around 60–70 years, although can occur at any age. The incidence is increasing [2]. If confined to the kidney, surgical resection is the treatment of choice, and cure can result. However, most patients with metastatic disease survive less than 1 year [3], and chemotherapeutic or hormonal approaches are generally ineffective. The natural history of renal cancer characteristically manifests an indolent course, with long periods of stable disease. In addition, the ‘spontaneous regression’ of metastases has often been reported in the literature, and Evenson & Cole [4] made the observation that renal cancer appeared to have the highest incidence of this controversial and intriguing phenomenon. The actual frequency of spontaneous regression in renal tumours is not known, but estimates put it at around 0.3% [5]. A higher frequency has been reported following nephrect-omy in patients with established metastatic disease [6]. The existence of spontaneous regression has been put forward as evidence that a form of innate ‘host factor’ or immunological response may be involved in its pathogen-esis. Such a hypothesis is supported by the increase in renal cancer cases observed in patients receiving long-term immunosuppressive therapy for organ transplantation [7].

Oral cimetidine for the management of genital and perigenital warts in children.

It is believed that most warts are self-limiting and generally require little or no treatment. When numerous or almost complete infestation of the perineum, genital area and groin is encountered it can be distressing and a difficult problem to treat in children. Multiple treatments with caustic agents are sometimes necessary, and treatment of perigenital warts may require use of anesthesia for multiple procedures. Cimetidine is a histamine receptor antagonist that has been used mainly to treat peptic ulcer disease. Recently it has been reported to be useful for the treatment of mucocutaneous candidiasis, herpes simplex, herpes zoster and verruca because of its immunomodulatory effects. Several studies have been published indicating its effectiveness in the treatment of warts. We treated 4 children with extensive condylomata acuminata of the genital and perigenital areas with high doses of cimetidine in an attempt to eradicate the condyloma and avoid recurrence in 2 and as primary treatment in 2. All patients were treated with 30 to 40 mg./kg. cimetidine daily in 3 divided doses during a 3-month period. All patients are free of condyloma at 24 months following treatment. Our results show that cimetidine is useful for primary and adjunctive treatment of condyloma in young children. It also appears to be effective as first line therapy.

ORAL CIMETIDINE FOR THE MANAGEMENT OF GENITAL AND PERIGENITAL WARTS IN CHILDREN

Purpose: It is believed that most warts are self-limiting and generally require little or no treatment. When numerous or almost complete infestation of the perineum, genital area and groin is encountered it can be distressing and a difficult problem to treat in children. Multiple treatments with caustic agents are sometimes necessary, and treatment of perigenital warts may require use of anesthesia for multiple procedures. Cimetidine is a histamine receptor antagonist that has been used mainly to treat peptic ulcer disease. Recently it has been reported to be useful for the treatment of mucocutaneous candidiasis, herpes simplex, herpes zoster and verruca because of its immunomodulatory effects. Several studies have been published indicating its effectiveness in the treatment of warts.Materials and Methods: We treated 4 children with extensive condylomata acuminata of the genital and perigenital areas with high doses of cimetidine in an attempt to eradicate the condyloma and avoid recurrence in 2 and as pr...

Cimetidine treatment for recurrent respiratory papillomatosis

Effective adjuvant treatment for recurrent respiratory papillomatosis (RRP) is at present limited to alpha-interferon, which may have significant side effects including rebound growth of papillomata following its withdrawal, is given by injection and is expensive. High dose cimetidine is known to have immunomodulatory side effects and has been reported as a useful treatment for cutaneous warts. We report a case of very advanced RRP with tracheo-bronchial-pulmonary involvement treated with adjuvant cimetidine at a dose of 40 mg/kg for 4 months. The patient enjoyed a remarkable improvement in her clinical condition following treatment. The literature regarding cimetidine treatment for cutaneous warts is reviewed.

EFFECT OF ULCERATION ON RAT GASTRIC TISSUE POLYAMINE CONTENTS IN RESPONSE TO DIFFERENT PROCEDURES; INHIBITION OF THESE EFFECTS BY CIMETIDINE

The effects of cimetidine an H2receptor histamine antagonist on aspirin- and cold-restraint-stress-induced gastric lesions have been studied in rats. Cimetidine had a pronounced inhibitory effect on gastric lesions induced by either oral administration of aspirin (400 mg kg−1) or by cold-restraint stress in rats. These inhibitory effects were dose-related in the aspirin treatment group being 47 and 85% (P<0.05 and P<0.001) at 37.5 and 75 mg kg−1doses, respectively, when compared to the control. Cimetidine was found effective in cold stress but inhibition with the low dose was not significant. However, high dose (75 mg kg−1) showed a significant reduction (P<0.01) in lesion index. In another series of experiments with the same regimen, the effects of different ulcerogenic procedures on the rat gastric tissue polyamine contents (putrescine, spermine and spermidine) and monoacetyl derivatives (N1- and N8-acetylspermidine) have been investigated by using HPLC method. The procedure permits use of n-octane sulphonate as an ion pairing agent on the reversed-phase column. The treatment of rats with aspirin caused a substantial decrease in the concentration of different polyamine contents in the glandular part of stomach tissue. Pretreatment with cimetidine showed a marked protection against this decline in polyamine contents at both the doses tested (37.5 mg kg−1and 75 mg kg−1) and increased the contents of spermidine and spermine above the control values. In the other part, cold-restraint stress also declined the polyamine contents. Low dose of cimetidine was found ineffective in this model. However, a high dose of cimetidine caused a significant rise in the levels of spermidine and spermine (P<0.001 and P<0.01, respectively) above the control levels. These findings suggest that cimetidine, besides being a H2-receptor antagonist, prevents ulcer formation due to its growth promotional properties, possibly through an increase in tissue polyamine contents that offer a defense barrier against the oxygen-derived free radicals involved in the etiology of ulceration. It is also suggested that the rise in polyamine contents of gastric tissue is a crucial event in cytoprotection against destructive stimuli.

Long-term disease-free survival following surgery and active specific immunotherapy with allogeneic vaccine in a patient with high-risk malignant melanoma of the vulva

Vulvar malignant melanoma with deep vertical penetration of the tumor and involvement of regional lymph nodes carries a very poor prognosis. The case of a 25-year-old woman with a history of a Breslow depth 6.0 mm and Clark Level IV primary vulvar malignant melanoma, involving the anterior part of the left labium major, 1 cm from the clitoris, is reported. The patient had undergone a left radical hemivulvectomy and bilateral groin dissection. There were two of thirteen superficial left groin nodes containing metastatic melanoma. The patient had been treated postoperatively with an allogeneic specific anti-melanoma vaccine in combination with high-dose cimetidine and has survived without disease for more than five years. To the best of our knowledge this is the first case report in the literature of active specific immunotherapy with allogeneic vaccine in vulvar malignant melanoma. This case illustrates that the behavior of malignant melanoma, including vulvar malignant melanoma, is unpredictable and active specific immunotherapy with allogeneic vaccine may have a role in the postoperative treatment of high risk vulvar malignant melanoma.

The mechanism of excretion of paraquat in rats

Paraquat (PQ) (1,1′-dimethyl-4,4′-bipyridinium) is a toxic herbicidal cation. The renal excretory mechanisms of PQ and its interactions with organic cations and anions were investigated in anaesthetised rats. The renal clearance of PQ was studied in male Wistar rats using inulin as the marker of glomerular filtration rate. The fractional excretion of paraquat (FEpq) decreased from 2.1 ± 0.01 to 1.2 ± 0.03 as the plasma concentration rose from 0.4 ±0.02 to 21.2 ±1.6 μM. These results demonstrated that the excretion of PQ was greater than glomerular filtration, concentration dependent and saturable, indicating that it was secreted by an active transport system. The excretion of PQ was dependent predominantly on the glomerular filtration rate with a small secretory component ( K m = 8.5 ± 3.1 μM, V max = 114 ± 19 nmol/kg per min). The clearance of PQ was not inhibited by high doses of cimetidine, or p-aminohippurate. However, quinine (P = 0.001) and N-methylnicotinamide (NMN) (P = 0.03) reduced the FEpq, suggesting that they share a similar cation transport system with PQ. In summary, PQ is actively secreted by the rat kidney via a cation transport system.

Cimetidine Therapy for Recalcitrant Warts in Adults

Common warts, or verrucae vulgaris, occur most often in children. However, many adults are plagued by this ubiquitous viral infection. Various modalities have been used to treat warts, but none is uniformly effective or directly antiviral. A recent study showed cimetidine to be effective in the treatment of multiple warts in children. Anecdotal reports have suggested that the administration of high doses of cimetidine, through various proposed immunomodulating mechanisms, can improve recalcitrant warts in adults. There have been no data published to date supporting these claims. An open-label study was conducted to determine the safety and efficacy of high-dose cimetidine in 20 adult patients with recalcitrant warts. Of the 18 patients who completed the study, 16 patients (84%) had either dramatic clinical improvement or complete resolution of their wart lesions after 3 months of cimetidine therapy without any adverse effects. No patient demonstrated disease progression while receiving the medication and complete responders remained free of lesions at 1-year follow-up. This study further confirms that high-dose cimetidine therapy appears to be beneficial and safe in the treatment of recalcitrant warts in adults. Further placebo-controlled studies are needed to determine its true efficacy.

Safety issues relating to long-term treatment with histamine H2-receptor antagonists.

H2-receptor antagonist therapy is associated with a low incidence of adverse reactions. Adverse events reported in clinical trials of ranitidine in daily doses of up to 1200 mg include headache, tiredness and mild gastrointestinal disturbances, but the incidence is similar to or less than that for placebo. High doses of cimetidine (> 5 g/day) can cause reversible impotence or gynaecomastia. While ranitidine exhibits no clinically significant drug-drug interactions, cimetidine interacts with many drugs metabolized by cytochrome P450. In contrast to ranitidine and cimetidine, where safety data are available for up to 10 years of continuous therapy, experience with famotidine and nizatidine is limited. The safety of long-term H2-receptor antagonist therapy needs to be considered in relation to the potential consequences of prolonged acid suppression, including the risk of proliferation of gastric flora and the risk of developing enterochromaffin-like cell hyperplasia, which could in turn, theoretically, lead to gastric malignancy. Such problems have not been observed in patients during long-term therapy at low or full doses of H2-receptor antagonists. Standard doses of currently available H2-receptor antagonists permit acid secretion in response to food and other stimuli, and this daily acid tide prevents persistent bacterial colonization.

High-Dose Cimetidine for the Treatment of Metastatic Renal Cell Carcinoma

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.

Phase II Trial of Cimetidine in Metastatic Melanoma

Fifteen evaluable patients with metastatic malignant melanoma who had received no prior chemotherapy were treated with high-dose cimetidine orally, 600 mg q.i.d. Although three patients had stable disease lasting 2-4 months, there were no objective responses. Median survival was 5.3 months (range 1-18 months). Toxicity was essentially negligible except for severe diarrhea in one patient and worsening liver function abnormalities in another. High-dose cimetidine does not have any significant activity in metastatic melanoma.

Omeprazole in the treatment of erosive oesophagitis refractory to high dose cimetidine and ranitidine.

Forty five patients with refractory oesophagitis, defined as persisting erosive changes or ulceration despite a minimum of three months' treatment with cimetidine 3.2 g daily or ranitidine 0.9 g daily, were treated in an open trial with omeprazole 40 mg daily for up to eight weeks. Endoscopically defined healing was observed in 73% of patients after four weeks' treatment and in 91% after eight weeks' treatment. Symptoms were completely relieved in 60% of patients, improved in 34%, unchanged in 4%, and worsened in 2%. After healing patients returned to maintenance treatment with cimetidine 1.6-3.2 g daily, depending on the severity of their illness before treatment with omeprazole. By six months and 12 months only 55% and 33% of patients respectively were still in remission. This study suggests that when erosive oesophagitis is refractory to treatment with high dose cimetidine or ranitidine, treatment with omeprazole 40 mg daily for up to eight weeks is effective in inducing healing and relieving symptoms.

Omeprazole in the Treatment of Erosive Oesophagitis Refractory to High-dose Cimetidine

Omeprazole in the Treatment of Erosive Oesophagitis Refractory to High-dose Cimetidine