Postmarketing Surveillance of the Safety of Cyclic Etidronate

To evaluate the safety of cyclic etidronate in routine clinical practice, we obtained information from 550 general practices in the United Kingdom that provide the medical records to the General Practice Research Database. A group of 7977 patients taking cyclic etidronate and two age-, gender-, and practice-matched control groups, one with osteoporosis and one without, were analyzed. For the group taking cyclic etidronate, the average age was 71.6 years and follow-up was 10,328 person-years. Conditions that do not induce osteoporosis generally occurred in these patients at a rate comparable to that in the control groups. The incidence of osteomalacia was low and comparable between patients taking cyclic etidronate and controls with osteoporosis. No medically significant increases in frequency were observed among patients taking cyclic etidronate for a broad group of diseases that may potentially be induced by exposure to the drug. These data support the favorable risk:benefit ratio of cyclic etidronate.     

间断和周期性羟乙膦酸二钠防治绝经后骨质疏松观察

目的：观察羟乙膦酸二钠间断和周期性防治绝经后骨质疏松的临床疗效。方法：７２例腰椎（Ｌ２￣４）骨矿密度（ＢＭＤ）低于本地区２０￣４０岁健康女性均值减１．０标准差的绝经后妇女,双盲随机分为两组各３６例。羟乙膦酸二钠治疗组３６例,给予羟乙膦酸二钠４００ｍｇ／日,连服２周,停药１０周,重复３次共３６周。对照组服安慰剂,程序同治疗组。观察期间两组均每日加服钙剂和维生素Ｄ。试验前后用双能Ｘ线吸收法（ＤＥＸＡ）     

Kynurenine pathway metabolism in patients with osteoporosis after 2 years of drug treatment

1. Metabolism of tryptophan along the oxidative pathway via kynurenine results in the production of quinolinic acid and kynurenic acid, which can act on glutamate receptors in peripheral tissues. We have now measured the concentrations of kynurenine pathway metabolites in the plasma of patients with osteoporosis before treatment with drugs, throughout and after 2 years of treatment with the drugs raloxifene or etidronate. Oxidative stress was assessed by measuring levels of the lipid peroxidation products malondialdehyde and 4-hydroxynonenal. Kynurenines were analysed by HPLC. Bone density was measured using dual-energy X-ray absorptiometry scans. 2. Patients with osteoporosis showed significantly lower baseline levels of 3-hydroxyanthranilic acid compared with healthy controls, but significantly higher levels of anthranilic acid and lipid peroxidation products. After 2 years treatment with etidronate and calcium, we observed significant therapeutic responses quantified by bone densitometric scanning. Significant improvements were not seen in patients treated with raloxifene. 3. In parallel, the levels of 3-hydroxyanthranilic acid, anthranilic acid and lipid peroxidation products were restored to control values by both drug treatments studied and tryptophan levels were increased significantly compared with baseline values. 4. The results suggest that tryptophan metabolism is altered in osteoporosis in a manner that could contribute to the oxidative stress and, thus, to progress of the disease. The oxidative metabolism of tryptophan (the kynurenine pathway) could represent a novel target for the development of new drugs for the treatment of osteoporosis. In addition, we noted that etidronate is a more effective drug than raloxifene, but that the simultaneous use of non-steroidal anti-inflammatory drugs may reduce the efficacy of etidronate.     

The Safety Profile of Fluvoxamine in Elderly Patients

The safety profile of fluvoxamine was assessed in 4843 elderly, mainly depressed patients (65 years or older; range 65 to 97 years) enrolled in worldwide post-marketing studies. This cohort of elderly patients was extracted from a population of 34 587 patients in whom the safety profile of fluvoxamine has been extensively assessed (Wagneret al., 1994). The daily dose of fluvoxamine ranged from less than 50 to 300 mg and the studies were conducted over periods of up to 1 year. The most conservative category was chosen throughout the analysis in situations where more than one category was applicable. Overall, 3250 patients (67·1 per cent) completed the full study period. At least one adverse event was reported by 2228 patients (46·0 per cent), the most frequently affected body systems being the ‘gastrointestinal’ and ‘nervous’ systems, followed by the ‘body as a whole’. Nausea was the most common adverse event. At least one serious adverse event was experienced by 135 patients (2·8 per cent), hospitalization being the most widespread classification (113 patients; 2·3 per cent). The incidence of overall suicidality with fluvoxamine was low. Thus, these findings indicate that fluvoxamine is a well tolerated drug in elderly patients.     

Pharmacokinetics of Bisphosphonates in Rabbits

Abstract: Clodronate, pamidronate and etidronate are commonly used bisphosphonates, which accumulate extensively in arteries and some other tissues. We compared their pharmacokinetics in rabbits with those of tiludronate, the drug newly introduced to clinical use. The ¹⁴C-labelled drugs were given intravenously and plasma drug levels were monitored for up to 24 hr. The dose-related plasma concentrations of tiludronate and etidronate were clearly higher and decreased more slowly than those of clodronate and pamidronate (P<0.001). Already at 5 min., the concentrations of tiludronate and etidronate were higher than those of clodronate and pamidronate (P=0.016). At 24 hr, plasma concentration of tiludronate was 12±6.6%, of etidronate 18±2.5%, of clodronate 0.8±0.2%, and of pamidronate 1.4±0.4% of the dose per body weight. With the same dose (25 mg/kg), absolute AUC_0–24hr for tiludronate and etidronate was 9–11 times larger than for clodronate. AUC_0–24hr for pamidronate (2.5 mg/kg) was 11% of that for clodronate. Plasma clearance of tiludronate and etidronate was 9–15 times slower than that of clodronate and pamidronate. At 24 hr, the mean tissue-to-plasma ratio of tiludronate for aorta was 1.2–1.6. For bone, spleen, liver and kidneys the ratio varied from 5.4 to 52.6. The results suggest that 1) tiludronate and etidronate are removed from plasma much slower than clodronate and pamidronate, and 2) the potential of tiludronate to concentrate in arteries and bone is generally smaller than previously found with the other bisphosphonates.     

Patient awareness of the adverse effects of aspirin and non-aspirin non-steroidal anti-inflammatory drugs

Objective — To determine the extent to which patients reported having been informed about the adverse effects of aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) Method — Questionnaire survey of 26 patients who had suffered an acute gastrointestinal bleed while taking aspirin, and 100 patients who had suffered an acute gastrointestinal bleed while taking a non-aspirin NSAID Setting — Admissions to three United Kingdom hospitals. Patients were identified from endoscopy clinic records Key findings — Five (19 per cent) of the aspirin-treated patients and 45 (45 per cent) of the non-aspirin NSAID-treated patients remembered having been informed of potential adverse effects, an odds ratio of 3.4 (95 per cent confidence interval 1.2–9.8, P<0.05). Five (19 per cent) of the aspirin-treated patients recalled having been advised what to do should adverse symptoms develop, whereas 44 (44 per cent) of the non-aspirin NSAID-treated patients did so, an odds ratio of 3.3 (95 per cent CI 1.2–9.5, P<0.05). Three (12 per cent) of aspirin-treated patients reported having been given an information leaflet, whereas 29 (29 per cent) of non-aspirin NSAID-treated patients did so, an odds ratio of 3.1 (95 per cent CI 0.9–11.2, P=0.08) Conclusion — Our results suggest that aspirin-treated patients are less informed about their drug than are patients taking non-aspirin NSAIDs, in spite of the risk of gastrointestinal bleeding with which aspirin is associated     

Cost-effectiveness of alternative treatments for women with osteoporosis in Canada

BACKGROUND: During the years following menopause, estrogen levels decline leading to accelerated bone loss and an increased risk of osteoporosis and osteoporosis-related fractures. METHODS: Using a Markov model and decision analytic techniques, the long-term costs and outcomes of five treatment and secondary prevention strategies for osteoporosis were compared: 'no intervention', alendronate, etidronate, risedronate, and raloxifene. The base case analysis examined postmenopausal (65 year old) osteoporotic women without prior fracture. Probabilistic sensitivity analysis (PSA) was used to incorporate the impact of parameter uncertainty, and deterministic sensitivity analysis (DSA) was used to compare alternative patient populations and modeling assumptions. Life years and Quality Adjusted Life Years (QALYs) were used as measures of effectiveness. RESULTS: In the base case analysis, risedronate was dominated by etidronate and alendronate. Alendronate and etidronate were projected to have similar costs and QALYs, and the efficiency frontier was represented by 'no intervention', etidronate, alendronate, and raloxifene (Can$32 571, Can$38 623 and Can$114 070 per QALY respectively). Alternative assumptions of raloxifene's impact on CHD and breast cancer, alternative discount rates and alternative patient risk factors (e.g., starting age of therapy, CHD risk, and prior fracture risk) had significant impacts on the overall cost-effectiveness results for both the bisphosphonates and raloxifene. DISCUSSION: Using conventionally quoted benchmarks and compared to no therapy, alendronate, etidronate, and raloxifene would all be considered cost-effective alternatives for treating women with osteoporosis. Potential limitations of this study include the usual caveats and cautions associated with long-term projection models and the fact that not all inputs into the model are Canadian data sources.     

Panic Disorder: Results of a Patient Survey

A series of European Panic Forum meetings presented a unique opportunity to gather data on patients with panic disorder and their treatment. Data were collected on nearly 1200 panic disorder patients by means of a postal questionnaire. The survey gathered data on patient history, presentation, healthcare resources and management. The average patient was in their mid-thirties and had suffered panic disorder for a mean period of almost 5 years. In addition to panic disorder, many patients experienced comorbid depression, agoraphobia or generalized anxiety. Over half the patients were seen by a cardiovascular specialist prior to being seen by a psychiatrist, suggesting poor recognition of panic disorder in general practice. Almost 50 per cent of patients were treated with tricyclic antidepressants (TCAs), almost 60 per cent with selective serotonin reuptake inhibitors (SSRIs) and over 80 per cent with benzodiazepines. Of the drug treatments, SSRIs were considered to be markedly or moderately effective in 68 per cent of patients, compared with 59 per cent receiving benzodiazepines and 58 per cent receiving TCAs. Few patients received psychological interventions. In patients receiving combined treatment with either a benzodiazepine plus an antidepressant, or cognitive-behavioural therapy plus drug therapy, treatment was considered effective in 98–99 per cent of cases. © 1997 John Wiley & Sons, Ltd.     

Efficacy of antiresorptive agents for preventing fractures in Japanese patients with an increased fracture risk: review of the literature

The aim of the present review was to clarify the efficacy of currently available potent antiresorptive agents for preventing fractures in Japanese patients with an increased fracture risk. PubMed was used to search the literature for randomized controlled trials (RCTs), with the following search terms: fracture, etidronate, alendronate, risedronate, minodronate, raloxifene, bazedoxifene and Japan. The inclusion criteria were papers written in English, ≥50 subjects per group and a study period of ≥1 year. Fourteen RCTs met these criteria. The efficacy of antiresorptive agents for preventing vertebral, nonvertebral and hip fractures was investigated. There was evidence that raloxifene reduced the incidence of clinical vertebral fractures, while etidronate, alendronate and minodronate (but not bazedoxifene) reduced the incidence of morphometric vertebral fractures in patients with postmenopausal or involutional osteoporosis. Head-to-head trials showed that alendronate and raloxifene had similar efficacy for preventing vertebral fractures in patients with postmenopausal osteoporosis, while risedronate was not inferior to etidronate for reducing the incidence of morphometric vertebral fractures in patients with involutional osteoporosis. Alendronate reduced the incidence of hip fractures in patients with Parkinson's disease, and risedronate reduced the incidence of nonvertebral fractures and hip fractures in patients with Alzheimer's disease or stroke. In conclusion, the present review confirmed the efficacy of etidronate, minodronate and raloxifene for the prevention of vertebral fractures, the efficacy of alendronate for vertebral and hip fractures, and the efficacy of risedronate for vertebral, nonvertebral and hip fractures in Japanese patients with an increased fracture risk.     

尿Crosslaps的检测和临床应用

目的：探讨尿Crosslaps／Cr的测定对判断甲亢、糖尿病、骨质疏松患者骨代谢状况的临床价值。方法：ELISA检测甲亢、糖尿病、骨质疏松患者的尿Crosslaps／Cr，对骨质疏松患者进行血钙和24h尿钙、骨密度测定并与正常对照组比较。结果：甲亢患者的尿Crosslaps／Cr较正常对照组显著增高。2型糖尿病患者的尿Crosslaps／Cr与正常对照组之间无显著性差异。骨质疏松患者尿Crosslaps／Cr与骨密度无相关性，血钙和24h尿钙都与股骨颈的骨密度呈显著正相关。结论：尿Crosslaps／Cr测定是临床观察代谢性骨病骨转换动态变化的重要指标。     

Antibiotic use in elderly hospital inpatients before and after the introduction of treatment guidelines

Objective — (1) To establish the pattern of antibiotic use in elderly hospital inpatients, using data to draw up antibiotic treatment guidelines; (2) To assess the short-term and longer-term impact of the guidelines on antibiotic use and their acceptability to medical staff. Method — Antibiotic use was assessed in relation to suitability for site and severity of infection, appropriateness of drug choice, outcome of therapy and cost, before, immediately after and 10 months after guideline introduction. Acceptability to medical staff was gauged through a questionnaire. Setting — Geriatric hospital inpatients in long-stay, assessment and GP-supervised wards in the Grampian region of Scotland (phase 1: 324 patients; phase 2: 302 patients; phase 3: 263 patients). Key findings — The antibiotic prescribed was appropriate for site and severity of infection in 92 per cent of patients in phase 1, but was a policy drug in only 56 per cent. After guideline introduction, adherence to policy did not improve, but use of non-policy drugs without identified reason fell from 24 per cent in phase 1 to 13 per cent in phase 3. Adjustment of antibiotic dose for renal function increased from 73 per cent in phase 1 to 86 per cent in phase 3. Duration of treatment for a single infection was significantly reduced in phase 3, but outcome and cost were unchanged after guideline introduction. Medical staff were supportive of the guidelines and felt they had changed their prescribing practices. Conclusion — Antibiotic treatment guidelines did not have a major impact on antibiotic use, although some positive trends were observed. New ways of promoting adherence to guidelines need to be explored.     

An audit of thrombolysis and adjunct drug use in acute myocardial infarction

This study looked at outcomes of acute myocardial infarction patients following administration of streptokinase or alteplase. For 150 patients (155 thrombolytic drug administrations), the median time delay between onset of symptoms and thrombolytic therapy was 3.6 hours. Only 65 per cent of streptokinase-treated patients tolerated the recommended dose, compared with 85 per cent of those treated with alteplase. Aspirin usage was uncommon (9 per cent) prior to admission but rose to 68 per cent on discharge. However, β-blocker usage only increased from 16 per cent to 24 per cent. Parenteral and oral anticoagulant usage was numerically greater in the alteplase group. There was no significant difference between streptokinase or alteplase in the incidence of any observed adverse effects. There were no allergic type reactions in the alteplase group. The incidence of such reactions in the streptokinase group was not affected by pre-treatment with anti-allergy drugs. Patients in both thrombolytic drug groups experienced similar falls in blood pressure but severe hypotension was more common in the streptokinase group.     

Bisphosphonates in bone diseases

Bisphosphonates are a class of drugs which are strongly attracted to the bone where they influence the calcium metabolism, mainly by inhibition of the osteoclast-mediated bone resorption. This property makes these compounds suited for the treatment of several diseases of the bone. In Paget's disease, several bisphosphonates can reduce bone pain and decrease the bone turnover 6070%. Cyclical oral etidronate and daily oral alendronate both proved to reduce the vertebral fracture rate for postmenopausal osteoporotic woman, while most investigated bisphosphonates can increase spinal bone mass in osteoporosis. Bisphosphonates can help lowering serum calcium and reverse skeletal complications in malignancy mediated bone diseases. Oral and intravenous administration of therapeutic doses is relatively safe. In general, gastrointestinal disturbances are described most often and the oldest, least potent, bisphosphonate etidronate can induce osteomalacia. The various characteristics of bisphosphonates: physicochemical, biological, therapeutic and toxicological, vary greatly depending on the structure of the individual bisphosphonate. Even small changes in the structure can lead to enormous differences in potency. Overall, this class of drugs offers several prospects for the future.     

Measuring Outcomes in a Health Service Addiction Clinic

The aim of the study was to identify a method for the routine monitoring of outcomes in a busy city centre health service addiction clinic. The setting for the study was a health service addiction clinic serving a population of seven hundred and fifty thousand people. Study participants were two hundred and thirty consecutive attenders for treatment of alcohol and heroin dependence and misuse. A brief interview to obtain demographic and use data and a short battery of self completion questionnaires measuring dependence, psychological health and social satisfaction were administered at three data collection points. Different methods of follow-up were explored. The instruments used were capable of measuring change in levels of consumption, degrees of dependence, psychological health and social satisfaction over a three month period in over sixty-five per cent of the original sample while over eighty per cent of the original sample were accounted for. It was concluded that routine monitoring of outcomes of a busy National Health Service can provide meaningful clinical data for an acceptable sample of patients within a realistic resource limit.     

二膦酸盐应用于血液透析患者及其对胰岛素样生长因子的影响

目的:观察维持性血液透析(MHD)骨量异常患者使用二膦酸盐治疗前后骨密度和胰岛素样生长因子等骨代谢生化指标的变化。方法:45例骨量异常(骨量减少或骨质疏松)血液透析患者,在补充钙剂和骨化三醇基础上,应用阿仑膦酸钠70mg/周治疗,分别于治疗前和治疗12个月后检测骨密度及血胰岛素样生长因子-1(IGF-1)、Ⅰ型前胶原氨基端前肽(PINP)、I型胶原C末端肽(CTX),记录不良反应。结果:治疗后血IGF-1水平较治疗前升高(P<0.05),髋部(股骨颈、大转子、全髋)骨密度值较治疗前升高(P均<0.01),血PINP、CTX水平较治疗前明显下降(P均<0.01),但腰椎部位骨密度值改变差异无统计学意义(P>0.05),个别患者出现轻度消化道反应。结论:MHD骨量异常患者应用二膦酸盐治疗,可降低骨转换,有效减少骨量丢失,安全性好。二膦酸盐可能通过提高与骨形成密切相关的血IGF-1水平,提高MHD骨量异常患者的骨量。     

Intranasal salmon calcitonin. A review of its pharmacological properties and potential utility in metabolic bone disorders associated with aging.

Salmon calcitonin, a polypeptide hormone secreted by the parafollicular C cells of the thyroid gland, lowers serum calcium levels by decreasing bone resorption and renal tubular calcium reabsorption. An analgesic action, possibly mediated via beta-endorphins, is also evident. In the past, parenteral formulations of salmon calcitonin have been used in the management of metabolic bone disorders, but their routine use has been limited by the inconvenience of this route of administration and by poor tolerability. The development of an intranasal preparation of salmon calcitonin will provide a more convenient means of administering the drug. In clinical trials published to date intranasal salmon calcitonin has been effective and well tolerated in small numbers of recently postmenopausal women at risk of developing osteoporosis, and in patients with established osteoporosis, Paget's disease, or osteoporosis secondary to corticosteroid usage, multiple myeloma or ovariectomy. For periods of up to 2 years the drug reduces bone resorption and improves bone architecture, relieves pain and increases functional status. Further research is needed to confirm longer term efficacy (in particular, effects on fracture rate), optimal dosage schedules and the role of intermittent and combination treatment regimens.     

Cost-effectiveness of alternative treatments for women with osteoporosis in Canada

ABSTRACT

Background: During the years following menopause, estrogen levels decline leading to accelerated bone loss and an increased risk of osteoporosis and osteoporosis-related fractures.

Methods: Using a Markov model and decision analytic techniques, the long-term costs and outcomes of five treatment and secondary prevention strategies for osteoporosis were compared: ‘no intervention’, alendronate, etidronate, risedronate, and raloxifene. The base case analysis examined postmenopausal (65 year old) osteoporotic women without prior fracture. Probabilistic sensitivity analysis (PSA) was used to incorporate the impact of parameter uncertainty, and deterministic sensitivity analysis (DSA) was used to compare alternative patient populations and modeling assumptions. Life years and Quality Adjusted Life Years (QALYs) were used as measures of effectiveness.

Results: In the base case analysis, risedronate was dominated by etidronate and alendronate. Alendronate and etidronate were projected to have similar costs and QALYs, and the efficiency frontier was represented by ‘no intervention’, etidronate, alendronate, and raloxifene (Can$32?571, Can$38?623 and Can$114?070 per QALY respectively). Alternative assumptions of raloxifene's impact on CHD and breast cancer, alternative discount rates and alternative patient risk factors (e.g., starting age of therapy, CHD risk, and prior fracture risk) had significant impacts on the overall cost-effectiveness results for both the bisphosphonates and raloxifene.

Discussion: Using conventionally quoted benchmarks and compared to no therapy, alendronate, etidronate, and raloxifene would all be considered cost-effective alternatives for treating women with osteoporosis. Potential limitations of this study include the usual caveats and cautions associated with long-term projection models and the fact that not all inputs into the model are Canadian data sources.     

Osteoporosis assessment tool for Sunderland city hospitals

Patients prescribed oral steroids are at high risk of developing osteoporosis Discharge medication data was obtained from pharmacy records This study shows that approximately 30 per cent of males at 80, and 60 per cent of females received osteoporosis preventative treatment This osteoporosis assessment tool provides a relatively simple but comprehensive method to inform prescribing within the hospital     

Pharmacokinetics and hemodynamic effects of tiapamil: exercise performance, thallium stress scintigraphy, and radionuclide ventriculography

The pharmacokinetic behavior and hemodynamic effects of tiapamil, a calcium antagonist, were studied in 16 cardiac patients during an eight-day treatment course, giving oral doses of 600 mg daily. The hemodynamic effects were investigated using exercise performance tests, thallium stress scintigraphy, and radionuclide ventriculography. The areas under the plasma concentration-time curve after the final dose were greater than after the first dose for both tiapamil (+53 per cent) and its metabolite (+24 per cent). One possible explanation is that tiapamil undergoes saturable intestinal wall metabolism. Alternatively, like verapamil, it may undergo a saturable hepatic elimination process. The hemodynamic test series showed that, despite increasing the exercise tolerance, tiapamil significantly reduced the rate-pressure product, an index of myocardial oxygen requirement. Regional myocardial perfusion clearly improved. Ventriculography showed a significant increase in ejection fraction (+18 per cent), cardiac index (+12 per cent), and stroke volume index (+19 per cent). At the same time, the measured mean arterial pressure decreased significantly by about 10 per cent and the calculated peripheral vascular resistance, by about 19 per cent.