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Background: Results from short-term studies of histamine type 2 (H2) receptor antagonists on survival of patients with solid tumours are debatable. In this study the efficacy of the H2-receptor antagonist ranitidine on long-term survival of patients with colorectal cancer was evaluated., Methods: Patients scheduled for elective resection of primary tumours were consecutively included in a randomized double-blind placebo-controlled clinical study designed to evaluate the effect of ranitidine on survival. Before skin incision ranitidine 100 mg or placebo was given intravenously twice daily followed by oral ranitidine 150 mg or placebo twice daily for 5 years. Adjuvant cytotoxic or radiation therapy was not given. An observer-blinded interim analysis performed after 40 months showed that there was no effect of ranitidine on overall survival, and the study was discontinued in accordance with the protocol. The patient cohort has been followed continuously without loss of any patient, and a final statistical analysis was performed on an intention-to-treat basis after more than 5 years; this included a subgroup analysis of perioperative blood transfusion and postoperative infectious complications., Results: The median observation period of the 740 patients included was 6.8 (range 5.4-7.9) years. A univariate analysis of all 740 patients and of the subgroup of 560 who underwent curative resection showed no significant effect of ranitidine on survival. Furthermore, ranitidine had no survival benefit in curatively resected patients who received a perioperative blood transfusion (n = 358), but it improved the survival of non-transfused patients (n = 202; hazard ratio (HR) 0.6 (95 per cent confidence interval (c.i.) 0.4 to 0.9), P = 0.02) and of non-transfused patients who did not develop postoperative infectious complications (n = 170; HR 0.6 (95 per cent c.i. 0.4 to 0.9), P = 0.01). In multivariate analysis of patients who had a curative resection, including Dukes' stage, age, gender, tumour location, blood transfusion, postoperative infectious complications and treatment, ranitidine still had an independent, beneficial effect on survival (HR 0.6 (95 per cent c.i. 0.4 to 1.0), P = 0.04) within the subgroup of patients who did not receive perioperative blood transfusion and did not develop postoperative infectious complications., Conclusion: Ranitidine may prolong the survival of patients who undergo curative resection of colorectal cancer and who do not receive perioperative blood transfusion and do not develop postoperative infectious complications.

Background: Immunoglobulin E (IgE) is important in allergic reactions and in host defense against parasites. IgE may also participate in the acute-phase response to physical stress. This study aimed to determine whether major abdominal surgery induced increased serum IgE levels, and whether treatment with ranitidine or prednisolone influenced the IgE response to surgery., Methods: For assessment of the IgE response to surgery and the effect of ranitidine, 24 patients scheduled for major abdominal surgery were randomized to receive either perioperative treatment with ranitidine or no treatment. To evaluate the effect of glucocorticoids, 24 patients undergoing major elective abdominal surgery were randomized to receive preoperative treatment with either prednisolone or placebo. IgE levels were determined in serum samples drawn pre- and postoperatively., Results: In the ranitidine study, both the control group and the ranitidine-treated group displayed a postoperative increase (P<0.001) of serum IgE. In the prednisolone study, a postoperative increase (P<0.05) of serum IgE was detected in the placebo group. No significant increase was found in the prednisolone-treated group., Conclusions: Major abdominal surgery induces an increase of serum IgE. This increase can be prevented by preoperative treatment with prednisolone, but not with ranitidine.

Objective and Design: To study the potential effect of ranitidine on postoperative infectious complications following emergency colorectal surgery. A randomized, placebo-controlled, double-blind trial was carried out in three university clinics and two county hospitals in Denmark., Patients and Treatment: One hundred and ninety-four consecutive patients undergoing acute colorectal surgery for perforated and/or obstructed large bowel were randomized in a double-blind fashion to receive ranitidine 100 mg i.v. twice a day commencing at induction of anesthesia and continued for five days (group I) or i.v. placebo (group II). All patients were given 1.5 g metronidazole plus 3.0 g cefuroxime at the time of surgery. Patients with perforation of the colon or rectum were given metronidazole and cefuroxime for further 3 days. All patients were assessed daily until discharge from the hospital. Thirty patients were withdrawn from the study (for reasons such as other diagnosis, refused to continue, medication not given as prescribed)., Main Outcome Measures: Patients were observed for signs of infectious complications; such as wound infection, intra-abdominal abscess, septicemia, and pneumonia., Results: Both groups were similar with respect to age, sex, weight, duration of surgery, blood transfusions, and site of the procedure, as well as the histologic nature of the underlying disease process. However, the Mannheim Peritonitis Index (MPI) was significantly higher in group I compared with group II (p < 0.05). Wound infection, intraabdominal abscess, septicemia, and pneumonia were 12.9%, 5.2%, 3.8% and 14%, respectively in group I. In group II, the infectious complications were 16.1%, 6.8%, 6.9% and 22%, respectively. Twelve patients (13.8%) in the placebo group developed more than one complication compared with 5 patients (6.5%) in the ranitidine group., Conclusion: Ranitidine may have a beneficial effect on postoperative infectious complications in patients following acute colorectal surgery.

We report the results of an open, prospective study of 20 patients with moderate to severe psoriasis (median PASI score: 15.7) treated with oral ranitidine 300 mg twice daily for six months. No other medication was allowed during the study period. The median PASI score was reduced to 14.5, 9.1 and 5.7 after one, three and six months of treatment, respectively (p < 0.00001). A mild to moderate worsening was observed in 15 patients within the first month of treatment, but this was not followed by exclusion from the study, and long-term treatment improved disease status in most patients. Eight patients continued therapy with ranitidine 300 mg twice daily after the study was completed. None of these patients relapsed during a follow-up period of 12-18 months. The results of the present study suggest that ranitidine may be beneficial in the treatment of some patients with psoriasis.

We report the results of an open, prospective study on the efficacy of systemic ranitidine in the treatment of psoriasis. Twenty patients suffering from moderate to severe psoriasis were included in the study. The median pretreatment PASI score was 15.7 (range 6.0-24.7). The patients were treated with oral ranitidine 300 mg twice a day for 6 months; no other medication was allowed during the study period. Eighteen patients completed the study. The median PASI score was reduced from 15.7 to 14.5, 9.1 and 5.7, after 1, 3 and 6 months of treatment, respectively (P < 0.00001). A significant reduction in PASI score was evident at 3 months of treatment. A mild to moderate deterioration occurred in 15 patients within the first month of treatment, but this was followed by improvement during prolonged treatment in most patients. No other clinical and/or biochemical side-effects were observed. Eight patients continued therapy with ranitidine after the study was completed, and none of these patients relapsed during a follow-up period of 12-18 months. The results of the present study suggest that ranitidine may be a beneficial and safe treatment for psoriasis. In addition, high-dose, long-term ranitidine treatment appears to be free from severe adverse effects.

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.

The histamine H-2-receptor antagonist ranitidine hydrochloride has been shown to alleviate trauma-, blood transfusion- and sepsis-induced immunosuppression. We evaluated the effect of ranitidine on the postoperative impairment of monocyte and neutrophil function in 24 patients undergoing major elective abdominal surgery. The patients were randomized to receive postoperative adjuvant treatment with ranitidine hydrochloride (100 mg) administered intravenously twice daily for four days, followed by oral ranitidine hydrochloride (150 mg) administered twice daily for five days (n = 11), or no adjuvant treatment (n = 13). Blood monocyte and neutrophil chemotaxis and chemiluminescence were analyzed before the operation and on post-operative days one, three and nine. Monocyte chemotaxis to C5a in the 13 control patients was significantly decreased on day one compared to day 0. Chemotaxis in the 11 ranitidine-treated patients increased significantly from day 0 to day one (p < .01 between groups). Neutrophil chemiluminescence to zymosan and N-f-methionyl-leucylphenylalanine was significantly increased in control patients on day one compared to day 0 (p < .05), while ranitidine reduced chemiluminescence to zymosan insignificantly on day one (p < .07 between groups). Five of the 13 control patients developed postoperative infectious complications, which were related to decreased monocyte chemotaxis to C5a and increased neutrophil chemiluminescence to zymosan when compared to noninfected patients. A significant difference (P < .05) in chemiluminescence to zymosan between infected and noninfected control patients was observed on day three, before clinical signs of infectious disease could be detected. There were no infectious complications in ranitidine-treated patients. These results support previous studies on the effect of ranitidine in reducing postoperative immunosuppression.

Background: The mechanism of post-traumatic immunosuppression is still not known in detail. However, histamine released during trauma and major surgery may play a significant role in the process. Previously, we showed that the histamine-2 receptor antagonist (H2RA), ranitidine, reduced trauma-induced suppression of certain immunological parameters., Study Design: The effect of perioperative ranitidine on postoperative change in plasma interleukin-6 (IL-6) and serum C-reactive protein (CRP) levels was assessed in 23 women undergoing elective abdominal hysterectomy. The patients were randomized to receive intravenous ranitidine, 100 mg twice a day from skin incision, for two days, followed by oral ranitidine, 150 mg twice a day, for a further three days, or no ranitidine. Interleukin-6 and CRP were analyzed in plasma and serum, respectively, drawn preoperatively and six, 24, 48, and 120 hours after skin incision., Results: Routine blood analyses, clinical data (except age), duration of surgery, anesthesia, antibiotic prophylaxis, blood loss, and perioperative blood transfusion were similar in the two groups. Interleukin-6 levels were significantly increased in all patients and without difference between the ranitidine-treated and non-ranitidine-treated patients after six, 24, and 48 hours compared to preoperative levels, respectively. C-reactive protein levels were also significantly increased in all patients after 24, 48, and 120 hours, respectively; however, at 48 hours, CRP was significantly reduced in ranitidine-treated patients compared with non-ranitidine-treated patients (p = 0.02)., Conclusions: These results suggest that histamine-2 receptor activation mechanisms may not be involved in postoperative IL-6 synthesis. However, the reduced CRP level in ranitidine-treated patients suggests that H2RAs modulate IL-6 signal transduction in hepatic cells.

The effect of perioperative immunomodulation with the H2-receptor antagonist ranitidine on postoperative changes in soluble interleukin (IL) 2 receptor and soluble CD8 levels was assessed in 24 patients undergoing major elective abdominal surgery. Eleven patients were randomized to receive intravenous ranitidine 100 mg twice daily for 4 days from skin incision, followed by oral ranitidine 150 mg twice daily for a further 5 days; 13 control patients received no ranitidine. Routine blood analysis, clinical data, duration of surgery, anaesthesia, antibiotic prophylaxis and perioperative blood transfusion were similar in the two groups. Serum concentrations of soluble IL-2 receptor and CD8 were measured before operation (day 0) and in the morning of postoperative days 1, 3 and 9 using commercial enzyme-linked immunosorbent assay kits. In patients treated with ranitidine, the serum level of soluble IL-2 receptor increased from day 0 to day 9 (P < 0.01); in control patients it decreased from day 0 to day 1, did not change significantly by day 3 and increased by day 9. The change from day 0 to day 1 was significantly different between the two groups (P < 0.01). Five of the 13 control patients developed postoperative infectious complications. No significant differences were shown in soluble CD8 concentration during the postoperative period. The postoperative change in soluble IL-2 receptor level may reflect lymphocyte activation status; ranitidine appears to promote activation of mainly CD4-positive lymphocytes since serum levels of CD8 were unchanged. Ranitidine may, therefore, improve immune function during major surgery.

Background: The histamine H2-receptor antagonist ranitidine hydrochloride has been shown to improve trauma-, blood transfusion-, and sepsis-induced immunosuppression., Objective: To evaluate the effect of ranitidine on postoperative impairment in monocyte and neutrophil function., Methods: Twenty-four patients undergoing major elective abdominal surgery were randomized to receive adjuvant treatment with ranitidine hydrochloride (100 mg) administered twice a day intravenously from skin incision for 4 days, followed by oral ranitidine hydrochloride (150 mg) administered twice a day for 5 days (n = 11), or no adjuvant treatment (n = 13). Blood monocyte and neutrophil chemotaxis and chemiluminescence were analyzed before the operation and on postoperative days 1, 3, and 9., Results: Monocyte chemotaxis to C5a in the 13 control patients was significantly decreased on day 1 compared with day 0. Chemotaxis in the 11 ranitidine-treated patients increased significantly from day 0 to day 1 (P < .01 between groups). Neutrophil chemiluminescence to zymosan and N-f-methionyl-leucyl-phenylalanine was significantly increased in control patients on day 1 compared with day 0 (P < .05), while ranitidine reduced chemiluminescence to zymosan insignificantly on day 1 (P < .07 between groups). Five of the 13 control patients developed postoperative infectious complications, which were related to decreased monocyte chemotaxis to C5a and increased neutrophil chemiluminescence to zymosan, compared with noninfected patients. A significant difference (P < .05) in chemiluminescence to zymosan between infected and noninfected control patients was observed on day 3 before clinical signs of infectious disease could be detected. There were no infectious complications in ranitidine-treated patients., Conclusion: These results support previous studies on the effect of ranitidine to improve postoperative immunosuppression.

The effect of the histamine-2 receptor antagonist ranitidine (100 mg intravenously every 12 hours for 72 hours) on postoperative serum antibody responses to preoperative immunization with six limit of flocculation tetanus toxoid and six limit of flocculation diphtheria toxoid was assessed in a double-blind, placebo-controlled randomized study in 26 patients undergoing major abdominal surgery. The preoperative antitetanus antibody level was less than 0.1 IU/ml in all patients, and they were inoculated with both antigens 48 hours before surgery. Serum samples for analysis of antitetanus toxoid and antidiphtheria toxoid were drawn before skin incision and on postoperative days 1, 3, 5, 7, 10, 14, 21, and 28. Ranitidine significantly increased the postoperative antibody response to tetanus toxoid, (p less than 0.01) and insignificantly increased that to diphtheria toxoid vaccination (p less than 0.2) compared with placebo.

Multiple myeloma is characterized by an increased susceptibility to infections and to other malignancies. In a double-blind, placebo-controlled study the potential impact of immunomodulation by ranitidine was studied in 20 patients with multiple myeloma. Three patients were untreated, while 17 after previous cytotoxic therapy were in a stable phase of their disease. All were without clinical signs of infections and at that time had not been treated with other immunomodulating agents. The patients were randomized to oral ranitidine 300 mg twice a day for 21 days or placebo, and several immunological parameters related to multiple myeloma were studied. The blood monocyte chemotactic response was improved in patients treated with ranitidine, and superoxide anion production increased from 2.02 nmol/min to 3.86 nmol/min (median values), while it was unchanged in patients given placebo (2.19-2.25 nmol/min) (P less than 0.005 between groups). Among ranitidine-treated patients spontaneous NK cell activity was unchanged, while in vitro interleukin-2- and interferon-alpha-stimulated NK cell activity decreased (P less than 0.03, respectively). As production of oxygen radicals constitutes an important mechanism of monocyte killing activity against microorganisms and probably against malignant cells, it is suggested that ranitidine may be of beneficial impact in the treatment of multiple myeloma.

Twenty-five patients admitted to intensive or high-dependency surgical care units were randomized to receive ranitidine intravenously 50 mg every 6 hours for 8 days or no ranitidine. All had septicemia or intra-abdominal sepsis, with body temperature greater than or equal to 38.5 degrees C for more than 48 hours despite comprehensive medical and/or surgical treatment. Cell-mediated immunity was assessed by skin testing with seven common delayed type hypersensitivity antigens applied on days 1, 4 and 7 and all tests were read at 48 hours, i.e. on days 3, 6 and 9. The ranitidine/non-ranitidine regimen was initiated on day 1 and continued until day 9. Severity of illness was evaluated before and 3, 6 and 8 days after initiating the study, using the APACHE II scoring system. The scores before and during the study were similar in the ranitidine and non-ranitidine groups. Delayed type hypersensitivity improved in patients treated with ranitidine (p less than 0.001), but was unchanged in the untreated group (p greater than 0.7). These observations may suggest potential beneficial effects of ranitidine therapy in patients with trauma-induced immunosuppression.

Cell-mediated immunity was assessed by skin testing with seven delayed-type common antigens in 20 patients undergoing major abdominal surgery and in 20 nonoperative control subjects. The 20 surgical patients were randomized to perioperative ranitidine (50 mg every 6 hours for 72 hours) or no ranitidine. The 20 control subjects received either no ranitidine or ranitidine in the same dosage as the surgical patients. Skin tests were performed 2 days before and 1 day after operation with the same time schedule in the control subjects. Postoperatively, the diameter of the positive skin test area decreased in each of 10 patients without ranitidine (p less than 0.006) but increased in 9 and was unchanged in 1 of the ranitidine-treated patients (p less than 0.01). The skin test changes were similar during the two tests in ranitidine-treated surgical patients and the nonoperative control subjects. Ranitidine did not amplify the response in the nonoperated group. The potential role of histamine blockade in reversal of other aspects of postoperative immunosuppression and reduction in the risk of infection should be explored.

In a randomized study of patients undergoing major elective abdominal surgery, 12 received i.v. ranitidine (50 mg every 6 hours for 72 hours from the skin incision) and 12 had no ranitidine. Cell-mediated immunity was assessed pre- and postoperatively by skin testing with seven common delayed type hypersensitivity (DTH) antigens, and blood drawn immediately before and 24 hours after skin incision was analyzed for spontaneous and in vitro stimulated (IL-2, IFN-alpha or indomethacin) natural killer (NK) cell activity and PHA and PPD-stimulated lymphocyte proliferation. Lymphocyte subsets (helper/inducer-T cells, suppressor/cytotoxic-T cells, Pan-T cells and NK-cells) were counted by flow-cytometry. Perioperative ranitidine diminished the expected postoperative reduction in DTH responses (p less than 0.0001), as well as in spontaneous NK-cell activity (p less than 0.03) and in vitro IL-2 stimulated NK-cell activity (p less than 0.02). Postoperative decrease in helper/inducer-T cell numbers was not significantly lessened (p = 0.07), and ranitidine did not influence the levels of suppressor-T cells. PHA and PPD responses in peripheral blood mononuclear cells were unaltered. The results may suggest potential benefit from ranitidine as regards postoperative infectious complications and recurrence of malignancy.

The influence of perioperative blood transfusion on postoperative depression of cell-mediated immunity (CMI) and the effect of ranitidine on transfusion-induced changes in postoperative CMI were investigated. CMI was assessed preoperatively and postoperatively by skin testing with seven common delayed-type antigens in 83 consecutive patients undergoing major elective abdominal surgery. Sixty-six of these patients were randomly divided into ranitidine or no-ranitidine-treatment groups, and the remaining 17 patients were operated on without ranitidine. Thus, 50 patients were operated on without ranitidine therapy, and whole blood transfusion was given to 24 of these patients. Postoperative skin test response was more reduced in transfused vs nontransfused patients (-57% vs -38%, p less than 0.0001). Fourteen of the 24 patients receiving blood transfusion could be exactly matched to 14 patients not receiving transfusion (age, sex, B-hemoglobin, S-albumin, type and duration of surgery, etc.), which confirmed that a more pronounced reduction in postoperative skin test response was found in transfused patients (-55% vs -31%, p less than 0.0001). Seventeen of the 33 patients treated with perioperative ranitidine, 50 mg intravenously every 6 hours for 72 hours, received perioperative blood transfusion. Eleven of these patients could be matched to 11 transfused patients not receiving perioperative ranitidine. Ranitidine prevented postoperative reduction in skin test response (+6% vs -55%, p less than 0.0001). It is concluded that perioperative transfusion with whole blood amplifies the postoperative impairment in delayed hypersensitivity and that transfusion-induced postoperative impairment in delayed hypersensitivity may be prevented by perioperative ranitidine treatment.