Oestrogen and cyclical progestogen in postmenopausal hormone replacement therapy.

OBJECTIVE: To ascertain the effectiveness, safety and incidence of side effects of a postmenopausal hormone replacement regimen consisting of continuous conjugated equine oestrogens and cyclical medroxyprogesterone acetate given for the first 14 days of each calendar month. DESIGN: A six month, prospective, open label, two centre, outpatient study of continuous Premarin (0.625 mg; Wyeth-Ayerst) and cyclical Provera (10 mg; Upjohn). Dosage adjustment was allowed in one centre. STUDY POPULATION: Seventy-six postmenopausal women in Adelaide and Brisbane. MAIN OUTCOME MEASURES: Menopausal symptom score, serum lipid levels, routine biochemical and haematological indices, endometrial histology and clinical bleeding pattern, blood pressure, weight changes, side effects, withdrawal from the study, compliance and necessary dose adjustment. MAIN RESULTS: Eight women withdrew from the study and nearly 50% experienced some minor side effect. Where dosage adjustment was allowed, almost all side effects were eliminated. Most patients had acceptable regular withdrawal bleeds although some were deemed heavy. There was a statistically highly significant 54% reduction in the menopausal symptoms score at three months and a 62% reduction at six months. Endometrial biopsy at six months showed atrophic or secretory endometrium with no inappropriate proliferation or hyperplasia. Total cholesterol and low density lipoprotein (LDL) cholesterol levels were significantly decreased. The high density lipoprotein (HDL) cholesterol level remained unchanged and triglyceride levels were raised within the normal range. There were no other clinically relevant biochemical, haematological or clinical changes. CONCLUSION: Continuous conjugated equine oestrogens (0.625 mg) and cyclical medroxyprogesterone acetate (10 mg) for the first 14 days of each calendar month proved to be a safe and effective postmenopausal therapy regimen. Initial minor side effects were common but could be readily ameliorated with early follow-up and dose titration.     

Methods for estimating days of hospitalization due to nosocomial infections.

While there is little agreement at the individual patient level of analysis, estimates of mean NI-attributed days of stay for the two methods were essentially the same. The lack of agreement at the individual patient level may reflect fundamental differences in the methods used to derive these estimates: incorporation of noninfected patient data versus exclusive reliance on data from infected patients; and, focus on length of stay rather than the actual care being received. The potential advantages of the AEP-based method include the following: 1) all patients with NI can be included in developing estimates; 2) estimates are based on the care provided rather than simple length of stay differences; 3) data on which to form the NI-day estimates are readily available in the medical record; 4) the AEP is a validated and commonly used utilization review instrument; 5) the AEP-based method has acceptable reliability; 6) this method is designed to provide individual and group estimates of NI-attributed days; 7) because every day of stay is reviewed, additional information is available, which results in greater precision of study of the development, diagnosis, and treatment of the NI relative to the other care that originally brought the patient into the hospital. The AEP-based method for estimating NI-days is a promising alternative to the historical cohort approach. Additional applications of this approach are encouraged to further assess its reliability,validity, and additional information yield.     

Der Weg zur Nachzulassung von Vasopressin und anderen „alten“ Medikamenten

Seeking approval for new indications of unpatented “old” medications is only of limited financial interest to industry. Accordingly, it was difficult to file for approval of vasopressin for use in cardiopulmonary resuscitation. In our own academic study of >1,200 patients with sudden cardiovascular arrest in Germany, Austria, and Switzerland, either the standard medication adrenaline or as an alternative vasopressin was administered. The impressive results with improved overall survival rate led to amendment of European and American guidelines. Aided by the results of this study, an application is now pending on approval of a new indication for vasopressin, for which a positive outcome is expected at the earliest by the end of 2006. This article describes the problems involved in the approval process for medications that have already been on the market for a longer period of time and presents possible ways out of this dilemma.     

A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. The XOMA Sepsis Study Group

OBJECTIVE: To assess the efficacy of adjunctive monoclonal antibody antiendotoxin immunotherapy in patients with gram-negative sepsis. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Thirty-three university-affiliated centers, including Veterans Affairs, community, and municipal hospitals. PATIENTS: Hospitalized adults with signs of gram-negative infection and a systemic septic response. INTERVENTION: Patients were assigned to receive either 2 mg/kg of a murine monoclonal antibody directed against gram-negative endotoxin (E5) or placebo. A second infusion was administered 24 hours later. MAIN OUTCOME MEASURES: Mortality over the 30-day study period, resolution of organ failures, and safety. RESULTS: Four hundred eighty-six patients were enrolled. Three hundred sixteen had confirmed gram-negative sepsis (54% bacteremic, 46% nonbacteremic). The survival difference was not statistically significant for all patients. Among patients with gram-negative sepsis who were not in shock at study entry (n = 137), E5 treatment resulted in significantly greater survival (relative risk, 2.3; P = .01). Resolution of individual organ failures was more frequent among these patients, occurring in 19 (54%) of 35 patients in the E5 group vs eight (30%) of 27 in the placebo group (P = .05). Four reversible allergic reactions occurred among 247 patients (1.6%) receiving E5. No other toxicity was identified. CONCLUSIONS: Treatment with E5 antiendotoxin antibody appears safe. It reduces mortality and enhances the resolution of organ failure among patients with gram-negative sepsis who are not in shock when treated.     

Biological activity of lymphocytotoxic antibodies in Graves' disease and Hashimoto's thyroiditis

Sera of 48 patients with Graves' disease (GD) and 23 with Hashimoto's thyroiditis (HT) were tested for lymphocytotoxic (LCT), granulocytotoxic (GCT) and monocytotoxic (MCT) activity. In GD, 12 patients (25%) had cold-reacting LCT and 13 patients (27%) had warm-reacting LCT. LCT were cytotoxic to both B and T cells but the majority of sera with cold-reacting LCT and eluates from lymphocytes were more cytotoxic to B lymphocytes. Warm-reacting LCT were directed exclusively against B cells. LCT did not correlate with peripheral lymphocyte counts, antithyroglobulin or antimicrosomal antibodies, sex, age, pregnancies, thyroid status or medication. However the mean duration of the disease was 15 months in LCT positive group and 55 months in LCT negative group (p less than 0.01). Weak GCT were found in 8 of 35 sera (23%). Six of 33 sera (18%) contained cold-reacting MCT and 9 (27%) had warm-reacting MCT. Some cytotoxins were directed against several types of cells as evidenced by cytotoxicity of eluates from lymphocytes against PMN and/or monocytes. Of 23 patients with HT, 11 (48%) had cold-reacting LCT. None had warm-reacting LCT. Sera and eluates from lymphocytes showed predominant cytotoxicity toward B cells. No correlation to the presence of antibodies, sex, age, pregnancies, thyroid status or medication was detected. Four of 23 sera had weak cold-reacting GCT, 5 had cold-reacting MCT which killed on average 31% of monocytes and 4 had weak warm-reacting MCT. Twelve of 22 sera from GD and HT had cytotoxic activity against thyroid cells (TCT). TCT correlated with LCT at p less than 0.05.(ABSTRACT TRUNCATED AT 250 WORDS)