Australian And New Zealand Journal Of Medicine[JOURNAL]

BACKGROUND: Single agent continuous infusional 5 fluorouracil (CI-5FU) via a central venous catheter (CVC) is usually reserved for breast cancer patients who have previously failed one or more chemotherapy regimens. The... BACKGROUND: Single agent continuous infusional 5 fluorouracil (CI-5FU) via a central venous catheter (CVC) is usually reserved for breast cancer patients who have previously failed one or more chemotherapy regimens. The patients are usually heavily pre-treated with later stage disease. Previously published studies of CI-5FU have reported response rates as high as 54%. It is considered an approach with an acceptable side effect profile in such patients. AIMS: To evaluate the efficacy and toxicity of CI-5FU in previously treated metastatic breast cancer. METHODS: A retrospective review of advanced breast cancer patients treated with CI-5FU between October 1992 and October 1996 was performed. Response to treatment, toxicity, CVC complications and patient survival were analysed. RESULTS: Twenty-four patients with metastatic breast cancer were treated with CI-5FU. All had received previous chemotherapy, including 19 patients (79%) with prior 5FU exposure and eight patients (33%) who had previous high dose chemotherapy with autologous stem cell transplantation. The median duration of CI-5FU treatment was 3.1 months. Nineteen patients had evaluable disease, three (16%) of whom demonstrated a partial response and four patients had stable disease. There were no complete responses. All responses occurred in soft tissue sites with no objective evidence of response in liver or bone metastases. The survival rate at one year was 21% (five of 24) and the median survival of all patients was 6.1 months. Five patients (21%) stopped treatment due to treatment related morbidity (two CVC complications and three CI-5FU side effects). Diarrhoea, nausea, and palmar-plantar erythrodysaesthesia were the major side effects of chemotherapy. CVC complications requiring intervention, the most notable of which were infection and thrombosis, occurred in 11 patients (46%). There were no treatment related deaths. CONCLUSIONS: Single agent CI-5FU has modest activity in women with previously treated advanced breast cancer. The efficacy is lower than in previously published series. This may reflect patient selection factors. The toxicity was mainly related to CVC complications. Important issues relating to quality of life need to be objectively measured in future studies of CI-5FU.

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Helicobacter pylori treatment and antibiotic susceptibility: results of a five-year audit.

Fraser AG, Moore L, Hackett M … +1 more , Hollis B

Aust N Z J Med · 1999 Aug · PMID 10868529 · Publisher ↗

BACKGROUND: Helicobacter pylori eradication treatment has been a rapidly evolving field. Audit of treatment results provides reassurance that trial data can be translated into routine clinical practice. METHODS: Data wer... BACKGROUND: Helicobacter pylori eradication treatment has been a rapidly evolving field. Audit of treatment results provides reassurance that trial data can be translated into routine clinical practice. METHODS: Data were collected prospectively over five years. Patients were given four different treatment regimens over the audit period 'standard' triple therapy, two types of clarithromycin-based treatment or ranitidine, amoxycillin and metronidazole. Eradication was proven by a urea breath test at least four weeks after completing treatment. RESULTS: Eradication treatment for H. pylori was given to 665 patients; 89% had follow-up data. H. pylori eradication was significantly associated with treatment type (p<0.0001) and smoking (p=0.04) by univariate analysis, but was not associated with sex, age, alcohol consumption, endoscopic diagnosis, recent treatment with anti-secretory drugs or NSAIDs. By logistic regression analysis, only treatment type was significant (p=0.0001). H. pylori culture and sensitivities were available for 255 patients. Metronidazole resistance was shown for 84 isolates (32%) and clarithromycin resistance for 18 isolates (6.8%). Metronidazole resistance was significantly associated with younger age (p=0.02), ethnicity (p=0.02), female sex (p=0.02), and year of endoscopy (p=0.04), but was not associated with clarithromycin resistance. Clarithromycin resistance was not associated with age, sex, or ethnicity. Metronidazole resistance significantly affected H. pylori eradication for regimens containing metronidazole without clarithromycin. Eradication with metronidazole without clarithromycin was achieved in 90% of sensitive strains but only 55% of resistant strains (p<0.001). Metronidazole resistance was not significantly associated with treatment failure when metronidazole was combined with clarithromycin. Eradication with metronidazole and clarithromycin was achieved in 86% of sensitive strains and 78% of resistant strains (p=0.42). CONCLUSION: Treatment type and antibiotic susceptibility are the most important determinants of treatment success.

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Review of Emergency Department thrombolytic therapy and changes in inpatient mortality of acute myocardial infarction on the NSW Central Coast 1986 to 1994-96.

Hooi H

Aust N Z J Med · 1999 Aug · PMID 10868528 · Publisher ↗

AIMS: To examine changes in inpatient mortality of acute myocardial infarction (AMI) from 1986 to 1994-96 and to review the Emergency Department (ED) use of thrombolytic therapy (TT) for AMI on the NSW Central Coast. MET... AIMS: To examine changes in inpatient mortality of acute myocardial infarction (AMI) from 1986 to 1994-96 and to review the Emergency Department (ED) use of thrombolytic therapy (TT) for AMI on the NSW Central Coast. METHOD: A retrospective review of medical records of patients presenting to the EDs of Gosford and Wyong Hospitals with a discharge diagnosis of AMI (ICD9 code 410.x) from 1 January 1986 to 31 December 1986 and 1 January 1994 to 31 December 1996. Data were collected on patients' age, sex, duration of symptoms on arrival at the ED, ECG changes and presence of positive ECG criteria for thrombolysis, agent used, contraindications to TT, and inpatient mortality. The main measure of outcome was inpatient mortality. RESULTS: There were 423 admissions for AMI in 1986 and 1,220 admissions in 1994-96. The overall inpatient mortality has declined from 18.9% in 1986 to 9% in 1994-96 (p<0.0001). The mean age of patients has increased from 67.5 years to 68.1 years (p=0.35). The proportion of patients over age 75 years has increased significantly from 24.6% to 30.3% (p<0.0001). Presentation times from onset of symptoms have not changed significantly from a median time of two hours in 1986 to 2.5 hours in 1994 to 1996 (p=0.52). The overall proportion of patients with ECG criteria for TT was 53.2% in 1994-96. TT was administered to 42.9% of patients with a mean door to needle time of 67 minutes (median 45 minutes). The Australasian College for Emergency Medicine benchmark door to needle time of 60 minutes was achieved in 71.3% of patients. Streptokinase was the predominant agent given in 78%, while recombinant tissue plasminogen activator accounted for 15.7% of patients. Patients not receiving TT due to negative ECG criteria showed a decline in mortality from 18.6% to 6.7% (p<0.0001). Patients who underwent mechanical revascularisation (by bypass graft or angioplasty) increased from 8.7% to 17.4% (p<0.0001). Inpatient mortality has declined for all age groups, for both sexes, and for all sites of AMI. CONCLUSION: There have been significant declines in inpatient mortality of patients with AMI on the Central Coast. TT has had a significant impact on this decline but has an eligibility rate of less than half. Significant declines in mortality have also been seen in patients ineligible for thrombolysis. These patients have benefited from other therapies introduced or more widely used in the last decade. The results achieved on the Central Coast compare favourably with published reviews in Australia and overseas despite the lack of facilities for coronary angiography, coronary angioplasty and cardiothoracic surgery.

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Monoclonal gammopathy of undetermined significance (MGUS)-31 year follow up of a community study.

Colls BM

Aust N Z J Med · 1999 Aug · PMID 10868527 · Publisher ↗

BACKGROUND: When unselected healthy adults in the community have their serum screened by cellulose acetate or paper electrophoresis, monoclonal gammopathy of undetermined significance (MGUS) may be found in 0.5-1%. AIM:... BACKGROUND: When unselected healthy adults in the community have their serum screened by cellulose acetate or paper electrophoresis, monoclonal gammopathy of undetermined significance (MGUS) may be found in 0.5-1%. AIM: To report upon a 31 year follow up of MGUS in a New Zealand community. METHODS: Serum from 2,192 subjects (82% of the adult population) of a New Zealand town was collected in 1967 and subsequently screened by cellulose acetate electrophoresis. Eleven of the 2,192 (0.5%) were found to have MGUS. Clinical correlation was sought in 1970 and subsequently to elucidate the underlying cause. RESULTS: Seven of the 11 patients have developed a haematological malignancy. Two have been diagnosed as having Waldenstrom's macroglobulinaemia, one malignant lymphoma and acute myelomonocytic leukaemia and four developed myeloma. Myeloma developed at one, nine, 23 and 25 years after the original screening. One myeloma patient and one patient with MGUS are currently alive and well, 31 years after discovery of their gammopathy. CONCLUSIONS: The incidence of MGUS in this community is only half that detected in a comparable study. The association with haematological malignancy in this study (64%) is considerably higher than that found in the Swedish study (6%), possibly because of the longer follow up in New Zealand. MGUS should not only be studied in depth at the time of its discovery, but needs very long term follow up as the underlying disease may not surface until the third decade.

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Profile of people referred to an emergency department from residential care.

Finucane PM, Wundke R, Whitehead C … +2 more , Williamson L, Baggoley CJ

Aust N Z J Med · 1999 Aug · PMID 10868526 · Publisher ↗

BACKGROUND: Elderly people in residential care are among the most infirm in society and are at high risk of developing acute medical problems. There are no Australian data on the use of acute hospital emergency services... BACKGROUND: Elderly people in residential care are among the most infirm in society and are at high risk of developing acute medical problems. There are no Australian data on the use of acute hospital emergency services by this group. AIM: To determine patterns of use of a major public hospital's Emergency Department (ED) by elderly people living in residential care, their presenting problems and the outcome of attendance. METHODS: Prospective study of 300 consecutive referrals to a teaching hospital's ED involving people aged over 65 years and living in residential care in southern Adelaide, South Australia. Case records were examined and residential care staff were interviewed by telephone when information required clarification. This occurred in 25% of referrals. RESULTS: The 300 referrals were seen over a three month period and accounted for 2.43% of the 12,371 ED attendances during this period. During this time, at least 4.9% of people in residential care in the region were referred to the ED. The referrals involved 239 residents, 196 (82%) who were referred once only, 32 (13%) twice and 11 (5%) three or more times. Residents had a mean age of 84 years and 70% were female. A broad range of acute medical problems precipitated referral and 61% of people referred were immediately hospitalised. There was no general practitioner (GP) involvement in the management of the presenting illness in 58% of all referrals and in 45% of those where symptoms had been present for over three days. CONCLUSIONS: People living in residential care are frequently referred to an ED service, often bypassing their GP in the process. They present with a wide range of acute medical problems for which most are hospitalised. Strategies that anticipate, prevent and manage health breakdown in residential care and so minimise the need for ED referral should be trialed.

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The addition of allogeneic peripheral blood-derived progenitor cells to bone marrow for transplantation: results of a randomised clinical trial.

Szer J, Curtis DJ, Bardy PG … +1 more , Grigg AP

Aust N Z J Med · 1999 Aug · PMID 10868525 · Publisher ↗

BACKGROUND: The use of cytokine-mobilised peripheral-blood-derived progenitor cells (PBPC) has resulted in a significant improvement in the safety of autologous transplantation. Collections of PBPC contain large numbers... BACKGROUND: The use of cytokine-mobilised peripheral-blood-derived progenitor cells (PBPC) has resulted in a significant improvement in the safety of autologous transplantation. Collections of PBPC contain large numbers of haemopoietic progenitors and T-lymphocytes when compared with bone marrow (BM). AIMS: To assess the clinical effects and safety of filgrastim-mobilised allogeneic PBPC, in particular whether PBPC would alter the kinetics of engraftment or the incidence and severity of graft-versus-host disease (GVHD). METHODS: Twenty-seven patients undergoing allogeneic transplantation were randomised to receive BM or BM supplemented by PBPC. Patients were conditioned with busulphan 16 mg/kg and cyclophosphamide 120 mg/kg. GVHD prophylaxis was with methotrexate and cyclosporin. Ganciclovir prophylaxis was administered to all cytomegalovirus seropositive patients. No haemopoietic growth factor was used after BMT. Donors of PBPC underwent a single, seven litre apheresis after four days of filgrastim, 10 microg/kg/day by subcutaneous injection. RESULTS: Donor toxicity was mild, with the most frequently reported being bone pain in the cytokine-treated donors. The patients transplanted with BM+PBPC received an eight-fold increase in CD3+ T-lymphocytes (1.65X 10(8)kg vs 0.22 x 10(8)/kg, p=0.04) and the cytokine product contained a median of 5 x 10(6) CD34+ cells/kg. BM+PBPC patients had more rapid engraftment of neutrophils to 0.5x 10(9)/L (17 days vs 19 days, p=0.02) and platelets to 50X 10(9)/L (22 days vs 35 days, p=0.04). BM megakaryocyte numbers were significantly enhanced at days 14 and 28 after BMT (both p=0.04), however platelet transfusions were not significantly different. The incidence, organ distribution, severity and time to onset of acute and chronic GVHD were not different between the treatment groups and there was no difference in overall survival or event-free survival. CONCLUSIONS: Allogeneic PBPC from HLA-identical siblings may speed engraftment of neutrophils and platelets without detrimental effects on GVHD or survival.

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Overprescribing: have we made any progress?

Pillans PI, Roberts MS

Aust N Z J Med · 1999 Aug · PMID 10868524 · Publisher ↗

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Stemming the tide: reducing cardiovascular disease and renal failure in Australian Aborigines.

Hoy W, Kelly A, Jacups S … +9 more , McKendry K, Baker P, MacDonald S, Wang Z, Punguatji N, Kerinauia J, Tipiloura E, Tipiloura E, Harrison C

Aust N Z J Med · 1999 Jun · PMID 10868523 · Publisher ↗

An epidemic of cardiovascular disease (CVD) and end stage renal disease (ESRD) has developed among Aborigines in the Northern Territory; CVD deaths increased over the 1980s (tripling among women!), and are now more than... An epidemic of cardiovascular disease (CVD) and end stage renal disease (ESRD) has developed among Aborigines in the Northern Territory; CVD deaths increased over the 1980s (tripling among women!), and are now more than five times those of non-Aboriginal people, while ESRD rates are increasing more than 20-fold and are doubling every three to four years. Dialysis costs (>$75,000 per person/year) pose a crisis for health care budgets, but premature mortality is the greater human catastrophe. Health services are not meeting the challenge of timely diagnosis, prevention and containment. We screened 90% of adults (20+ years) in one community, with CVD mortality among the highest in Australia, and ESRD rates increased 60-fold. Seventy-five per cent of persons were smokers. Central obesity was common, but BMIs only modestly increased by Caucasian standards, 23% had hypertension (>140/90), 29% had diabetes or impaired glucose tolerance (IGT) (peaking at 65% of persons aged 40-49 years), high triglyceride and insulin levels were common, and 55% had albuminuria (albumin/creatinine ratio (ACR), >3.4 gm/moL). Progressive albuminuria predicted renal failure. ACR was correlated with age, BMI, blood pressure, lipid, glucose and insulin levels, heavy drinking and past and current skin infections, and, inversely with birth weight. ACR correlated strongly with a composite CV risk score, and in a two to five year follow-up, microalbuminuria (ACR 3.4-33) and overt albuminuria (ACR 34+) have both predicted increased rate of premature death from natural causes of lower ACRs. Thus albuminuria marks CV risk/disease. This implies that renal and CV disease share common risk factors, and should respond to the same interventions, and that this response might be monitored through ACR levels. Robust public health programmes could reduce all these reversible risk factors, lowering disease rates over the intermediate term, however, few such programmes are in place. Modification of disease in persons already afflicted is a parallel responsibility. To this end, in November 1995, we introduced a treatment programme with Coversyl (perindopril, Servier) for all persons in the study community with hypertension (>140/90), for all diabetics with ACR 3.4+ and for all nondiabetic, non-hypertensive persons with progressive overt albuminuria (ACR 34+). One-quarter of all adults, or 224 persons have enrolled; 162 have reached one year of treatment and 100 have passed two years. Compliance is reasonable and enthusiasm high. Average SBP has fallen 12 mmHg (24 mmHg in hypertensive persons), while average ACR and estimated glomerular filtration rate (GFR) have stabilised. This contrasts favourably with the pretreatment course (average 2.7 years) in the same persons, when SBP had increased by 3 mmHg, ACR had increased by 15% and GFR had decreased by 3.5 mL/min each year. Cautious estimates suggest a >50% fall in ESRD, and a reduction in all-cause and CV deaths, even at this early stage, although more extended observation is needed. These data predict a dramatic and rapid fall in morbidity, premature deaths and health care costs if these basic principles of medical care are extended to all Aboriginal people. A national, concerted, multi-disciplinary effort to implement a coherent, effective strategy to this end is of great urgency.

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Oestrogen and vascular disease.

Harvey P

Aust N Z J Med · 1999 Jun · PMID 10868522 · Publisher ↗

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in postmenopausal women. Epidemiological studies consistently suggest that oestrogen administered to postmenopausal women confers an estimated... Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in postmenopausal women. Epidemiological studies consistently suggest that oestrogen administered to postmenopausal women confers an estimated 30-50% reduction in risk of development and progression of CVD. The long term effect on the cardiovascular system of the addition of a progestogen to the replacement regimen is currently unknown. In addition, it may be argued that it remains to be proven whether the magnitude of the oestrogen-induced cardioprotective effect demonstrated in these observational studies is a real biological phenomenon. No prospective, randomised, controlled studies examining the effect of oestrogen on primary and secondary prevention of CVD have been completed. However, a large number of biologically plausible mechanisms have been identified which provide evidence to support the proposed oestrogen-induced cardioprotection. These include oestrogen mediated favourable changes in metabolic profile, in particular changes in lipid metabolism, insulin resistance and the fibrinolytic system. In addition, recent data have shown that oestrogen may affect vascular structure and function by a variety of mechanisms. It has been shown that oestrogen may induce acute and chronic coronary and cerebral vasodilation through both direct (vascular smooth muscle) and indirect (endothelium dependent) mechanisms. Oestrogen also has recently been shown to have complex anti-atherogenic and antioxidant properties. Much less is known of the vascular effects of progestogens. Progestogens currently in clinical use have androgenic properties and may attenuate the beneficial effects of oestrogen by neutralising or opposing the lipid lowering, vasodilatory and anti-atherogenic actions of oestrogen. Thus further studies are required to elucidate the effects on arterial physiology and CVD outcome of the oestrogens and progestogens of different types, doses and routes of administration which are collectively referred to as postmenopausal 'hormone replacement therapy'.

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Non-rheumatic atrial fibrillation and stroke.

Tonkin A

Aust N Z J Med · 1999 Jun · PMID 10868521 · Publisher ↗

The risk of systemic embolism and stroke in patients with non-rheumatic atrial fibrillation (NRAF) should not be underestimated. The annual embolic rate is approximately 5% and in those with left atrial enlargement and/o... The risk of systemic embolism and stroke in patients with non-rheumatic atrial fibrillation (NRAF) should not be underestimated. The annual embolic rate is approximately 5% and in those with left atrial enlargement and/or left ventricular (LV) dysfunction, or who have already had systemic embolism, this rate may be as high as 20%. Decisions on patient management and the prophylaxis of stroke must always be individualised. The risk of bleeding related to warfarin is almost certainly greater than that encountered in the previous randomised trials. Also, clinical and echocardiographic features can further define absolute risk in an individual patient with NRAF. Clinical markers of increased risk of embolism in patients with NRAF include older age, previous cerebral embolism, recent congestive heart failure, hypertension and diabetes mellitus. Transthoracic echocardiography improves risk stratification and should be performed in the vast majority of patients. Embolic risk is greatest in those with increasing left atrial dilation, atrial dysfunction and LV dysfunction. Transoesophageal echocardiography sharpens the risk profile in selected patients. Overall randomised trials show greater benefit with warfarin than aspirin. In general, increasing age is associated with a greater incidence of structural heart disease and probably implies greater potential benefit with warfarin. Increasing age per se may not increase the risk of warfarin-related bleeding. When the decision is made to warfarinise patients, at the present time data suggest that the target INR should be in the range of 2.0-3.0.

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Reperfusion therapy for stroke.

Dunbabin D

Aust N Z J Med · 1999 Jun · PMID 10868520 · Publisher ↗

Stroke is a heterogeneous disease, but about 85% of strokes are as a result of cerebral ischaemia due to arterial occlusion. It seems logical to assume that, as in myocardial infarction, treatment designed to dissolve cl... Stroke is a heterogeneous disease, but about 85% of strokes are as a result of cerebral ischaemia due to arterial occlusion. It seems logical to assume that, as in myocardial infarction, treatment designed to dissolve clots should be helpful. We now have a substantial amount of data on the use of aspirin, heparin and thrombolytic drugs in the treatment of acute ischaemic stroke. Aspirin 300 mg daily has a modest effect in reducing mortality and handicap when used within 48 hours of stroke onset. The beneficial effects of low dose, medium dose subcutaneous unfractionated heparin, and various low molecular weight heparins in reducing early recurrent ischaemic stroke seem to be outweighed by haemorrhagic side effects. Streptokinase used within six hours of stroke onset results in excess mortality with some reduction in handicap in survivors, while in carefully selected patients recombinant tissue plasminogen activator (r-TPA) may be less hazardous. At the moment it is unclear which stroke patients will benefit from the use of r-TPA, and the use of criteria, as outlined by the NINDS group, means that only a very small proportion of stroke victims are suitable for thrombolytic therapy. Further research is necessary, while the concept of a 'Brain Attack' with appropriate urgency being used in the assessment of possible stroke needs development.

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Platelet adhesion receptors: novel targets for anti-thrombotic therapy.

Williamson D, Giuliano S, Jackson SP

Aust N Z J Med · 1999 Jun · PMID 10868519 · Publisher ↗

The critical role of platelets in the development of the acute coronary syndromes is now well recognised, and a great deal of effort has therefore focused on elucidating the key adhesion receptors mediating platelet-vess... The critical role of platelets in the development of the acute coronary syndromes is now well recognised, and a great deal of effort has therefore focused on elucidating the key adhesion receptors mediating platelet-vessel wall and platelet-platelet interactions. The vascular adhesion protein von Willebrand factor (vWf) plays a key role in supporting platelet adhesion to the damaged vessel wall and binds to two adhesion receptors on the platelet surface, the glycoprotein (GP) Ib-V-IX complex and glycoprotein IIb-IIIa. The GP Ib-V-IX complex is a unique adhesion receptor which enables platelets to roll on a vWf matrix under conditions of rapid blood flow as well as transducing signals leading to the activation of GP IIb-IIIa. This latter receptor binds to a distinct site on vWf and is essential for stabilising platelet adhesion to the site of vessel wall injury. In addition to supporting platelet adhesion, GP IIb-IIIa plays a key role in a number of other platelet responses including platelet spreading, aggregation, the release of procoagulant-rich microvesicles, and clot retraction. Given its central role in platelet function GP IIb-IIIa has become an attractive target for the development of novel anti-thrombotic agents. In this paper, we consider the advantages of inhibitors of GP IIb-IIIa compared with other established anti-platelet drugs including aspirin and ticlopidine, and also discuss some potential problems associated with the inhibition of GP IIb/IIIa and other platelet adhesion receptors.

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Antithrombins and the importance of good control.

Tideman PA

Aust N Z J Med · 1999 Jun · PMID 10868518 · Publisher ↗

The generation of thrombin and the formation of platelet rich intra-coronary thrombus in response to atherosclerotic plaque rupture is pathognomonic of acute coronary syndromes. An understanding of the process of thrombi... The generation of thrombin and the formation of platelet rich intra-coronary thrombus in response to atherosclerotic plaque rupture is pathognomonic of acute coronary syndromes. An understanding of the process of thrombin generation and the unique relationship between the structure and function of thrombin is essential to developing more effective anti-thrombotic strategies than the use of standard unfractionated heparin in the acute coronary syndromes. The mechanisms of action of heparin, low molecular weight heparins (LMWHs) and the newer direct anti-thrombins, recombinant hirudin and Hirulog, are reviewed. Evidence from the currently available phase 2 and 3 trials of these drugs regarding their efficacy in the acute coronary syndromes is also reviewed.

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Troponin and other cardiac markers: role in management of acute coronary syndromes.

Ohman EM

Aust N Z J Med · 1999 Jun · PMID 10868517 · Publisher ↗

Many adjuncts to the traditional history, physical examination, and baseline ECG have been developed to improve the differential diagnosis of acute coronary syndromes in the Emergency Department (ED). These include seria... Many adjuncts to the traditional history, physical examination, and baseline ECG have been developed to improve the differential diagnosis of acute coronary syndromes in the Emergency Department (ED). These include serial ECGs, continuous ST-segment monitoring, and serum markers of myocardial necrosis. In general, the serum markers of coronary ischaemia, particularly the troponins, provide the most information toward initial and later risk stratification. Serial marker measures not only increase the sensitivity and negative predictive value for acute infarction (thus reducing hospital costs) but also can add to prognostic ability. More importantly, a positive marker result indicates an increased risk of an early event, which could allow earlier intervention and thus a better outcome.

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New thrombolytic drugs.

Thomson A

Aust N Z J Med · 1999 Jun · PMID 10868516 · Publisher ↗

Thrombolytic drugs reduce mortality from myocardial infarction and research is focused on newer drugs with improved clinical efficacy. The ideal thrombolytic drug should be effective in dissolving fresh and older thrombi... Thrombolytic drugs reduce mortality from myocardial infarction and research is focused on newer drugs with improved clinical efficacy. The ideal thrombolytic drug should be effective in dissolving fresh and older thrombi, be rapid in its action with complete dissolution of the thrombus, be able to be given as a bolus and be safe without hypotensive or allergic or immunogenic reactions. The types of agents being developed fall into five broad categories: * mutants or variants of single chain urokinase type plasminogen activator; * mutants or variants of tissue type plasminogen activator; * recombinant chimaeric plasminogen activators; * conjugates of plasminogen activators and anti-fibrin monoclonal antibodies; * compounds derived from haemophagous animals. Within the mutant and variant groups there may be single point mutations which increase the half life or deletion of various amino acid sequences to increase resistance to plasma protease inhibitors or cause more selective binding to fibrin. The recombinant chimaeric plasminogen activators are designer drugs where the kringle regions, the growth hormone domain region, the finger domain region and the serine protease part of the molecules are all cleaved and recombined in various ways to improve potency. The conjugates of plasminogen activators and anti-fibrin and monoclonal antibodies improve the targeting of the agent to fibrin clot. Monoclonal antibodies are commonly used against the seven aminoterminal residues of the beta chain of fibrin. These are cross linked and bound to plasminogen activators. A variety of substances from haemophageous animals are currently being studied including salivary plasminogen activator from vampire bats, venom from southern copperhead snakes and staphylokinase from bacteria. Currently available thrombolytic agents have many limitations, but the novel thrombolytic agents have yet to be tested in clinical trials. With few exceptions, they all act via the plasminogen system and it may be in the future that combinations of anti-platelet and thrombolytic agents may prove to be more efficacious than thrombolytics and aspirin alone.

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The role of diastolic ventricular interaction in abnormal cardiac baroreflex function in chronic heart failure.

Atherton JJ, Frenneaux MP, Thomson HL

Aust N Z J Med · 1999 Jun · PMID 10868515 · Publisher ↗

Baroreflex abnormalities have been well documented in both patients with chronic heart failure and experimental animal models of heart failure. These abnormalities are associated with increased mortality and probably con... Baroreflex abnormalities have been well documented in both patients with chronic heart failure and experimental animal models of heart failure. These abnormalities are associated with increased mortality and probably contribute to neurohumoral activation. While it is likely that several mechanisms contribute to reduced baroreflex sensitivity, it has been difficult to explain why baroreflex control mechanisms during acute volume unloading in patients with severe chronic heart failure should be directionally opposite to those in normal subjects. Volume unloading normally causes a reduction in baroreceptor activity, and hence an increase in sympathetic outflow; however, patients with chronic heart failure develop attenuated increases or paradoxical reductions in forearm vascular resistance, muscle sympathetic nerve activity, and noradrenaline spillover. It has been suggested that this probably represents paradoxical activation of left ventricular (LV) mechanoreceptors, but why LV receptors should behave in such a fashion has not been determined. In the setting of diastolic ventricular interaction, the filling of the left ventricle is constrained by the surrounding pericardium and right ventricle. In these patients, the reduction in right ventricular (RV) volume that normally occurs during acute volume unloading allows for an increase in LV end-diastolic volume (as opposed to the reduction in LV volume that normally occurs). We have demonstrated this to be important in some patients with chronic heart failure, and observed that baroreflex control of forearm vascular resistance was markedly impaired in these patients. We propose that the increase in LV volume that occurred during volume unloading would increase LV mechanoreceptor activity, and could therefore explain the paradoxical reductions in sympathetic outflow. As discussed, this has important therapeutic implications.

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Sympathetic activation and the role of beta-blockers in chronic heart failure.

Krum H

Aust N Z J Med · 1999 Jun · PMID 10868514 · Publisher ↗

Chronic heart failure (CHF) is associated with activation of the sympathetic nervous system. This activation provides short term haemodynamic support to the failing myocardium, but may be deleterious over longer periods... Chronic heart failure (CHF) is associated with activation of the sympathetic nervous system. This activation provides short term haemodynamic support to the failing myocardium, but may be deleterious over longer periods as chronic catecholamine excess appears to contribute to disease progression and increased mortality in this condition. Therefore, blockade of sympathetic activation represents a logical, if somewhat counter-intuitive, approach to the management of the patient with systolic CHF. Pharmacological approaches to blockade of this system include inhibition of central sympathetic outflow (using central sympatholytics, e.g. rilmenidine, moxonidine), blockade of the catecholamine biosynthetic pathway (dopamine beta hydroxylase antagonists) and blockade of the cardiac effects of sympathetic activation (beta-adrenoceptor blocking agents). Beta-blockers have now been extensively studied in patients with symptomatic CHF of the New York Heart Association (NYHA) Class II and III severity. Provided beta-blocker therapy is carefully up-titrated from sub-therapeutic doses and given for at least three to four months, these agents have been associated with favourable long term haemodynamic, functional and mortality outcomes. Furthermore, beta-blockers delay disease progression in CHF by reversing the pathological myocardial remodelling process that accompanies the disease. Non-selective beta-adrenoceptor blocking drugs appear to be of particular benefit in CHF therapy. Myocardial beta2 receptors are down-regulated to a lesser extent than beta1 receptors in CHF, therefore blockade of the beta2 receptor sub-type may assume greater importance in inhibiting the deleterious effects of sympathetic activation on the myocardium in this disease. Newer agents that possess additional vasodilator properties (carvedilol, bucindolol, nebivolol) may be useful in overcoming the initial negative inotropy of the beta-blocking component of the drug, however, it is unlikely that vasodilation contributes greatly to long term clinical benefits. Drugs such as carvedilol are also anti-oxidant, anti-proliferative and have anti-endothelin actions; the clinical significance of these properties is yet to be determined. Unanswered questions remain regarding the use of beta-blockers in heart failure. Ongoing studies are further examining mechanisms underlying the clinical benefits of these agents as well as their therapeutic potential in NYHA Class IV patients, heart failure post-myocardial infarction and patients with asymptomatic left ventricular dysfunction.

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Australian And New Zealand Journal Of Medicine[JOURNAL]

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