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Objective: The aim of this project was to assess whether rural pharmacist involvement in the management of patients receiving warfarin has the potential to lead to safer and more effective anticoagulation, and is valued and welcomed by patients and their general practitioners (GPs)., Methods: A convenience sample of rural pharmacists was trained in the use of the CoaguChek S International Normalized Ratio (INR) monitor and then conducted pharmacy-based testing for approximately 3 months. Two types of testing were performed in the pharmacy: (i) comparison testing was defined as pharmacy-based tests taken within 4 h of conventional laboratory testing or (ii) additional testing, which was a pharmacy-based test with no direct comparison laboratory test taken. Pharmacists, GPs and patients completed anonymous satisfaction surveys after the completion of the pharmacy-based testing., Results: Pharmacists from 16 rural pharmacies were trained to use the CoaguChek S monitor. During the trial period, 518 INR tests were performed in the pharmacies on 137 different patients. A total of 120 tests were evaluated against results from laboratory testing. The pharmacy-based INR values were significantly correlated with the laboratory INR values (mean of 2.32+/-0.77 and 2.32+/-0.59 respectively; r=0.88, P<0.0001). A total of 398 additional pharmacy-based tests were conducted in the pharmacy and 8.5% of the additional tests resulted in a subsequent dosage change. The monitoring was well received by pharmacists, GPs and patients., Conclusions: The results of the trial were very positive. The CoaguChek S monitor in pharmacy-based testing performed accurately compared with conventional laboratory testing. Further research needs to be conducted on the impact of community pharmacy-conducted INR monitoring on patient care and outcomes.

Background: Despite evidence that antithrombotics are effective in reducing the risk of stroke in atrial fibrillation (AF), they remain underused., Objective: To perform a controlled trial of a comprehensive educational program promoting the rational prescribing of antithrombotics for stroke prevention in AF., Methods: The intervention was conducted in Southern Tasmania, Australia, using Northern Tasmania as a control area. General practitioners were sent locally produced guidelines on stroke risk stratification and antithrombotic drug use in AF, which were followed by academic detailing visits. Outcomes were measured using evaluation feedback from the general practitioners, and drug utilization data were provided by a series of patients presenting to the hospital with an admission diagnosis of AF and dispensing of antithrombotic therapy under the Australian Pharmaceutical Benefits Scheme., Results: During the educational intervention, 272 guidelines were mailed and, subsequently, 162 general practitioners were visited and the guidelines discussed. Hospital admission data before and after the intervention revealed a significant increase in the use of warfarin in patients at high risk of stroke (33% vs 46% of eligible patients; p < 0.05). Analysis of prescription data for warfarin also indicated that the increase in use of warfarin within the intervention region was significantly greater than for the control region (p < 0.001)., Conclusions: The educational program described here led to a significant increase in the prescribing of warfarin for stroke prevention in patients with AF.

Objectives: A number of studies have reported that the risk of bleeding associated with warfarin is highest early in the course of therapy. This study examined the effect of a programme focused on the transition of newly anticoagulated patients from hospital to the community., Design: Open-label randomized controlled trial., Setting: Home-based follow-up of patients discharged from acute care hospital in southern Tasmania, Australia., Subjects: A total of 128 patients initiated on warfarin in hospital and subsequently discharged to general practitioner (GP) care were enrolled in the study. Sixty were randomized to home monitoring (HM) and 68 received usual care (UC)., Interventions: HM patients received a home-visit by the project pharmacist and point-of-care international normalized ratio (INR) testing on alternate days on 4 occasions, with the initial visit two days after discharge. The UC group was solely managed by the GP and only received a visit 8 days after discharge to determine anticoagulant control., Results: At discharge, 42% of the HM group and 45% of the UC group had a therapeutic INR. At day 8, 67% of the HM patients had a therapeutic INR, compared with 42% of UC patients (P < 0.002). In addition, 26% of UC patients had a high INR, compared with only 4% of HM patients. Bleeding events were assessed 3 months after discharge and occurred in 15% of HM patients, compared with 36% of the UC group (P < 0.01)., Conclusions: This programme improved the initiation of warfarin therapy and resulted in a significant decrease in haemorrhagic complications in the first 3 months of therapy.

Objective: To compare the accuracy and clinical usefulness of the near-patient testing CoaguChek S INR monitor in rural medical practice. DESIGN, SETTING AND MAIN OUTCOME MEASURES: General practices were identified through Australian university departments of rural health. Study investigators trained general practitioners and/or practice nurses in the use of the CoaguChek S INR monitor. General practices obtained a fingerprick sample for testing with the INR monitor to compare with conventional pathology testing for accuracy. An evaluation questionnaire was administered to users of the machine to assess ease of use and clinical usefulness., Results: A total of 169 patients from 15 general practice sites provided 401 paired (CoaguChek S and laboratory) INR results. The CoaguChek S was found to be accurate when compared to laboratory INR (r = 0.89), despite complicating variables such as multiple users of the monitor and multiple laboratories used for comparison with the CoaguChek S INR. Overall, 88% of dual INR measurements were within 0.5 INR units of each other. For laboratory INR /= 3.6, 97%, 90% and 57% of readings were within 0.5 INR units, respectively. Clinical agreement occurred 93% and 90% of the time against published expanded and narrow criteria, respectively., Conclusions: The routine use of near-patient testing, with appropriate training and quality assurance programs, has the potential to increase the safety and efficacy of warfarin therapy in rural and remote communities.

Objective: To evaluate a pharmacist-conducted educational and monitoring programme, designed to promote dietary and lifestyle modification and compliance with lipid-lowering drug therapy, for patients with dyslipidaemia., Methods: This was a prospective, randomized, controlled study. The participants were 94 adults, with 81 completing the study (intervention group: 39; control group: 42), with a cardiovascular-related diagnosis and discharged from hospital, between April and October 2001, on lipid-lowering drug therapy. Patients in the intervention group were visited at home monthly by a pharmacist, who educated the patients on the goals of lipid-lowering treatment and the importance of lifestyle issues in dyslipidaemia and compliance with therapy, assessed patients for drug-related problems, and measured total blood cholesterol levels using point-of-care testing. Patients in the control group received standard medical care. The main outcome measure was total blood cholesterol levels after 6 months, and an evaluation of patient and general practitioner satisfaction with the programme., Results: There was no significant difference in baseline total blood cholesterol levels between the two groups. The reduction over the course of the study in cholesterol levels within the intervention group was statistically significant (4.9 +/- 0.7 to 4.4 +/- 0.6, P<0.005), whereas there was no change within the control group (P=0.26). At follow-up, 44% of the intervention group patients and 24% of the control group patients had cholesterol levels below 4.0 mmol/L (P=0.06). The reduction in total cholesterol in the intervention group should translate to an expected 21% reduction in cardiovascular mortality risk and a 16% reduction in total mortality risk--more than twice the risk reduction achieved in the control group. In addition, the programme was very well received by the patients and their general practitioners, by satisfaction questionnaire., Conclusion: A pharmacist-conducted educational and monitoring intervention improved the outcomes of lipid-lowering drug therapy.

The accuracy and reproducibility of the CoaguChek S, and its clinical agreement with conventional laboratory international normalized ratio (INR) determination, were evaluated in an outpatient anticoagulation clinic setting. Forty-three patients provided 248 paired INR measurements for analysis. The paired results were highly correlated (r = 0.90). The mean coefficient of variation for the CoaguChek S for a random sample of 21 patients with three repeated tests each, was 4%. Clinical applicability was also measured by discrepant INR values, as defined in the literature by expanded and narrow agreement, and by INR values resulting in a different clinical decision by a blinded haematology registrar. Expanded agreement and narrow agreement between the two INR values occurred 90 and 88% of the time, respectively. The stricter criteria set down by the clinician resulted in 73% of paired results producing the same dosage decision. The CoaguChek S displayed good correlation with laboratory determination of INR and compared relatively well with expanded and narrow clinical agreement criteria.

Aim: Guidelines for the management of patients with chronic heart failure have undergone change in recent years, with beta-blockers and spironolactone shown to reduce mortality when added to angiotensin converting enzyme (ACE) inhibitors, diuretics and digoxin. The aim of this study was to examine the therapeutic management of heart failure in patients admitted to Tasmania's three major public hospitals, with an assessment of the appropriateness of the therapy according to contemporary published guidelines., Methods: An extensive range of clinical and demographic data was retrospectively extracted from the medical records of consecutive adult patients admitted to the medical wards of the hospitals with heart failure, either as a primary diagnosis or as a comorbidity, during a 6-month period in late 1999-early 2001., Results: The 450 patients (57% females) had a mean age of 77.8 +/- 10.2 years, and were being treated with a median of seven drugs on hospital admission. The percentages of patients being treated with the major drugs of interest were: ACE inhibitors (50%), beta-blockers (22%), spironolactone (15%), digoxin (24%), loop diuretics (65%) and angiotensin-II receptor antagonists (8%). Almost 10% were taking a non-steroidal anti-inflammatory agent. Less than one-half the patients who were receiving an ACE inhibitor were taking a target dose for heart failure. There were no significant differences in the pattern of drug use between the three hospitals. Underuse of heart failure medications was most pronounced in women and elderly patients., Conclusions: The data suggest that current guidelines for the treatment of heart failure are still not being reflected in clinical practice. The relatively low use of drugs shown to improve survival in heart failure is of concern and warrants educational intervention.

Objective: To examine the use of ipratropium bromide in adults with acute exacerbation of either asthma or chronic obstructive pulmonary disease (COPD) during admission and at discharge from 3 teaching hospitals., Methods: An extensive range of clinical and demographic data was retrospectively extracted from the medical records of consecutive patients aged >/=12 years admitted to the medical wards of the hospitals during 1999-2001 with acute exacerbations of asthma or COPD, either as a primary diagnosis or as a major comorbidity., Results: Data were gathered for 302 patients (97 with asthma, 205 with COPD). Almost 90% of all patients received ipratropium bromide during their hospital admission. The indication for using ipratropium bromide during hospitalization was considered appropriate in 84% of the asthma patients and 68% of the COPD patients. Over 20% of the patients with asthma had been using ipratropium bromide prior to the hospital admission, and almost one-third of the patients with asthma were discharged with ipratropium bromide, even though its role in chronic asthma is limited. More than 90% of the patients received nebulized drug therapy during their hospital stay, with 41% being prescribed nebulized therapy at discharge. This was often considered inappropriate, given that >50% of all patients had been using inhaler devices and nebulizers concurrently while hospitalized., Conclusions: In the majority of cases, ipratropium bromide had been used during hospitalization in accordance with guidelines for the management of acute exacerbations of asthma or COPD. However, there was also evidence of potentially inappropriate prolonged use of the agent in the community setting, particularly for asthma. Also of concern was the relatively high use of nebulized drug therapy when delivery via other means was appropriate.

Aims: To assess the attitudes of Australian doctors towards the use of antithrombotic drug therapy for stroke prevention in patients with non-valvular atrial fibrillation (AF), and investigate the barriers to prescribing warfarin., Methods: A postal survey was undertaken among approximately 10% of all registered general practitioners (GPs), cardiologists and physicians in Australia. The anonymous questionnaire used case scenarios to assess doctors' knowledge of current guidelines for the therapeutic management of AF and sought opinions on potential barriers to the use of anticoagulation., Results: Completed questionnaires were received from 711 doctors (30% response rate). The GPs performed better than the cardiologists and other specialists in estimating the risk of stroke in case scenarios. However, the cardiologists were more likely to select the recommended treatment, with GPs being more hesitant to use anticoagulation and tending to underestimate its reported benefit for stroke prevention in non-valvular AF. The GPs were also more likely to overestimate the reported risk of major bleeds with warfarin. In contrast, over one-third of the cardiologists went as far as to give warfarin to a low-risk patient and they were more likely to overestimate the reported benefit of aspirin and warfarin in AF. Only half the doctors correctly classified a patient without a previous stroke (but with other risk factors) as being at high risk. Increased experience as a registered medical practitioner was generally related to a poorer performance on classifying patients according to the risk of stroke. The principal barriers to the use of anticoagulation were nominated as: (i) active gastrointestinal bleeding, (ii) previous intracranial haemorrhage, (iii) alcoholism, (iv) a history of daily falls, (v) liver disease, (vi) severe anaemia and (vii) concurrent use of non-steroidal anti-inflammatory drugs., Conclusion: There is scope for improvement in doctors' knowledge about the appropriate use of antithrombotic drug therapy in non-valvular AF and awareness of the results of recent clinical trials. Compilation and dissemination of clear guidelines and focused education on some of the other risk factors (apart from previous stroke or transient ischaemic attacks) in patients with non-valvular

Background: The benefits of antithrombotic therapy in chronic atrial fibrillation (AF) have been established in clinical trials, but there is a paucity of data on outcomes in practice., Aims: The objective was to establish a large ongoing database of patients with non-valvular AF, to enable the accurate determination of clinical outcomes., Methods: A retrospective review of the medical records for consecutive patients who had AF documented on electrocardiogram at the major teaching hospital in Tasmania between 1 January 1997 and 30 June 1999 was performed. An extensive range of demographic and clinical variables was recorded for all patients with chronic or paroxysmal non-valvular AF., Results: The 505 patients (60% males) included in the database had a median age of 76 years. According to risk stratification criteria, 79% of the patients with previously diagnosed chronic or paroxysmal AF had a high risk of developing stroke at the time of admission to hospital care. However, only one-third (34%) of these patients were receiving warfarin (or warfarin plus aspirin), with almost one-quarter (24%) receiving no antithrombotic agent. The annual incidence of ischaemic strokes was 3.4% (1.5-6.4%; 95% CI) when taking warfarin, compared to 7.0% (5.2-9.4%) for patients not taking warfarin and 7.8% (5.4-11.1%) for patients taking aspirin. The annual incidence of bleeding complications in patients taking warfarin was 14.2% (10.0-19.5%) overall and 3.4% (1.5-6.4%) for major bleeds. In patients not taking warfarin, the overall annual incidence of bleeds was 8.4% (6.3-10.9%) and 3.9% (2.5-5.7%) for major bleeds., Conclusions: Warfarin is underused in patients with AF. In clinical practice, warfarin confers a similar stroke risk reduction to that observed in trials, with an increase in incidence of only minor bleeding complications. Aspirin did not appear to reduce the risk of stroke.

Background: Previous studies of adverse drug events (ADE) as a cause of hospital admission in the elderly have often been limited in their ability to assess fully the impact and potential for prevention because they either did not include all categories of ADE and/or did not assess severity and preventability., Aims: To assess the frequency, severity and preventability of ADE causing emergency medical admissions in the elderly., Methods: Cross-sectional survey of 219 patients aged 75 years and over who were consecutive unplanned admissions to acute medical units of the Royal Hobart Hospital in an 8-week period during August and September 1998., Results: Seventy-three of 240 (30.4%) admissions may have been a result of ADE. Patients admitted because of ADE were taking more drugs than those admitted for other reasons. Most ADE were adverse drug reactions to a single (46%) or multiple drugs (25%). Non-compliance, omission or cessation of indicated treatment accounted collectively for 26% of admissions. Of all ADE admissions 53.4% were considered definitely preventable. The commonest causative drugs were cardiovascular drugs (48.4%), and the commonest manifestations were falls and postural hypotension (24.1%), heart failure (16.9%) and delirium (14.5%). ADE categories in which a high proportion of admissions was both severe and definitely preventable were non-compliance and omission of indicated treatment., Conclusions: Adverse drug events are a common preventable cause of unplanned medical admissions in the elderly. Non-compliance and omission of indicated treatment are causes of ADE-related admissions that are both preventable and frequently associated with severe ADE.

Background: Recent studies have revealed considerable scope for improvement in preventing postoperative venous thromboembolism. This project comprised a baseline assessment of the use of preventive measures within the Royal Hobart Hospital, followed by the implementation and evaluation of an educational program directed at hospital staff., Aim: To determine whether the Royal Hobart Hospital's guidelines for the prophylaxis of postoperative venous thromboembolism were being utilized effectively and, if necessary, attempt to improve use of the guidelines through an educational programme., Methods: Data were collected retrospectively from the medical records of 250 surgical patients undergoing a procedure during February 1997. Patients were classified as being at a low, medium or high risk of venous thromboembolism using two sets of criteria. The percentage of patients receiving the appropriate prophylaxis was determined. An educational programme to promote the hospital's guidelines for the prophylaxis of postoperative venous thromboembolism was then implemented. Included were presentations to staff, posters placed throughout the hospital and the wide distribution of the results and a glossy card showing the hospital's guidelines. Follow-up data were subsequently collected from another 250 surgical patients., Results: Only 59% of patients received appropriate prophylaxis according to the hospital's approved guidelines, with little change when those patients with possible contraindications to thromboprophylaxis were excluded. When those patients at a high risk of venous thromboembolism were examined, only 25% were prescribed the recommended preventive measures. There was no difference between elective versus emergency surgery and the use of appropriate prophylaxis. Following the implementation of the educational programme, data collection from another 250 surgical patients revealed a significant increase (P < 0.05 by chi-square test) in the level of appropriate thromboprophylaxis to 70% of patients, with 77% of the high-risk patients being prescribed the recommended preventive measures., Conclusions: A pharmacy-based educational intervention significantly improved adherence to the hospital's guidelines for the prophylaxis of postoperative venous thromboembolism.

Background: Commonly used drugs for type 2 diabetes are not ideal. The sulphonylureas, especially potent and long-acting agents such as glibenclamide, can induce hypoglycaemia, while metformin carries the risk of lactic acidosis., Aim: To review the management of type 2 diabetes at the major teaching hospital in Tasmania, Australia, principally to determine the extent of use of glibenclamide and metformin in the elderly and patients where published contraindications are present., Methods: A retrospective review of the medical records for 150 consecutive patients with type 2 diabetes admitted to the hospital in mid-1997, was performed. An extensive range of demographic and clinical variables was recorded for each patient. These included the duration of type 2 diabetes, the presence of other medical conditions, medication history, presence of any contraindications to the use of metformin or sulphonylureas, biochemical measures of diabetic control, and the presence of any diabetic complications., Results: The mean (+/-SD) age of the 150 patients included in the study was 70.1+/-11.8 years. The mean body mass index was 28.7+/-6.2 kg/m2 and the mean recent HbA1c level was 86+/-21%; only 24.7% of patients had a HbA1c level of 7% or lower. Of the 45 patients using glibenclamide, 40 (88.9%) had one or more risk factors for hypoglycaemia: over 65 years of age, renal impairment, or cognitive impairment and living alone. The study also found an extensive use of metformin in patients with contraindications and at highest risk of developing lactic acidosis. Sixty-six out of 70 patients (94%) using metformin had at least one contraindication according to the manufacturer's prescribing information, 57% of patients had two or three contraindications and 14% of patients had more than three contraindications. More than 20% of the patients had a renal function below published exclusion criteria., Conclusions: There was evidence of over-utilization of metformin and glibenclamide in type 2 diabetes patients most at risk of adverse reactions. Insulin therapy could be a safer and more effective management strategy in many of these patients.

Background: The important prophylactic role of antithrombotic therapy against stroke in nonrheumatic atrial fibrillation (AF) has been clearly established in recent clinical trials. There have been suggestions, however, that practice has been slow to change in light of the findings of these trials., Aim: To review cases of AF at the major teaching hospital in Tasmania, Australia, to determine whether the recommendations from the results of the trials had been translated into local clinical practice., Methods: A retrospective review of the medical records for consecutive patients who had AF documented on ECG between 1 January and 30 June 1997 was performed. An extensive range of demographic and clinical variables were recorded for patients with chronic or paroxysmal nonrheumatic AF. These included antithrombotic and other drug therapy at admission and discharge from hospital care, risk factors for stroke, contraindications to antithrombotic use, and incidents of ischaemic stroke and bleeding complications that occurred during the period from January 1996 up to 3 months after the hospital admission that was studied., Results: The 228 patients included in the study had a mean (+/-SD) age of 75.3+/-10.9 years. Sixty-eight per cent had chronic AF and 32% had paroxysmal AF. According to two risk stratification criteria, 91% and 86% of the patients with previously diagnosed chronic or paroxysmal nonrheumatic AF (n=186) had a high risk of developing stroke at the time of admission to hospital care. However, less than one-third of these patients were receiving warfarin (or warfarin plus aspirin), with almost another one-third receiving no antithrombotic agent. Of those who were not taking warfarin, about 60% had no apparent contraindication to warfarin. For those high risk patients who had a possible contraindication to warfarin, only approximately one-third had been prescribed aspirin. Only a slight increase in the use of antithrombotic agents had occurred by the time of discharge from hospital care. The majority of international normalized ratio (INR) values on admission for patients who had been taking warfarin were subtherapeutic. The estimated annual incidence of bleeding complications in patients taking warfarin was 15.0% overall, 5.0% for major bleeds and 3.8% for intracranial haemorrhages., Conclusions: While a number of published trials have demonstrated that antithrombotic agents confer substantial protection against stroke in patients with nonrheumatic AF, the drugs were underused in our setting. There is a need to improve antithrombotic use and to develop a better monitoring system for the provision of safer and more effective antithrombotic therapy.

Objective: To assess the postgraduate achievements of graduates of the University of Tasmania Medical School., Design: Postal questionnaire survey in October 1994 and March and May 1995., Participants and Setting: 262 of the 400 medical graduates of the University of Tasmania who graduated between 1970 and 1983 for whom addresses were held (65.5% response rate)., Main Outcome Measures: Achievement of postgraduate qualifications; senior hospital and university appointments; publications in the medical literature; practice location (rural or urban); and sex distribution., Results: College fellowships had been obtained by 56%, other formal postgraduate qualifications by 24%. MDs or PhDs by 7%, senior hospital appointments by 46%, and senior university appointments by 21%; 30% had published in the medical literature. Equal proportions of men and women had obtained postgraduate qualifications, but women were less likely to have a college fellowship, a senior hospital or university appointment, or to have published (P < 0.05). 56% worked in Tasmania, and of the 95% working in Australia 17% were in rural or remote locations., Conclusions: More than two-thirds of Tasmanian medical graduates achieved postgraduate qualifications and a small majority were practising in Tasmania. Postgraduate career path was significantly influenced by the sex of the graduates.

Objective: A range of functional, biochemical, and psychological indicators was used to test the concept of "responders"/"nonresponders" and to seek predictors of response to 2 nonsteroidal antiinflammatory drugs in 9 patients with rheumatoid arthritis (RA) and 11 with osteoarthritis (OA)., Methods: In a balanced, randomized, double-blind, latin-square study design that involved four 4-week treatment periods, patients received ketoprofen or piroxicam (each for 2 of the 4 periods). Clinical and laboratory responses (pain, tenderness, swelling, patient and physician global assessments, acute-phase protein levels, and disability) were assessed in the last 2 weeks of each period. Responders were those who showed >30% improvement in at least 5 of 7 measures of disease activity. Mood was also assessed., Results: At baseline, variables were higher in RA than in OA patients. The drugs produced clear improvements in patients' visual analog scale scores, physicians' overall assessments, and patients' responses to the McGill Pain Questionnaire, as well as plasma prostaglandin concentrations. In patients with either RA or OA, responders could be distinguished from nonresponders; about one-third of patients were unambiguous responders. In RA, there were responder/nonresponder differences in lymphocyte counts, erythrocyte sedimentation rate (ESR), and levels of tumor necrosis factor alpha, but no differences were seen in OA patients. However, caution in interpretation of the data is necessary because of the small number of patients. Responders had improved mood scores compared with nonresponders in both disease groups. Baseline ESR and white blood cell counts were correlated with responder status in RA patients., Conclusion: This study provides support for the responder/nonresponder concept. It also indicates that in RA, pretreatment ESR and lymphocyte counts are possibly useful indicators of therapeutic response.

It has been postulated that exposure to high concentrations of oxygen results in increased oxygen radical production which may account for the toxic effects of excessive exposure to oxygen. Examination of blood from persons undergoing hyperbaric oxygen (HBO) exposure, by low temperature electron spin resonance (ESR) spectroscopy, demonstrated a marked increase in the magnitude of a signal with properties consistent with a free radical (g = 2.006). The signal diminished to baseline levels within 10 minutes of cessation of HBO exposure. Further in vitro studies of blood revealed an ESR signal generated in red blood cells by oxygen, and dependent on oxyhaemoglobin, which had characteristics indistinguishable from those of the ESR signal of ascorbate radical and the signal in blood from persons undergoing HBO exposure. It is postulated that HBO exposure increases ascorbate radical levels in blood, which is likely to reflect increased ascorbate turnover in human red blood cells.

1. In the chronic, awake, instrumented sheep model NG-nitro-L-arginine (NOLA) an inhibitor of nitric oxide synthesis, injected at a dose of 40 mg/kg, produced a significant increase in systolic blood pressure (from 110 +/- 6 to 145 +/- 8 mmHg after 5 min) which persisted for at least 1 h but returned to baseline after 24 h. 2. When NOLA was repeated 1 and 4 days after the first injection, the blood pressure response was significantly attenuated, and at 1 day was no greater than the response to an equivalent volume of saline. The blood pressure response returned to the initial response with an 8 day interval between injections. 3. There was no significant blood pressure response to 100 mL of saline before the NOLA injection; however, 1 and 4 days after NOLA there was a significant rise in blood pressure.

The hypothesis that slow administration of low doses of aspirin may selectively inhibit platelet cyclooxygenase and thromboxane A2 formation was evaluated using controlled release aspirin formulations. In the first study, doses of either 50, 100, 325 and 1,300 mg of these formulations and 300 mg soluble aspirin were ingested daily by healthy volunteers for one week. In the second study, doses of 5, 10, 25 and 50 mg controlled release aspirin, 50 mg soluble aspirin and 100 mg aspirin and glycine formulation were ingested daily for ten days. Platelet function and urinary prostaglandin production were assessed immediately before and on the seventh day of dosing in both studies and in the second study, repeated on the tenth day of dosing. Platelet function and serum thromboxane B2 production were fully inhibited by all formulations of 50 mg aspirin and above, but not by doses of controlled release aspirin below 50 mg doses. The excretion of urinary 6-keto-PGF1 alpha (a major metabolite of prostacyclin) was significantly reduced at controlled release aspirin doses above 100 mg and at all doses of rapidly absorbed aspirin tested. As no significant reduction in the urinary 6-keto-PGF1 alpha production was observed at doses of controlled release aspirin of 50 and 100 mg and below, it appeared that these doses did not inhibit the systemic vascular cyclooxygenase. These data are consistent with a selective inhibition of platelet function by daily doses of 50 and 100 mg of the controlled release formulation of aspirin.

The variability of structural changes along individual arterioles in deoxycorticosterone acetate (DOCA) hypertensive rats was measured by coefficients of variation of: (a) serial lumen diameters along microfil casts of individual mesenteric arterioles; and (b) wall and lumen indices in serial histological cross-sections along individual renal arterioles. The mean lumen diameter of third-order mesenteric arterioles decreased with increasing duration of hypertension. There was increased variability of lumen diameter along lengths of DOCA arterioles, the coefficient of variation at 10 weeks DOCA treatment being 20.2 +/- 0.6% compared to 9.2 +/- 0.2% in controls (P less than 0.001). Medial area to internal elastic lamina (IEL) radius ratio of renal arterioles was increased in DOCA rats compared with control rats (P less than 0.025) and its variability along individual arterioles expressed as the coefficient of variation was 31.70 +/- 3.87% in DOCA rats compared with 15.29 +/- 1.72% in controls (P less than 0.005). The observed increase in variability of lumen diameter and medial area along short lengths of individual arterioles in DOCA hypertensive rats indicates that hypertensive structural changes are probably not directly related to local blood pressure. We suggest that irregular functional vasoconstriction in hypertensive rats could account for this distribution of structural changes.

Structural changes in resistance vessels were studied by (a) hindquarter perfusion; and (b) planimetry of cross-sections of renal arterioles in uninephrectomized rats treated for 10 weeks with saline and either DOCA (deoxycorticosterone acetate), DOCA plus hydrallazine, vehicle plus hydrallazine or vehicle only. DOCA-treated rats developed hypertension and structural change. Addition of hydrallazine prevented both hypertension and the development of structural change. Structural arteriolar change in DOCA/salt hypertension is related to the high blood pressure or a closely associated factor rather than some other effect of DOCA.

1. Structural changes in resistance vessels were studied sequentially (a) by hindquarter perfusion and (b) by planimetry of renal arterioles less than or equal to 20 micrometers radius, for 10 weeks during development of DOCA (deoxycorticosterone acetate)/salt hypertension in uninephrectomized rats and 5 weeks after cessation of DOCA treatment. 2. Blood pressure and haemodynamically significant structural change increased progressively during DOCA treatment and both had partially reversed 5 weeks after cessation of DOCA. 3. Arteriolar structural changes contribute progressively to the hypertension during 10 weeks DOCA treatment. Partial reversal of structural changes contributes to the fall in blood pressure after cessation of DOCA. The persisting postDOCA hypertension can be attributed to relatively irreversible structural changes.

It is now well established that structural changes in resistance vessels contribute to the long-term maintenance of many forms of hypertension. This study measured the time course of structural change in smaller resistance vessels during the development of deoxycorticosterone acetates (DOCA) hypertension and after cessation of DOCA in Wistar rats by histometric assessment of cross-sections of renal arterioles. The relationship of structural change to blood pressure was assessed by preventing hypertension during DOCA treatment with hydralazine. Blood pressure rose progressively during DOCA treatment reaching 192 +/- 3 mmHg compared with 132 +/- 2 mmHg in controls after 10 weeks. Five and 10 weeks after cessation of DOCA, following 10 weeks of DOCA treatment, post-DOCA reversal of hypertension was only partial. Medial area to internal elastic lamina (IEL) radius ratio, wall to lumen ratio and intimal area to IEL radius ratio of renal arterioles increased progressively during 10 weeks of DOCA treatment with partial reversal of the increased medial area and wall to lumen ratio 5 weeks post-DOCA. Hydralazine completely prevented hypertension in DOCA rats and also largely prevented structural change.

In an attempt to find the most appropriate dose and formulation(s) of acetylsalicylic acid (ASA) for thrombosis prophylaxis, healthy volunteers were given doses of ASA for 1 wk daily ranging from 50 to 3900 mg as either Aspro-Clear (soluble), Astrix (enteric coated pellets) or Ecotrin (enteric coated tablets). Platelet function and bleeding times were monitored. All doses of ASA significantly inhibited platelet function (p less than 0.05) and increased bleeding times (p less than 0.05) relative to control values. Irrespective of the formulation, maximum increases in bleeding time and platelet dysfunction were obtained with daily doses of about 100 mg, and no further changes were observed with higher doses.

This study measured the time course of the development and reversal of structural change in resistance vessels during deoxycorticosterone acetate (DOCA) hypertension and after cessation of DOCA in Wistar rats by hindquarter perfusion. The relationship of structural change to blood pressure was further assessed by preventing hypertension during DOCA treatment with hydralazine. Blood pressure rose progressively during DOCA treatment reaching 198.6 +/- 2.0 (s.e.) mmHg at 10 weeks. Five weeks after the cessation of DOCA, when it had been given for 2 weeks, hypertension reversed completely but after 4, 8 and 10 weeks of treatment, post-DOCA reversal of hypertension was only partial. Hindquarter perfusion pressure at maximum vasodilatation and maximum vasoconstriction increased with increasing duration of DOCA treatment and reversed 5 weeks post-DOCA to a similar degree to the blood pressure with only partial reversal of both perfusion pressures and hypertension when DOCA had been given for 8 and 10 weeks. Hydralazine did not completely prevent heart hypertrophy in the DOCA rats and caused some cardiac hypertrophy in the control ('vehicle' only) rats, although it both prevented hypertension and evidence of vascular structural change in DOCA rats.

The extent to which a controlled release acetylsalicylic acid (ASA) formulation inhibited platelet function has been evaluated in single and chronic dosing studies. In the single dose study, the platelet inhibitory effect of the controlled release formulation was compared with that of an equivalent dose of soluble ASA and an equimolar dose of sodium salicylate (SA). In the chronic dosing study, ASA dose-response curves for platelet function, including cyclooxygenase activity, were determined for various doses (20-1300 mg) of the controlled release (enteric coated pellets) ASA formulation taken by volunteers daily for one week. Platelet function was assessed by the degree of inhibition of aggregation for several aggregating agents, and the degree of inhibition of activity of platelet cyclooxygenase quantified by the estimation of malondialdehyde (MDA) production. Plasma ASA and SA concentrations were also determined in each study. The controlled release product inhibited platelet function to the same extent as an equimolar dose of soluble ASA, but did so with much lower and sometimes undetectable peak systemic plasma ASA concentrations. SA, the direct metabolite of aspirin, did not have any effect on platelet function. The ASA dose-platelet function response curves obtained from chronic dosing with the controlled release formulation appeared to be similar to those reported previously for the soluble product. The inhibition of platelet function appeared to be unrelated to plasma ASA concentrations.