Clodronate as a Cause of Aminotransferase Elevation

Adverse events (AEs) associated with bisphosphonates are usually gastrointestinal, but elevation of aminotransferases (alanine and aspartate aminotransferase) has also been described in many cases. The frequency of such elevation is, however, poorly investigated. The Probone study is a continuing phase II trial of 610 osteopenic women randomized for 3 years to receive placebo or clodronate at the following clodronate doses: 65 mg, 400 mg and 800 mg daily, and 400 mg for 15 days out of 90 (intermittent group). During the first study year, gastrointestinal AEs were reported by 20–26% of the patients in the five study groups, but no differences appeared between groups. The high-dose clodronate groups (400 mg and 800 mg daily) had no more hepatic side-effects than the low-dose groups, and no serious AE due to liver disease was reported. These higher doses of clodronate caused, however, a mean alanine aminotransferase (ALT) elevation of 5.4–5.8 U (25–24%) which differed significantly from the change in the placebo group (p = 0.002 and p<0.0001, respectively). In those volunteers with initially normal aminotransferase values the risk ratio for an aminotransferase increase to an above-normal value (compared with the placebo group) during the study year was up to 1.8 in the clodronate 400 mg group and up to 2.5 in the clodronate 800 mg group. Among these groups an elevation above the normal limits occurred in up to 11.7% of the volunteers for aspartate aminotransferase (AST) and up to 17.7% for ALT. The respective percentages in the placebo group were 6.2% and 7.2%. All analyzed bilirubin values were normal. We conclude that oral clodronate use may elevate serum aminotransferase levels, and that these enzymes most likely come from the liver. This elevation has also been described for several other bisphosphonates. However, clinically significant liver injury is unlikely. Received: 23 October 1997 / Accepted: 8 January 1999     

Intensive chemotherapy with combinations containing anthracyclines for refractory and relapsing multiple myeloma. Finnish Leukaemia Group

94 patients with refractory multiple myeloma were treated in a multicentre trial with combinations of cytotoxic drugs including anthracyclines. All were refractory to a 5-drug combination containing 3 alkylating agents, vincristine and methylprednisolone (MOCCA). With a combination of epirubicin and iphosphamide a 50% response was achieved in 9% of 22 patients. The response rate after schedule VAP (vincristine, doxorubicin and prednisolone) was 8% of 13 patients and that after schedule VAD (vincristine, doxorubicin and dexamethasone) 20% of 59 patients. The previous chemotherapy had lasted for less than 12 months in 13 cases from among all these patients, and 5 of these (38%) responded. In contrast, there were only 10 responders (12%) among the 81 patients with longer previous chemotherapy.     

Tc-99m labeled leukocytes in imaging of patients with suspected acute abdominal inflammation

One hundred patients with suspected acute abdominal inflammation were imaged at 0.5, 2-3, 4-6, and 24 hours after the administration of Tc-99m HMPAO labeled autologous leukocytes. Scan findings were retrospectively compared with final diagnosis, serum C-reactive protein (CRP), and antibiotic treatment. Clinical findings were confirmed with surgery, barium enema, or sigmoidoscopy in 61 patients, and diagnosis was based only on clinical findings in 13 patients. In 26 patients, symptoms subsided before a final diagnosis was made. Tc-99m leukocyte images were positive in 45 of the 61 patients with a confirmed diagnosis, including all patients with acute cholecystitis (N = 4) and inflammatory bowel disease (N = 8). They were also positive in nineteen out of 25 patients who had acute colonic diverticulitis and in 6 out of 7 who had intra-abdominal abscesses. Abnormal activity was found in patients with colonic carcinoma, small bowel infarction, and acute appendicitis. Abnormal activity was visualized in 0.5-hour images in all but one of the positive cases. With the exception of two postoperative cases, malignant lymphoma, and a liver abscess, a CRP level of greater than 75 mg/L was associated with positive image findings. Antibiotic treatment did not affect imaging findings. Imaging with Tc-99m labeled leukocytes appears to be valuable for detecting and localizing abdominal inflammation, and three-phase imaging during the first 4-6 hours is recommended. In some cases, 24-hour images may be useful for distinguishing small bowel from large bowel inflammation.     

Neurotensin and cholecystokinin microinjected into the ventral tegmental area modulate microdialysate concentrations of dopamine and metabolites in the posterior nucleus accumbens

Neurotensin and cholecystokinin, neuropeptides which coexist with dopamine in many ventral tegmental neurons, were microinjected into the ventral tegmental area during in vivo microdialysis in the posterior nucleus accumbens. Neurotensin significantly elevated concentrations of dopamine and its metabolites at doses of 10 pmol, 1 nmol, and 10 nmol, while cholecystokinin significantly elevated dopamine metabolite concentrations only at a dose of 10 nmol. These data suggest that neurotensin potently mediates the release of dopamine from the mesolimbic pathway via direct actions on the cell body.     

Chronic bronchitis and chronic obstructive pulmonary disease: Finnish National Guidelines for Prevention and Treatment 1998-2007.

1. A national recommendation for the promotion of prevention, treatment and rehabilitation in relation to chronic bronchitis and COPD from 1998 to 2007 has been prepared on the basis of extensive collaboration by order of the Ministry of Social Affairs and Health. The Programme needs to be revised as necessary, because of rapid developments in medical knowledge, and in drug therapy in particular. 2. COPD is a disease characterized by slowly progressing, irreversible airways obstruction. Over 5% of the population suffer from symptomatic forms of the disease. It is estimated that a further 5% of the population may suffer from latent COPD. Most patients (75%) suffer from mild forms of the disease. The disease is often preceded by chronic bronchitis. A total of 400,000 Finns suffer from chronic bronchitis or COPD. Occurrence of these diseases in future will be particularly affected by decreased smoking by men, increased smoking by the young and by women, and aging of the population. 3. In 1997, the annual treatment costs of chronic bronchitis and COPD were estimated to be FIM 1.5 thousand million, total costs FIM 5 thousand million. Without intensification of measures to prevent and treat the diseases, costs will rise significantly. Costs arising from severe COPD (5% of patients with COPD) account for roughly 65% of costs overall and are primarily related to hospitalizations. 4. The goals of the Programme for the Prevention and Treatment of Chronic Bronchitis and COPD are as follows: (a) to decrease the incidence of chronic bronchitis; (b) to ensure that as many patients as possible with chronic bronchitis recover; (c) to maintain capacity for work and functional capacity of patients with COPD; (d) to reduce the percentage of patients with moderate to severe COPD; (e) to decrease the number of hospitalization days of COPD patients by 25% overall; and (f) to decrease annual costs per patient. 5. The following means are suggested for achieving the goals: (a) reduction in smoking; (b) reduction in work-related and outdoor air pollutants and improvement of quality of indoor air; (c) enhancement of knowledge about risk factors and treatment of the diseases is in key groups; (d) promotion of early diagnosis and active treatment, in smokers in particular; (e) improvement of guided self-care; (f) early commencement of rehabilitation, individual planning and implementation, primarily as an element in treatment; and (g) encouragement of scientific research. 6. COPD and exacerbation of its symptoms can be prevented through choices relating to life habits, such as not smoking, maintaining good general condition, and protection against exposure to dusts. The Programme gives examples of such measures and appeals to various authorities and voluntary organizations to increase their cooperation. Preventive methods should be individualized, and based on due consideration. 7. Chronic bronchitis and COPD should be diagnosed at early stages, and treated appropriately from the outset. Treatment consists of: (a) treatment according to causes, such as stopping smoking and work hygiene; (b) early rehabilitation such as patient education and guided self-care: (c) drug therapy; (d) hospital treatment; and (e) rehabilitation. 8. The hierarchy of referrals in the treatment of COPD should be revised to accord a greater role to the primary health care sector. Good exchanges of information and cooperation between the primary health care and specialized medical care sectors will all be necessary if this hierarchial model is to have the desired effect. 9. Hospital districts and health centres should ensure that different levels of the health-care system are capable of fulfilling the tasks assigned to them appropriately. One specialist in each hospital district should be given charge of prevention and assembly of know-how relating to treatment, and of quality of treatment at regional level. (ABSTRACT TRUNCATED)     

Intertrochanteric varus osteotomy for Perthes' disease: Radiographic changes after 2-16-year follow-up of 126 hips

We analyzed various prognostic factors in 112 children operated on for Perthes' disease (Catterall's groups II-IV); special attention was paid to acetabular changes and postoperative containment. The radio-graphic results of 126 intertrochanteric femoral varus osteotomies were analyzed 2-16 years postoperatively. Catterall's grouping or head-at-risk phenomenon, bicompartmentalization of the acetabulum, and preoperative subluxation of the femoral head did not correlate with the result. The result was worse in cases operated on in the healing phase of the disease and in patients operated on at the age of 9 years or older. The strongest prognostic factor was containment of the femoral head after osteotomy.     

Methodological variation in systolic time intervals

Summary. Systolic time intervals (STI) were recorded six times in 12 male students. All 72 recordings were measured twice by a physician and once by two nurses. By comparing these measurements an intra- and interobserver (= methodological) variation was obtained. For measured parameters (QS₂- interval and LVET) variation was less than 2%. For calculated parameters the variation was larger, but did not reach the level of statistical significance. Methodological variation was smaller than physiologic variation. The internal consistency was almost perfect for measured parameters and only slightly worse for calculated parameters.     

Retinopathy predicts cardiovascular mortality in type 2 diabetic men and women

OBJECTIVE: To investigate the association of retinopathy with the risk of all-cause, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality in type 2 diabetic subjects in a population-based 18-year follow-up study with particular emphasis on sex differences. RESEARCH DESIGN AND METHODS: Our study cohort comprised 425 Finnish type 2 diabetic men and 399 type 2 diabetic women who were free of CVD at baseline. The findings were classified based on standardized clinical ophthalmoscopy to categories of no retinopathy, background retinopathy, and proliferative retinopathy. The study end points were all-cause, CVD, and CHD mortality. RESULTS: Adjusted Cox model hazard ratios (95% CIs) of all-cause, CVD, and CHD mortality in men were 1.34 (0.98-1.83), 1.30 (0.86-1.96), and 1.18 (0.74-1.89), respectively, for background retinopathy and 3.05 (1.70-5.45), 3.32 (1.61-6.78), and 2.54 (1.07-6.04), respectively, for proliferative retinopathy and in women 1.61 (1.17-2.22), 1.71 (1.17-2.51), and 1.79 (1.13-2.85), respectively, for background retinopathy and 2.92 (1.41-6.06), 3.17 (1.38-7.30), and 4.98 (2.06-12.06), respectively, for proliferative retinopathy. CONCLUSIONS: Proliferative retinopathy in both sexes and background retinopathy in women predicted all-cause, CVD, and CHD death. These associations were independent of current smoking, hypertension, total cholesterol, HDL cholesterol, glycemic control of diabetes, duration of diabetes, and proteinuria. This suggests the presence of common background pathways for diabetic microvascular and macrovascular disease other than those included in the conventional risk assessment of CVD. The sex difference observed in the association of background retinopathy with macrovascular disease warrants closer examination.     

Exercise alters the pharmacokinetics of midazolam.

Six healthy volunteers received 15 mg midazolam, 50 mg ephedrine, or placebo orally before a 50-minute aerobic treadmill exercise and in a control session. Plasma drug concentrations for pharmacokinetic calculations were estimated from samples drawn up to 24 hours after drug intake. Heart rate, blood pressure, critical flicker fusion test, Maddox wing test, and visual analog scales relating to mood and feelings of tiredness were included in the sessions as pharmacodynamic measures. These tests were made at 35, 55, and 75 minutes and at 2, 2 1/2, 3 1/2, and 5 hours after drug intake. Exercise impaired the absorption of midazolam and counteracted the midazolam-induced decrement in flicker fusion threshold. Whether the effect on flicker fusion was caused mainly by the pharmacokinetic changes or by a general alerting effect of exercise cannot be verified by this experiment. The kinetics of ephedrine was not affected by exercise, but exercise enhanced the tachycardic response to ephedrine and abolished its pressor effect.