Assessment of the relationship between hyperalgesia and peripheral inflammation in magnesium-deficient rats.

Magnesium-deficient rats develop simultaneously a significant lowering of nociceptive threshold and a generalized inflammation. We investigated the relationship between these two phenomena by testing drugs that are able to suppress the inflammation in this model. In weaning rats fed a magnesium-depleted diet for ten days, the nociceptive threshold was assessed by the paw pressure test and the inflammation by a clinical score. A non-steroidal anti-inflammatory drug (piroxicam); antagonists of H1 and H2 receptors (astemizole and cimetidine. respectively); a glucocorticoid (dexamethasone); an inhibitor of mastocyte degranulation (cromoglycate); and estradiol benzoate were used to block the inflammatory response. Dexamethasone and estradiol significantly suppressed the inflammation (p < 0.001 vs control group). Cromoglycate showed a delayed anti-inflammatory effect (p < 0.01 vs control group on D10). The combination of astemizole and cimetidine partially blocked the inflammation process, whereas astemizole and piroxicam were without effect. Regardless of the effect of the test drugs on inflammation, no change in the time course of hyperalgesia was observed. These data support the view that hyperalgesia induced by the magnesium-depleted diet is not a consequence of the inflammatory process.

Drug interactions avoided-a useful indicator of good prescribing practice.

AIMS: To develop an index of quality prescribing in general practice by investigating the incidence of potential drug interactions when medicines were coprescribed within the State supported General Medical Services (GMS) in Ireland. METHODS: We determined an odds ratio (OR), as a measure of the relative risk of being exposed to a potential interaction, comparing the use of the H2-receptor antagonist, cimetidine, with that of the noninteracting agents ranitidine, famotidine and nizatidine in users and nonusers of warfarin, phenytoin and theophylline. RESULTS AND CONCLUSIONS: In 86 510 prescriptions for the H2-receptor antagonists potentially interacting drugs were dispensed to 8188 (9%) patients in the Eastern Health Board Region of the GMS. We found that prescribers were significantly less likely to use cimetidine (OR = 0.20,95% CI 0. 17-0.21, P < 0.001) in those patients who were coprescribed warfarin, suggesting good prescribing practice within the GMS. Similarly there was preferential use of the noninteracting H2-receptor antagonists in patients receiving phenytoin or theophylline and the extent of this selective prescribing was in keeping with the rank order of severity of interaction with these drugs. This novel pharmacological index may be a sensitive marker of good prescribing practice.

Assessment of decisions in the treatment of Helicobacter pylori-related duodenal ulcer: a cost-effectiveness study.

AIMS: Many treatment trials for Helicobacter pylori have been reported but few have evaluated treatment in terms of both cost and effectiveness. It is important to find a therapy with a high eradication rate and low cost, especially in China. The aim of the study is to assess the efficiency of therapy for duodenal ulcers, including ulcer healing, H. pylori eradication and ulcer recurrence. METHODS: Ninety-six consecutive patients with duodenal ulcers and H. pylori infection were randomly allocated into two groups: AMT group (amoxycillin + metronidazole + tagamet); OA group (omeprazole + amoxycillin). Side-effects were recorded during the treatment period. Endoscopic examinations were repeated at the 7th or 8th week to assess ulcer healing. Patients were followed up for 6 months and repeat endoscopy was performed. Ulcer healing rate, H. pylori eradication rate and ulcer recurrence rate were compared. All costs were recorded and a cost-effectiveness analysis was conducted. RESULTS: In the AMT and OA groups, the ulcer healing rate was 83.7 and 93.5%, respectively (P = 0.27). The eradication rate of H. pylori was 65.1 and 69.6%, respectively and was significantly higher in patients with an ulcer diameter < or = 1 cm compared with those with an ulcer diameter > 1 cm, irrespective of treatment group. There was no difference in recurrence rate, duration of pain or the time lost because of the disease. Moderate or severe side-effects were found in 8.9% in AMT group and 6.5% in OA group. The cost of treatment for ulcer healing, H. pylori eradication and reduction in ulcer recurrence were all lower in the AMT group than in the OA group. Sensitivity analysis supported the result that AMT was more cost effective than OA. CONCLUSIONS: The AMT therapy was more effective and less costly than the OA therapy, especially in patients with H. pylori-related duodenal ulcers < 1 cm diameter.

Randomized trial of preoperative cimetidine in patients with colorectal carcinoma with quantitative assessment of tumor-associated lymphocytes.

BACKGROUND: Previous studies have suggested that cimetidine, a histamine-2 receptor antagonist with immunostimulatory effects, may improve survival in patients with colorectal carcinoma. This effect may be apparent by an increase in the number of peritumoral lymphocytes. A prospective, double blind, randomized, placebo-controlled trial of a short course of preoperative treatment with cimetidine in patients with colorectal carcinoma was performed to assess the effect of cimetidine on survival and on the number of peritumoral lymphocytes. METHODS: One hundred and twenty-five patients who were scheduled to undergo elective colon or rectal excision for carcinoma were randomized to receive either placebo or cimetidine preoperatively for 5 days. In addition to standard histopathology, immunohistochemistry and computer video image analysis were used to assess the number of peritumoral lymphocytes in an objective manner. Interim survival analysis according to the Kaplan-Meier method was performed. RESULTS: A trend toward a survival advantage in the group of patients receiving cimetidine (800 mg twice daily) compared with the placebo group was observed (P = 0.20, log rank test) that was most marked in patients with replication error negative tumors (P = 0.04). Similarly, in these two groups there was a trend toward an increase in the number of patients with a conspicuous lymphocytic infiltration (P = 0.10, chi-square test). However, there was no difference in the number of peritumoral lymphocytes as measured by image analysis. CONCLUSIONS: Based on the results of the current study, a short course of preoperative treatment with cimetidine does appear to have an effect on patient survival; however, the exact mechanism is unknown. The failure of this study to demonstrate a clear increase in the local lymphocyte response does not exclude an immunologic mechanism of action.

Therapeutic-interchange program for oral histamine H2-receptor antagonists.

A therapeutic-interchange (TI) program for oral histamine H2-receptor antagonists at a hospital is described. In 1992 the pharmacy and therapeutics committee at a large teaching hospital accepted cimetidine as the preferred oral H2 antagonist. However, the program to promote cimetidine met with little success. The manufacturer of nizatidine then offered the hospital that drug at a reduced cost relative to all other members of the drug class. The committee recommended including nizatidine on the formulary; implementing a TI program so that when an order for an oral H2 antagonist was written nizatidine would be dispensed; deleting cimetidine and ranitidine tablets from the formulary; and retaining cimetidine and ranitidine oral liquid and i.v. formulations. The program was approved by the medical executive committee and was implemented in August 1994. Extensive efforts to inform the pharmacy, medical, and nursing staffs about the program were undertaken, and the pharmacy established mechanisms for monitoring compliance. Two months into the program, 97% of eligible patients were receiving nizatidine. Actual cost savings in the first four months exceeded $40,000. In July 1997 the same program was applied to famotidine, which had replaced nizatidine as the most cost-effective H2 antagonist. A successful TI program for oral H2 antagonists was achieved by gaining physician support for the program, educating providers, monitoring compliance, and responding to changes in drug costs.

Using multiple pharmacoeconomic methods to conduct a cost-effectiveness analysis of histamine H2-receptor antagonists.

A formulary decision at a health care institution was studied by using two pharmacoeconomic methods. A pharmacoeconomic study was undertaken to assess the impact of a 1995 formulary decision to designate cimetidine as the primary histamine H2-receptor antagonist (H2RA) and to restrict the use of famotidine. Consecutive patients receiving either i.v. cimetidine or famotidine for stress ulcer prophylaxis were reviewed during a two-month period in 1997, and information on demographics, dosage and duration of H2RA therapy, admission date, laboratory test values, and adverse drug reactions was collected. Data for 62 patients (43 cimetidine recipients and 19 famotidine recipients) were evaluated. Therapy was categorized as successful or failed, and the data were then evaluated by decision analysis to evaluate the cost-effectiveness of the agents and by multiattribute utility theory (MAUT) to incorporate a humanistic evaluation of the treatments, namely, the number of doses administered and the number of times dosages were changed. The decision tree revealed that the average cost of receiving cimetidine was $82.01 and the average cost of famotidine therapy was $92.45. The MAUT analysis showed that cimetidine was the preferred agent as long as cost was valued at greater than 60% of the decision-making process and efficacy remained equal between the two agents. Two pharmacoeconomic methods lent support to a formulary decision at a health care institution.

Cimetidine in the treatment of acute intermittent porphyria.

Treatment options for AIP remain limited. Although no single therapy has been proven superior in clinical trials, intravenous hemin appears to be more effective than increased carbohydrate intake, and remains the treatment of choice. At usual dosages the average wholesale price of hemin is $120-475 per day (for a patient weighing 70 kg), compared with $2.50 per day for cimetidine. Cimetidine may offer a more cost-effective and easily administered alternative to hemin therapy. The optimal dosage and duration of treatment with cimetidine have not been established and are likely to be patient-specific. Oral doses of 800 mg/d have been used. In addition to its potential for treatment, cimetidine may also have a role in prophylaxis of acute episodes by maintaining a baseline suppression of ALA synthase activity. Until well-designed, controlled clinical trials demonstrate its efficacy and compare it with other treatment options, cimetidine should be reserved for use only after standard treatment modalities have failed.

Promoting use of a preferred histamine H2-receptor antagonist in managed care organizations.

A program to promote generic cimetidine as the preferred histamine H2-receptor antagonist (HRA) in the managed care organizations (MCOs) served by a pharmacy benefit management company is described. A pharmacy benefit management company conducted a literature review to substantiate the therapeutic equivalence of the HRAs and to set conservative criteria for identifying candidates for conversion to oral cimetidine therapy. During the third quarter of 1994, the prescriber for each patient identified was sent a document listing the patient's current HRA therapy, the date of his or her last prescription refill, and the name and telephone number of the dispensing pharmacy. A letter summarized the literature; outlined the criteria used to identify candidate patients; gave the current indications, dosages, and average wholesale prices of the HRAs; and asked the prescriber to switch the patient to generic cimetidine. HRA use in an MCO that participated in the program was compared with HRA use in a nonparticipating MCO for the second quarter of 1994 (the baseline period), the fourth quarter of 1994, and the first quarter of 1995. The nonparticipating MCO showed no change between baseline and 1995 in the proportion of HRA prescriptions accounted for by brand-name and generic cimetidine combined (14% for each period). The average acquisition cost per HRA prescription remained about $75 for each study quarter. In the participating MCO, the proportion of HRA prescriptions accounted for by brand-name plus generic cimetidine increased from 18% at baseline to 39% in the first quarter of 1995. The average acquisition cost per HRA prescription fell from $71 at baseline to $65 in the first quarter of 1995. A program to shift the use of brand-name HRAs to generic cimetidine in MCOs successfully altered prescribing patterns and reduced expenditures for these agents.

Prophylaxis for stress-related gastrointestinal hemorrhage: a cost effectiveness analysis.

OBJECTIVE: To assess the cost-effectiveness of prophylaxis for stress-related gastrointestinal hemorrhage in patients admitted to the intensive care unit. DESIGN: Decision model of the cost and efficacy of sucralfate and cimetidine, two commonly used drugs for prophylaxis of stress-related hemorrhage. Outcome estimates were based on data from published studies. Cost data were based on cost of medications and costs of treatment protocols at our institutions. MEASUREMENTS AND MAIN RESULTS: The marginal cost-effectiveness of prophylaxis, as compare with no prophylaxis, was calculated separately for sucralfate and cimetidine and expressed as cost per bleeding episode averted. An incremental cost-effectiveness analysis was subsequently employed to compare the two agents. Sensitivity analyses of the effects of the major clinical outcomes on the cost per bleeding episode averted were performed. At the base-case assumptions of 6% risk of developing stress-related hemorrhage and 50% risk-reduction due to prophylaxis, the cost of sucralfate was $1,144 per bleeding episode averted. The cost per bleeding episode averted was highly dependent on the risk of hemorrhage and, to a lesser degree, on the efficacy of sucralfate prophylaxis, ranging from a cost per bleeding episode averted of $103,725 for low-risk patients to cost savings for very high-risk patients. The cost per bleeding episode averted increased significantly if the risk of nosocomial pneumonia was included in the analysis. The effect of pneumonia was greater for populations at low risk of hemorrhage. Assuming equal efficacy, the cost per bleeding episode averted of cimetidine was 6.5-fold greater than the cost per bleeding episode averted of sucralfate. CONCLUSIONS: The cost of prophylaxis in patients at low risk of stress-related hemorrhage is substantial, and may be prohibitive. Further research is needed to identify patient populations that are at high risk of developing stress-related hemorrhage, and to determine whether prophylaxis increases the risk of nosocomial pneumonia.

Serum creatinine levels in older adults: relationship with health status and medications.

We aimed to examine the association of serum creatinine with health status and current medications in the population of older adults. We employed a cross-sectional study within an ongoing cohort of 3999 residents of three communities of the Established Populations for Epidemiologic Studies of the Elderly who had venepuncture at the 6-year follow-up when they were aged 71 years and older. Serum creatinine levels, history of diabetes and heart attack, current medications, and blood pressure were measured. Creatinine levels were higher in men than in women, and in blacks than in whites. Higher creatinine levels were observed in persons with a history of diabetes or heart attack, and in those reporting use of cimetidine and diuretic medications. Persons taking frusemide and the potassium-sparing diuretics had higher creatinine levels than those taking thiazides. This study confirms associations of higher creatinine with male sex, older age, black race, history of diabetes and cimetidine use reported from cross-sectional research in younger populations and in smaller, more selected groups of older adults. Longitudinal studies will be necessary to strengthen our understanding of the causes of changes in kidney function in the older population.

The development of cimetidine: 1964-1976. A human story.

There was still controversy regarding the physiology of acid secretion in 1964 when a team at Smith Kline & French Laboratories in England started a project to prove the existence of more than one receptor for histamine and to find a substance capable of blocking the effects not blocked by the commonly used antihistamines. The team was convinced that histamine was the final mediator of acid secretion. After 8 years, James Black and his coworkers published evidence of the first histamine2-receptor antagonist, burimamide. As this substance was not suitable for oral therapy, the research continued. Metiamide was synthesized with promising clinical effects but questionable safety. The final answer was cimetidine (Tagamet), approved in England in November 1976. Cimetidine was a breakthrough in the treatment of peptic ulcers. In this article I focus on the human factors lying behind many of the decisions made during the years of research. Without personal courage under stressful conditions, the H2-receptor antagonists might never have reached the market.

Endoscopic assessment of blood flow in duodenal ulcers.

The importance of blood flow in duodenal ulcer healing is unclear. Endoscopic reflectance spectrophotometry measures the index of oxygen saturation (ISO2), which is significantly correlated with blood flow. In 97 consecutive patients who presented with duodenal ulcer bleeding, the difference in the index of oxygen saturation (delta ISO2: ulcer margin ISO2 minus adjacent mucosa ISO2) was determined during the initial endoscopic examination. Endoscopic examinations were repeated until the ulcers had healed (n = 86). Relative to the adjacent mucosa, 78% of the ulcer margins had increased blood flow (positive delta ISO2) and 22% had decreased blood flow (negative delta ISO2). Stepwise multi-linear regression analysis selected delta ISO2, ulcer size, and stigmata of recent hemorrhage as predictors of delayed healing. A significant negative linear correlation between delta ISO2 and ulcer healing time (r = -0.35, p < 0.001, n = 86) was demonstrated. The scatter in the data precludes prediction of ulcer healing based on delta ISO2 measurement in an individual patient. Multi-variate logistic regression analysis selected concurrent medical illness, duodenal deformity, frequent use of non-steroidal anti-inflammatory drugs, and stigmata of recent hemorrhage as factors significantly associated with delayed (longer than 5 weeks) ulcer healing. The results support the hypothesis that prognostic factors are identifiable at the time of ulcer diagnosis, even in patients who present with bleeding. Blood flow remains an equivocal factor that deserves to be re-studied taking multiple measurements around the ulcer and including a larger number of slow healers.

A pharmacoeconomic analysis of IV H2-receptor antagonist use in 40 hospitals.

The objectives of this study were to determine (1) the expenditures of hospitals for IV histamine2-receptor antagonists (H2-RA), and (2) the cost savings that might be realized if only a single IV H2-RA was purchased for use. Forty hospitals provided data about purchase prices for each IV H2-RA dosage form purchased (cimetidine, ranitidine, and famotidine), the number of each dosage form used during the 12-month study period, purchase price and extent of usage for supplies, labor costs for preparing and administering IV H2-RAs, and IV H2-RA dosage schedules. The study showed that most hospitals were spending more money for IV H2-RAs than necessary given the pricing structures of the three products available to them at the time of this study. Also, that significant cost savings could be realized if a single H2-RA was used exclusively.

Pharmacologic management of herpes zoster and postherpetic neuralgia.

Herpes zoster is an infection caused by reactivation of dormant varicella-zoster virus. The acute course of herpes zoster is generally benign; however, some patients will experience postherpetic neuralgia characterized by severe, relentless, and at times disabling pain that is often refractory to treatment. While herpes zoster responds to acyclovir, cost-benefit considerations limit the drug's usefulness to only a select group. Postherpetic neuralgia requires a holistic approach, including pharmacologic therapy using several different classes of drugs.

[Costs and effectiveness of diagnosis and treatment of patients with dyspepsia, determined with the aid of a computer model]. / Kosten en effectiviteit van diagnostiek en behandeling van patiënten met dyspepsie, bepaald met een computermodel.

A theoretical investigation was carried out to determine whether the use of an antibody test for Helicobacter pylori (HP) and the use of bismuth oxide with optional antibiotics, would be cost effective in the diagnosis and treatment of patients with dyspepsia. With literature data on therapeutic effectiveness a computer simulation was carried out. A quick antibody test reduced the number of gastroscopic investigations necessary. Gastroscopic investigation still had to be carried out for patients suffering from non-HP-related dyspepsia. This strategy not only reduced costs, but enabled the general practitioner to start treating the patient immediately. The treatment of a HP-related gastritis with histamine receptor blockers (cimetidine, ranitidine) proved less effective than treatment with bismuth oxide, and more expensive. The treatment with bismuth oxide combined with antibiotics, the so called triple treatment, proved to be the most effective, however disproportionately more expensive. Although the interpretation of the serological test is not without problems, treating dyspepsia with bismuth oxide, especially when the HP serological test result is positive, is the cheaper option and achieves the required effectiveness.

Economic evaluation of health care technologies.

Despite two decades of developments, economic evaluation of medical therapies is still in its infancy. The first decade was mainly a search for a relevant methodology, a period when it was important to establish that new medical technologies carried not only costs but also economic benefits. The costs-of-illness methodology was the most convenient to use and served well to show that new medical technology produced economic benefits. It was obvious, however, that the method had its limitations, particularly in health care systems devoting more and more resources to the elderly, not an economically active part of the population. For other people also, health per se is more important than health as a human capital that improves work capacity. The studies undertaken in the 1970s were mainly based on epidemiological data and undertaken at arms' length from clinical activities in hospitals and in general practice. At the beginning of the 1980s, it became clear that in order to become more relevant, economic evaluations have to be linked much more closely to the clinical evaluation of new technologies. Clinicians and economists have to work together to produce good and relevant studies. The beginning of the 1980s saw such an increase in collaboration between economists and clinicians, and some important studies were undertaken. These studies were mainly concerned with calculating costs for different clinical actions and determining cost-effectiveness using, for example, number of life-years gained. During the last 5 years, interest has been focused on the problems and opportunities of including quality of life and utility estimates in economic evaluations.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmaco-economic considerations in the long-term management of peptic ulcer disease.

Pharmaco-economic consequences of available therapeutic strategies in the management of duodenal ulcer disease are of increasing importance. Terminology and methodology in economic evaluation need to be clarified: direct and indirect costs of duodenal ulcer disease have to be calculated, and results expressed in terms of efficacy, utility or benefits. The economic analysis then compares costs or cost-effectiveness ratios of various strategies. Macro-economic evaluations conducted in France have shown that the overall cost of duodenal ulcer disease was FF 3.5 billion in 1987 in private practice. Several evaluations have shown that indirect costs accounted for more than 50% of the total expense. From a microeconomic point of view, several studies have been conducted with ranitidine and cimetidine. Our own study has shown that one year of treatment with ranitidine 150 mg/day resulted in a decrease in the use of medical resources (clinic visits, endoscopic investigations, duration of hospital stay) and work days lost, when compared with placebo. This resulted in a smaller cost of the ranitidine strategy (FF 2031 per patient for one year for the community, vs. FF 2823 for the placebo strategy). Similar cost-effectiveness ratios for the ranitidine strategy have been shown in the USA. Costs savings have also been demonstrated during long-term treatment with cimetidine for up to 3 years. Studies performed according to Markov's chain model have shown that the costs of continuous and intermittent treatments are identical, the expenses related to investigations and mortality being greater with the latter. More studies are warranted to evaluate the efficiency of the different strategies used in the treatment of duodenal ulcer disease.(ABSTRACT TRUNCATED AT 250 WORDS)